> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **PULMONARY-ALLERGY DRUG PRODUCTS**
>
> **ADVISORY COMMITTEE**
>
> Friday, September 5, 2003
>
> 8:00 a.m.
>
> Holiday Inn Gaithersburg
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Polly E. Parsons, M.D., Acting Chairman
>
> Kimberly Littleton Topper, M.S., Executive Secretary
>
> MEMBERS:
>
> Vernon Chinchilli, Ph.D.
>
> Peter E. Morris, M.D., FACP, FCCP
>
> CONSUMER REPRESENTATIVE:
>
> Karen Schell, RRT
>
> VOTING SPECIAL GOVERNMENT EMPLOYEES:
>
> Andrea J. Apter, M.D., M.S.C.
>
> Jesse Joad, M.D.
>
> Carolyn M. Kercsmar, M.D.
>
> Carroll Cross, M.D.
>
> Lee S. Newman, M.D., M.A., FCCP
>
> Christina M. Surawicz, M.D.
>
> NON-VOTING ACTING INDUSTRY REPRESENTATIVE:
>
> William Kennedy
>
> FDA STAFF:
>
> Raymond F. Anthracite, M.D.
>
> Badrul Chowdhury, M.D.
>
> James Gebert, Ph.D.
>
> Robert Meyer, M.D.
>
> Sandra Suarez-Sharp, Ph.D.
>
> Virgil Whitehurst, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Introductions, Polly E. Parsons, M.D. 4
>
> Welcome, Statement of Conflict of Interest,
>
> Linda Kimberly L. Topper, M.S. 5
>
> Topic Introduction, Badrul Chowdhury, M.D. 8
>
> GlaxoSmithKline Presentation:
>
> Introduction, David Wheadon, M.D. 9
>
> Rationale for the Use of Ariflo in COPD,
>
> Katharine Knobil, M.D. 17
>
> Ariflo Clinical Development Program,
>
> Katharine Knobil, M.D. 24
>
> Safety of Ariflo, Kathy Rickard, M.D. 47
>
> Assessment of Outcome in COPD,
>
> Frank Sciurba, M.D. 65
>
> Summary Remarks, David Wheadon, M.D. 75
>
> Committee Discussion and Clarification 78
>
> FDA Presentation:
>
> Introduction, Raymond Anthracite, M.D. 80
>
> Preclinical Pharmacology-Toxicology,
>
> Virgil Whitehurst, Ph.D. 81
>
> Dose-Finding, Sandra Suarez-Sharp, M.D. 86
>
> Statistics, James Gebert, Ph.D. 92
>
> Efficacy and Safety, Raymond Anthracite, M.D. 96
>
> Committee Discussion and Clarification 130
>
> Questions 205
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Introductions**
>
> DR. PARSONS: I am Polly Parsons. I am at the University of Vermont and
> Chief of Pulmonary and Critical Care Medicine and Chief of Critical
> Care Services there.
>
> DR. KENNEDY: I am Dr. Bill Kennedy. I am a regulatory consultant and I
> am the non-voting industry representative on this panel.
>
> DR. KERCSMAR: Dr. Carolyn Kercsmar, pediatric pulmonologist at Case
> Western Reserve University, in Cleveland.
>
> DR. JOAD: Jesse Joad, pediatric pulmonologist at the University of
> California at Davis.
>
> DR. NEWMAN: Lee Newman. I am a pulmonologist at the National Jewish
> Medical and Research Center in Denver, and Professor of Pulmonary
> Medicine at the University of Colorado.
>
> DR. APTER: I am Andrea Apter, Associate Professor of Medicine at the
> University of Pennsylvania. I am and adult allergist, immunologist,
> epidemiologist.
>
> MS. TOPPER: Kimberly Topper. I am the executive secretary for the
> committee.
>
> DR. CHINCHILLI: I am Vernon Chinchilli. I am a biostatistician at the
> Penn State Hershey Medical Center.
>
> MS. SCHELL: My name is Karen Schell and consumer representative. I am
> a respiratory therapist in Emporia, Kansas.
>
> DR. CROSS: I am Carroll Cross. I am an adult pulmonary-critical care
> specialist at University of California in Davis, Sacramento.
>
> DR. MORRIS: I am Pete Morris. I am in the Division of Pulmonary and
> Critical Care Medicine at Wake Forest University.
>
> DR. ANTHRACITE: My name is Ray Anthracite. I am a lung specialist at
> the FDA.
>
> DR. CHOWDHURY: I am Badrul Chowdhury, at the FDA.
>
> DR. MEYER: Bob Meyer. I am the Director of the Office of Drug
> Evaluation II at FDA.
>
> DR. PARSONS: We are going to move on to the conflict of interest
> statement from Kimberly Topper.
>
> **Conflict of Interest Statement**
>
> MS. TOPPER: The following announcement addresses the issue of conflict
> of interest with regard to this meeting and is made a part of the
> record to preclude even the appearance of such at the meeting.
>
> Based on the submitted agenda for the meeting and all financial
> interests reported by the committee participants, it has been
> determined that all interests in firms regulated by the Center for
> Drug Evaluation and Research which have been reported by the
> participants present no potential for an appearance of a conflict of
> interest at this meeting, with the following exceptions:
>
> Dr. Andrea Apter has been granted waivers under 18 U.S.C. 208(b)(3)
> and 21 U.S.C. 355 (n)(4), an amendment of Section 505 of the Food and
> Drug Administration Modernization Act, for ownership of stock in one
> of Ariflo\'s competitors valued between \$25,001 to \$50,000.
>
> Dr. Carroll Cross has been granted waivers under 18 U.S.C. 208(b)(30
> and 21 U.S.C. 355 (n)(4), an amendment of Section 505 of the Food and
> Drug Administration Modernization Act, for ownership of stock in two
> firms that make competing products to Ariflo and in the sponsor of
> Ariflo. Each stock is valued between \$5,001 and \$25,000.
>
> Dr. Carolyn Kercsmar has been granted a waiver under 18 U.S.C.
> 208(b)(3) for membership on a competitor\'s Speaker\'s Bureau. She
> receives from \$5,001 to \$10,000 annually.
>
> Dr. Kercsmar has also been granted a waiver under 21 U.S.C. 355(n)(4),
> an amendment of Section 505 of the Food and Drug Administration
> Modernization Act, for ownership of stock in the sponsor of a
> competing product to Ariflo. The stock is valued at less than \$5,001.
> Because this stock interest falls below the de minimis exemption
> allowed under 5 CFR 2640.202(a)(2), a waiver under 18 U.S. 208 is not
> required.
>
> A copy of these waiver statements may be obtained by submitting a
> written request to the agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> In addition, we would like to disclose that Dr. William Kennedy is
> participating in this meeting as an acting industry representative, on
> behalf of regulated industry. Dr. Kennedy reports that he owns a
> nominal amount of stock valued at less than \$5,000.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need to exclude themselves
> from such involvement and their exclusion will be noted for the
> record.
>
> With respect to all other participants, we ask in the interest of
> fairness that they address any current or previous financial
> involvement with any firm whose products they may wish to comment
> upon. Thank you.
>
> DR. PARSONS: We are now going to ask Dr. Chowdhury to start the
> discussion.
>
> **Topic Introduction**
>
> DR. CHOWDHURY: Good morning, Madam Chairperson and members of the
> Pulmonary-Allergy Advisory Committee. I welcome you to this meeting
> and thank you for your participation.
>
> This meeting is to discuss the new drug application for cilomilast
> tablets by GlaxoSmithKline. GlaxoSmithKline is seeking approval of
> cilomilast tablets for the maintenance of lung function in patients
> with chronic obstructive pulmonary disease who are poorly responsive
> to albuterol.
>
> Please keep in mind that the indication of maintenance of lung
> function is unique amongst all drugs that are currently approved in
> the U.S. for chronic obstructive pulmonary disease. All clinical
> issues related to cilomilast are open for discussion.
>
> As you can see from the agenda, GlaxoSmithKline will present first and
> give an overview of the clinical data, followed by the agency\'s
> presentation. As you listen to the presentation, I request you to keep
> in mind the questions that are in the FDA briefing book and also
> attached to the agenda since you will discuss and deliberate on these
> questions later in the day.
>
> We look forward to an interesting meeting and, again, thank you for
> your time, effort and commitment in this important public health
> service. Thank you.
>
> DR. PARSONS: We will now move to the presentation by GlaxoSmithKline.
>
> **GlaxoSmithKline Presentation**
>
> **Introduction**
>
> DR. WHEADON: Thank you, Dr. Parsons. Good morning.
>
> \[Slide\]
>
> I am David Wheadon, Senior Vice President of U.S. Regulatory Affairs
> at GlaxoSmithKline. On behalf of GSK, I would like to thank the
> committee and the agency for the opportunity to share information on
> Ariflo, the first PDE4 inhibitor to be considered for approval for the
> treatment of COPD. This morning I will start GSK\'s presentation by
> sharing with you the background information about the serious nature
> of COPD, as well as treatment options currently available to this
> group of patients.
>
> \[Slide\]
>
> Chronic obstructive pulmonary disease is a debilitating, progressive
> illness. As many of you will recall based on these elegant
> illustrations by Dr. Frank Netter, patients may present with emphysema
> or chronic bronchitis but most patients have elements of both.
> Typically, after many years of smoking patients who develop COPD will
> begin exhibiting progressive symptoms such as chronic cough, increase
> in mucus production and worsening lung function.
>
> However, patients usually do not seek medical attention until they
> experience significant breathlessness. They often modify their life
> styles to compensate for both the breathlessness and activity
> limitation associated with reduced expiratory airflow. As the disease
> progresses, the systemic manifestations such as weight loss, muscle
> wasting and cyanosis become increasingly evident, as we can see from
> these illustrations.
>
> \[Slide\]
>
> The societal burden of COPD is enormous and the disease currently
> affects an estimated 24 million Americans. During the past year direct
> and indirect costs associated with COPD were estimated to be over 32
> billion dollars in the U.S. alone and it is likely that these costs
> will continue to increase. COPD is currently the fourth leading cause
> of death in the U.S. and by the year 2020 it is expected to become the
> third leading cause of death worldwide.
>
> \[Slide\]
>
> COPD continues to be a significant global public health challenge. In
> the U.S. it remains a major cause of morbidity and mortality and,
> sadly, as we can se from this graphic, in contrast to such other
> debilitating illnesses as HIV infection and coronary-artery disease,
> the mortality rate for COPD continues to increase.
>
> Airflow obstruction is one of the clinical hallmarks of COPD. As you
> know, we all lose lung function after the age of 25 but patients with
> COPD lose lung function at two to three times the normal rate. This is
> important since lung function, as measured by FEV1, has been shown to
> correlate with clinical outcome.
>
> \[Slide\]
>
> This study by Anthonisen et al. shows that patients with the highest
> mortality are those with the lowest percent predicted FEV1. These data
> imply that preventing or delaying progressive decline in lung function
> should result in improved diagnostic outcome. This is particularly
> important to keep in mind as you review the data we will present
> today.
>
> \[Slide\]
>
> There are limited treatment options for patients with COPD. Due to the
> irreversible nature of the lung damage that occurs in this disease,
> treatment has been directed at improving symptoms and is largely
> palliative. The only medications approved for COPD are
> bronchodilators. These do not address the complex nature of COPD and
> often do not adequately control the disease. The only therapeutic
> modality that has been shown to slow the rate of decline of FEV1 is
> smoking cessation. However, even in patients who stop smoking there
> may be continued inflammation in the lungs and a persistence of
> symptoms that require treatment.
>
> \[Slide\]
>
> As I have previously stated, COPD is a progressive and complex disease
> which involves inflammation, bronchoconstriction and structural
> changes within the lung. These pathological processes lead to airflow
> limitation and hyperinflation which are responsible for the clinical
> sequelae of the disease. Because of the complex nature of the disease
> bronchodilators may not meet many of the needs of patients and new
> treatment options are, indeed, needed.
>
> \[Slide\]
>
> Ariflo is a second generation PDE4 inhibitor, which was designed to
> retain the therapeutic activity of the first generation compounds with
> an improved safety profile. It has 100 percent oral bioavailablity,
> low plasma variability and a low potential for drug interactions.
> These attributes are important because they are associated with
> consistent and reliable drug delivery and obviate the need to monitor
> blood levels during treatment. Ariflo, an orally administered PDE4
> inhibitor taken twice daily, broadens the approach to the treatment of
> COPD by targeting inflammatory mediators as well as airway smooth
> muscle activity. Thus, it provides an important new option for the
> treatment of COPD.
>
> \[Slide\]
>
> Since theophylline has been used widely in respiratory disease for
> decades, it is natural to want to compare theophylline, a
> non-selective PDE inhibitor, to Ariflo, a highly selective PDE4
> inhibitor. However, it is important to note that these drugs belong to
> two distinct classes of medications. Theophylline, a xanthine
> structurally related to caffeine, exhibits adverse effects that may be
> related to broader, non-selective PDE inhibition. In addition,
> theophylline has other pharmacologic properties including antagonistic
> effects on adenosine receptors but the exact mechanism of therapeutic
> activity has not been fully elucidated.
>
> Also unlike Ariflo, the pharmacokinetic profile of theophylline is
> unpredictable due to drug and food interactions. Additionally, wide
> blood level variability can lead to the requirement for dosage
> adjustments in many patients, including elderly patients and smokers,
> thereby requiring blood level monitoring.
>
> \[Slide\]
>
> Ariflo has been extensively studied in patients with COPD. The initial
> clinical development program for Ariflo was global in scope and
> consisted of one pivotal study in North American and two in Europe.
> Due to the variability in some of the results between North American
> and European trials, GSK conducted, following consultation with the
> FDA, an additional pivotal study of similar design in North America.
> As is always the case in drug development, additional studies were
> conducted to evaluate the mechanism of action and to evaluate
> long-term safety.
>
> The eight placebo-controlled clinical trials evaluated over 3,400
> patients with greater than 2,000 patients receiving Ariflo and over
> 1,400 patients receiving placebo. The two open-label long-term trials
> evaluated over 1,000 patients for up to three years. Overall, there
> were nearly 3,000 patient years of exposure to Ariflo in the clinical
> development program.
>
> \[Slide\]
>
> The American Thoracic Society and European Respiratory Society have
> differing definitions of COPD. The American Thoracic Society does not
> base the diagnosis of COPD on reversibility, whereas the European
> Respiratory Society definition includes only patients who are poorly
> reversible to bronchodilators.
>
> As this was a global program, GSK chose the more conservative
> definition and evaluated only patients who were poorly reversible to
> albuterol in the pivotal studies, as shown by the shaded area in this
> diagram. It is important to note that this patient population may be
> more difficult to treat and are known to have a decreased FEV1
> response to medication as compared to more reversible patients. This
> is the population that is reflected in the proposed indication.
>
> \[Slide\]
>
> The indication for which we are seeking approval is the maintenance of
> lung function in patients with COPD who are poorly responsive to
> albuterol. We certainly believe that the data that we will share with
> you this morning is supportive of the approval of Ariflo for this
> indication.
>
> \[Slide\]
>
> Following me this morning will be three other speakers, starting with
> my colleague, Dr. Katharine Knobil who will briefly discuss the
> mechanism of action and the pharmacological rationale for the use of
> PDE4 inhibitors in the treatment of COPD. Dr. Knobil with follow this
> with the efficacy data from the Ariflo clinical trial program.
>
> The safety profile of Ariflo will then be reviewed by Dr. Kathy
> Rickard. Following Dr. Rickard, Dr. Fran Sciurba will provide an
> insight into the benefit of Ariflo in treating patients with COPD. I
> will then return with some concluding remarks and the presenters will
> be available for questions. Dr. Knobil?
>
> **Rationale for the Use of Ariflo in COPD**
>
> DR. KNOBIL: Thank you, Dr. Wheadon.
>
> \[Slide\]
>
> At this time I would like to discuss some of the features of
> inflammation in COPD, the rationale for using PDE4 inhibitors for the
> treatment of COPD, and then I will discuss some data specific to
> Ariflo. Cilomilast is the active ingredient in Ariflo and, since some
> of the studies use different formulations of cilomilast, I will use
> both Ariflo and cilomilast interchangeably.
>
> \[Slide\]
>
> As you know, smoking accounts for at least 80-90 percent of cases of
> COPD. Smoking causes inflammation in the airways and the destruction
> of lung parenchyma that is associated with emphysema, as well as
> increased mucus production that is associated with chronic bronchitis.
> Bronchoconstriction results as a direct result of cigarette smoking or
> as a result of uncontrolled inflammation. Bronchoconstriction,
> inflammation and structural changes all contribute to the airflow
> limitation that is characteristic of COPD.
>
> One of the clinical manifestations of airflow obstruction and loss of
> elastic recoil is hyperinflation. This is important because, when
> hyperinflated, a patient is forced to breathe at a higher lung volume,
> increasing the work of breathing and amplifying the feeling of
> breathlessness. Hyperinflation may be exaggerated during activity when
> expiratory time is shortened, resulting in further shortness of
> breath. The pathophysiologic changes in the lung are progressive and
> lead to chronic symptoms such as breathlessness, coughing, wheezing,
> sputum production and can lead to exacerbations. Together, these can
> have a significant impact on a patient\'s health status and lead to
> severe disability and premature death.
>
> \[Slide\]
>
> In contrast to the inflammatory response seen in patients with asthma,
> the predominant inflammatory cells in the lungs in patients with COPD
> are CD8-positive T-cell lymphocytes, macrophages and neutrophils. This
> study, by Retamales and colleagues, shows that these inflammatory
> cells are increased in the peripheral airways of ex-smokers with COPD
> and the increase in these inflammatory cells correlated with COPD
> severity. In this study COPD severity was determined by the degree of
> emphysema that was established on quantitative CT scanning. The study
> on the next slide confirms this result.
>
> \[Slide\]
>
> This study, by Saetta and colleagues, evaluated the peripheral airways
> from surgical specimens from smokers with normal lung function and
> from patients with COPD. This study confirms the results on the
> previous slide that there is a correlation between COPD severity and
> the numbers of CD8-positive T-cell lymphocytes. In this case severity
> was measured by FEV1 percent of predicted. The significant correlation
> observed between increased CD8-positive T-cell lymphocytes and
> increased airway obstruction suggests a possible role for these cells
> in the pathogenesis of smoking-related airflow obstruction.
>
> \[Slide\]
>
> There are at least 11 phosphodiesterase isoenzymes which are expressed
> in many different cell types in the body. Each has a different
> function, depending on the predominant isoenzyme, as expressed in each
> cell type. For example, PDE5, which is expressed predominantly in
> vascular smooth muscular cells, has become quite popular lately for
> its effect on erectile dysfunction. PDE4 is the predominant isoenzyme
> expressed in many other cell types that are important in the
> pathophysiology of COPD, including the inflammatory cells that I have
> just discussed, as well as mucus secreting cells and fibroblasts.
> Cilomilast was chosen for clinical development because it had early
> evidence of activity in many of these cell types and has the potential
> to provide important clinical benefits in patients with COPD.
>
> \[Slide\]
>
> Phosphodiesterase inhibitors act by increasing intracellular cyclic
> AMP. Intracellular cyclic AMP can be elevated by one of two distinct
> pathways. It can be elevated by activation of adenyl cyclase which
> converts ATP to cyclic AMP, or elevated by preventing the breakdown of
> cyclic AMP by phosphodiesterase. Ariflo selectively inhibits
> phosphodiesterase-4 which results in an increase in cyclic AMP in the
> cells that express this isoenzyme. In the smooth muscle of the airways
> the elevation of cyclic AMP leads to bronchodilation. This is a well
> recognized effect of increasing cyclic AMP so I will not discuss this
> one further.
>
> In other cells, such as epithelial cells and fibroblasts, the
> inhibitory effects of cyclic AMP may lead to a reduction in fibrosis
> and remodeling, and in inflammatory cells, such as neutrophils and
> CD8-positive T-cells and macrophages, elevation of cyclic AMP produces
> an inhibitory effect on the release of mediators and cytokines and may
> also increase the numbers of these inflammatory cells in the lung.
>
> \[Slide\]
>
> Structural changes in the lung that occur in COPD are mediated by
> proteolytic enzymes or MMPs, proteolytic enzymes that are known to
> play a role in tissue destruction that leads to emphysema in patients
> with COPD, as shown in this photomicrograph, here.
>
> [In vitro]{.underline} cilomilast significantly inhibited MMP-1 and
> MMP-9 release from fibroblasts and inhibited the conversion to their
> active forms. It also inhibited the degradation of collagen gels,
> which is a model of extracellular matrix, by fibroblasts. These
> effects were not seen with the PDE3 inhibitor amrinone, nor with the
> PDE5 inhibitor zaprinast, thus suggesting that these effects are
> specific to PDE4. These [in vitro]{.underline} data suggest Ariflo may
> have a clinically important effect on tissue remodeling [in
> vivo]{.underline}.
>
> \[Slide\]
>
> The data on this slide show that cilomilast attenuates release of
> chemoattractants for human neutrophils. The Y axis shows the
> neutrophils for high power field, and a reduction in the number of
> neutrophils is a measure of reduced neutrophil chemotaxis, bronchial
> epithelial cells, shown on the left, and sputum cells, shown on the
> right, which were obtained from patients with COPD were cultured in
> the presence or the absence of cilomilast. The cell culture media from
> both the bronchial epithelial cells and the sputum cells incubated
> standard cilomilast had significantly less chemoattractant activity
> for neutrophils than culture media from the cells that were untreated
> with cilomilast. Thus, cilomilast may play a role in reducing the
> numbers of neutrophils that migrate to the airways or to the lung
> parenchyma in patients with COPD.
>
> \[Slide\]
>
> The preclinical observations with Ariflo suggested a potential to
> modulate the inflammatory response in patients with COPD. Two studies
> were done to assess this result. Study 110 showed a trend in the
> reduction of sputum neutrophils in favor of Ariflo and study 076
> showed a trend toward a decrease in subepithelial neutrophils in
> bronchial biopsies in patients with COPD.
>
> Even more importantly, as shown here, study 076 also showed a
> significant reduction in the number of airway macrophages after 12
> weeks of treatment with Ariflo, and these airway macrophages were
> obtained from the bronchial biopsies.
>
> \[Slide\]
>
> In addition to a decrease in the number of subepithelial macrophages
> relative to placebo, treatment with Ariflo also resulted in a decrease
> in the number of subepithelial CD8-positive T-cell lymphocytes, with
> an approximate 40 percent decrease from baseline. Given the
> correlation of CD8-positive T-lymphocytes in relation to COPD severity
> and the importance of inflammation in COPD, these results provide the
> rationale for the use of Ariflo in patients with COPD.
>
> \[Slide\]
>
> This slide is similar to the one I showed earlier but now shows the
> cells that express PDE4 and the processes that potentially could be
> mitigated by the PDE4 inhibitor Ariflo. In the interest of time I have
> only shown a small portion of the data, but there are also data to
> support the actions of Ariflo in each of these cell types. The
> processes underlying the pathophysiology of COPD provide targets for
> therapeutic intervention and PDE4 inhibitors represent a promising
> class of molecules for the treatment of COPD.
>
> **Ariflo Clinical Development Program**
>
> \[Slide\]
>
> Now I would like to switch gears and discuss the Ariflo clinical
> development program. I will discuss the efficacy data and Dr. Rickard
> will discuss the safety results from the clinical studies.
>
> \[Slide\]
>
> The Ariflo Phase III development program included over 3,400 patients
> with COPD. The 15 mg dose evaluated in the Phase III development
> program was selected on the basis of the results of the Phase II
> studies. There were four 24-week pivotal studies, two conducted in
> North America and two conducted in Europe. Since patient care and
> diagnosis of COPD are different in North America and Europe this
> global program allowed the evaluation of Ariflo in these different
> patient groups.
>
> \[Slide\]
>
> Six supporting studies were also conducted. Studies 110 and 076 have
> already been discussed. Study 168 was primarily a cardiovascular
> safety study and efficacy data are presented in your briefing
> document. Studies 041 and 040 were also primarily safety studies that
> followed patients from the pivotal trials in an open-label fashion for
> up to three years. The FEV1 data from these studies will be briefly
> discussed as it supports the indication for which we are seeking
> approval. Study 111 evaluated static lung volumes and provides
> complementary information to the pivotal trials.
>
> \[Slide\]
>
> The core design of all the pivotal trials was similar. The studies
> included a four-week run-in period during which time patients
> discontinued all COPD medications with the exception of scheduled
> albuterol, and all patients were given albuterol for use as needed.
> Eligible patients were then randomized to either Ariflo 15 mg twice
> daily or placebo for 24 weeks of treatment. Patients were evaluated at
> 11 regularly scheduled visits during the course of the study.
>
> \[Slide\]
>
> The key inclusion criteria were a COPD diagnosis. Patients were to be
> 40-80 years of age and patients were required to have greater than or
> equal to a 10-pack year history of smoking. Patients were also
> required to be symptomatic prior to randomization, including symptoms
> of cough, sputum production and breathlessness. However, patients were
> not required to be symptomatic for entry into study 156.
>
> \[Slide\]
>
> Lung function requirements included a post bronchodilator FEV1 between
> 30 and 70 percent of predicted, and an FEV1/FVC ratio of less than or
> equal to 70 percent of predicted. Patients also had to be poorly
> reversible to bronchodilators as defined by an increase in FEV1 of
> less than or equal to 15 percent, or less than or equal to 200 ml in
> response to albuterol. For reversibility testing patients were given
> 400 mcg of albuterol in the European studies, whereas patients were
> given 200 mcg of albuterol in the North American studies. These
> inclusion criteria led to the evaluation of a COPD population that has
> not been traditionally studied in large COPD development programs.
>
> \[Slide\]
>
> This slide puts the population studied in the Ariflo clinical
> development program into perspective with the other COPD clinical
> development programs. In contrast to the Ariflo program, other COPD
> programs did not exclude patients on the basis of reversibility to
> albuterol. To orient you to this graph, the Y axis is reversibility to
> albuterol in milliliters and the X axis shows the individual clinical
> development programs. In these studies the FEV1 response to albuterol
> ranged from 240 ml at screening in the Advair studies to 330 ml on day
> one in the Combivent studies. By comparison, the population in the
> Ariflo studies demonstrated a mean FEV1 response to Ariflo of only 80
> ml. Poor reversibility has been associated with an increased rate of
> decline in FEV1 and, as Dr. Wheadon has already mentioned. Lower FEV1
> is associated with higher mortality. Since it is well accepted that
> reversibility is associated with response to many medications used to
> treat COPD, the efficacy data that will be presented today needs to be
> interpreted in the context of the population that was evaluated in the
> Ariflo clinical program.
>
> \[Slide\]
>
> Patients were excluded if they had a diagnosis of asthma, and patients
> were not randomized if FEV1 was not reproducible within 20 percent
> during the run-in period or if an exacerbation of COPD requiring oral
> steroids occurred in the run-in period.
>
> \[Slide\]
>
> In all pivotal trials there were two co-primary endpoints. The first
> was the change from baseline in FEV1 at trough levels of Ariflo. This
> was measured in the morning at the end of the dosing interval when
> serum concentrations were at their lowest. The second was change from
> baseline in the total score of the St. George\'s Respiratory
> Questionnaire, or SGRQ. Co-primary endpoints are required in European
> clinical programs so these were also included in the North American
> program for consistency with the European studies.
>
> \[Slide\]
>
> Secondary measures of efficacy included in the pivotal trials were
> FVC, COPD exacerbations, post exercise breathlessness as measured by
> the Borg scale, summary symptom scores and exercise tolerance as
> measured by the six-minute walk. Summary symptom scores were not
> collected in study 156 as patients were not required to be symptomatic
> on entry into this study.
>
> \[Slide\]
>
> On this slide are the baseline characteristics for all four pivotal
> trials. Age, race and smoking history were similar across the four
> studies. There was a higher proportion of women in the North American
> studies and this is consistent with the demography of COPD in the
> United States.
>
> Average FEV1 post albuterol was approximately 50 percent of predicted
> with an FEV1 reversibility to albuterol of approximately 6.5 percent
> across the clinical trials.
>
> Mean DLCO as a percentage of predicted was lower in North American
> studies, which is indicative of significant emphysema in this
> population.
>
> Fewer patients in the North American studies reported a history of
> chronic bronchitis, and this was particularly true for study 156. This
> may be due to the fact that patients were not required to be
> symptomatic upon entry into this study.
>
> Overall, the patients represented in the clinical program had moderate
> to severe COPD and, importantly, were poorly reversible to albuterol.
> Additionally, the data on this slide suggest that the COPD populations
> in North American and Europe were different, as shown by differences
> in gender, degree of emphysema, degree of chronic bronchitis and, to a
> smaller extent, reversibility to albuterol.
>
> \[Slide\]
>
> This graph represents the change in trough FEV1 over 24 weeks for
> Ariflo compared to placebo in North American study 039. The Y axis
> shows the change from baseline in FEV1 in liters and the X axis shows
> the study week. The primary analysis for FEV1 was the average change
> over 24 weeks. Ariflo, illustrated here in yellow, maintained FEV1
> over the 24-week study period whereas the placebo group showed a
> decline in the same period of time. The decline in the placebo group
> was seen throughout the study period and this resulted in an average
> change of 40 ml between the treatment groups.
>
> As you can see, the difference between Ariflo and placebo continued to
> widen over time, and this suggests that endpoint analysis, or last
> on-treatment observation, may be a more appropriate way to evaluate
> the FEV1 response. At endpoint there was an 80 ml difference between
> Ariflo and placebo and this difference was also statistically
> significant.
>
> \[Slide\]
>
> Now I will show all four pivotal trials. I have already shown you
> study 039 where Ariflo showed a maintenance of FEV1 over the 24 weeks
> whereas the placebo group showed a steady decline. North American
> study 156 was conducted after the other three pivotal trials and
> confirmed the results of study 039. Ariflo was associated with a
> maintenance of FEV1 over time, over the six-month treatment period,
> whereas there was a decline in the placebo group.
>
> Like studies 039 and 156, European study 091 showed a similar result,
> with a maintenance of FEV1 with Ariflo and a steady decline in the
> placebo group.
>
> European study 042\--in this study the placebo group did not show a
> similar decline in FEV1 as the other three studies and it is unclear
> why the results were different in this study.
>
> All four studies showed a consistent treatment difference between
> Ariflo and placebo. However, the results of the European studies were
> not statistically significant. The p value is here. While it is less
> than 0.05, when adjustment was made for multiple comparisons this was
> not statistically significant. Therefore, all four trials showed
> maintenance or improvement in FEV1 during treatment with Ariflo, shown
> here in yellow, while three of the four studies showed a decline in
> the placebo group, shown here in blue. In this poorly reversible
> population the decline in FEV1 observed in these trials is not
> surprising and has been seen in other large studies of patients with
> COPD.
>
> \[Slide\]
>
> As I mentioned, the consistent decline in the placebo arms of the
> pivotal trials has also been seen in other large studies of patients
> with COPD. In these four studies, the Lung Health Study, the ISOLDE
> Study, EUROSCOP and the Copenhagen City Study, evaluated poorly
> reversible patients. In patients receiving placebo or active treatment
> it can be seen that they all had declined in FEV1 over time, and this
> is a well recognized clinical manifestation of COPD.
>
> \[Slide\]
>
> Due to the incurable and progressive nature of COPD care for patients
> mainly focuses on the reducing symptoms and improving quality of life.
> The St. George\'s Respiratory Questionnaire, SGRQ, has been widely
> used to assess quality of life in patients with respiratory disease.
> It is self-administered and divided into three domains, symptoms,
> activity and impact on daily life. A total score ranging from 0-100 is
> calculated from the questionnaire, with higher numbers indicating more
> impaired quality of life. A decrease in score indicates an improvement
> in quality of life, with a change of minus four units considered to be
> a clinically meaningful improvement. It is important to note that no
> pharmacologic intervention for COPD has consistently shown an
> improvement of four units over placebo.
>
> \[Slide\]
>
> Shown here are the results of the mean change from baseline in SGRQ
> over 24 weeks in North American studies 039 and 156. The SGRQ was
> assessed at baseline, week 12 and week 24 or early withdrawal. The Y
> axis, on the left, shows the mean change from baseline in total SGRQ.
> As I have mentioned, a decrease in score reflects in improvement in
> quality of life.
>
> In study 039, shown here, the patients in the Ariflo group experienced
> an improvement in quality of life from baseline of 3.7 points while
> patients in the placebo group had a decline of 0.4 points. When
> compared to patients in the placebo group, patients in the Ariflo
> group experienced a clinically meaningful improvement of 4.1 points.
>
> Similarly, in study 156, shown on this side of the slide, patients in
> the Ariflo group experienced an improvement in quality of life of 3.2
> points. Unlike study 039, patients in the placebo group also
> experienced an improvement in quality of life of 1.3 points. The
> difference between Ariflo and placebo was statistically significant
> but did not reach the predefined clinically meaningful difference of
> four points. However, overall in the North American studies the
> Ariflo-treated patients demonstrated a consistent improvement from
> baseline in quality of life.
>
> \[Slide\]
>
> On this slide the North American studies I have just shown you are
> shown here and the European studies are shown on this side of the
> slide. In the European studies the change from baseline in SGRQ for
> patients treated with Ariflo was similar to the North American studies
> but the placebo groups also improved, resulting in no significant
> differences between the groups. The reasons for the differences
> between the placebo response between the North American and European
> studies are not clear but may be related to some of the differences in
> baseline characteristics.
>
> \[Slide\]
>
> The secondary endpoints, as I have already mentioned, included FVC,
> six-minute walk, symptom scores, post-exercise breathlessness and COPD
> exacerbations. A check mark indicates that Ariflo was significantly
> improved over placebo whereas a T indicates a trend in favor of
> Ariflo. FVC at endpoint was significantly improved by 110 ml and 60 ml
> in North American studies 039 and 156 respectively.
>
> Changes in FVC were not significant in the European trials but trended
> in favor of Ariflo. The results were not consistent for the six-minute
> walk or summary symptom scores but there was a trend in favor of
> Ariflo for post-exercise breathlessness across the pivotal trials.
> Time to first moderate or severe COPD exacerbation was significantly
> improved for patients receiving Ariflo in study 039.
>
> While study 091 did not achieve either primary endpoint, this study
> also showed a significant improvement in time to first COPD
> exacerbation. Because of the high morbidity and mortality that is
> associated with COPD exacerbations, reducing exacerbations is one of
> the most important goals of the treatment of COPD. Although these
> studies were not specifically designed to evaluate COPD exacerbations,
> they are included as secondary endpoints and these results are shown
> in more detail on the next slide.
>
> \[Slide\]
>
> This slide shows the exacerbation-free survival for all four pivotal
> trials. As you can see and as I have already mentioned, study 039 and
> study 091 showed a statistical significant improvement between the
> treatment groups in favor of Ariflo. These studies also showed a
> decrease in oral steroid use associated with exacerbations in these
> two studies.
>
> Study 156, shown in this corner, may not have shown a difference in
> exacerbations since patients were not required to be symptomatic upon
> entry into the study as was required for all the other pivotal trials.
> As a result, this may have led to a lower rate of exacerbations and,
> in fact, the placebo group in this study had an exacerbation rate that
> was nearly 20 percent lower than any of the placebo groups in the
> other three studies.
>
> In European study 042 the relative risk of experiencing a COPD
> exacerbation was comparable between Ariflo and placebo-treated
> patients. These data suggest that Ariflo may have positive effect on
> COPD exacerbations, however, a study specifically designed to evaluate
> exacerbations needs to be conducted to confirm this result.
>
> As I have discussed, the pivotal trials achieved statistical
> significance in both primary endpoints in the North American studies,
> and the supporting data from the secondary endpoints provides support
> for the approval of Ariflo.
>
> \[Slide\]
>
> I will now discuss the remaining supporting studies. The long-term
> extension studies were conducted primarily to evaluate the long-term
> safety and tolerability of Ariflo. They also further evaluated FEV1
> over time. Subjects from North American study 039 were eligible to
> enter long-term study 041, and subjects from European studies 042 and
> 091 were eligible to enter study 040. While these were not controlled
> studies and patients could be on other medications to treat COPD, they
> provide important long-term data.
>
> \[Slide\]
>
> Shown here is the long-term extension study 041. The first part of the
> graph, right here, shows the double-blind, pivotal trial 039. For this
> part of the study Ariflo is shown in yellow and the placebo group is
> shown in blue. At 24 weeks all patients received open-label Ariflo.
> Patients previously receiving Ariflo through open-label extension
> remained, in yellow, while patients previously receiving placebo who
> then received Ariflo are shown here in orange.
>
> During the open-label period the use of concomitant COPD medications
> was similar between the treatment groups. For the former Ariflo group
> FEV1 was maintained out to 84 weeks at a value similar to the baseline
> value on entry into study 039.
>
> \[Slide\]
>
> This slide shows the results from European study 040. The results are
> similar to those seen in 041, with the maintenance of FEV1 for as long
> as 60 weeks and a value similar to baseline in the patients that were
> previously treated with Ariflo. Even with the caveats of uncontrolled
> studies, these data indicate that Ariflo may maintain FEV1 at a value
> similar to baseline substantially beyond 24 weeks.
>
> \[Slide\]
>
> Traditionally clinical development programs for COPD have evaluated
> FEV1 as the primary efficacy measure. However, there are other
> physiologic measures that provide clinically relevant information for
> patients with COPD. Pictured here is a chest x-ray that shows normal
> lung parenchyma and a chest x-ray from a patient with severe COPD. As
> you can see, the lungs of the patient with COPD are severely
> hyperinflated, with a flattened diaphragm and evidence of emphysema.
> There is evidence to indicate that FEV1 alone may have some
> limitations as a clinical outcome measure for the evaluation of
> efficacy in COPD. For this reason we have used the measurement of lung
> volumes as another complementary method to evaluate the effects of
> Ariflo in this patient population.
>
> \[Slide\]
>
> This diagram shows the relationship between the different lung
> volumes. Total lung capacity, shown here, is the total volume of gas
> in the chest after full inspiration. Functional residual capacity is
> the volume at the end of a tidal exhalation and residual volume is the
> amount of gas in the chest after a full expiration.
>
> With progressive disease, as shown here on the right, the loss of
> elastic reflow leads to hyperinflation with an increase in total lung
> capacity, functional residual capacity and residual volume. These
> changes cause the patient to breathe at a higher lung volume and FRC
> and RV increase the work of breathing and reduce the respiratory
> reserve that is needed for normal ambulatory function. Reduction of
> hyperinflation is important because it reduces the work of breathing
> and is associated with improved exercise capacity. Lung volume
> reduction surgery is very effective in this regard but is quite
> invasive. So, an effective pharmacologic intervention to achieve a
> reduction of hyperinflation would be preferable.
>
> \[Slide\]
>
> Study 111 was designed to evaluate the trough effect of Ariflo on
> static lung volumes over 12 weeks. The entry criteria into this study
> were similar to the pivotal trials, with the exception that patients
> had to be hyperinflated with a residual volume of greater than or
> equal to 120 percent of predicted at baseline. Demographics and
> pulmonary function characteristics were similar between the Ariflo-
> and placebo-treated patients and similar to the pivotal trials. It is
> important to note that these patients were also poorly reversible to
> albuterol.
>
> \[Slide\]
>
> The primary efficacy variable was volume of trapped gas at trough as
> measured by the difference between TLC measured by plethysmography and
> total lung capacity, or TLC, measured by single breath helium
> dilution. Ariflo reduced the mean volume of trapped gas by 140 ml.
> However, this difference was not quite statistically significant.
>
> Since plethysmography is generally better than single breath helium
> dilution to measure lung volumes in patients with COPD, the results of
> these measurements are shown on the next few slides.
>
> \[Slide\]
>
> Using plethysmography, Ariflo demonstrated a significant improvement
> in residual volume at trough that continued to improve over time.
> Again, here is the placebo group and the patients treated with Ariflo.
> The difference between Ariflo and placebo was nearly 300 ml at
> endpoint.
>
> \[Slide\]
>
> Again, with plethysmography Ariflo demonstrated a significant
> improvement in functional residual capacity, with a difference from
> placebo of nearly 300 ml at endpoint. Again, the difference in FRC
> continued to widen over the 12 weeks of treatment. This substantial
> decrease in air trapping was not associated with a significant
> improvement in trough FEV1 and again highlights the utility of
> evaluating lung volumes in addition to FEV1 in patients with COPD.
> Later Dr. Sciurba will speak to you about these results and the
> important clinical benefits that they provide to patients.
>
> \[Slide\]
>
> Given the clinical experience with theophylline and the fact that
> there are some similarities in their mechanisms of action, it is
> inevitable that a comparison will be made between Ariflo and
> theophylline. However, a direct comparison with data currently
> available is really difficult to make, and this is for several
> reasons.
>
> First, there are no studies of similar design that can be compared
> directly. For example, most of the studies in the recent Cochrane
> meta-analysis were very small, ranging from 8-60 patients, of short
> duration, one day to eight weeks, and have varying entry criteria for
> reversibility, and were primarily designed to show a bronchodilator
> effect of theophylline.
>
> Theophylline is a non-selective phosphodiesterase inhibitor and the
> bronchodilator response is thought to be predominantly due to the
> activity or the inhibition of phosphodiesterase-3, while Ariflo
> selectively inhibits phosphodiesterase-4. Phosphodiesterase-3 is
> thought to have more activity in smooth muscle whereas
> phosphodiesterase-4 is more prominent in inflammatory cells. In fact,
> theophylline at therapeutic levels has very little activity on PDE4.
>
> It has also been proposed that theophylline has some anti-inflammatory
> properties, however this has not been well characterized in patients
> with COPD. It is not thought to be due to phosphodiesterase
> inhibition. One of the largest studies with theophylline is shown on
> the next slide.
>
> \[Slide\]
>
> This study, by ZuWallack and colleagues, evaluated serial FEV1 after
> the first dose of theophylline, on day one, and after 12 weeks of
> treatment, and there are about 170 patients in this analysis shown
> here. These data illustrate three major points: Theophylline had
> bronchodilator activity with an acute FEV1 response within one hour
> which did not change significantly from week one to week 12. This
> study only enrolled patients that could tolerate the theophylline
> titration period during the run-in so these are really the
> theophylline tolerators and 44 percent of patients who withdrew during
> the run-in dropped due to adverse events due to theophylline. An
> additional 12 percent dropped because they could not achieve
> appropriate serum theophylline levels.
>
> This slide also shows the importance of the population chosen for
> inclusion. When all patients were considered without regard to
> reversibility, as shown here, there is a 100 ml increase in peak FEV1,
> which is consistent with what was shown by the Cochrane meta-analysis.
> However, when only the poorly reversible patients were analyzed there
> was about a 50 ml increase in peak FEV1 and when theophylline was at
> trough the FEV1 was back to near baseline levels.
>
> As you recall from the data that I have already shown you, Ariflo did
> not have a bronchodilator effect in a similar population. Therefore,
> theophylline is predominantly a bronchodilator whereas the predominant
> effect of Ariflo in this population is anti-inflammatory.
>
> \[Slide\]
>
> So, in summary, Ariflo demonstrated statistically significant benefits
> over placebo for both co-primary endpoints, FEV1 and SGRQ, in the
> North American studies. While the European studies did not meet
> statistical significance, the trends in magnitude of effect from
> baseline were consistent with the North American studies.
>
> \[Slide\]
>
> Supporting data provided additional evidence for the efficacy of
> Ariflo in patients with COPD. Ariflo demonstrated significant benefits
> in relative risk of moderate to severe exacerbations in two of the
> four pivotal trials. The long-term extension studies confirmed the
> efficacy seen in the pivotal trials. FEV1 was maintained beyond 24
> weeks and as long as 84 weeks in the open-label studies. Finally,
> Ariflo demonstrated a substantial reduction in lung hyperinflation at
> trough in a poorly reversible population.
>
> \[Slide\]
>
> As we have discussed toady, COPD is a complex and progressive disease,
> and since there are few medications that treat the underlying
> pathophysiology of this disease there is a clear unmet and urgent
> medical need. The population studied in the Ariflo clinical program
> was poorly reversible to albuterol and these patients are felt to be
> the most difficult to treat. They also have a faster rate of decline
> in FEV1 and low FEV1 is associated with worse outcome. Patients with
> COPD have had to rely on the same drugs developed for asthma and have
> not had drugs with mechanisms of action specifically targeted to treat
> the very different inflammation that is seen in COPD. Ariflo is a
> novel medication that was specifically developed to treat the
> processes that are important in this disease.
>
> The data from the pivotal trials are supported by the studies that
> show the long-term maintenance of FEV1, the anti-inflammatory effects
> and substantial reduction in hyperinflation with Ariflo, and support
> the proposed indication.
>
> I would like now to introduce Dr. Kathy Rickard who will review the
> safety analysis from the Ariflo clinical program.
>
> **Safety of Ariflo**
>
> DR. RICKARD: Good morning.
>
> \[Slide\]
>
> My name is Kathy Rickard and I am the Vice President of Respiratory
> Clinical Development and Medical Affairs for GlaxoSmithKline. In the
> next 20 minutes I will review safety data for Ariflo. The safety
> database for the Ariflo program is extensive and the level of scrutiny
> that we have performed in this program is sufficient to support the
> approval of Ariflo for COPD.
>
> We believe that the safety data that we will present today
> demonstrates that Ariflo has an acceptable and well defined safety
> profile for an oral treatment in patients with COPD.
>
> \[Slide\]
>
> As part of the evaluation of the safety of Ariflo, the Phase II and II
> clinical program included over 50 studies including clinical
> pharmacology studies and dose-ranging studies. I will present data
> from three clinical pharmacology studies that address specific issues
> raised during the Phase II/III development program. However, my review
> today will focus on the Phase III clinical program which consisted of
> extensive safety monitoring in COPD patients. This included adverse
> events, measurement of specific parameters to assess effects of both
> gastrointestinal and cardiovascular and studies that address long-term
> safety.
>
> \[Slide\]
>
> The safety database is extensive and Phase III consisted of over 3,400
> patients with COPD, over 2,000 of whom were treated with Ariflo. The
> vast majority were enrolled in four 24-week pivotal trials and our
> presentation will primarily focus on these patients. For three of the
> four pivotal trials patients were randomized in a 2:1 ratio of Ariflo
> to placebo. These safety data were further augmented by the long-term
> extension studies which evaluated over 1,000 patients treated with
> Ariflo for up to three years, providing nearly 3,000 patient years of
> exposure.
>
> \[Slide\]
>
> This table presents adverse events that occurred in greater than or
> equal to five percent of patients in either treatment group. As you
> will see, the total percentage of patients experiencing adverse events
> was similar between Ariflo- and placebo-treated patients. Symptoms of
> gastrointestinal intolerance, which included nausea, diarrhea,
> abdominal pain, dyspepsia and vomiting, occurred more frequently in
> Ariflo treated patients. However, it is important to note that the
> investigators designated the majority of these as mild to moderate in
> intensity. Symptoms of COPD, upper respiratory tract infection and
> coughing, tended to be higher in placebo-treated patients.
>
> Of note, there were no clinically significant differences in central
> nervous system effects, including headache, between Ariflo and
> placebo. Unlike the known CNS effects associate with theophylline,
> there was no increased risk of seizure with Ariflo.
>
> \[Slide\]
>
> This slide includes adverse events that led to withdrawal in greater
> than or equal to 0.5 percent of patients in either treatment group.
> Overall, the percentage of patients withdrawn due to adverse events
> was higher in Ariflo treated patients and this was largely related to
> withdrawals for GI intolerance. However, symptoms of COPD led to a
> higher percentage of withdrawals in patients treated with placebo.
>
> To further evaluate GI intolerance, patients were specifically asked
> to report GI adverse events. The next slide will discuss the rationale
> behind the gastrointestinal safety monitoring performed during the
> clinical trials.
>
> \[Slide\]
>
> Extensive safety monitoring was performed to assess GI effects. This
> was done to evaluate both the adverse events associated with symptoms
> of gastrointestinal intolerance seen in humans, a known class effect
> of PDE inhibitors including theophylline and caffeine, as well as a
> finding of medial necrosis of mesenteric arteries in rat nonclinical
> studies. This finding was specific to rodents and was not seen in
> primates even at high exposure for up to a year.
>
> Furthermore, there was no mesenteric ischemia and no downstream
> effects seen in any organ, including the intestine and the liver, in
> the rodents. It is also reassuring that although medial necrosis has
> been seen in rats administered theophylline and caffeine, no
> clinically relevant effects have been seen after years of theophylline
> use in patients with asthma of COPD.
>
> \[Slide\]
>
> During the Ariflo Phase III clinical program regularly scheduled
> safety monitoring was conducted. These tests included physical exams,
> laboratory assessments, orthostatic vital signs, fecal occult blood
> testing and the collection of adverse events at regularly scheduled
> visits. Along with the routine safety monitoring, comprehensive
> testing of patient-reported GI adverse events of potential concern was
> conducted. GI adverse events of concern were a subset of adverse
> events and were characterized as such because they were of concern to
> the patient or interfered with their daily activities. Additional
> fecal occult blood tests, orthostatic vital signs, laboratory testing
> and physical exams that specifically evaluated the GI system were
> conducted for any patient reporting a gastrointestinal adverse event
> of concern.
>
> Relatively late in the program, following completion of studies 039,
> 042 and 091 and after initiation of studies 156, 041 and 040, these
> last three studies were amended at the request of the FDA to include a
> requirement for colonoscopy. Colonoscopies were recommended for
> patients with a GI adverse event of concern and a positive fecal
> occult blood or for direct observation of blood in the stool. This was
> also a requirement for study 168.
>
> \[Slide\]
>
> An example of the extensive monitoring performed in patients in the
> Ariflo program is seen here. Patients who completed the study on
> average had six fecal occult blood tests, ten sets of laboratory
> evaluations, 13 sets of vital signs and four sets of orthostatic vital
> signs checked throughout the six-month period of the study. Patients
> were questioned on each monthly visit about GI effects. We feel sure
> that with such close monitoring we were unlikely to miss serious GI
> effects if they occurred.
>
> \[Slide\]
>
> This slide presents GI adverse events of concern occurring in greater
> than or equal to 0.5 percent of patients in either treatment group.
> Although GI adverse events of concern were more frequent in Ariflo
> treated patients, again, it is important to note that the majority was
> designated by the investigator as mild to moderate in intensity.
>
> \[Slide\]
>
> GI adverse events of concern generally occurred early in treatment,
> within the first three weeks. On this slide the Y axis shows the
> cumulative percentage of patients reporting a GI adverse event of
> concern. The X axis shows the study day. As you can see, after the
> first 30 days of treatment the lines of this graph are parallel,
> showing that these events occurred at approximately the same rate in
> both Ariflo- and placebo-treated patients.
>
> \[Slide\]
>
> Fecal occult blood tests were performed routinely at baseline and at
> the end of treatment. Additional fecal occult blood tests were
> performed in patients who experienced GI adverse events of concern. As
> shown on this slide, \"total\" refers to all fecal occult blood tests
> performed including routine and those done for GI adverse events of
> concern. In the total population the percentage of patients with
> positive fecal occult blood tests was similar between Ariflo- and
> placebo-treated patients. The same was true for fecal occult blood
> tests that were specifically performed for GI adverse events of
> concern.
>
> As stated earlier, several studies were amended to include the
> requirement for colonoscopy for a GI adverse event of concern and
> positive fecal occult blood. In those patients who underwent
> colonoscopy the findings were consistent with conditions expected for
> the population studied, including diverticular disease, polyps and
> hemorrhoids and did not identify any safety concerns. Of note, though
> the data are not presented here, laboratory tests and vital signs were
> performed every four weeks. There were no differences between
> treatment groups in any laboratory value or vital sign obtained
> routinely or for a GI adverse event of concern, including liver
> function tests, hemoglobin hematocrit, electrolytes, BUN, creatinine,
> urinalysis, amylase or lipase. Fecal occult blood tests and
> colonoscopy results suggest that the symptoms reported with GI
> intolerance were not associated with GI pathology.
>
> \[Slide\]
>
> As stated previously, because of the nonclinical findings of medial
> necrosis of the mesenteric arteries in rats, there was an increased
> interest in serious potential effects of the GI tract. It is important
> to note that incidence of several GI conditions, including bowel
> ischemia and perforation, is found to be generally higher in patients
> with COPD.
>
> In the Ariflo clinical program including the 24-week pivotal trials
> and the subsequent long-term extensions there are five cases of
> ischemic bowel reported, two in study 156 in placebo and three in the
> Ariflo patients in the long-term extension studies. In the Ariflo
> patients one was after a vascular procedure; one experienced a COPD
> exacerbation associated with constipation and a bowel perforation; and
> one was admitted for exacerbation of rheumatoid arthritis. This last
> patient was reported to have sequelae of ischemic colitis by abdominal
> x-ray. However, the patient continued on Ariflo and completed the
> study. None of the cases was attributed to study medication and all
> had other contributing factors.
>
> As a reminder, the patients on placebo had only six months of exposure
> compared to up to three years on Ariflo. As you can see from this
> data, the incidence rate overall was lower in the Ariflo group
> compared to the placebo group. As you can see, the clinical findings
> do not support the occurrence of mesenteric vasculopathy in man that
> was observed in rats.
>
> \[Slide\]
>
> Finally, the incidence of serious adverse events reported in the GI
> body system is shown here. A serious adverse event included any event
> that was fatal, life-threatening, disabling or resulted in
> hospitalization. Serious adverse events were lower in Ariflo-treated
> patients than patients receiving placebo in the pivotal trial. Taken
> together, extensive GI monitoring demonstrated no increased risk of
> serious GI pathology with Ariflo treatment.
>
> \[Slide\]
>
> As shown, the clinical evidence supports that Ariflo is not associated
> with increased risk of bowel ischemia. As with other PDE inhibitors
> and caffeine, Ariflo was associated with mesenteric vasculopathy in
> rodents that was not associated with bowel ischemia. The clinical
> program included extensive monitoring of GI events and demonstrated no
> serious GI effects. In fact, the incidence of bowel ischemia was very
> low and comparable in the patients receiving Ariflo compared to those
> receiving placebo, thus providing reassurance that there is no
> association between Ariflo treatment and bowel ischemia.
>
> \[Slide\]
>
> As a result of the cardiovascular safety concerns with non-selective
> phosphodiesterase inhibitors and mild cardionecrosis seen in rats
> given high lethal doses of Ariflo extensive cardiovascular safety
> monitoring was performed. This included vital signs, ECGs and Holters.
> Since cardiovascular disease is common in patients with COPD,
> potential cardiovascular effects of any new drug are of particular
> interest.
>
> \[Slide\]
>
> During the clinical development program more than 70,000 ECGs were
> done, greater than 68,000 in patients with COPD and, of these, greater
> than 6,000 were performed at Cmax. In addition, over 1,000 Holters
> were performed. Holter monitoring results were integrated from three
> of the pivotal trials of 24 weeks in duration and study 168 of 12
> weeks in duration. The Holters were obtained at baseline, week one and
> the end of treatment in these studies. All ECGs and Holters were read
> in a blinded fashion by independent cardiologists.
>
> It is important to remember that many patients with COPD have
> significant underlying cardiovascular disease. In fact, approximately
> 50 percent of the patients in the Ariflo Phase III clinical trials
> reported at least one medical condition that involved the
> cardiovascular system. Thus, in this population it is important to
> ensure that any new therapy does not increase cardiovascular risk.
>
> \[Slide\]
>
> This slide presents the incidence of new onset ECG abnormalities in
> greater than five percent of patients in either treatment group. There
> are small differences in some categories of nuance of ECG
> abnormalities, however, these are unlikely to be of clinical
> relevance. In general, the percentages of new onset ECG abnormalities
> are similar between Ariflo and placebo treatment groups. Thus,
> extensive ECG monitoring revealed no safety issues with Ariflo.
>
> \[Slide\]
>
> Again, there were no differences in corrected QT interval between
> Ariflo- and placebo-treated patients. As you can see, both groups had
> a change from baseline in corrected QT interval of less than 0.5 msec
> using Bazett\'s correction. At any time point on therapy a similar
> percentage of Ariflo- and placebo-treated patients had a change from
> baseline in corrected QT interval greater than or equal to 30 msec.
> The number of patients with greater than a 60 msec change in baseline
> in corrected QT interval was also similar between treatment groups.
> Similar results were seen when QT interval was corrected by
> Fridericia\'s. Thus, there is no evidence of QT interval prolongation
> with Ariflo.
>
> \[Slide\]
>
> As observed with ECGs, there was no difference between Ariflo and
> placebo treatment groups in percentage of new onset of cardiac
> abnormalities during 24-hour Holter monitoring. Of note, there was no
> sustained ventricular tachycardia observed.
>
> \[Slide\]
>
> Lastly, the incidence of serious adverse events affecting the
> cardiovascular body system was lower in the Ariflo-treated patients
> compared to placebo. Taken together, the extensive cardiac monitoring
> demonstrated no increased risk of cardiac events associated with
> Ariflo treatment.
>
> \[Slide\]
>
> Death occurred infrequently, with death reported in five, or 0.5
> percent, of placebo-treated patients and seven, or 0.4 percent, of
> Ariflo-treated patients. The deaths were all due to cardiovascular or
> respiratory causes and none was deemed related to study medication or
> was unexpected for a COPD population who exhibited a significant
> number of co-morbidities.
>
> \[Slide\]
>
> As mentioned earlier, patients completing three of the 24-week studies
> had the option to continue into an open-label long-term extension
> study. Safety data was obtained for greater than 1,000 patients for up
> to three years, including extensive monitoring of gastrointestinal and
> cardiovascular events, laboratory evaluations, fecal occult blood
> tests and physical exams. The results were similar to the data from
> the pivotal studies and identified no serious safety issues during the
> long-term Ariflo administration. These findings further support the
> safety of Ariflo for patients with COPD.
>
> \[Slide\]
>
> In addition to the clinical trials I have just reviewed, clinical
> pharmacology studies were performed to investigate specific findings
> in animal models and to establish the potential for specific drug
> interactions relative to the population studied. Areas investigated
> included testicular degeneration seen in rats and rabbits, adrenal
> cortex hypertrophy in rats and changes in the reproductive organs of
> female mice, consistent with increased exposure to prolactin. As you
> will see, none of these findings in animals was found to be of
> clinical relevance in humans.
>
> Finally, studies were conducted to confirm findings from animal
> studies that Ariflo would have no significant pharmacokinetic and
> pharmacodynamic interactions with other drugs, particularly those
> likely to be used in a population of COPD patients.
>
> \[Slide\]
>
> Nonclinical data show testicular degeneration in rats and rabbits, but
> this was not observed in other species, including primates. A clinical
> study was performed to definitively assess the effect in humans. In
> order to investigate possible effects in a human reproductive system
> Ariflo or placebo was administered at a dose of 15 mg twice a day to
> 100 healthy, young male subjects for 12 weeks. The subjects were
> followed for an additional 12 weeks after the end of dosing. This
> study did not identify any clinically significant changes in the total
> number of sperm per ejaculate or progressive and overall motility and
> morphology following chronic dosing with Ariflo.
>
> \[Slide\]
>
> In other nonclinical studies adrenocortical hypertrophy was seen in
> rats. This is a well recognized response of rats to PDE inhibitors and
> is due to stimulation of ACTH release in response to increased cyclic
> AMP concentrations in the hypothalamus and anterior pituitary gland.
> Additionally, in the mouse carcinogenicity study a weak effect per
> mammary tumor induction was observed at high doses. These tumors
> showed microscopic changes that have been seen with elevated prolactin
> levels. Studies in mice showed no change in prolactin levels, however,
> evidence of persistent diesterase was observed. Therefore, the mammary
> tumor induction was likely related to a state of pseudopregnancy, an
> event that has no analogy in humans.
>
> A clinical pharmacology study was conducted in humans to explore the
> effects of Ariflo on the HPA axis and prolactin secretion and
> additional assessments of HPA axis function were made in six other
> clinical pharmacology studies. The results of these studies indicated
> that levels of prolactin, ACTH, serum cortisol and urinary cortisol
> were similar from repeat dosing with Ariflo or placebo.
>
> \[Slide\]
>
> Finally, Ariflo had no significant interactions or tolerability issues
> with the range of drugs likely to be co-administered in patients with
> COPD, including albuterol, ipratropium, theophylline, prednisolone,
> warfarin and digoxin.
>
> There was also no significant effect of smoking on plasma levels of
> Ariflo. There was no effect on the bioavailability of Ariflo
> administered with food or with the antacid Maalox. Co-initiation of
> Ariflo and erythromycin should be avoided due to increased incidence
> of GI intolerance, and since unbound plasma concentrations were
> increased in patients with severe hepatic impairment and severe renal
> impairment, there is a potential to have increased GI intolerance in
> these patients.
>
> \[Slide\]
>
> In conclusion, the safety of Ariflo was extensively evaluated with up
> to three years of exposure, which translates to nearly 3,000 patient
> years of exposure. For patients with GI adverse events. They
> predominantly occurred in the early weeks of therapy and most were
> mild to moderate in intensity. While some patients may experience
> gastrointestinal intolerance upon initiation of Ariflo treatment,
> there is no evidence to suggest that Ariflo is associated with an
> increased risk of serious GI sequelae. Extensive cardiac monitoring
> throughout the clinical development program demonstrated no evidence
> of an increased risk of cardiovascular events associated with Ariflo
> therapy. In summary, extensive safety monitoring identified no
> clinically significant safety concerns in patients with COPD treated
> with Ariflo for up to three years.
>
> I thank you for your attention today and would like now to turn the
> podium over to Dr. Frank Sciurba.
>
> **Assessment of Outcome in COPD**
>
> DR. SCIURBA: Thank you. Good morning.
>
> \[Slide\]
>
> I have been asked today to present some concepts in the assessment of
> outcome in patients with COPD, and particularly to place it in the
> context of the data we have seen today on Ariflo. As we have heard,
> COPD still remains a problem in our society and particularly with
> respect to symptoms and difficulty in treatment of individual
> patients.
>
> \[Slide\]
>
> As you can see in these photographs of two of our patients, these
> drawings to reflect real patients. Unlike asthma, COPD is a disease in
> which, despite maximal available treatment, patients remain
> symptomatic and continue to decline over time. The patient on the left
> panel is in the typical tripod position, and the reason he is in this
> position is because his lungs are hyperinflated. He uses his accessory
> muscles. He uses his arms to anchor his accessory muscles of
> inspiration; to pull in that final teacup of air by pulling up on his
> first rib and his clavicle.
>
> New drugs are needed to treat these patients. The many new classes of
> anti-inflammatory drugs, including PDE4 inhibitors and many products
> that are evolving, are necessary and offer significant hope for these
> patients.
>
> Unlike asthma, COPD has a great toll on mortality. This study reflects
> the data, the catastrophic data from the support study showing the
> follow-up of patients admitted to the hospital with hypercapnia and
> exacerbation, while there is an 11 percent in-hospital mortality rate.
> At 60 days 20 percent of these patients are dead. By two years a full
> 50 percent of patients have died.
>
> \[Slide\]
>
> Unfortunately as expressed in this NIH consensus statement in 1994 by
> Dr. Fishman, no single parameter in patients with COPD is sufficient
> to be considered the gold standard to assess outcome in this disease.
>
> \[Slide\]
>
> This concept was reiterated in a very recent NIH consensus committee
> statement on clinical research and COPD needs and opportunities, and
> among the questions raised in this statement by the workshop was what
> measures of disease status are useful indices of therapeutic benefit?
> What can be done to promote the development in testing of novel agents
> for the treatment of COPD? And, suggested that efforts to reduce these
> barriers include the exploration of alternative outcome measures.
>
> I sincerely believe we need to look at alternatives, including
> expiratory flow limitation, if we are going to be able to address the
> positive impacts of these anti-inflammatory agents as they are going
> to be increasingly presented to the scientific community and the
> administration.
>
> \[Slide\]
>
> FEV1 has been an important proven parameter. On average it does
> reflect lung function and prognosis. It is a reproducible measure and
> is responsive to various therapies, which is well established.
>
> \[Slide\]
>
> As we have seen in this earlier slide, in fact on average FEV1, in
> this Anthonisen\'s retrospective analysis, does reflect prognosis.
> Unfortunately, there are, indeed, limitations to using this as a sole
> parameter. There is marked individual variation in symptoms and
> disability independently of FEV1. Symptomatic and functional response
> to therapy may be independent of FEV1 and it may not reflect changes
> in important disease activity which could lead to long-term functional
> decline or frequency of exacerbations.
>
> \[Slide\]
>
> This slide, Dr. Jones\' data, shows the relationship between a symptom
> quality of life index, the St. George\'s Respiratory Questionnaire,
> and the FEV1 as a percent of predicted. While there is, in fact, a
> significant correlation, the r squared relationship shows that only 10
> percent of the variation in symptom scale is related to the baseline
> FEV1 parameter. If we focus on patients with a value of 40 percent of
> predicted, we see a range from nearly normal to nearly completely
> disabled and the full range in between.
>
> \[Slide\]
>
> So, what other parameters in an individual explain the symptoms and
> explain the disease? Well, one aspect that we can look at is
> hyperinflation. Other parameters include the assessment of
> inflammation both on the lung and the systemic consequences of
> inflammation.
>
> This slide shows volume time curves in patients with progressive lung
> disease. In spirometry maneuver, as most of you know, patients are
> asked to take a deep breath all the way into the top and blow it out
> as forcefully and as long as they can. Patients with progressive
> disease take longer and longer to get the air out. Note that as
> disease gets more severe, in fact patients do not get all the air out.
> It is not that their lungs are getting smaller, the lungs are very
> large but the air remains trapped in the lungs.
>
> \[Slide\]
>
> The physiologic consequences of that can be measured. In a normal
> individual residual volume\--the air trapped at the end of a forced
> expiration\--and the functional residual capacity\--the air left in
> the lungs at the end of a normal exhalation\--are compared to COPD
> where there are dramatic increases in residual volume and functional
> residual capacity.
>
> \[Slide\]
>
> The consequences of that are significant hyperinflation of the chest
> with flattening of the diaphragm and shortening of the inspiratory
> muscles on inspiration. One of my patients put this in their terms. A
> patient who is a poet told me, \"if you want to experience what I feel
> take a deep breath all the way to the top, let out a teacup of air;
> don\'t go down to your level of relaxation but a teacup of air. Now
> breathe in again from that point and try and stay up there.\" What you
> feel is the discomfort of dyspnea from operating your muscles of
> inspiration in suboptimal positions.
>
> \[Slide\]
>
> The reason why we have this sensation is that in fact the entire
> mechanics of the chest wall and muscles are in suboptimal
> configuration. As opposed to a normal individual where at the end of
> an inspiration, the chest wall is recoiling outward to balance the
> inward recoil of the lungs, patients with COPD remain with inward
> recoil of the chest wall. So, when we start our next inspiration we
> have to overcome that inward recoil and only then can the increased
> inspiratory muscle activity result in movement of air in the thorax.
> We already discussed the impact of flattened diaphragm, decreased air
> movement for a given amount of muscle contraction and effort.
>
> \[Slide\]
>
> The clinical consequences are real in patients who have x-rays such as
> this with hyperinflation. These patients often will describe, \"I have
> difficulty with inspiration.\" They may have trouble performing the
> FEV1 maneuver once a year on their birthday but they have to inspire
> 16-20 times a minute.
>
> \[Slide\]
>
> That is really the disability in these patients. During exercise
> things only get worse. These are the resting tidal volumes from
> expiration and expiratory lung volume to inspiration in a normal
> individual. As we discussed, patients with COPD are markedly
> hyperinflated. As exercise progresses they have less time to exhale. A
> normal individual will exhale more completely and breathe deeper and
> have significant reserve. They can increase their rate. They can
> increase their flow. Patients with COPD are limited in this air
> trapping. It gets more extensive and the end expiratory lung volume
> gets closer and closer to the maximal lung capacity and ceiling and
> their symptoms get worse.
>
> \[Slide\]
>
> This study by Dr. O\'Donnell shows the disconnect in therapeutic
> response to albuterol between FEV1 and lung volume response. Dr.
> O\'Donnell investigated a group of patients with irreversible COPD and
> found that 83 percent of them did have significant reductions in lung
> volume despite limited improvements in FEV1. Recall, this is a post
> bronchodilator maximum therapeutic effect of this drug in this study.
>
> \[Slide\]
>
> Another aspect that FEV1 does not directly track is the degree of
> inflammation. This study, which we collaborated on with Dr. Hogg\'s
> group at the University of British Columbia, shows the fact that in
> severe COPD patients who had undergone lung volume reduction surgery,
> when the tissue is analyzed in patients who had discontinued smoking,
> there is ongoing, continued inflammation with the important increases
> in neutrophils, macrophages and the killer CD8 lymphocytes both in the
> air space and in the tissue.
>
> \[Slide\]
>
> An editorial by Dr. Shapiro really summarizes this: \"The cigarette
> burns out but the inflammation rages on.\"
>
> \[Slide\]
>
> It occurs to me that, in fact, an anti-inflammatory study has been
> published. The American Lung Health Study shows the impact of the
> anti-inflammatory effects of smoking cessation, resulting in
> stabilization of FEV1 relative to the ongoing relentless decline in
> FEV1 that occurs in the continued smoking group.
>
> \[Slide\]
>
> So, if we interpret these concepts in the context of the data that we
> have seen today, in fact the Ariflo group, cilomilast group, relative
> to placebo shows a result that could be very similar to that. In fact,
> this may be the effect we see from these classes of anti-inflammatory
> drugs\--stabilization relative to decline that would normally occur.
>
> \[Slide\]
>
> This study again shows the data on improvement in residual volume,
> decreasing residual volume over time relative to the placebo group. At
> end of study greater than 500 cc difference, 500 cc difference in the
> Ariflo group relative to the placebo group. Recall, this is a trough.
> These values were obtained at trough pharmaceutical concentrations. In
> addition, you see this occurring over time. It is not an abrupt
> response. This may be what we might expect to see with the control of
> inflammation in the peripheral airways.
>
> \[Slide\]
>
> These surrogate markers of inflammation are present in the cilomilast
> last, decreases in the CD8 and the macrophage concentrations relative
> to the placebo group.
>
> \[Slide\]
>
> In conclusion, clinically relevant outcomes of novel anti-inflammatory
> agents for COPD may need to include stabilization of FEV1, reduction
> in lung hyperinflation and surrogates indicating changes in airway
> inflammation. These may be most important when measured at trough
> levels of therapeutic concentrations.
>
> FEV1, while it is indeed a useful measure of severity and outcome in
> COPD, may not reflect other clinically important measures of lung
> hyperinflation and inflammatory activity.
>
> I appreciate your attention. Thank you.
>
> **Summary Remarks**
>
> DR. WHEADON: For those of you suffering the caffeine effects, diuretic
> not mesenteric, I promise you, we are in the home stretch.
>
> Ariflo is a novel medication that was specifically developed to treat
> the processes that are important in COPD. Until now patients with COPD
> have had to rely on the same drugs developed to treat asthma. We
> believe that the data we have reviewed this morning supports the
> approval of Ariflo for the treatment of COPD.
>
> \[Slide\]
>
> Based on the increasing mortality of this disease, it is clear that
> COPD has been neglected for far too long. It is only beginning to
> receive the attention that it deserves. New pharmacological therapy
> based on the pathophysiology of this disease may change the way
> physicians approach the management of this progressive and
> debilitating disorder.
>
> \[Slide\]
>
> As you have seen, Ariflo effects are a wide variety of processes that
> are important in the complex pathophysiology of COPD. There is an
> urgent need for treatments that address the underlying processes of
> this disease. Unlike bronchodilators, the novel mechanism of action of
> Ariflo addresses multiple components of COPD. Therefore, Ariflo
> represents a promising step forward in the treatment of COPD.
>
> \[Slide\]
>
> In conclusion, Ariflo offers an important advancement in the treatment
> of COPD. The objectives of the Ariflo clinical program were achieved
> in this population for which we are seeking approval. In this poorly
> reversible population Ariflo demonstrated greater improvements in the
> co-primary efficacy endpoints of FEV1 and quality of life assessments.
>
> Some patients experienced GI intolerance. This generally occurred
> early in treatment and was mild to moderate in intensity. There were
> no clinically significant safety concerns noted with the long-term use
> of Ariflo in patients with COPD.
>
> In this population that has many co-morbidities and commonly receives
> multiple medications, Ariflo\'s lack of interactions with frequently
> prescribed drugs is important. In addition, since Ariflo is an oral
> treatment it may, indeed, improve patient compliance. Therefore, we
> believe Ariflo would be a valuable treatment option for patients with
> COPD.
>
> I would also like to introduce four additional experts that we have
> joining us this morning. Dr. Loren Laine is Professor of Medicine at
> the University of Southern California Medical School and is Chief of
> the GI Section, LA County, U.S.C. Medical Center.
>
> Dr. Jeremy Ruskin is Associate Professor of Medicine at the Harvard
> Medical School and Director of the Cardiac Arrhythmia Service at the
> Massachusetts General Hospital.
>
> Dr. Christina Wang is a Professor of Medicine at the David Geffen UCLA
> School of Medicine and Program Director, General Clinical Research
> Center, Harbor, UCLA Medical Center.
>
> Dr. Gay Koch is Professor of Biostatistics at the University of North
> Carolina.
>
> This ends our formal presentation and the presenters, as well as our
> experts, are available for any questions we may answer for you. Thank
> you.
>
> **Committee Discussion and Clarification**
>
> DR. PARSONS: There are two minutes left in the Glaxo presentation. If
> there are, I would say, very specific questions we could start now but
> I would save more broad questions for discussion later. Are there
> specific questions regarding specific details for the company that the
> committee has right now? Dr. Apter?
>
> DR. APTER: I congratulate you on your presentation and I agree that
> COPD is a neglected disease. Can you tell me why 95 percent of the
> subjects in the focused trials were white and minorities and other
> patient groups weren\'t included?
>
> DR. WHEADON: Well, I will take the first stab at that and then Dr.
> Knobil can add. Certainly, it is continually a target and an effort
> that we have very much focused upon, that is, to increase the
> variability or the diversity of the patient populations in all of our
> clinical trials. Unfortunately, as we have seen over and over again in
> all sorts of chronic illnesses, it is very hard to widen that
> diversity. We are focusing on it; we are trying to do it very hard in
> a very focused fashion. Unfortunately, in this particular circumstance
> in the North American studies we were not able to get the diversity of
> patients that we were hoping to get.
>
> DR. APTER: COPD dramatically affects other patient groups, does it
> not?
>
> DR. WHEADON: Certainly we recognize that. Dr. Knobil?
>
> DR. KNOBIL: Yes, COPD does affect all patient groups but traditionally
> Caucasians have been sort of the largest population of patients with
> COPD, and we see this in our clinics as well as our clinical trials.
> The other patient groups are probably somewhat under-represented in
> our clinical trials and, as Dr. Wheadon has already said, we are
> working to change that. But especially in European trials, it is
> difficult to increase the diversity based just on the patient
> populations in those regions.
>
> DR. PARSONS: I have been told we are going to take exactly a 15-minute
> break and we will resume for the FDA presentation. Thank you very
> much.
>
> \[Brief recess\]
>
> DR. PARSONS: The next part of the program will be the FDA
> presentation. I just want to remind people that the plan for this
> morning was that there would be 90 minutes for the Glaxo presentation,
> which we have had. There is an additional 90 minutes for the FDA
> presentation. If the FDA presentation finishes earlier, the plan will
> be for discussion open to both sides until approximately twelve
> o\'clock, and which time we will break for lunch. So, that is the
> current schedule that we are on. I would like to now start with Dr.
> Anthracite who is going to start the presentation.
>
> **FDA Presentation**
>
> **Introduction**
>
> DR. ANTHRACITE: Good morning.
>
> \[Slide\]
>
> SB 2077499, also called Ariflo, also called cilomilast, is a
> phosphodiesterase-4 inhibitor, as you have heard. It is a new
> molecular entity and the first drug in its class, and it is orally
> dosed twice daily.
>
> The indication will be for the maintenance of lung function, as
> defined by the FEV1, in patients with chronic obstructive pulmonary
> disease who are poorly responsive to albuterol. This has, as you have
> heard, been a multinational development program in Europe, Australia,
> Japan, New Zealand, North America and South Africa.
>
> \[Slide\]
>
> Our presenters this morning are going to be several. Dr. Virgil
> Whitehurst first will present preclinical pharmacology-toxicology from
> our perspective; followed by Dr. Sandra Suarez who will discuss dose
> finding; Dr. James Gebert who will talk about statistics and I will
> return to discuss safety and efficacy. Dr. Whitehurst?
>
> **Preclinical Pharmacology-Toxicology**
>
> \[Slide\]
>
> DR. WHITEHURST: Toxicology studies are a major part of the preclinical
> safety evaluation. These studies determine the toxicity profile of a
> drug. The characterization of the toxicological profile attempts to
> identify target organs of toxicity; the no-observed adverse effect
> level in animals, commonly referred to as the NOAEL; determine
> severity, reversibility and monitorability of toxicity; as well as
> determine the margin of safety, which is a ratio based on exposure
> comparison between animals and humans. There are several ways to
> compare the exposure. In this case we used the plasma area under the
> curve of the drug in both animals and humans.
>
> \[Slide\]
>
> The toxic effects of cilomilast in animals was studied in mice, rats,
> rabbits and monkeys. These studies revealed that cilomilast induces
> arteritis, testicular degeneration, adrenal cortex hypertrophy,
> myocardial necrosis and GI disturbances in animals. For the purpose of
> today\'s discussion, we will focus on the findings related to
> arteritis due to the severity of the lesion. We are asking your
> opinion on how to resolve this issue.
>
> \[Slide\]
>
> First some brief background information on arteritis. Arteritis is
> inflammation, hemorrhage and necrosis of the blood vessels. Arteritis
> appears to be a class effect of PDE inhibitors, rolipram for one and
> others. There are about 12-15 at the agency, most of which cause
> arteritis in animals.
>
> The Division\'s current conclusion based on our experience with PDE
> inhibitors is that arteritis is irreversible in animals. The sponsor
> has submitted preclinical data which they feel show that arteritis may
> be reversible. However, we feel that these data do not adequately
> address irreversibility.
>
> In addition, the sponsor suggests that arteritis observed in the rat
> is likely a consequence of vasal dilation and resulting hemodynamic
> changes. However, we do not believe that the sponsor has adequately
> demonstrated this association, whether the lesion may be the result of
> direct drug-induced toxicity.
>
> We are concerned about arteritis in this application because of its
> lack of a margin of safety. If a safety margin is based on AUC, as in
> this case, we generally consider a margin of 1 or greater to be
> adequate to support the safety. A narrow margin of safety suggests
> that the drug is more likely to cause similar toxicity in humans at
> the recommended clinical dose.
>
> We derive the margin of safety from the most relevant animal species.
> When there is a lack of evidence of human relevancy among the animal
> species the margin of safety is derived from the most sensitive
> species. In many cases, including cilomilast, the most sensitive
> species is the most relevant species. As I will show you later, the
> cilomilast exposure at the NOAEL in the rat, the most sensitive and
> relevant species, was only a fraction of that in human at the proposed
> dose.
>
> \[Slide\]
>
> This table illustrates my point of the lack of safety margin of the
> cilomilast application. The table also provides a glance at the
> dose-response relationship of the drug and arteritis. Species tested
> are listed in the far left column. The doses at which arteritis occurs
> or is absent is listed in columns two and four. Columns three and five
> present plasma drug levels, AUC correspondent to these doses. The far
> right column represents the safety margin derived from the AUCs.
>
> Human AUC here is 22 mcg/hour/ml. As you can see, arteritis was
> observed in rats and mice but not in monkeys. Note that the dose
> response of arteritis is very steep. Take the rat data as an example.
> No lesions were seen at 20 mg/kg. Lesions were noted at 30 mg/kg and
> higher. Death occurred at 40 mg and higher. The safety margin derived
> from the rat data is 0.2. Furthermore, arteritis in rats occurred at
> an AUC that was only half of that in humans at the proposed clinical
> dose.
>
> As was mentioned earlier, arteritis was not found in the monkey. The
> monkey does not appear to be a sensitive animal model for the
> detection of arteritis based on the lack of information in the
> literature and the agency\'s experience with PDE inhibitors.
>
> You might ask why clinical trials at such a dose were allowed to
> proceed given the lack of an adequate safety margin. The answer is
> that the kinetic data was incomplete in the developmental phase and
> that initially a safety margin for arteritis was present. We
> recommended that these toxicities be closely monitored during the
> clinical trials.
>
> \[Slide\]
>
> To summarize, cilomilast-induced arteritis and death in rats, the
> severity of the toxicity in rats increases over a narrow range of
> exposure. Human exposure at the proposed clinical dose is higher than
> the toxic dose in the rat.
>
> \[Slide\]
>
> Therefore, the data provide no margin of safety for arteritis compared
> to the proposed clinical dose regimen, and arteritis is a significant
> safety concern. Thank you.
>
> **Dose-Finding**
>
> DR. SUAREZ-SHARP: Good morning, everyone.
>
> \[Slide\]
>
> I will focus my presentation on study 032, which was a Phase II
> dose-response study following multiple administration of oral
> cilomilast at doses of 5, 10 and 15 mg twice daily given to patients
> with COPD, for six weeks. I would like to mention that I will be
> mainly talking about two issues, dose-response for efficacy issue and
> dose-response for safety issue.
>
> This study, 032, had a parallel design and included around 100
> subjects for treatment, and it had a dropout rate which was around 16
> percent and was similar across treatments. What I have plotted here,
> as you can see, is the mean change from baseline in trough FEV1 as a
> function of visit and treatment. In this case the blue profile
> corresponds to placebo. The black profile corresponds to the 10 mg
> dose, the green to 5 mg, and, in grey, to the 15 mg dose.
>
> It can be observed from this slide that only the 15 mg dose was seen
> to be different from placebo at all visits, including endpoint. Also,
> you can observe from this that the 10 mg dose had a lower efficacy
> than the 5 mg dose. From this study, it was concluded that there was a
> lack of dose order response for cilomilast at doses of 5, 10 and 15 mg
> given twice a day, and also that only the 15 mg dose was significantly
> different from placebo.
>
> \[Slide\]
>
> What I have plotted here is the relationship between cilomilast trough
> concentrations as a function of dose just to show you that lack of
> dose response that I showed in the previous slide has nothing to do
> with lack of dose proportionality. In other words, as the dose of
> cilomilast increased the cilomilast trough concentrations increased,
> as you see here, proportionally.
>
> \[Slide\]
>
> Further analysis by the FDA showed that the 10 mg dose had a higher
> baseline FEV1. In fact, both the mean and the median baseline FEV1 was
> higher for the 10 mg dose. When we would correct for this discrepancy
> in baseline, we would obtain this plot.
>
> \[Slide\]
>
> What I have done here is to plot the change from baseline and FEV1
> after baseline adjustment as a function of treatment and visit. In
> this case the green profile corresponds to placebo, white to 5, yellow
> to 10 and 15 mg is depicted here by blue. It appears that the 10 mg
> dose may be significantly different from placebo. Also, it might be
> that we might have a dose order response relationship. However, a lack
> of existence of dose response or the clinical relevance of this 10 mg
> dose with respect to placebo cannot be determined because the 10 mg
> dose was not tested in Phase III clinical trials.
>
> \[Slide\]
>
> So far I have talked about the relationship between dose and response.
> Now I am going to show you a correlation between concentration of
> cilomilast, in this case trough, with efficacy, in this case FEV1.
> What I have plotted here is the change from baseline in FEV1 as a
> function of cilomilast concentrations. It is clear here that it
> appears that there is not a clear correlation between cilomilast
> trough concentrations and this clinical endpoint based on FEV1. The
> reason for that may be that the data was highly variable, as you can
> see here. Both the trough concentrations and FEV1 were highly
> variable. You see a high imbalance in the data. Or, it may be because
> maximum response was achieved at concentrations covered by the 10 mg
> and 15 mg dose.
>
> \[Slide\]
>
> Now let\'s move to the relationship between safety and dose. What I
> have plotted here is the percentage of adverse events occurring in
> more than five percent of patients in any treatment group as a
> function of dose and side effect. You can see here that as the dose
> increases this percentage of either abdominal pain, diarrhea, nausea
> and vomiting increased.
>
> \[Slide\]
>
> How do we know about the relationship between concentrations and
> safety? Well, what I have done here is to show you the relationship
> between cilomilast trough concentrations in patients having
> gastrointestinal side effects against those having no side effects. It
> is observed here that I have plotted the cilomilast trough
> concentrations as a function of visit and dose for abdominal pain,
> nausea, vomiting and those patients having no adverse events.
>
> It is shown in this slide that these patients having gastrointestinal
> side effects had cilomilast trough concentrations which ranged from as
> low as 35 and as high as 1,500 ng/ml, and those patients having no
> side effects had plasma trough concentrations which were between six
> and higher than 2,000 ng/ml. This tells us that there is not a clear
> correlation between cilomilast trough concentrations and side effects.
> The reasons for that may be various. It may be because of the high
> variability of the data, or maybe because simply there is no
> correlation between cilomilast trough concentrations and safety.
>
> However, I want to mention that the sponsor submitted the data from
> 032. This study was a multiple dose study conducted in healthy
> volunteers, given doses from 2-20 ml twice a day. From that study it
> was shown that the frequency of side effects was correlated to Cmax of
> cilomilast.
>
> \[Slide\]
>
> In conclusion, we can say that the dose-response relationship was not
> fully addressed by the sponsor. I showed you that the 10 mg dose may
> be significantly different from placebo. However, the clinical
> relevance of the 10 mg dose cannot be determined because the data from
> this study was not robust enough and the 10 mg dose, as I mentioned,
> was not tested in Phase III clinical trials.
>
> We observed that there was a lack of concentration-response
> relationship and, as I said, that may be due to the large degree of
> variability in the cilomilast plasma trough concentrations. The
> coefficient of variation was rather high, higher than 60 percent. The
> data was highly unbalanced.
>
> A higher incidence of side effects, such as nausea, abdominal pain and
> diarrhea, was observed with increasing doses of cilomilast.
>
> \[Slide\]
>
> Finally, as I said, plasma concentrations increased proportionally to
> dose, however, no clear correlation between was observed between
> trough concentrations of cilomilast and some adverse events, and this
> may be due to the high variability of the data or just because there
> is no correlation between cilomilast trough concentrations and side
> effects.
>
> \[Slide\]
>
> Finally, I would like to acknowledge some people who contributed in
> the review of this study. Thanks for your attention.
>
> **Statistics**
>
> DR. GEBERT: Good morning.
>
> \[Slide\]
>
> I have been asked to give some background material. The results of the
> individual studies will be given by Dr. Anthracite.
>
> \[Slide\]
>
> The topics I am going to talk about are the Hochberg procedure which
> was the procedure the sponsor used to declare significance of the two
> primary endpoints. I will talk about the repeated measures analysis. I
> will talk about properties of the endpoint analysis which was the
> sponsor\'s supportive analysis. Then, I will talk about sample size
> and delta of the sponsor\'s.
>
> \[Slide\]
>
> The Hochberg procedure is a modified Bonferroni procedure with two
> endpoints. If both of them are significant at the 0.05 level, they are
> both significant. If one fails to be significant at the 0.05 level,
> the other is significant if it is significant at the 0.025 level.
>
> This is statistical significance, not clinical significance. In a
> regulatory setting this may not be appropriate in some situations
> because in some situations, because of risk/benefit considerations,
> you may need both to be significant. It also might cause some troubles
> about writing a label if you didn\'t have one study where both of them
> were significant.
>
> Another kind of subtle thing is that the 95 percent confidence limits
> on the differences between treatment means are not really appropriate
> in this situation because sometimes you don\'t use the 0.05 to judge
> significance; it is the 0.025 level which you use to judge
> significance. In some cases 97.5 percent confidence limit might be
> more appropriate.
>
> \[Slide\]
>
> The repeated measures analysis compared treatment over the whole
> treatment period, in this case 24 weeks. There is no imputation of
> missing values for the visits. It tends to underweigh dropouts a
> little bit because they contribute less data to the analysis. It
> overweighs earlier visits. You have to make some types of assumptions
> for the analysis about what the correlation structure of the visit
> date is. This means there are multiple p values. In this case, for the
> sponsor\'s results it really didn\'t matter very much. No matter what
> assumption was made, they tended to get the same results.
>
> \[Slide\]
>
> The sponsor used endpoint analysis, which was their supportive
> analysis which did tend to support the results that they saw for the
> primary analysis. It gives little or no weighting to the earlier
> visits. All patients, including dropouts, get equal weight. There is
> no imputation of missing values in this type of analysis because it
> uses the last observation for each patient. However, it is equivalent
> to doing a last visit analysis after you do last observation carried
> forward for all dropouts. Usually the delta in this particular
> analysis is larger than the delta in the repeated measures analysis.
> However, there is also more variability in this because extreme values
> are used for those people who dropout because of lack of efficacy, and
> also because you are using one value from an observation as opposed to
> the repeated measurement that is using a mean overall visit data.
>
> However, since these are somewhat acting at cross purposes, you don\'t
> really know how the p values will compare. Sometimes the p value of
> the repeated measurement might be smaller than the p value for the
> endpoint analysis.
>
> \[Slide\]
>
> The sponsor, in his choosing a sample size, used 90 percent power.
> Three of the four studies used 2:1 weighting. The alpha level was
> chosen to be 0.025 for both endpoints. They may have done this to
> ensure if one failed to be significant the other one could be
> significant.
>
> Delta is the true differences between the means. It was assumed to be
> 120 ml for FEV1. It was assumed to be 4 for the St. George\'s
> Respiratory Questionnaire total score. Four happens to be the value
> that is declared to be a minimally important difference by the
> developers of the instrument. This may give statistical significance,
> again, but not clinical significance. A large sample size\--it can
> become significant even if you misjudge what your true delta is. A
> large sample size also is good for getting the best estimate of what
> the true delta is in that particular population.
>
> \[Slide\]
>
> One of the things that I somewhat reflected upon is why did they get
> significance in this situation when their true delta was smaller than
> what they had assumed? The two factors that I think influenced it most
> is the fact that they did choose 90 percent power. They chose high
> power. Also, they chose an 0.025 significance level. In some cases
> they only had to get 0.05 to be significant for both.
>
> One of the things that you are going to be asked to reflect on is
> whether the amount of efficacy observed is adequate for approval. I
> will turn it over to Ray Anthracite right now.
>
> **Efficacy and Safety**
>
> DR. ANTHRACITE: Hello again.
>
> \[Slide\]
>
> The background for this presentation is that there are four
> preclinical toxicities of which you heard some. Mesenteric arteritis
> was our chief concern because it appeared to be the most serious
> animal toxicity and, in fact, was found in two species. The remaining
> three will not be addressed because it is only mesenteric arteritis
> that really reflects on approvability ultimately of this compound.
>
> In terms of dose selection, as you have heard from Dr. Suarez, we do
> agree that the dose selected at the time it was selected was
> appropriate for development. In terms of the statistics, we certainly
> agree with the appropriateness of the analyses chosen.
>
> \[Slide\]
>
> With that out of the way, this is the outline of what I hope to
> present to you today. Efficacy will be shown, hopefully, or at least
> will be demonstrated by four pivotal trials. There will be co-primary
> endpoints, the trough FEV1 and the SGRQ. Because of the indication,
> which is maintenance of lung function as defined by the FEV1, although
> the SGRQ is technically a co-primary, most of the heavy lifting must
> be done by the trough FEV1, with the SGRQ, the St. George\'s
> Respiratory Questionnaire, filling in as a supportive study for
> approval. Secondary endpoints were also investigated for support of
> approval.
>
> The safety analysis which will follow will deal with the usual things
> one sees with safety analyses, adverse events, serious adverse events,
> withdrawals due to those adverse events and deaths. We will emphasize
> gastrointestinal adverse events of concern and the adequacy of the
> evaluation for the mesenteric arteritis that raised concerns in the
> preclinical data.
>
> \[Slide\]
>
> Thanks to the work done by GlaxoSmithKline, I think we can move
> through many of these slides relatively more quickly than I would have
> thought. There are four asthma trials with over 1,000 patients in them
> which will benefit us mostly for safety.
>
> The COPD studies numbered over 5,000 people, most of which we will
> look at for efficacy will be the well-controlled pivotal trials. The
> remainder of them are long-term, uncontrolled safety trials which will
> speak to safety, and there will be some safety data picked up from the
> mechanism of action and cardiology safety studies.
>
> \[Slide\]
>
> This has pretty much been gone over by GSK. These are multinational.
> There is a four-week run-in period with a 24-week double-cling period.
> This is in COPD patients and they are all current or former smokers.
>
> \[Slide\]
>
> I think you have also seen that the pre-albuterol FEV1/final capacity
> ratio of 0.7 was an inclusion criterion, and all of these folks had to
> have a post-albuterol forced expiratory volume in one second of 30-70
> percent of predicted.
>
> Poor responsiveness to albuterol, ultimately called fixed airway
> obstruction, was defined as post-albuterol forced expiratory volume in
> one second of less than or equal to a 15 percent increase over
> baseline, or by a less than or equal to 200 ml increase over baseline.
>
> \[Slide\]
>
> I will just contrast some of the similarities and differences.
> Virtually all the four co-primary or primary efficacy endpoints were
> the same in the four studies, and so was the statistical analysis. The
> primary efficacy endpoints were a little difficult to appreciate
> qualitatively. They were the difference between treatments in mean
> changes from baseline, so a difference of differences.
>
> Three of the studies had the same randomization strategy, which was
> 2:1 randomization of cilomilast to placebo. All five of the secondary
> endpoints were common for studies 039, 042 and 091. Study 156 came
> later, after the results of the first three were known, and that was
> changed slightly to provide for 1:1 randomization, plus a couple of
> other minor changes that wouldn\'t affect our primary endpoints.
>
> \[Slide\]
>
> The sponsor has covered this rather nicely too. There has been a
> slight difference in responsiveness to albuterol by the amount of
> albuterol given. There was some pharmacokinetic sampling. To point out
> one thing I believe they did not cover, in study 091 there was a
> two-week double-blind run-out period, during which placebo patients
> continued to take placebo and cilomilast patients were re-randomized
> 1:1 to either receive cilomilast or placebo. We will see the results
> of that.
>
> \[Slide\]
>
> These are the demographics and disposition of the Phase III patients.
> You are going to see some difference in numbers in my presentation and
> theirs. In some cases I am talking about the Phase III pivotal trials
> and in some cases later, in safety, I will be talking about all asthma
> and COPD patients. So it gets a little confusing and I will attempt to
> define the denominator as I hit it.
>
> These are all the pivotal trials. You can see here, as has been said
> before, there is male predominance in both groups at randomization.
> They are mostly Caucasians. They are 65 years of age. They have a mean
> FEV1 of about 50 percent of predicted, and they have a reversibility
> of about 6.5 to 6.7 percent. This is the percent reversibility induced
> by albuterol. I will ask you to remember that number. The smoking
> history was over 50-pack years. Those who completed the study
> constituted 75 percent approximately, in round numbers, of the placebo
> group and 70 percent of the cilomilast group. So, we have 35 or 30
> percent dropouts.
>
> \[Slide\]
>
> Now we will display the data in a somewhat different fashion than you
> have seen it before. Prior to this you have seen small differences
> magnified. This is a little bit complicated. Let me explain it to you.
> This is the trough FEV1 for one of the pivotal trials, study 039, at
> each week or visit. On the Y axis is the trough FEV1 in liters and the
> categories on the X axis are seen in the title to the table. The first
> two bars are blue and red. Blue is placebo; red is cilomilast. The
> first two bars are for baseline, followed by week 2, week 4, week 8,
> 12, 16, 20 and 24. The last column is reserved for the mean change
> from baseline.
>
> I think you can most expeditiously see the mean change from baseline
> in the last column of the table, and the mean change is shown to be 30
> ml for the placebo group in the negative direction and 10 ml for the
> cilomilast group. Looking at the 30 ml drop in the placebo group,
> where in fact does that occur? I think you can see, just by inspection
> of the placebo row, that most of it occurs in the first two weeks.
> There is some data variability thereafter but the drop in the placebo
> group occurs early.
>
> \[Slide\]
>
> Moving on to the second pivotal trial with the trough FEV1, this is
> study 042, we have exactly the same setup and exactly the same size of
> axes and representations. Again, placebo is in blue; cilomilast is in
> red. The FEV1 trough is on the Y axis and the visits are given on the
> X axis. The mean change from baseline again is way over in the right
> column. The mean change from baseline for placebo is nothing. The mean
> change from baseline for cilomilast was an improvement of 30 ml, and
> this seemed to have occurred probably over the first four to eight
> weeks, if you can trust changes over time in tables like this.
> Remember the 25-30 percent dropouts? Clearly, any change over time in
> any of these tables reflects a combination of things, both a change
> over time and the results of the dropouts.
>
> \[Slide\]
>
> In study 091, again moving the right column, the placebo group here
> shows a mean drop of 30 ml and cilomilast shows no change at all. The
> drop in the placebo group seems to have occurred predominantly over
> the first four weeks, although there is an additional drop apparently
> at the end of about 10 cc. In any event, we look at this as the
> placebo group having most of its drop early on.
>
> \[Slide\]
>
> This is the same study, 091, for the two-week run-out. The placebo, in
> blue, at the 24th week continued to get placebo, unknown to them. The
> brown and orange columns are SB 207499-treated patients at week 24 on
> the left, and run-out on the right. The ones in brown were randomized
> to continue taking cilomilast and the ones in orange were randomized
> to be switched to placebo.
>
> Rather than trying to interpret small differences in the columns, take
> a look at the cell entries. The placebo-placebo group, which is in
> blue, shows at week 24 a 1.39 trough FEV1 and a mean trough FEV1 at
> run-out of 1.38, for a 10 ml drop. The cilomilast group that was
> continued on cilomilast went from 1.46 to 1.45, a 10 ml drop. The
> cilomilast group that started taking placebo also showed the same 10
> ml drop. So, there seems to be very little difference when cilomilast
> is replacing the placebo at least over two weeks.
>
> \[Slide\]
>
> This is the last and final study, the one done with 1:1 randomization.
> It is again shown in the same graphical setup as the previous ones
> have been. If we move to the table in the last column over, you can
> see that here the mean change from baseline of the placebo group was a
> negative 20 ml. An improvement was shown in the cilomilast group of 10
> ml. If you track back over the placebo visits, I think you can see
> that most of that drop occurred over the first four weeks.
>
> I will mention too that, again, changes in time are confounded by
> dropouts. So, it is very difficult to know what this means, at least
> in terms of maintenance of lung function.
>
> \[Slide\]
>
> This simply attempts to show all the studies together. BL stands for
> baseline, as you might imagine. MC stands for mean change. Here you
> can see that for placebo, just looking across the placebo group for
> all studies, the mean change was 30 ml down for study 039; no change
> in study 042; a 30 ml decline in study 091; and a 20 ml decline in
> study 156. This could equally represent the dropouts or a change over
> time.
>
> The apparent improvement of cilomilast, which could also represent an
> effect of dropouts, was 10 ml in study 039; 30 ml in study 042. There
> was no real change in study 091, and a change of 10 ml in study 156.
>
> Looking at the first yellow column, the difference of differences was
> 40 ml and this was statistically significant. In study 156, which was
> a much larger study and also took the heavy advantage of the
> efficiency of 1:1 randomization, a 20 ml difference of differences was
> standardly significant.
>
> Recall that I asked you to remember the albuterol reversibility. It
> turns out that the best difference of differences of 40 ml in study
> 039 is less than three percent of the baseline.
>
> \[Slide\]
>
> Moving on to the so-called co-primary endpoint, which in fact was
> called primary but here serves a secondary role, we have the total St.
> George\'s Respiratory Questionnaire. There are only three visits at
> which this was determined, baseline, week 12 and week 24. The setup
> for this graphic is very much like the last. It is noted that this is
> a 100-point scale and we are showing about half of it on the Y axis so
> this magnifies the differences. The last column in the table again
> shows the mean change. The placebo shows a 0.4 unit mean change; the
> cilomilast shows a 3.7 mean change in the negative direction. That
> mean change in the negative direction is an improvement. As in the
> Borg scale, you will see that the negative direction is less symptoms,
> better outcome.
>
> For the purposes of interpreting this, Dr. Jones who developed the
> instrument has studied it and found that a change of greater than or
> equal to four units is slightly efficacious. Greater than or equal to
> eight units is moderately efficacious, and greater than or equal to 12
> units is very efficacious. These don\'t meet either of these criteria.
>
> \[Slide\]
>
> Here, in study 042, jumping to the right-most column of the table we
> find the mean difference by the placebo over time is negative 4.9
> units which does, in fact, reach the criteria of slightly efficacious.
> Cilomilast shows an important of minus 4.2 units, which is slightly
> efficacious but less so than placebo.
>
> \[Slide\]
>
> In study 091 the St. George\'s Respiratory Questionnaire, again moving
> the right-most column in the table, shows an improvement of negative
> 2.3 units for placebo and negative 2.7 units for cilomilast. So,
> improvement is shown by both treatments with a slight edge to
> cilomilast.
>
> \[Slide\]
>
> Finally study 156, the placebo shows an improvement of 1.3 units;
> cilomilast of 3.2 units. This has improvement in both treatments with
> an edge to the cilomilast.
>
> \[Slide\]
>
> I think overall you can see, just looking at the yellow for example as
> most of these are not going to be terribly germane, the improvement in
> cilomilast in study 039 was negative 3.7 units. There was actually a
> worsening of symptoms on placebo of 0.4 units, to make a difference of
> differences of 4.1 units. Again, this would be considered slightly
> efficacious.
>
> In study 156, which is the last two column over, there was improvement
> in both of the treatments, with a difference of differences of minus
> 1.9 which did achieve statistical significance. It is, however, not
> even close to slightly efficacious. So, by our judgment this has
> provided support in one of four studies.
>
> \[Slide\]
>
> There was a host of secondary efficacy endpoints and we could have
> belabored them as well as the tertiaries but, since the indication is
> maintenance of lung function by FEV1, it seems less needful to delve
> into things that aren\'t germane to that particular endpoint.
>
> The trough vital capacity was one. This did tend to track with the
> forced expiratory volume in one second because they are highly
> correlated.
>
> The post-exercise six-minute walk for breathlessness by the modified
> Borg scale, an 11-point scale, we felt unconditionally supported
> efficacy of some kind in cilomilast. There was a summary diary COPD
> symptom score; a six-minute walk in meters; and a percent of patients
> who were COPD exacerbation-free through 24 weeks. Our feeling was,
> after looking at these qualitatively, that the post-exercise Borg
> scale did, in fact, support the efficacy of cilomilast.
>
> \[Slide\]
>
> The Borg scale is an ordinal scale that emphasizes severe dyspnea.
> Seven of the 11 categories are varying degrees of \"severe.\"
>
> \[Slide\]
>
> This is a little bit complicated. It is unlike the last several slides
> you have seen. This attempts to look at baseline and the mean change
> for each of the separate studies. Again, the Borg scale has a 10-point
> scale and about half of that scale is represented on the Y axis, which
> tends to make the differences magnified. In fact, in every case I
> think you can see that the orange or beige columns tend, in fact, to
> be negative, while the blue columns are positive, as a mean change.
> That represents an improvement, much like the St. George\'s
> Respiratory Questionnaire did. Negative changes are very good when you
> are talking about symptoms. So, 039 showed a mean change that was an
> improvement or a decrease in symptoms that was superior for cilomilast
> over placebo, as was 042, as was 091 and 156.
>
> \[Slide\]
>
> So, in summary of these efficacy trials, the forced expiratory volume
> at trough in one second was shown over 24-week trials. Now, do recall
> that the support for maintenance of lung function or the investigation
> of maintenance of lung function of the four published trials shown
> were all shown over three to five years. This is over a considerable
> period of time less than that, with confounding by 25-30 percent
> dropouts.
>
> We feel that a placebo decline in three trials occurred over the first
> few weeks and did not occur at all in the fourth trial. Two of the
> four pivotal trials statistically supported significance of this
> endpoint.
>
> In the SGRQ, St. George\'s Respiratory Questionnaire, a supportive
> trial for our considerations, one of four pivotal trials was
> statistically significant and slightly efficacious. We felt that a
> secondary endpoint, one of five, showed some support for SB 207499.
>
> \[Slide\]
>
> The question to the committee, that cannot be divorced from showings
> of efficacy, is has cilomilast shown a magnitude and consistency of
> efficacy that is sufficient to approve it for the indication of
> maintenance of lung function?
>
> \[Slide\]
>
> Having said that, we will go to the integrated safety outline. This
> will include a variety of different denominators. We choose to look at
> all of safety together for all patients exposed to a drug. So, in this
> case we have chosen to look at asthma and COPD. The hope is to find
> very infrequent events that might be clinically significant to
> patients.
>
> Additionally, we look at COPD controlled trials only and COPD
> uncontrolled long-term safety extensions. Again, as I said before, we
> look at adverse events, serious adverse events and withdrawals due to
> adverse events as well as deaths, and we will emphasize
> gastrointestinal adverse events of concern, as well as the adequacy of
> evaluation for mesenteric arteritis.
>
> \[Slide\]
>
> The demographics for all the asthma and COPD patients are not very
> different from the demographics for safety of COPD patients because
> the COPD patients mostly drive the numbers. There were only 1,000
> asthma patients in all the controlled trials but, if memory serves me,
> close to 3,000 COPD patients. In any event, it should be no surprise
> that the male gender predominates, as do Caucasians. The mean age has
> been dragged down slightly by the presence of the asthma patients,
> from 64 to 60. But the smoking pack-years of 50 is roughly the same as
> it was before. The mean percent predicted FEV1 is around 50 percent of
> predicted.
>
> I think from this we should note that 74 percent of patients who are
> represented here took the 15 mg twice a day dose of cilomilast. The
> remaining, less than 900, too doses somewhat less than that, 10, 5 or
> 2.5 mg.
>
> \[Slide\]
>
> This is a disposition of the asthma and COPD patients in the
> controlled trials. On the top yellow line, total withdrawn, the
> placebo patients had 19 percent withdrawal\--percent here is given as
> percent of column total. The cilomilast 15 mg twice daily group had 26
> percent withdrawals. I think we will concentrate on those two. The
> lesser doses that are shown in the total cilomilast group are of less
> interest.
>
> So, sticking with the second and third columns, the placebo and the SB
> 15 mg columns, adverse events in the placebo group accounted for 9
> percent of that group and accounted for 16 percent of the cilomilast
> group. When these are divided into adverse events that were COPD
> exacerbations and those that were not, the majority of them in the
> cilomilast group, 14 percent, were due to adverse events that were not
> COPD exacerbations and, in fact, were gastrointestinal adverse events,
> as shown in the third yellow line. In the placebo patients only two
> percent of the patients withdrawn were withdrawn because of
> gastrointestinal adverse events. This is given in support of the
> statement that these adverse events are hardly trivial; they are
> causing people to withdraw from the study.
>
> \[Slide\]
>
> This is again a little complicated. Let me try to lead you through it.
> We were interested in those adverse events that might be dangerous to
> people receiving a new molecular entity. So, we focused on those
> adverse events where the frequency in the 15 mg twice daily cilomilast
> group was greater than the frequency in the placebo group. Thereafter,
> we put up those that were also ascribed to lesser doses to see if
> there was in fact a dose response or dose ordering.
>
> I think you can see from this that with the criterion that the adverse
> events had to be greater in the 15 mg cilomilast group than in
> placebo, of the top six adverse events five of them are GI adverse
> events. If you look at nausea for example, just looking at the active
> treatments, 2.5 mg was associated with 3 percent nausea; 5 mg, 5
> percent nausea; 10 mg, 8 percent nausea; and 15 mg, 15 percent. You
> can kind of see a hint of dose ordering through most, if not all, of
> the gastrointestinal adverse events as you inspect this. I think the
> point is that adverse events are largely dose related with this drug
> despite the hope that this drug would have very good efficacy with
> less side effects than theophylline.
>
> \[Slide\]
>
> This is deaths in all controlled asthma and COPD studies. There were
> two deaths during the studies in placebo patients, one during the
> placebo run-in period. It was a suicide; hard to blame anyone for
> that, and one as an MI during the double-blind phase.
>
> During the double-blind phase in the cilomilast group six patients
> succumbed and though the frequency in the cilomilast group was
> probably greater than the frequency in the placebo group\--in fact, it
> is; these are things to which old people succumb. They are not
> necessarily anything that would pose a unique signal that there might
> be something associated with cilomilast. During the post-therapy
> section of the trials about similar numbers of people died and they
> died for similar reasons, things elderly people succumb to.
>
> \[Slide\]
>
> Now we are looking at serious adverse events. Again, this is looking
> at those that are more frequent in the 15 mg cilomilast group than the
> placebo group. The one salient point here is that there are very few
> serious adverse events. How exactly that equates to events serious
> enough to cause withdrawal is not exactly clear. In any event, I think
> very little can be gleaned from this in terms of dose ordering of
> events. Virtually all of them have a frequency of less than an integer
> amount.
>
> \[Slide\]
>
> These are the withdrawals due to adverse events once, again, where the
> frequency in the cilomilast twice daily 15 mg groups exceeds that of
> placebo in all controlled asthma and COPD trials. I think you can see,
> just focusing on the ones in the yellow which are the gastrointestinal
> adverse events, arrayed in descending order of frequency in the last
> column on the right, that these are the leading causes of withdrawals.
> This is what is causing the withdrawals in the cilomilast group, once
> again speaking to the seriousness of these events.
>
> \[Slide\]
>
> GI adverse events of concern is something we come to find in the
> middle of these studies, in partnership with GSK. Once again our
> problem was with clinical arteritis. It was mostly mesenteric in
> distribution, although not exclusively. It was seen in two species.
> There is no safety margin between animals and humans. Early on GSK
> made an effort to find biomarkers by which we could track this.
> Regrettably, they were unsuccessful.
>
> \[Slide\]
>
> It is fair to let you know that GI adverse events are thought to be
> centrally mediated for phosphodiesterase inhibitors. But, because we
> have seen results in animals and now some publicly acknowledged
> results in humans, mesenteric arteritis certainly may be a consequence
> of this class of drugs. Certainly, the GI adverse events were severe
> enough to cause premature patient termination and did, in fact,
> account for the majority of the early terminators in the cilomilast
> groups. In order to permit continued drug development we required a
> plan for evaluating patients for arteritis.
>
> \[Slide\]
>
> We settled on or tried to find a prospective evaluation. The plan was
> to single out cases with gastrointestinal adverse events for thorough
> evaluation. We were to search for a pre-fatal and possibly monitorable
> manifestation, fecal blood loss, and by valuating that clinically
> establish a database of colonoscopies from which human safety could be
> inferred.
>
> The justification for this rationale was that colonoscopy is becoming
> a standard of care for adenocarcinoma surveillance in asymptomatic
> adults over the age of 50. I won\'t embarrass anyone by asking them to
> raise their hands to acknowledge how many have had them. Certainly,
> symptomatic individuals of the same age range with GI blood loss would
> be candidates for the same procedure.
>
> \[Slide\]
>
> Initially it was agreed that all pivotal controlled trials, 039, 042,
> 091 and 156, that we analyzed in depth for efficacy, both uncontrolled
> trials, the cardiac safety study and all three mechanisms of action
> studies would be evaluated for the GI adverse events of concern. These
> were defined, as previously stated, as symptoms that caused the
> patient concern, specifically bloody or black stools, pain, cramps,
> diarrhea and vomiting, and/or things that interfered with patient\'s
> daytime activities or sleep.
>
> \[Slide\]
>
> Within 24 hours a physician evaluation was to include examination of
> the patient and fecal occult blood. Either the patient could have used
> the previously distributed fecal occult blood test, or a digital
> rectal exam with fecal occult blood testing to be done on examination.
> This was obviously intended to signal the need for further clinical
> evaluation. Orthostatic vital signs were to be gotten on these same
> patients within 24 hours to signal acute volume depletion from blood
> loss or fluid third-spacing.
>
> \[Slide\]
>
> In terms of the follow-up of these gastrointestinal adverse events, we
> encouraged the company to evaluate each of them on a daily basis with
> clinical examination, fecal occult blood and orthostatic vital signs.
> They were unable to do that and, instead, agreed to the daily
> monitoring in study 039 and 156, the two pivotal trials, and 168, the
> cardiac safety study. They also agreed to daily monitoring in two
> mechanism of action studies and the long-term safety extension. These
> were all the North American trials.
>
> As time went on it was apparent that we were not getting that safety
> database of colonoscopies that would permit us to have a feeling of
> safety about the non-presence of arteritis. So, we requested, and the
> company kindly acquiesced to requiring complete colonoscopies within
> two weeks in two of the studies for melena or fecal occult blood
> positive stools. Unfortunately, this amendment was done midway between
> beginning and ending of these studies and it didn\'t allow for very
> many patients to be included under this particular mandate.
>
> \[Slide\]
>
> Well, what were the GI adverse events of concern? Again, the
> percentages in parentheses do represent the percent of the column
> totals. There were 56 placebo patients and 264 COPD patients who had
> GI adverse events of concern, and now the denominator is COPD trials,
> not COPD and asthma trials. You can see the relative types of adverse
> events associated with the GI system in the left-most column.
>
> \[Slide\]
>
> How well were these eventually evaluated? Now the column totals have
> the number of patients with GI adverse events in it from the placebo
> group and those in the cilomilast group. Fecal occult blood was gotten
> at some time after the GI adverse event of concern in 82 percent of
> the placebo patients and 90 percent of the cilomilast patients.
> Although mandated within 24 hours, it was gotten within 14 days in 55
> percent of the placebo patients and 58 percent of the cilomilast
> patients. It was, in fact, positive in 11 percent of the placebo
> patients and six percent of the cilomilast patients. The conjoint
> event of a GI adverse event of concern and fecal occult blood
> positivity, regardless of how many times it was sought, as well as
> colonoscopy performed on those individuals at some point in time was a
> total of six patients.
>
> \[Slide\]
>
> The colonoscopy results showed in the placebo patients common things,
> diverticulae, polyps and internal hemorrhoids. In the
> cilomilast-treated patients, diverticulae, villotubular adenomas,
> polyps and internal hemorrhoids. In fairness, none of these showed
> ischemic colitis.
>
> \[Slide\]
>
> Fecal occult blood tests were also determined at baseline and endpoint
> for all patients as a matter of course. This table doesn\'t really
> show that. What it shows is the patients who were baseline negative,
> positive or missing and who became positive or negative sometime in
> the double-blind period. Sixteen patients that were negative at
> baseline became positive during the double-blind period in the placebo
> group and 33 patients became positive in the cilomilast group.
> Percentages are calculated on the row totals for each treatment. So,
> we have 49 patients here who are positive who previously were
> negative, and these are the total patients, 16 and 33.
>
> \[Slide\]
>
> Fecal occult blood positive stool samples were not unique. There were
> on the average two fecal occult blood positive stool samples per
> patient, 31 for the 16 placebo patients and 67 for the 33 cilomilast
> patients. Among those, a total of 22 patients, 7 placebo and 15
> cilomilast, had a positive GI adverse event of concern. The number of
> patients receiving colonoscopy was 2 in the placebo group, 3 in the
> cilomilast group, and these 3 were previously presented to you because
> this represents a duplication of information.
>
> \[Slide\]
>
> Here are the demographics and disposition in uncontrolled trials. The
> uncontrolled trials had feeder studies from the pivotal trials so it
> is really no surprise here, again, that the demographics mimic those
> seen in the feeder trials. These were 76-79 percent male. Caucasians
> represented 96 or 97 percent of the group. They were of the same age,
> 64 years of age; 50 percent FEV1 percent of predicted, and close to
> 50-pack years of smoking history on the average.
>
> \[Slide\]
>
> Now we look at dispositions in uncontrolled trials and this slide is a
> little bit misinforming because \"prior to treatment\" refers to the
> placebo and SB 15 mg groups, and total SB represents a combination of
> the two. So, just looking at the total withdrawn from placebo, there
> was 46 percent withdrawals. For cilomilast 15 mg it was 38 percent
> withdrawals. Recall those declines in FEV1 over time in the long-term
> trials; just imagine what 40 percent withdrawals will do to that
> number.
>
> Adverse events in patients who previously received placebo accounted
> for 24 percent of the total and in those patients previously treated
> with cilomilast, 15 percent of the total patients. So, I think you can
> see from the percentages and the second yellow line and the first
> yellow line that more patients were withdrawn from the placebo group
> than the previous cilomilast group because of adverse events. In fact,
> those adverse events, again, were gastrointestinal for the previous
> cilomilast group. The implication here is that there is something
> about having made it to the end of the feeder studies and being
> enrolled in the uncontrolled trials that perhaps selected for patients
> who were not responsive to GI adverse events. Certainly when exposure
> was continue they had a very small percentage, four percent, of their
> group withdrawn because of gastrointestinal adverse events as compared
> to the placebo, who were relatively naive to the drug at the time they
> entered the uncontrolled trial and had the same large number of
> withdrawals, or percentage of withdrawals, that was seen in the feeder
> trials.
>
> \[Slide\]
>
> This is the treatment exposure in all uncontrolled trials including
> the feeder trials. I show it simply to demonstrate that greater than
> 180 days exposed was given by 973 patients, and there were 865
> patients who were exposed for greater than a year. This certainly
> lives up to the criteria of the International Committee on
> Harmonization for minimum required safety.
>
> \[Slide\]
>
> These are the adverse events in uncontrolled trials, and there were
> relatively fewer of them that are gastrointestinal adverse events,
> which is shown in capital letters, and they were prior, possibly
> because of the preselection for those folks who could tolerate them.
>
> \[Slide\]
>
> These are deaths on therapy in uncontrolled trials. There were eight
> deaths and one reported late, just prior to going to press. These
> deaths were caused roughly by things that elderly people succumb to.
> The last death reported was a 68-year old male with ischemic colitis
> who became ill, had an intestinal perforation; had a colon resected
> and died several hours thereafter. The pathology specimens at autopsy
> did not section the mesenteric arteries, regrettably, and the
> pathology from the resected transferase colon was not supplied.
>
> \[Slide\]
>
> This is the number of patients and percent of patients with serious
> adverse events. Here, the serious adverse events were few in number
> and less in frequency, much as we saw with the feeder trials. Here we
> have withdrawals from the uncontrolled trials due to various reasons.
> I think you can see that leading the list for the top five are
> gastrointestinal adverse events. So, even in the uncontrolled trials
> we again have the recurring theme that these are meaningful to
> patients regardless of how they were thought to look to the
> investigators.
>
> \[Slide\]
>
> These are the gastrointestinal adverse events of concern in
> uncontrolled COPD trials. There was a grand total of 141 or 13 percent
> of the total patients exposed in the uncontrolled trials, which is
> approximately the amount in the feeder trials. They include abdominal
> pain, diarrhea, nausea, vomiting, dyspepsia, melena, etc.
>
> \[Slide\]
>
> How did we implement the plan for fecal occult blood monitoring of the
> GI adverse events of concern in the follow-up and uncontrolled COPD
> trials? Now the column total on the right is the number of patients
> with GI adverse events in the uncontrolled trials, and 91 percent had
> fecal occult blood at some time in the follow-up period following the
> adverse event. Nine of these patients were positive. In fact, less
> than half of these people had fecal occult blood tested within 14 days
> of the GI adverse event. The conjoint event of a GI adverse event of
> concern and positive fecal occult blood and a colonoscopy occurred in
> four patients.
>
> \[Slide\]
>
> On treatment four patients had colonoscopies and they showed polyps,
> diverticulae and hemorrhoids. There was one post-treatment colonoscopy
> in such patient and that was totally normal. In fact, these patients
> did not have ischemic colitis.
>
> \[Slide\]
>
> So, the conclusion to the integrated summary of safety is that
> gastrointestinal adverse events were a feature of treatment with
> cilomilast. They were of sufficient severity to cause most of the
> withdrawals in patients treated with cilomilast.
>
> In terms of GI adverse events of concern that were to help us build
> our colonoscopy database, only 50-60 percent of the patients with them
> were tested for fecal occult blood within two weeks, and fecal occult
> blood positive patients with GI adverse events of concern were not all
> evaluated for ischemic colitis by colonoscopy.
>
> \[Slide\]
>
> Hence, our database for colonoscopy patients with GI adverse events
> and fecal occult blood devolved to four patients in controlled trials
> treated with cilomilast, five patients in uncontrolled trials treated
> with cilomilast, and two placebo-treated patients, for a grand total
> of 11 patients.
>
> \[Slide\]
>
> Overall, to remind you what we saw with efficacy\--it is kind of
> anticlimactic, isn\'t it? FEV1 as the trough was the primary endpoint
> and, in fact, the target of the indication in four 24-week trials, not
> three to five-year trials. The change over time in FEV1 for any of the
> treatments was contaminated by the 25-30 percent dropouts. Where a
> placebo decline was seen, it arguably occurred over the first two
> weeks. Two of the four pivotal trials were statistically significant
> with mean changes from baseline that were small.
>
> Support for effective of cilomilast was found in one of four of the
> co-primary endpoint trials, the St. George\'s Respirator
> Questionnaire. Two showed statistical significance but only one showed
> statistical significance and slight efficacy. We feel support for the
> efficacy for cilomilast was also four in one of five secondary
> endpoints, the post-exercise Borg scale dyspnea.
>
> \[Slide\]
>
> Overall, safety we considered a concern because of the preclinical
> findings of mesenteric arteritis. There were prominent dose-related
> gastrointestinal adverse events and prominent withdrawals in the
> cilomilast group due to them. There is a very limited safety database
> of colonoscopies in fecal occult blood positive patients with
> gastrointestinal adverse events of concern. Without beating a dead
> horse, there are only 11 patients in that database.
>
> \[Slide\]
>
> So, we pose the following four questions to the advisory committee,
> and I think we can let you chew on these as we take our break. They
> are:
>
> Has cilomilast, at a dose of 15 mg twice daily, shown a magnitude and
> consistency of efficacy that is sufficient to support approval for the
> maintenance of lung function, FEV1, in patients with COPD?
>
> Is the safety database, aside from the concern about vasculitis, for
> cilomilast for the maintenance of lung function, FEV1, in patients
> with COPD sufficient to support approval?
>
> Do you feel that the concern about mesenteric arteritis has been
> adequately studied to be dismissed as a safety concern in humans?
>
> Finally, do the efficacy and safety data provide substantial and
> convincing evidence that support the approval of cilomilast at a dose
> of 15 medication twice daily for the maintenance of lung function,
> FEV1, in patients with COPD?
>
> Thank you very much.
>
> **Committee Discussion and Clarification**
>
> DR. PARSONS: I am going to open it up now for discussion and
> clarification for both GSK and the FDA. I would actually like to
> clarify one thing quickly, Dr. Anthracite, before you sit down. The
> last question, if I could just clarify very quickly, the question
> specifically ends with \"in patients with COPD\" and, yet, my
> understanding from looking at the documents is that the request is for
> approval for patients with COPD who are not responsive to
> bronchodilator. Is that correct?
>
> DR. ANTHRACITE: Yes, that is.
>
> DR. PARSONS: So, do we want to modify that last question, or do you
> want the question to stand as it is?
>
> DR. ANTHRACITE: Either way, I have no objections. DR. PARSONS: Thanks.
> Other questions? Dr. Joad?
>
> DR. JOAD: I would like to hear, from both the FDA and from the
> company, the GI physicians\' interpretation of that patient who died.
> I don\'t know if the FDA has somebody who can comment on that but what
> is bowel ischemia with perforation? How suggestive is that of
> mesenteric arteritis? And also, just to double check that there were
> no other autopsy results of any of the other patients. I am assuming
> that is correct.
>
> DR. ANTHRACITE: We will address the autopsy question to GSK. In terms
> of that individual patient, we have an autopsy report. I believe GSK
> has no more than we do. Is that correct?
>
> DR. WHEADON: Yes, that is all we have.
>
> DR. JOAD: I guess what I am looking for is, is there an expert who has
> commented on how clinically suggestive this case is of mesenteric
> arteritis since that is not an area of expertise I think for the
> people on this panel.
>
> DR. ANTHRACITE: Perhaps our gastroenterologist?
>
> DR. SURAWICZ: I am a gastroenterologist and I review these cases. Dr.
> Laine is here as well as a consultant for the company. I am sure we
> would both be happy to comment.
>
> DR. LAINE: Again, I think everybody has similar information. There
> were actually five cases of intestinal ischemia that were identified
> in the overall safety database of this. Three, as you saw, were in the
> active drug treatment and two were in the placebo control group. This
> particular case that you are asking about was basically somebody who
> came in with a COPD exacerbation and basically developed abdominal
> pain, was found to have a perforation and was taken to the operating
> room. We don\'t really have much information, except that the autopsy
> report specifically stated that they felt it was consistent with
> ischemic colitis leading to the perforation.
>
> I would just remind you again that people who have COPD, as we talked
> about, who are smokers and have concomitant cardiovascular problems
> have a fairly high incidence, compared to the general population, of
> developing ischemic colitis, probably about a four-fold higher
> incidence.
>
> Again, you know, one of the tenets of evidence-based medicine, of
> course, is when you ask a specific question, that is, does intestinal
> ischemia occur, you look at the clinical outcome of interest. That is
> your primary outcome you want to look at and when you look at that, as
> was shown, there were three cases versus two cases. The incidence that
> was identified with the patients receiving Ariflo was the same as
> would be expected in the general population based on another
> epidemiologic study. As we mentioned, there was no evidence of any
> increase with the patients receiving after treatment so there was
> actually no suggestion at all of a signal in the entire safety
> database of patients having intestinal ischemia with the active
> treatment.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: Did you want to have a follow-up here? I was going to ask
> a different question.
>
> DR. PARSONS: Yes, Dr. Surawicz, do you have a follow-up question?
>
> DR. SURAWICZ: I thought that the analysis of the patients who had the
> colonoscopies was very well done and there was nothing worrisome at
> all in any of the colonoscopy findings of the patients who had any
> sorts of adverse effects.
>
> One thing that was confusing to me was the upper GI symptoms and the
> lack of upper endoscopies. So, for all the people with evidence of
> lower GI bleeding, there were either normal colonoscopies or findings
> at colonoscopy that would have explained the lower GI bleeding. Until
> I looked at this sheet this morning that we just received, when I saw
> the term melena in a symptom, I assumed that that was upper GI
> bleeding and not lower GI bleeding because it is very, very rarely a
> cause of lower GI bleeding. So, I thought that many of those patients
> should have had an upper endoscopy.
>
> Now, it looks as though four or five patients did have upper
> endoscopies as part of their workup and half of them had gastritis.
> Now, gastritis is a very common abnormality but it did make me wonder
> whether some of that acute nausea, vomiting and abdominal pain might
> be due to upper GI side effects and there really isn\'t any
> information to address that. It may be that the gastritis is a more
> broad problem. Elderly people are more likely to have gastritis.
>
> I don\'t know how to reevaluate my comments with the change in the
> fact that you apparently used the term melena for all kinds of GI
> bleeding. Can you clarify that? Because traditionally melena\--for a
> GI doctor the definition is black, tarry stools because of blood from
> the stomach or the proximal duodenum.
>
> DR. RICKARD: Unfortunately, due to our dictionary, I guess the small
> majority of people who had positive FOBs were actually coded to
> melena. So a large part of these just had a positive fecal occult
> blood and did not have melena. But there were lots of other terms used
> that were coded to melena, which include black, tarry stools but also
> include things like blood on the stool; blood on the toilet paper;
> blood around the toilet, things like that. So, they were all coded to
> the dictionary for melena so it actually over-reported melena and the
> actual incidence of melena was very low and was not different between
> placebo-and Ariflo-treated patients.
>
> DR. SURAWICZ: Then, for the few people who did have gastritis, did you
> have any information on whether that might be due to their other
> medications? I am sure lots of them were taking non-steroidals or
> aspirin, or they were probably in an H. pylori group as well.
>
> DR. RICKARD: Well, there was a significant number of people who took
> non-steroidals. If you look at the entire GI database, there were 70
> other procedures performed in patients who had GI symptoms. Some of
> those were upper endoscopies. Some of them were other type of
> procedures. And, none of them really showed anything of significance.
> Now, I cannot tell you that a significant incidence of gastritis was
> actually found anywhere.
>
> DR. SURAWICZ: Another question I had was in the people who had had GI
> blood loss, was any of that significant enough to require a
> transfusion?
>
> DR. RICKARD: No. No, in fact, in all the orthostatic vital signs there
> were no differences in hemoglobin hematocrits at any time performed
> throughout the study. There were no differences at all to show that
> there was any effect on either hemoglobin hematocrit or orthostatic
> vital signs.
>
> DR. SURAWICZ: Good.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I have a question for Dr. Knobil and then a follow-up for
> Dr. Rickard. If you could, could you clarify for me the belief of what
> the mechanism of action is of this agent for its effect in COPD
> patients?
>
> DR. KNOBIL: Well, I did talk about that a bit. For a PDE4 inhibitor
> many of the cells that we think are important in COPD have
> phosphodiesterase-4 in them. The ones that have PDE4 as the
> predominant isoenzyme are the anti-inflammatory cells. So, we believe
> in this patient population the mechanism of action is predominantly an
> anti-inflammatory one.
>
> DR. MORRIS: My follow-up question for Dr. Rickard would be could you
> help us understand the mechanism of action of the GI toxicity?
>
> DR. RICKARD: So, for GI toxicity I assume you mean the symptoms of GI
> intolerance, which was nausea, vomiting and diarrhea. We are not
> really sure of the mechanism of action. We believe it may be central
> mediated. I would ask one of my colleagues to further comment on that
> if they can discuss it further.
>
> DR. DOWN: Geoff Down, clinical pharmacology, GSK. Looking at kinetic
> profiles when nausea commences, it appears to occur around Cmax or at
> attainment of Cmax. There is also an effect where with continued
> dosing you get attenuation of the effect. This will go through the
> central mechanism. There is evidence with other PDE4 inhibitors in
> dogs and ferrets that inhibition of that enzyme in the area
> post-treatment at the base of the fourth ventricle causes emesis. So,
> we are fairly certain that this is predominantly a central effect.
> There may be some augmentation by afferent vagals but we have no
> evidence for that.
>
> DR. PARSONS: I have a question that may help clarify things since I
> just realized, obviously, that not everybody on the committee is an
> adult physician and all of us that are adult physicians are certainly
> not gastroenterologists. I was wondering, Dr. Surawicz and maybe
> somebody from GSK, if you could just help the committee understand
> what are the presenting manifestations and symptoms of mild mesenteric
> arteritis, and what would you look for, and what do you do as a
> practicing clinician, so that we may maybe put some of this data in
> perspective?
>
> DR. SURAWICZ: Well, the major reason why mesenteric ischemia is of
> such concern is because the presentation can be very vague and there
> is really no good clinical diagnostic tool, especially for mesenteric
> ischemia involving the small bowel. For the large bowel we do have
> colonoscopy and the symptoms are a little bit more obvious. But for
> small bowel mesenteric ischemia, which would be involvement
> occasionally of the celiac access but usually the superior mesenteric
> artery, it is supposed to be pain that occurs after eating in elderly
> people, 50 or greater. We just had a case in my hospital in someone
> 45.
>
> The problem of this diagnosis is pain after eating, presumably because
> the blood is shunted away from those vessels because it is going to
> the stomach to help with digestion, so the compromised vascular
> system, then you develop ischemic small bowel pain. But when it is
> chronic it is very hard to diagnose. There is no good diagnostic test.
> There are some non-invasive tests like ultrasound Doppler which
> frequently are falsely positive. The gold standard then is
> angiography, which is a relatively invasive test. So, clinically we
> are often in the setting of making this diagnosis when the bowel is
> already dead and already ischemic.
>
> Happily, that is not as common as colon ischemia, which is what was
> looked for here where there is compromise of the interior mesenteric
> artery. In this case, the presentation is a little bit more obvious
> because usually there is diarrhea and bleeding. The pain is not such a
> big part of that; it is usually diarrhea and bleeding. Because of the
> ease of the flexible sigmoidoscopy and colonoscopy\--I guess as Loren
> and I are both endoscopists, we consider it the ease of the
> procedures, and this is usually readily diagnosed when it is
> suspected.
>
> Also, the course of colonic ischemia usually is milder than small
> bowel ischemia, maybe because the delay in diagnosis for small bowel
> ischemia means that it is through and through, whereas in colon
> ischemia usually it has a more mild course although, obviously, if the
> diagnosis is delayed there can be sever through and through
> perforation as well. Colon ischemia is more likely due to an acute
> drop in flow as opposed to chronic, either embolic or thrombotic or
> narrowing of the small bowel. I don\'t know at all how common this is
> in children, but I suspect not very.
>
> DR. PARSONS: Thanks. Now we will jump back to the regular order. Dr.
> Apter?
>
> DR. APTER: Changing the subject a little bit, I wanted perhaps Dr.
> Knobil to tell us how adherence to the study protocol drugs was
> monitored. Because if the side effects are significant and patients in
> the active arm stopped taking the drugs side effects will be
> underestimated. Likewise, the effect of the drug will also be
> underestimated.
>
> DR. KNOBIL: Well, compliance was monitored by pill counts at each
> study visit. So, that was the main mechanism by which compliance was
> monitored, as well as looking at the diary cards that were filled out
> in the three studies, 039, 091 and 042.
>
> DR. APTER: I am sure you know that there is no good way to really
> measure adherence and patients could conceivably dump their pills
> before they come to see you.
>
> DR. KNOBIL: Well, yes, that is a possibility but in general I think
> that we have to trust the patients and what they tell us, and we have
> to take everything at face value. I guess we could have asked whether
> the patients dumped their pills but I am not sure we would have gotten
> any more accurate than we already have.
>
> DR. APTER: Right. There are no blood levels or any other tests?
>
> DR. KNOBIL: There was pharmacokinetic monitoring but that was not used
> to check compliance.
>
> DR. PARSONS: Ms. Schell, you had a question?
>
> MS. SCHELL: Yes, I guess I want a little bit of clarification and also
> if you had other studies from the current studies. The FEV maintenance
> was looked at as the difference between the Ariflo group and placebo
> group. Correct?
>
> DR. KNOBIL: That is correct.
>
> MS. SCHELL: I wondered if there was a subset of patients you looked
> at, since the drop occurred in the placebo group of FEV in the first
> four weeks or so, did you look at an individual group of patients,
> say, on Ariflo that had their FEV1s and looked at their FEV1 as
> individual? Do you understand what I am saying? I am just wondering.
> You looked at the difference between the two groups, but did you look
> at individual patients? Did they maintain their FEV1 across the line,
> or did they improve on the individual basis?
>
> DR. KNOBIL: Well, we had patients who improved, who stayed the same
> and probably a minority who went down as well but on average the
> results are as we have shown you. One point that you brought up about
> the drop occurring in the first two to four weeks, I am not sure that
> I necessarily agree with that analysis because the graphs that Dr.
> Anthracite did show you showed the absolute FEV1 at each week and
> compared back to the baseline for the whole group. I don\'t know if it
> is completely appropriate to compare the patients that are in the
> study at the time with the total number of patients that were at the
> beginning of the study, just as it would be inappropriate for me to
> subtract the FEV1s at week 24 from the total baseline raw means
> because that would give a much larger treatment effect than we would
> expect.
>
> MS. SCHELL: Well, I was just curious because of the dropout rate and I
> just wondered, on the individual basis, if there was a group looked at
> for individual FEV maintenance. I am confused on the differences. You
> looked at the difference between the groups but I want to know on the
> individual, was there a steady maintenance?
>
> DR. KNOBIL: You mean individual treatment group or individual
> patients?
>
> MS. SCHELL: I just wondered if there was a subset or groups where you
> just looked at the individuals that were on the drug like, say, 50
> patients you looked at and did they maintain their group that weren\'t
> dropped out? I just wondered if there was a substudy. I am confused.
>
> DR. KNOBIL: I guess I don\'t entirely know what you are asking because
> we didn\'t look at each patient individually; we looked really at
> group means.
>
> MS. SCHELL: Okay, that is what I was asking.
>
> DR. KNOBIL: One other point is that the level of dropouts was actually
> quite similar to other COPD clinical programs. We do have a lot of
> experience with patients with COPD and we generally have about 30
> percent dropouts.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: I was confused about the anticholinergics. Were these
> patients taking or not taking anticholinergics as a group? You
> emphasized the albuterol, that they were allowed to take their
> maintenance scheduled albuterol and they were allowed to take extra
> albuterol. Is that right?
>
> DR. KNOBIL: No, that is not quite correct. If a patient was on
> scheduled epitropium prior to entry into the study they could continue
> that throughout the study. However, they were given albuterol for use
> as needed. There was nobody on scheduled albuterol.
>
> DR. CROSS: That clears it up. Thanks.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I have a question looking across the four pivotal studies.
> Am I right that the percent of people completing the 24-week study was
> similar in the two groups for the European studies but there was a
> difference between placebo and treatment arms in the North American
> studies?
>
> DR. KNOBIL: For those that went into the long-term? Yes, that is
> correct. About 70 percent of patients from the European studies in
> both arms went into the long-term extensions, whereas 85 percent of
> the placebo group in the North American trials went into the extension
> whereas it was somewhat lower in the Ariflo-treated group, about 68
> percent.
>
> DR. MORRIS: I don\'t know if that is exactly what I meant. Let me ask
> you in a different way. Could you give us some idea of the
> demographics of the patients not completing the 24-week study?
>
> DR. KNOBIL: We haven\'t actually looked at the demographics of the
> patients who dropped, but we looked at the demographics at the
> beginning of the pivotal trials and at the beginning of the long-term
> extensions. They are quite similar. So, I don\'t think that there can
> be a huge difference in those that dropped or else that would change
> the composition of those that went into the long-term extensions.
>
> DR. PARSONS: We have Dr. Kercsmar next.
>
> DR. KERCSMAR: I wondered, since there is a pretty significant
> imbalance in white versus black enrollment in all your pivotal studies
> and also male versus female, do you have any evidence that this drug
> will be metabolized differently in a minority population, or in
> females, or if there is any difference in response to the drug in
> those two populations?
>
> DR. KNOBIL: Yes, there was no difference in metabolism in men versus
> women. One patient population that we did look into was Japanese and
> Chinese individuals and they had slightly higher serum AUCs and it was
> felt to be more due to the smaller body size and lower body weight,
> but there were no other differences noted. There were no differential
> tests between Caucasians and other ethnic groups.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: I am still looking at the mechanism of action and if you
> could explain what we know about bronchodilators. I am trying to
> figure out how much those changes in FEV1 represent bronchodilation
> and how much don\'t. So, what is the evidence that you have for the
> amount of bronchodilation you get with this drug, especially at trough
> levels?
>
> DR. KNOBIL: Well, overall, as we have already seen from the data,
> there is really no bronchodilation. The most we get is about a 10 ml
> increase from baseline, except for study 042 which had a little bit
> higher, between 20-30 ml from baseline. So, there doesn\'t appear to
> be any bronchodilator activity. We have looked at serial FEV1\--
>
> DR. JOAD: Is that at Cmax where you get the 10 percent?
>
> DR. KNOBIL: That is at trough.
>
> DR. JOAD: Well, that is my question. As a bronchodilator at its
> maximum serum concentration, what is the change in FEV1?
>
> DR. KNOBIL: Right, and we have looked at serial FEV1 after dosing and
> there does not appear to be a bronchodilator response in this patient
> population. Again, you have to remember that this patient population
> was chosen not to have a bronchodilator response so it is not
> unexpected that we don\'t see that. We do have some preliminary data
> in a broader population that shows a little bit greater FEV1 response
> that may be due to bronchodilation.
>
> DR. PARSONS: Dr. Apter and then Dr. Newman?
>
> DR. APTER: Dr. Knobil, you have hypothesized that the proposed
> mechanism is immunologic and that it is an anti-inflammatory drug.
> Could you review for me what the evidence is, BAL or things where the
> number of anti-inflammatory cells decrease, where there is decrease in
> CD8 cells or cytokines or products of these cells?
>
> DR. KNOBIL: Yes, there were two studies, study 110 and study 076 which
> I referred to briefly. Study 110 mainly looked at sputum neutrophils.
> There were no large studies of BAL cellular counts. But in study 110
> there was a trend toward a decrease in sputum neutrophils. In study
> 076 there was no difference in sputum neutrophils, however there was a
> trend toward a decrease in subepithelial neutrophils. Also in 076, in
> biopsies there was a significant decrease in subepithelial macrophages
> and there was a trend toward a decrease, a 40 percent decrease, in
> subepithelial CD8 positive T-lymphocytes, which has not really been
> seen with any other medication for patients with COPD.
>
> DR. APTER: How many patients were in those trials?
>
> DR. KNOBIL: There were about 100 patients per arm.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: I guess you might as well stay up there\--save you the
> trip. A lot in this study seems to hinge around what happens at
> baseline. I wonder if you could go over with us how, in fact, the
> baseline FEV1 was generated and what, if anything, was done with the
> spirometry data that were obtained at screening and at the two-week
> prior to baseline visit.
>
> DR. KNOBIL: Well, the baseline FEV1 was done in a very rigorous
> fashion, as per ATS guidelines, with three efforts, taking the most
> appropriate effort. The screening FEV1 and the visit two weeks prior
> were not included in the analysis for the study. It was mainly
> included to make sure that there was not a great variation and that
> patients weren\'t rapidly deteriorating as they came off their other
> COPD medications.
>
> DR. NEWMAN: I think that speaks to my question then. What, in fact,
> did you find when you looked for that variability? Potentially you had
> people who could have stopped using any variety of medications that
> the day they came in for their screening visit and you might have only
> two weeks or potentially four weeks of them coming off other
> medications.
>
> DR. KNOBIL: So, you would like to see what happened to FEV1 over that
> time as they came off?
>
> DR. NEWMAN: Yes.
>
> DR. KNOBIL: Yes, we do have a slide to support that. Just one second.
> While we are waiting, there was not a large decline in FEV1 over time.
> Of course, if someone did have a precipitous decline, then it was felt
> that they would not be appropriate to continue in the study.
>
> DR. NEWMAN: Perhaps, while they are looking into this, could I ask a
> related question?
>
> DR. KNOBIL: Sure.
>
> DR. NEWMAN: It has to do with covariates. I know that the smoking
> status in terms of pack-years didn\'t differ among the groups, but
> could you tell us about what information, if any, you collected and
> what you found regarding change in smoking status? Were there any
> differences in people becoming former smokers or changing smoking
> status either up or down during the course of the study?
>
> DR. KNOBIL: As we have seen in all of our clinical trials including
> these, the number of patients who changed smoking status is incredibly
> small and it didn\'t differ between treatment groups.
>
> \[Slide\]
>
> So, this is for study 039, and I think this is representative of all
> the clinical trials, screening at baseline FEV1 is shown here. There
> is a small decline which is not unexpected, given that patients were
> discontinued from their medications, including inhaled steroids, but
> it wasn\'t a very large one.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: I have a couple of questions for Dr. Knobil. One is
> that, say, the two North American studies, were they the same set of
> clinical centers that were involved with both?
>
> DR. KNOBIL: I don\'t believe that there was. There might have been
> overlap of a few centers but, for the most part, they did not overlap.
>
> DR. CHINCHILLI: So, the same question for the European studies?
>
> DR. KNOBIL: Yes, since the European studies did run concurrently the
> centers did not overlap.
>
> DR. CHINCHILLI: Then a question about the spirometry, what did GSK
> have in place in terms of training and certification for the
> spirometry technicians? Did you have any type of training and
> certification program?
>
> DR. KNOBIL: Yes, we did. We had large investigator meetings during
> which the coordinators and pulmonary function techs would come to make
> sure that we had consistent procedures at all of the sites. If there
> were sites that were unable to come to the investigator meeting, then
> we would go to each site and train sites.
>
> DR. PARSONS: Dr. Apter?
>
> DR. APTER: This is a question for either the FDA or GSK. I am
> confused. You chose the endpoints together of FEV1. You chose patients
> that didn\'t have a variability in FEV1 as an entrance requirement and
> then, as an endpoint, you didn\'t have any variability. You are
> postulating another mechanism is possibly the way it works. It seems
> like the design has\--what do you have to say about the design here?
>
> DR. ANTHRACITE: I must confess to not quite understanding what you are
> asking. Could you just repeat it in more simple terms?
>
> DR. APTER: You chose patients who didn\'t have any variability in the
> endpoint at the beginning, having no bronchodilator reversibility.
> Then, at the end of the study, after randomizing them, there wasn\'t
> any change.
>
> DR. ANTHRACITE: Are you doing any better with this than I?
>
> DR. PARSONS: See if this helps and see if this is what you are
> actually asking, the initial study, as designed, was looking for a
> change in FEV1 of 120 ml.
>
> DR. ANTHRACITE: Yes.
>
> DR. PARSONS: And that apparently was between treated groups versus
> placebo. So, the question I think Dr. Apter is asking is since you
> specifically picked the patient population that you did not anticipate
> would have a change in FEV1, how was the study designed to look for a
> change that big in a 24-week period? Does that clarify it?
>
> DR. APTER: Thank you for interpreting for me.
>
> DR. ANTHRACITE: Considering that wasn\'t my choice, let me turn it
> over to Dr. Knobil.
>
> DR. KNOBIL: Well, I think that based on the Phase II clinical trial,
> which you have already seen, we actually did expect a little bit
> larger change in FEV1 than was actually seen. However, we did not
> expect the placebo group to decline so consistently, as we saw. So,
> even though we designed our trials to see a particular result, we did
> get another result which was clinically significant.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: Could you go over for us, please, how the notion of
> exacerbation-free from COPD over the 24-week period was defined and
> thought about?
>
> DR. KNOBIL: The four-panel slide? Would you like to see that again?
>
> DR. MORRIS: No, just tell us what went into that definition, percent
> of exacerbation-free days or percent of exacerbation-free time in the
> 24-week period.
>
> DR. KNOBIL: Is that from the briefing document, exacerbation on any
> given day or the exacerbation-free days? I am sorry if I am
> complicating it.
>
> DR. MORRIS: The exacerbation-free days.
>
> DR. KNOBIL: Okay, the exacerbation-free days is really a Kaplan-Meier
> plot so that as soon as someone has an exacerbation they are censored
> from the analysis. So, what we see over time\--actually, if we could
> just show the four-panel slide from the core\--is that over time
> patients tend to exacerbation at a certain frequency.
>
> DR. MORRIS: More specifically, what went into the definition\--
>
> DR. KNOBIL: Oh, the definition. I apologize.
>
> DR. MORRIS: That is okay.
>
> DR. KNOBIL: This is exacerbation-free time to moderate to severe, and
> moderate to severe exacerbations were defined as exacerbations that
> required physician intervention and medication, including oral
> steroids or antibiotics. A severe exacerbation was one that required
> hospitalization.
>
> DR. MORRIS: Could you tell us about what percent required
> hospitalization in both arms?
>
> DR. KNOBIL: It was actually quite low, less than ten percent.
> Actually, much less than five percent, I should say.
>
> DR. MORRIS: And what happened to study medication during the
> hospitalization?
>
> DR. KNOBIL: Well, that varied from patient to patient. I don\'t know
> the particulars for each patient that had an exacerbation but I would
> guess that some patients stopped taking their medication just because
> they were in the hospital but we do know that some patients did
> continue. I don\'t have any information to be able to differentiate
> between the two about outcomes or anything else.
>
> DR. MORRIS: Were the hospitalization records reviewed for AEs and
> SAEs?
>
> DR. KNOBIL: No, they were not.
>
> DR. PARSONS: We have Dr. Joad, Dr. Surawicz and Dr. Cross. Dr. Joad?
>
> DR. JOAD: Did you measure weight? Did these patients lose weight with
> all this GI symptomatology?
>
> DR. KNOBIL: We measured weight at the beginning but we did not measure
> weight at the end.
>
> DR. PARSONS: Next I think is Dr. Surawicz.
>
> DR. SURAWICZ: I want to go back to the ischemia because we have been
> reassured by the colonoscopy findings in the patients who had symptoms
> but we haven\'t really talked about the ischemic cases that were in
> the briefing document, and Dr. Laine I think mentioned five ischemic
> cases but there are only two here, which were both in placebo. Then we
> have this one death on treatment. Who were the other two patients and
> should we perhaps know which groups those were in?
>
> DR. RICKARD: As we showed earlier, there were two patients in the
> placebo group and three patients in the long-term extension trials
> that had a diagnosis of ischemic colitis. Now, the particulars\--I
> think the narratives should be in the briefing document. The three
> patients for Ariflo\--one patient was admitted for rheumatoid
> arthritis exacerbation and his diagnosis really was only based on a
> comment from the x-ray; we don\'t even know what type of x-ray it was,
> saying it looked like he had ischemic bowel. So, we don\'t know much
> more about that patient but he continued in the study on the drug and
> had no further problems for that.
>
> The other two patients, one had a COPD exacerbation with a bowel
> perforation, which you heard about. One patient underwent vascular
> procedures, you know, vascular dye procedures, and subsequently had
> significant complications after that, and at the time of his death
> also was shown\--whether it was due to the procedures or not\--to have
> ischemic colitis.
>
> The other two patients were in the placebo population. I think what we
> showed earlier was that you need to keep in mind that the patients on
> placebo only had six-month therapy and the patients who were on Ariflo
> had a much longer time and, in fact, one patient was on it for two and
> a half years at the time of his incident. The others were on it for
> about 18 months for over two years. So the exposure was quite a bit
> longer in the Ariflo patients.
>
> DR. SURAWICZ: So, one way you might look at it is that this is
> probably a significant problem that develops [de novo]{.underline} but
> it is possible that it exacerbates underlying vascular disease.
>
> DR. RICKARD: I think we need to keep in mind the fact, as mentioned
> earlier by Dr. Laine, that there was a significant increased incidence
> of ischemic colitis in COPD patients. Maybe we can show the M-7 slide
> which looks at the study in the UHC database that looked at COPD
> patients versus non-COPD patients and what the incidence could be
> expected to show.
>
> \[Slide\]
>
> As you can see here, if you look at COPD patients there was a 1.75
> incident rate compared to 0.44 for patients who did not have COPD. So,
> I think we need to realize, as I said earlier, that these are elderly
> patients who have a lot of problems and though this is a rare
> event\--it really is rare, it is not uncommon to see a couple of
> cases.
>
> DR. PARSONS: Dr. Cross is next.
>
> DR. CROSS: Was there any difference in the pharmacokinetics in smokers
> versus not smokers?
>
> DR. RICKARD: Smoking had no effect.
>
> DR. CROSS: Second, at the beginning you did a bronchodilator response
> and you found an average in all of these studies\--what was it?\--it
> was less than 200\--it was 60 or 70 ml or something like that. Is that
> right? It was two or three times\--
>
> DR. RICKARD: It was 80.
>
> DR. CROSS: It was 80. So, that is quite a bit different than what you
> found as your endpoint on your FEV1. Were any examinations done for
> the bronchodilator response at the end of your study, looking to see
> if that was the same 80 or whether you bit into some of that not very
> significant in terms of pulmonary function, but you are trying to make
> significance out of 30 ml in terms of the efficacy on the FEV1 side?
>
> DR. KNOBIL: Right. Yes, in some of the studies we did do
> bronchodilator response at the end of the study and the bronchodilator
> response was the same at the end as it was in the beginning. So, it
> was comparable.
>
> DR. CROSS: So, the data that is presented is, of course, all without
> the bronchodilator.
>
> DR. KNOBIL: That is correct.
>
> DR. CROSS: All right. Another one, your symptoms of GER were a little
> bit more in the treated group, as I remember. Is there any effect on
> the smooth muscle, the esophageal-gastric junction? That is pretty
> easy to look at in terms of zero and max, like is done with
> theophylline where there is relaxation of that muscle. You have not
> clarified too much whether smooth muscle has a significant effect. You
> think it doesn\'t in the airway.
>
> DR. DOWN: I will take the question. Geoff Down, clinical pharmacology.
> We performed one study with esophageal manometry and there was some
> increased relaxation of the lower esophageal sphincter in
> cilomilast-treated subjects compared to placebo. It was only a small
> effect and this is probably a class-related effect. Does that answer
> your question?
>
> DR. CROSS: Yes, it does but I would like to then push into the
> cardiology questions. You had more PVC by quite a bit in this study on
> the drug, and you had some cardiologic rule-outs for who you didn\'t
> take into the study. I know you have a cardiologist. I was just
> wondering if you had abnormalities on your baseline EKGs, or you were
> looking at long 2s, or 3s, etc. With theophylline there is quite a bit
> happening to that cardiogram on a Holter monitor, and I wanted to get
> a little bit more detail of what type of cardiac patients you excluded
> from the study because, as we all know, there is a fair amount of
> cardiac active patients in the COPD population.
>
> DR. RICKARD: Well, patients were excluded from the study if the
> physician thought they had significant underlying cardiac disease.
> Certainly, they were also excluded if they had significant QTc
> prolongation present before entering the study. They may not have been
> excluded if they had other type of background cardiac abnormality like
> evidence of an MI on EKG, or things like that.
>
> When we looked at the analysis we looked at people who did not have
> significant issues at baseline, and we looked at the number of people
> who had changed during therapy and what we saw was that there were no
> significant differences in those people who had changed. We also
> looked at people who had some issues at baseline and, again, when we
> looked at those people we didn\'t see any significant differences in
> what we saw in the EKG or the Holter monitor analysis for that.
>
> DR. CROSS: So, patients with significant CAD, and you are looking at a
> little bit younger population of COPD if they averaged around 60 to
> where you would find the maximal cardiac problems\--I am just
> wondering, for instance, on the cardiogram you had more PVCs but were
> more sophisticated tests, heart rate variability, etc., etc., looked
> at on your Holter monitors?
>
> DR. RICKARD: Well, if you are talking about QTc intervals, as we
> discussed, we did correct them by Bazett correction and Fridericia\'s.
> I certainly would have our cardiologist actually answer that for you,
> if you would like.
>
> DR. CROSS: Yes, the concern I still have is the mechanism of any
> cardiac activity of this drug and whether you have a population of
> cardiac patients with coexisting coronary disease or angina, etc.,
> that were studied.
>
> DR. RICKARD: Well, certainly anybody with unstable angina would not
> have been put into the study at the time that they came into the
> study. We can have Dr. Ruskin discuss his analysis of the cardiac
> data.
>
> DR. RUSKIN: Jeremy Ruskin, Mass. General, Boston. Based on the
> patients that were included in the data that is available, which is
> all that I can speak to, there was no signal of a cardiac risk based
> on a conventional evaluation, and this includes effects on vital
> signs, a very rigorous ECG analysis, 7,000 electrocardiograms, almost
> 10 percent of them at Cmax, serious adverse cardiovascular events and
> mortality. So, based on those parameters there certainly is no signal
> that I can see. In particular, obviously recent concern has focused on
> ECG intervals and there were no detectable changes there, particularly
> with regard to effects on repolarization.
>
> DR. CROSS: Lastly, in the basic studies was there any potentiation of,
> let\'s say, albuterol cardiac toxicity by this drug? In other words,
> there is overlap between even some of the betas and with theophylline
> which increases the toxicity of the betas a couple of orders of
> magnitude. I am still trying to get at are there any effects on the
> heart of this drug in terms of either rhythm or heart muscle, etc?
>
> DR. RICKARD: No, we studied albuterol and theophylline. In addition,
> we used them both together and we saw no differences in the cardiac
> assessments that we obtained.
>
> DR. CROSS: At the toxicity level?
>
> DR. RICKARD: Right.
>
> DR. PARSONS: Dr. Newman, then Dr. Joad, then Dr. Kercsmar.
>
> DR. NEWMAN: One of the questions that I wanted to ask, putting this in
> the perspective of figuring out that approximately 30 percent of
> patients are not going to tolerate the drug after a few weeks and
> trying to integrate this with what the statisticians have said about
> the repeated measures analyses, weighting for the 24-week study goes
> more heavily to the earlier time points. I guess what I am wondering
> from the statistical standpoint or from the clinical design standpoint
> is, is there a way to understand what the likelihood is of people who
> can tolerate the drug showing stability of FEV1. If we were to
> subtract out the 30 percent of people who in the first month, because
> of various toxicities, stopped using the drug, has there been an
> analysis to tell us that the people who can tolerate it for 24 weeks
> either improve or stay the same in FEV1?
>
> DR. KNOBIL: Yes. Actually, we have done all kinds of sensitivity
> analyses on all the studies. When you look at just the patients who
> are in the study for a significant period of time, either 8 or 16
> weeks, the results in FEV1 are the same or better than when the
> dropouts are still in the study. In fact, I can show you one example
> of this for 039. Can we look at the graph from 039 from the core,
> please?
>
> \[Slide\]
>
> This is the slide that I showed you before, looking at the effect of
> Ariflo over time with the maintenance of FEV1 and the decline in the
> placebo arm of this trial. Now, the concern has been raised that most
> of the decline occurred in the first two to four weeks, whereas when
> we did the repeated measures analysis we see that the decline is
> pretty steady over the course of the trial.
>
> \[Slide\]
>
> However, when we take out the patients who dropped out in this early
> part of the trial, we see the following result which is nearly an
> identical graph. So, really when you take the dropouts into account
> you see the same result.
>
> DR. PARSONS: Dr. Joad, you had a question?
>
> DR. JOAD: This is for the FDA. Do you have any other information about
> your PDE4 inhibitors with regard to vasculitis that you can share? You
> said it was a class effect.
>
> DR. MEYER: There is really very little information we can share. We
> can say that it has been seen with others. There apparently has been
> public acknowledgement that one manufacturer has stopped development
> because they had a case of colitis in humans and that caused them to
> stop development. That is something of a web page but, unfortunately,
> that is very little of what we have seen that we can share with you
> because it is not public data.
>
> DR. PARSONS: The last question will be from Dr. Kercsmar.
>
> DR. KERCSMAR: I might have a similar question that was just asked of
> GSK. You looked for a biomarker or something to try to predict serious
> GI adverse events or arteritis, but can you identify responders from
> non-responders? Do you have subgroups that will respond favorably to
> the drug and those that won\'t? Are there any biomarkers, or is it age
> related, FEV1, co-morbid conditions so that you can predict responders
> to the drug? I am not looking for adverse effect.
>
> DR. KNOBIL: Yes, there are some things that are correlated with a
> better response, although none of them is very definitive in terms of
> defining a very specific population. For example, in the North
> American studies, for SGRQ a lower FEV1 is correlated with a better
> SGRQ response, the most severe patients. Also, again for SGRQ a
> history of chronic bronchitis is associated with a better response, as
> well as a longer smoking history, a higher pack-year history of
> smoking is actually correlated with a better response for SGRQ. Most
> of these things don\'t really have any effect on the FEV1 response.
>
> DR. PARSONS: We still have lots of questions on the list so I am not
> trying to ignore anybody, but we need to let people break for lunch.
> We do need to meet back here at exactly one o\'clock and we will start
> with the open public hearing.
>
> I have an additional announcement that there is a table reserved at
> the front of the restaurant for members of the committee so that we
> can meet there. So, we will resume again at one o\'clock and start
> back with questions.
>
> \[Whereupon, at 12:00 noon the committee recessed for lunch, to
> reconvene at 1:00 p.m.\]
>
> [A F T E R N O O N S E S S I O N]{.underline}
>
> DR. PARSONS: I would like to welcome everybody back. We are getting
> ready to resume the meeting. The first item on the agenda this
> afternoon is the open public hearing. We currently don\'t have anybody
> scheduled to speak but if there is somebody from the audience who
> would like to speak, they can stand up and come to the microphone. Do
> we have anybody? No? We will then close that part of the public
> hearing and we will move on.
>
> We are going to resume now where we ended this morning. We are going
> to go back to general discussion with both clarification and questions
> to both GSK and to the FDA. We actually had a list of people who still
> had questions. We were going to start with Ms. Schell and Dr. Apter,
> and we can go from there.
>
> MS. SCHELL: I have a clarification again. It was my understanding that
> both the company and the FDA met early, before the trial started, on
> the protocol for testing of the safety issue regarding the fecal
> occult blood and the protocol to be followed. It is also my
> understanding that the FDA thought there was discrepancy in following
> that protocol. I was just wondering, from the company, if there was a
> particular reason or why it wasn\'t followed.
>
> DR. RICKARD: Well, I think we have a slightly different perspective
> and I think, on the contrary, we did follow the protocol to the best
> of our ability in a clinical trial setting. I know we have talked a
> whole lot about fecal occult bloods and we talked also about
> colonoscopies. Actually, the number of colonoscopies that were done in
> this trial, if you look at the point when the studies were amended and
> you go from that point forward, 39 patients would have qualified to
> have undergone a colonoscopy and there were actually 25 colonoscopies
> done. Again, none of those 25 colonoscopies showed anything, not even
> a hint of evidence of ischemic colitis.
>
> So, I think that in fact in this protocol we actually did a pretty
> good job of doing what was fairly difficult as far as getting people
> to follow procedures and doing procedures such as fecal occult blood
> and colonoscopies.
>
> DR. PARSONS: Dr. Apter?
>
> DR. APTER: I guess, Dr. Rickard, you mentioned that this drug is not
> to be used with erythromycin. Could you clarify that and then talk
> about the other macrolides, clarithromycin and azithromycin?
>
> DR. RICKARD: Right, for erythromycin, in the studies that we have
> done, if you initiate both of the drugs at the same time so you start
> them at the same time, you see an increased incidence of GI
> intolerance and you see more nausea and vomiting, something that you
> probably would expect. However, if you already have Ariflo at a steady
> state and then you add erythromycin you don\'t see as many GI adverse
> events. So, it seems to be the initiation of the two at the same time
> for that.
>
> Now, we don\'t have any other data I could talk to you about any other
> types of those drugs. We do have one study that has been done but we
> don\'t have any other significant data I can tell you about at this
> point.
>
> DR. PARSONS: I just have a quick follow-up question about some of the
> GI side effects, and this would be probably for either of the
> gastroenterology experts. Since a number of the patients that did drop
> out that got the drug had GI side effects, is there any preclinical
> data or any reason to suspect that those GI manifestations were
> manifestations of early mild ischemia that would ultimately be
> reversible? In other words, the question I am asking is I know it is
> very difficult even to diagnose full-blown mesenteric ischemia but are
> there early signs that people were exhibiting that cause them to drop
> out based on preclinical data? What is the likelihood that that
> reflects mild vascular impingement that may or may not be reversible?
>
> DR. SURAWICZ: I will let Dr. Laine go first.
>
> DR. LAINE: I guess I would say two things, it is hard to answer it
> directly. One, in the preclinical data even in the rodent model where
> there was this vasculopathy there was no ischemia of the intestine
> seen. So, there wasn\'t evidence of a downstream decreased perfusion.
> So, that is one bit of information.
>
> I think the other information, as Chris mentioned, when you are
> talking about mesenteric ischemia, arterial ischemia of the small
> intestine at least, usually it tends to be they get severe disease and
> they probably go on to have something bad if it continues for a while.
> But different than that, in ischemic colitis there is a group of
> people, at least half the people who get ischemic colitis, who
> actually get abnormalities that are probably only for the mucosa and
> the submucosa so only the superficial part, and that can resolve in a
> matter of weeks or months with no sequelae.
>
> So, I would think, if Chris agrees, that would be the main place where
> there can be, in the colon at least, transient abnormalities but there
> are no great studies because, you know, if a tree falls in the forest
> nobody is there kind of idea\--do you know it is really there?
>
> DR. SURAWICZ: I had pretty much the same thought. It may be that I am
> misinterpreting the data that most of the early dropouts were nausea
> and vomiting and that didn\'t seem like those would be ischemia type
> symptoms. It would be more if it was abdominal pain. Perhaps you ought
> to answer that, is it that the dropouts were more nausea and vomiting
> and diarrhea?
>
> DR. RICKARD: Yes, in fact the major ones were nausea and vomiting that
> people would withdraw for.
>
> DR. LAINE: The other thing, of course, as we heard rectal bleeding is
> one of the other major features of ischemic colitis and one of the
> problems that Chris did mention is that there was a whole bunch of
> different things that all fit into the same descriptor of melena, most
> of which really weren\'t rectal bleeding. It was only a small
> proportion that actually had the rectal bleeding, and I think those
> people had a higher incidence, although not 100 percent, for getting
> colonoscopies.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: I want to ask the company about the proposed indication
> for use of this medication. I guess my question is that it is fairly
> broadly stated this would be for people with COPD who have poor
> reversibility. When I look at the studies, it seems that the category
> of patients who were enrolled in the four pivotal studies are not in
> the most severe form of COPD and, yet, the application of the
> medication in practice could potentially be used by clinicians with
> this indication for more seriously affected individuals. For example,
> you excluded people who were on any form of long-term oxygen therapy.
> I am wondering what is the company\'s thought about the ability to
> take these data and extrapolate them to the universe of severe COPD
> patients without reversibility.
>
> DR. KNOBIL: Well, severity of COPD is generally defined by FEV1. So,
> we have a wide range of severity of disease in our trials.
> Additionally, as you have already mentioned, they are poorly
> reversible. Even in the other long-term trials of patients with COPD,
> even the milder patients have declines in FEV1 and would benefit from
> maintenance or stabilization of their therapy. So, I don\'t think that
> this should be relegated to more severe or less severe. I think right
> now we have the data in a broad population of moderate to severe
> patients who are poorly reversible and, as we have seen by these other
> trials, they can benefit from maintenance of their FEV1. I don\'t know
> if I answered your question.
>
> DR. NEWMAN: Well, maybe there isn\'t a direct answer to it but I think
> from my way of reading this the kind of exclusion criteria you had,
> even if it wasn\'t a direct impact on severity, it would have an
> indirect impact on the severity of patients that we see. I am thinking
> mainly about looking back, and maybe you can comment on this\--looking
> back at study 168 where you showed the difference in those who had
> more reversibility responding better in terms of FEV1 response
> compared to the ones with poor reversibility. I started thinking about
> what about the most severely affected COPD patients in my practice who
> have truly the least degree of reversibility and the worst DLCOs and
> the worst FEV1, the worst emphysema?
>
> DR. KNOBIL: Well, you mentioned 168 and for reference for everyone
> else we can show the data that you just referred to.
>
> \[Slide\]
>
> In study 168 any patient was allowed to participate\--well, not any
> patient but they weren\'t excluded on the basis of their
> reversibility, and it turns out the baseline characteristics were
> similar in this study except for the degree of reversibility, which
> was about 16 percent in this patient population versus the 6.5 over
> the four pivotal trials. Overall, we see a 16 ml increase in the total
> population, a 30 ml increase in the poorly reversible by the same
> definition as we said before, and 130 ml increase in the more
> reversible patients. This is on a par with what we have seen in the
> other studies. Just bear in mind that this study was small and not
> powered to detect a difference.
>
> But I think you have to look at a couple of things, one is that for
> patients who do have the ability to have a bronchodilator effect, they
> do have a larger effect. For patients who are poorly reversible to
> bronchodilators we have seen a consistent effect in FEV1 versus
> placebo. And, any patient who has COPD and has increased rate of
> decline of FEV1 would benefit from stabilization whether or not they
> are on the lower end of severity or on the upper end of severity. That
> is really all; I don\'t know how else to say it based on the data that
> we have.
>
> DR. PARSONS: Dr. Morris was next.
>
> DR. MORRIS: I have a question for Dr. Ruskin. Could you comment,
> please, on any preclinical or clinical data that might shed some light
> on the likelihood of this agent to cause dysrhythmias?
>
> DR. RUSKIN: I can\'t comment on any preclinical data because there is
> very little available with regard to the profile of the drug in
> preclinical models. The usual approach to profiling a drug with regard
> to cardiovascular risks involves the things that we have talked about,
> that is, an assessment of the drug\'s effect on heart rate, blood
> pressure, EKG parameters, and then looking at some outcome parameters
> within the confines of a clinical development program, that is,
> serious adverse cardiovascular events and mortality. If one uses those
> various parameters there are no signals of a cardiovascular risk.
>
> DR. MORRIS: Could I ask you to speculate, if serum concentrations of
> the drug rose, could there be arrhythmogenicity of this agent?
>
> DR. RUSKIN: I can\'t answer that question. I just don\'t have the data
> to answer it, except to say again that one worries about high
> exposures usually in a situation in which there is some signal at
> standard therapeutic concentrations, for example a modest QT effect
> that might be amplified markedly if exposures go up markedly. There
> were no such signals in this program.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: Can you give us a clue to say what percent of these
> patients were on ideal doses of anticholinergic inhalants? It is a
> little bit hard to say reversible and irreversible if they are already
> maxed out on anticholinergics.
>
> DR. KNOBIL: Yes, about 40 percent of the patients were on
> anticholinergics. When you say ideal doses\--
>
> DR. CROSS: Well, I mean properly administered.
>
> DR. KNOBIL: And that would be two or three puffs three to four times
> daily.
>
> DR. CROSS: Right.
>
> DR. KNOBIL: And that was the definition of scheduled epitropium. Now,
> we didn\'t track compliance with that medication because it wasn\'t a
> study medication.
>
> DR. CROSS: Did I read it right, you had over 40 percent smokers, 40,
> 45 percent smokers?
>
> DR. KNOBIL: That is correct, yes.
>
> DR. CROSS: Have you done any studies of airway challenging to see if
> you had, say, methacholine responsiveness, etc? Has there been
> anything done even in your asthma population in terms of are they more
> sensitive to airway reactivity when challenged in terms of this drug?
>
> DR. KNOBIL: You mean more sensitive or less sensitive to challenge?
>
> DR. CROSS: Correct.
>
> DR. KNOBIL: Yes, we don\'t have methacholine challenges in patients
> with COPD. I don\'t believe we have them in patients with asthma.
>
> DR. CROSS: Because you would expect with 40, 45 percent smokers you
> would have quite a few that had abnormal challenge tests.
>
> DR. KNOBIL: That is very possible, however we did not do methacholine
> challenges in these patients. It is important to note though that
> there was no difference in FEV1 response for current smokers\--
>
> DR. CROSS: Right. Now, you are presenting this as an anti-inflammatory
> and, of course, we are all aware that we are calling asthma a very
> inflammatory disease and we have recently been calling COPD a bit of
> an inflammatory disease. Can you say anything about this drug in terms
> of your asthmatic analysis of what is happening in terms of the drug?
> There are a couple of studies that were already mentioned in terms
> asthmatics studied. Can you give us any clue as to whether this is
> going to be doing anything in asthmatics?
>
> DR. KNOBIL: We don\'t have similar studies that I showed you in the
> COPD patients in asthma patients. We do have some preclinical data in
> some of the cell types that are important in the pathogenesis of
> asthma. Dr. Barnett?
>
> DR. BARNETT: Mary Barnett, GSK. What we did a lot during the
> development of the cilomilast program is to look at a lot of the
> inflammatory cells and asked the question how sensitive they were to
> PDE4 inhibitors. What we did find is that there is a variation in the
> level of sensitivity to suppressive effects of this class of drugs.
> Interestingly, in asthma one of the cell types, the mass cell type
> which is very important in at least allergic asthma, is one of the
> least sensitive cells to PDE4 inhibitors in general. So, it may be
> that the type of inflammation we see in COPD, with CD8 cells,
> macrophages and neutrophils, they are more sensitive to PDE4
> inhibition than the type of inflammation that you see in asthma, which
> is more of a CD4, mass cell, eosinophil type of inflammation and that
> may be the reason why we are seeing such nice effects in COPD.
>
> DR. CROSS: You focused a lot in the presentation on the decrease in
> the CD8 cells. Can you remind us what sort of evidence there is that
> decreasing the CD8 cells is going to be very helpful or not, and what
> role they are playing in immune reactions of the airway?
>
> DR. KNOBIL: Do you want to do the preclinical and then I will do the
> clinical?
>
> DR. BARNETT: Well, the evidence is probably circumstantial right now
> in terms of the fact that they are present there. If you look at the
> cytokine potentials that people are beginning to measure in COPD bowel
> fluids, it looks like a TH1, T-cell cytolytic response rather than a
> TH2 response and the fact that we have evidence to suggest
> preclinically that we can affect CD8 cell function and recruitment
> into the lungs. That is basically what we have.
>
> DR. KNOBIL: Also, I mentioned the clinical data that correlated
> increases and CD8 positive T-cells with COPD severity. Dr. Sciurba was
> one of the authors on the Retamales paper\--
>
> DR. CROSS: I guess what I am trying to ask is, is that good or bad?
>
> DR. KNOBIL: Yes, I would like him to comment on the clinical
> significance of that finding.
>
> DR. SCIURBA: I confess that I collaborate with basic scientists. I
> consider myself a physician and a physiologist but I have learned a
> little bit of the vocabulary.
>
> There is data from the Italian group, Saetta\'s group, and a lot of
> papers that CD8 cells are elevated in early, late COPD. CD8-CD4 ratios
> are elevated. The Retamales paper out of British Columbia that both
> Kate and I presented showed dramatic elevations in really all class
> inflammatory cells, dramatic increases in CD8 lymphocytes. There are a
> couple of papers that have been presented in abstract form that are
> currently in review, elaborating on potential mechanisms whereby in
> more chronic advanced COPD, in fact, there is low grade chronic
> colonization resulting in the ongoing deterioration; that it is a
> cytolytic type of response. There is no doubt CD8 cells are elevated
> in COPD. To say cause and effect, I guess this data is as good as any
> data that you can lower the CD8 cells and see an impact on lung volume
> and stabilization of FEV1, but the data is emerging and it is being
> looked at. I will tell you though that inflammation is an actor in
> COPD and there is a lot of research and a lot of work going on right
> now on that.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Yes, I wondered, if you have it available, if you could show
> us the graph of the hourly PFTs for four hours after the first and
> last dose. I would just be curious to see if you have it.
>
> DR. KNOBIL: Just a second.
>
> \[Slide\]
>
> Here is the first dose effect and the last dose effect, looking at
> serial PFTs over four hours. Again, the Ariflo group is shown in
> yellow and the placebo group is shown in blue. At the end of the
> four-hour period they were given albuterol. So, that is what we are
> seeing here. The response to albuterol was unchanged really from the
> first to last dose. As you can see, there is a small increase in FEV1
> following the first dose but certainly not appreciable bronchodilator
> effect.
>
> DR. PARSONS: I wanted to follow up on a question that Dr. Apter had
> this morning and that was about the original study design and what the
> initial anticipated results were compared to the results that you got.
> One question I had is when you initially powered the study and you
> were looking, hopefully, for an FEV1 change of 100-120 cc\--I have two
> questions. One is was that based on the fact that you were
> anticipating that the group that received drug would improve 120 cc,
> or did you anticipate a fall in FEV1 in the placebo group as well as
> an improvement? If so, based on data out there from the Lung Health
> Study and everything else, what degree of decrease in FEV1 were you
> thinking you were going to see in the placebo group at 24 weeks?
>
> DR. KNOBIL: Well, to be perfectly honest about it, after looking at
> the Phase II clinical trial 032, we did expect to see an increase in
> FEV1 with cilomilast and we didn\'t really expect to see the drop in
> FEV1 in the placebo group. Perhaps we should have, given the data that
> is out there with these long-term clinical trials. However, even
> though we didn\'t see what we expected to see, I think we did see a
> very clinically important result, basically the stabilization of FEV1
> over time while the placebo group did decline.
>
> I think the other important thing to note is the decline in FEV1 in
> the placebo group was seen in three of the four clinical trials. So,
> the weight of evidence suggests that this is a real finding. The
> maintenance of FEV1 of improvement, again, was also seen in four out
> of the four clinical trials. So, I don\'t think we can ignore what we
> are seeing, still a very clinically relevant result albeit not exactly
> what we expected, and supported by the lung volume reductions that we
> saw too. So, I do believe there is real activity going on in the lung.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I have a question for Dr. Knobil. In thinking about how
> this drug would come to be used and in thinking about how, since there
> is some percentage of the people on the active arm who did have GI
> intolerances, was there any information gained from looking at the
> concomitant med list on those people within study drug arms who had GI
> intolerances? Was there anything by analysis of the concomitant meds
> that might give us a clue to say to Mr. Smith, or Mrs. Jones, or Mr.
> Jones, you are on this drug. We know those people get more GI
> intolerance?
>
> DR. RICKARD: We looked in particular at one drug, such as
> non-steroidal anti-inflammatories which a lot of these people can be
> on at times. We didn\'t really see any difference in effect on GI
> intolerance if they were on non-steroidals or not. We really didn\'t
> have a lot of other concomitant meds that we looked at to see whether
> it was involved with GI intolerance.
>
> DR. MORRIS: Do you know particularly if diuretics were seen?
>
> DR. RICKARD: Well, certainly diuretics were used in some of the
> patients based on their underlying diseases but I don\'t have an
> analysis to tell you whether it correlated with anything or not.
>
> DR. SURAWICZ: Can I ask why you asked about diuretics?
>
> DR. MORRIS: I am just worrying when someone has nausea and vomiting
> and persists in taking a diuretic. They would become more dehydrated.
>
> DR. RICKARD: Again, I just want to remind you that we have done very
> many vital signs, hemoglobin hematocrits and laboratory values and at
> no time did we see any difference. So, we did not see any evidence of
> any type of blood volume loss per se or any effect of dehydration.
>
> DR. MORRIS: What would be the recommendation for use during an acute
> exacerbation of COPD?
>
> DR. KNOBIL: Well, the recommendation for use would be the same as what
> was done in the clinical trials, that patients should not stop taking
> their medication. There is no evidence to suggest that they should
> stop taking it and there is, you know, probably more evidence to
> suggest that as a maintenance medication it shouldn\'t be discontinued
> unless there is a physical reason why they can\'t take it.
>
> DR. MORRIS: In some of the safety studies there was some notion that
> in people with hepatic impairment there was an increase in serum
> levels.
>
> DR. RICKARD: In people who have severe hepatic impairment or people
> who have severe renal impairment there is an increase in the unbound
> portion of Ariflo. Now, interestingly, in these studies we did not see
> an increase in side effects but what we are saying is that there is a
> potential for increase in GI intolerance because of the fact that the
> unbound fraction is increased.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: Two things, I wonder if you could put that slide back up
> about the bronchodilator response, the first and last dose? The other
> question I had was if you give this drug to a patient with COPD who
> does have a reversible component is it an acute bronchodilator? In the
> 168 study, it looked like those patients who are reversible have a
> pretty sizeable response.
>
> DR. KNOBIL: Right, and that is the only study in which we did not
> restrict reversibility and we did not do serial FEV1s. So, I don\'t
> know the answer to that question.
>
> DR. KERCSMAR: You might expect drugs which are phosphodiesterase
> inhibitors to potentially in that patient population to have more of a
> bronchodilator effect. I want to see the magnitude of those responses.
>
> \[Slide\]
>
> Is that right, that you are still getting about 150 ml response in
> those patients to bronchodilator?
>
> DR. KNOBIL: To albuterol. Remember, we are getting a little bit more
> than the 80 ml because that is the average for all clinical trials,
> and the reversibility was slightly higher in the North American trials
> and this is North American trial 039. Again, we don\'t see much of a
> bronchodilator effect acutely but we don\'t see any diminution of
> response to albuterol either.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Part of what we have to deliberate on today is whether 30 ml
> is a clinically important difference and I wondered if you wanted to
> say why you think it is.
>
> DR. KNOBIL: Well, I think the clinical picture is very clinically
> significant because in the clinical trials we do see the stabilization
> of FEV1 over time whereas we do see this steady decline in the placebo
> group, albeit in three of the four trials. We also see the
> stabilization of FEV1 of up to 84 weeks in the open-label trials.
>
> So, I think that the clinical significance is quite compelling in that
> if we can potentially stabilize FEV1 over time, that would be one of
> the things that we haven\'t been able to do in patients with COPD.
>
> The other thing to remember is that we have seen significant decreases
> in lung hyperinflation which also are associated with improved
> exercise tolerance. Also, even though we didn\'t see a large increase
> in FEV1 in the cilomilast-treated groups, we did see a significant
> increase in quality of life. So, I think all those things taken
> together tell me that for patients this would be a clinically relevant
> medication for them, and I would invite also Dr. Sciurba to comment.
>
> DR. SCIURBA: I guess what I would ask the committee and the agency to
> consider is what would be the outcome you would expect with the broad
> class of anti-inflammatory agents that are currently in various stages
> in the pipeline, or at least being speculated upon in the literature.
> What response would we expect to see? It is not going to be in
> irreversible COPD 200 cc acute changes, yet there is a lot of effort,
> a lot of money, a lot research, basic science research developing
> products that we can then translate and test clinically.
>
> You know, when I look at it from that perspective, if we can stabilize
> COPD and prevent the decline and the symptoms, then I think we are
> doing the right thing for our patients. Do we have evidence here that
> that is occurring? Within the length of the trial we do see
> stabilization. We see other factors that I think are very important if
> we don\'t just focus on FEV1, things that I talked about in my formal
> presentation\--drop in hyperinflation, residual volume.
>
> The surrogates, while they are surrogates and I don\'t have absolute
> evidence, I don\'t know if in the next ten years we will have the
> absolute evidence that, in fact, drops in CD8 and neutrophils and
> macrophages do translate into the things that we think they will
> translate into, but there is pretty strong surrogate evidence that we
> are doing the right thing if we\--as the strong trend in our area of
> research is\--believe that, in fact, inflammation is the key agent
> resulting in progressive decline in COPD.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: Did you do any subgroup analysis, or can you remind us what
> you found when you took that beginning FEV1, 20, 30 percent of
> predicted, 60 percent of predicted\--can you tell us that improvement
> that you are trying to show, did it cross over all degrees of severity
> of the FEV1? Obviously, 30 ml is a lot more impressive to somebody
> whose FEV1 is 400 than somebody whose FEV1 is 1.9. I am sure you did
> some subgroup analyses because you had so many patients, and almost
> all these studies do subgroup analyses, to tell when you pegged it to
> the severity of the COPD.
>
> DR. KNOBIL: When we looked at severity of COPD, that by itself did not
> have significant impact on the FEV1 response. But as I mentioned
> before, the more severe patients, that is, less than 35 percent of
> predicted, tended to have a greater response in SGRQ than the less
> severe patients. So, just by looking at FEV1 severity, it really had
> more of an impact on the SGRQ.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: I just wanted to follow-up on something you said a few
> minutes ago about why you think this is an efficacious medication. I
> am trying to reconcile what is the proposed indication, which says the
> efficacy of the drug has not been established in clinical trials
> beyond 24 weeks and what you are inviting us to do here is to accept
> the open-label work that carries on for a few years thereafter.
>
> In light of the fact that you are making the statement, I think
> correctly, that you have efficacy data for 24 weeks, I have a two-part
> question. One is what would be the recommendation to patients and to
> their physicians in terms of prescribing this drug beyond 24 weeks?
> And, why were the studies as originally designed only 24 weeks in
> length?
>
> DR. KNOBIL: Well, I think I will answer the second part first. They
> were originally 24 weeks in length to establish efficacy and a
> six-month trial is what we have generally been using for our
> medications for COPD. Generally we also do longer-term trials mainly
> for safety and that is why we have the long-term extensions.
>
> As I mentioned before, what we were expecting to see and what we
> actually did see was slightly different. I think if we had expected
> what we saw we would have had a longer-term trial, placebo-controlled
> trial to fully look into that.
>
> I am sorry, now I have forgotten the first part of your question.
>
> DR. NEWMAN: Is it advisable for a patient to be prescribed this
> medication for more than 24 weeks?
>
> DR. KNOBIL: Well, certainly from a safety standpoint there are no
> issues seen, as you have heard, for up to three years in patients with
> COPD. The potential to stabilize FEV1 beyond the 24 weeks is very
> real. So, I would certainly expect that there would be no issues to
> prevent a physician from prescribing this beyond the 24 weeks. The
> reason that the label has been proposed that way is because that is
> the duration of the placebo-controlled trial but, again, with the
> safety information that we have there is no reason to limit it only to
> 24 weeks. The patients should be reevaluated periodically however.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Theophylline has been shown to increase excretion of
> calcium. Did you look at that at all with this drug, urinary
> excretion?
>
> DR. RICKARD: We did not look at urinary excretion of calcium. We did
> look at all the standard things you would look at\--electrolytes,
> potassium, glucose, and so forth and so on, and saw no differences in
> that. We did not specifically look at urinary excretion of calcium.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: This one is for Dr. Anthracite. I want to get a
> clarification on something that you said this morning when you were
> discussing adverse events versus serious adverse events. I thought I
> heard you suggesting, and I just want a clarification on this, that if
> a person had an adverse event and dropped out of the study in your way
> of thinking that would push it into the category of being a serious
> adverse event. Did I understand you correctly or could you clarify
> that, please?
>
> DR. ANTHRACITE: Something like that, I was commenting on the paucity
> of serious adverse events in the controlled and uncontrolled trials. I
> was kind of wondering if withdrawal from the study then moved it from
> the category of serious. There was, however, no way to ask that at the
> time.
>
> DR. PARSONS: I have one question, I think just one question left but
> you never know, I am afraid; I am sorry. The two pivotal trials that
> clearly showed statistical significant differences in efficacy were
> the two North American studies. The European studies were less
> significant. You just mentioned, and I just looked back in the book,
> and actually the degree of reversibility in the North American trials
> is actually very different than the European trials. Is there a
> statistical difference between those baseline values between the
> studies? It may be difficult to compare.
>
> My second part of the question is, is that why there is a statistical
> significance in the North American trials, because the reversibility
> is actually greater?
>
> DR. RICKARD: Could you please show the baseline characteristics?
>
> \[Slide\]
>
> As I mentioned, there are some differences between the populations,
> not just reversibility. You know, in the North American trials
> baseline reversibility is between 7.5 and 8 percent whereas ion the
> European trials it is about 5 percent. I don\'t believe this was
> statistically significant. I am not even sure that it was actually
> tested. It is hard to really say that that is a clinically significant
> difference just because there is some variability in reversibility
> testing, but it seemed to be pretty consistent across the trials.
>
> The other things that were different were the degree of DLCO
> impairment, the numbers of women, as well as history of chronic
> bronchitis. So, there are a number of differences between the
> populations that may have contributed to the differences that we have
> seen. Now, we have done analyses to try to tease this apart and, as I
> have mentioned before, we haven\'t come up with the one answer that
> explains all of this so, unfortunately, I can\'t give that to you. But
> I wouldn\'t doubt that some of these baseline characteristics have
> something to do with it.
>
> DR. PARSONS: Just doing quick math in my head, which is never very
> reliable, the difference is about 30-40 ml if you look at North
> American baselines and European baselines.
>
> DR. KNOBIL: Yes.
>
> DR. PARSONS: Which is the effect size that you are using for your
> efficacy in the two pivotal trials. Is that correct? That is
> approximately the effect that you saw?
>
> DR. KNOBIL: Yes.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: I have a question that pertains to the non-clinical
> evaluation of the drug in animal species. I know there has been
> nothing found in terms of carcinogenicity. I am just curious has there
> been any look at co-carcinogenic effects with animals that were
> exposed to tobacco smoke, since that is kind of the unique thing about
> this patient population?
>
> DR. RICKARD: No, there has not been.
>
> DR. PARSONS: Are there additional questions from the committee? Dr.
> Morris?
>
> DR. MORRIS: One last quick question, the Holter monitor data that we
> discussed before, you mentioned in your presentation that it was done
> at week 1 and then\--was it week 12 and week 24? Were any histories
> taken that you remember while people were experiencing GI
> intolerances?
>
> DR. RICKARD: You question is were any of the Holters done while they
> were experiencing GI intolerance. I don\'t believe I have the data to
> answer that question.
>
> DR. PARSONS: Any further questions from any committee members?
>
> DR. KNOBIL: Can I just make one clarification? You asked the question
> earlier about whether or not hospital records were reviewed when a
> patient had been hospitalized. While we did not review records, if an
> adverse event or a serious adverse event occurred during the
> hospitalization or prior to or after, that was reported by the site
> personnel to GSK. So, while we did not personally review hospital
> records, any event that occurred during hospitalization would have
> been reported to us.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: I want to come back to a question I asked earlier today
> which had to do with the baseline data. In terms of your randomized
> criteria, you would allow people into the study if the difference
> between their screening FEV1 and their baseline FEV1 was less than 20
> percent. I wonder if you would give me a clarification on the
> rationale for allowing that wide a range of potential variability
> during the pre-randomization period.
>
> DR. KNOBIL: The wider range of variability than reversibility?
>
> DR. NEWMAN: Yes, you basically would allow a 20 percent variability
> between those numbers. I just wanted to get a little better sense of
> how that number was picked and why that was picked.
>
> DR. KNOBIL: Well, I think it was a relatively arbitrary number, mainly
> chosen for safety purposes. We didn\'t want people who were rapidly
> declining because they had been removed from medications during the
> run-in period. Also, it was sort of a quality measure because if there
> was some variability in how FEV1 was done we didn\'t want to have
> unreliable FEV1s all over the place from patients potentially having
> an impact on the study. We wanted to have very strict rules for how
> FEV1 was performed and making sure patients who were deteriorating
> weren\'t getting in.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD I just had one question about that graph you had, A-72, in
> which you showed that people who were going to have GI adverse events
> were going to have them early. It was an incidence graph I think. My
> question is if they had GI adverse events did they quit having them,
> or did they continue to have them? As far as I understand, that is
> incidence of new patients presenting with adverse events on that
> graph.
>
> DR. RICKARD: Right. So, you question is if patients experienced it, in
> some patients did it go away?
>
> DR. JOAD: Like with theophylline\--
>
> DR. RICKARD: Right.
>
> DR. JOAD: \--if they had it early it usually went away.
>
> DR. RICKARD: Yes.
>
> DR. JOAD: And that wouldn\'t be reflected on this particular graph.
>
> DR. RICKARD: That is correct, but you are correct in saying when
> patients did experience GI intolerance many patients were able to
> tolerate them and they went away, and they continued in the studies.
> So, if you look at the withdrawal rates it was about 17.5 percent that
> withdrew from the study. Most of those were due to GI effects. But
> then greater than 80 percent of the patients were able to continue
> into the study and tolerate the medication.
>
> DR. JOAD: Did you formally look at that, you know, when they occurred
> and the people who had them?
>
> DR. RICKARD: As far as time\--
>
> DR. JOAD: To show that it really did go away and the people who
> initially had GI events later on didn\'t have them?
>
> DR. RICKARD: I don\'t think we have a specific analysis on that data
> but, certainly, the number of patients who did have it continued on.
> Otherwise, we would have had a much larger withdrawal rate from the
> study for it.
>
> I also just antibody to clarify something for Dr. Morris and when you
> asked me about the Holter. The first one was done at week one. As you
> know, in the early period when you are likely to see GI intolerance,
> certainly there were a lot of Holters done at week one when patients
> were having those symptoms but we didn\'t actually pull those patients
> out and look at them separately.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: I would just like to ask what the strategy and thinking was
> in having patients not take Combivent, which must be one of the more
> frequent drugs in this country that is used to treat COPD, in other
> words, the combination of an anticholinergic and a symptomatic.
>
> DR. RICKARD: Well, there are two reasons. One, when the first three
> pivotal trials were started Combivent was not available. So, when we
> designed the fourth one it was to be as similar as possible.
>
> Also, I think it was felt that patients could use albuterol as needed
> anyway. So, if they were allowed epitropium on a scheduled basis they
> could also augment that if necessary.
>
> DR. CROSS: Related to that, you probably had some discussions in
> comparing the post-bronchodilator FEV1s for your baseline versus the
> [de novo]{.underline} or without bronchodilator FEV1s but allowing
> them to take anticholinergics. I just wondered when you went into the
> study you thought it was going to be an anti-inflammatory and not have
> any effects on airway reactivity? Was that the thinking?
>
> DR. KNOBIL: Well, I have to admit since I wasn\'t around at the
> beginning when these trials were designed, I don\'t know what the
> discussions were about choosing post-bronchodilator FEV1 for inclusion
> versus pre-bronchodilator, and I would welcome any other input. But to
> reiterate something that I said earlier, based on the dose-ranging
> study I think we were expecting a little bit more of a bronchodilator
> effect. So, that is sort of the answer to your second part.
>
> **Questions**
>
> DR. PARSONS: Are there further questions from the committee? Any
> comments? No further questions? If there are no further questions from
> the committee we are going to move on to asking the specific
> questions. We have four of those that the FDA has asked us to address.
> What I will plan on doing is read the first question, then we will
> open it up for discussion among the committee members and once
> discussion is complete we will take a vote.
>
> We are going to start with the first question and we will go on from
> there. The first question that we have been asked to address is number
> one, has cilomilast at a dose of 15 mg twice daily shown a magnitude
> and consistency of efficacy that is sufficient to support approval for
> the maintenance of lung function, FEV1, in patients with COPD? If not,
> what further efficacy data should be obtained?
>
> I am going to open up that up for the group for discussion, comments.
>
> DR. JOAD: I am always happy to start.
>
> DR. PARSONS: Thanks!
>
> DR. JOAD: In my opinion the magnitude is too small and the
> replicability between the studies was too poor to convince me that it
> is an effective drug. I am intrigued with the fact that it doesn\'t
> appear to be a bronchodilator in this group of patients and that there
> may be something that is anti-inflammatory that is really going to get
> at the underlying structural problems with the disease and preventing
> it from progressing. So, that is very exciting, that there could be
> such a drug for these people but I am not convinced of that.
>
> What could convince me is really a longer study I think. If in the end
> all they ever get is a 30 ml, which is less than 3 percent,
> improvement of FEV1, that is never going to be clinically important.
> But if over the next six months or the next year it continues to widen
> then, of course, it would be just terrific. So, that is what I think.
>
> DR. PARSONS: Other comments or discussion? Dr. Cross?
>
> DR. CROSS: Yes, over a lifetime the 30 ml is going to cut a few months
> from disability and a few months from death I suspect if we take what
> the average yearly loss in FEV1 is and we relate the FEV1 to life
> expectancy, etc., etc. So, I think we are talking about something that
> might be in the long-run two, three months in terms of efficacy at the
> end that is critical where people are going on oxygen, etc. I
> otherwise agree with your comments.
>
> DR. SURAWICZ: Can I ask a question of the committee, not being a
> pulmonologist? How do you determine the importance of one criterion
> like that versus all of the other outcomes that they measured
> functionally? I guess what I am asking is if I were a patient with
> lung disease what would I be expecting if I took this drug long term,
> besides just that 30 ml?
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: Yes, I will take a crack at that. The lung community as a
> whole is very interested in using studies other than the FEV1 for
> COPD, and the FDA has had these discussions too. As a chest community
> of pulmonary docs, we have probably been too dependent on physiology
> and there are other things that we would like to measure in COPD. That
> has been pretty prevalent in our recent literature.
>
> DR. PARSONS: I think in part too, you know, the quality of life scores
> that were obtained\--that is another feature you would like to see in
> your patients. I can comment here. I think part of me is a little bit
> swayed by the change in FEV1. The study was not originally designed to
> look at what we are being asked to approve it for now, and that is
> just because the results were different than originally anticipated,
> and that happens, but I think the trial, from my point of view, if we
> were looking to stabilize lung function to start with, it would have
> been designed differently and for a longer period of time.
>
> I share Dr. Joad\'s concerns about the minimal efficacy, and that has
> further sort of hampered me because there is so little improvement in
> the other potential outcome, which is quality of life. Based on those
> scores there was really minimal improvement in only one of the trials.
> But I would like to hear from the other committee members. Dr. Apter?
>
> DR. APTER: Well, I agree with the other speakers. I am not convinced
> at all that FEV1 is the right endpoint. I think quality of life should
> be part of it. Therefore, I am not convinced of the efficacy of the
> drug.
>
> On the other hand, I am not sure that there is significant toxicity to
> hold it up and we have no good drugs for COPD, and that is the
> problem. The FDA perhaps could tell me how you could get what we all
> say is needed, a longer trial. How can you get a longer trial with
> economic considerations, aside from allowing the drug to be marketed?
>
> One other comment that you brought up is that there may be effect seen
> at a lower dose, 10 mg b.i.d., that may have less side effects.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: I was interested in the fact that the more severe the
> patient the better quality of life rating they gave from the drug. I
> know from a patient\'s point of view that is very important for the
> more severe patient because they don\'t have much to go on but the
> quality of life. But I was disappointed in that the less severe
> didn\'t see that same improvement. So, from a patient\'s standpoint,
> there is a large group of patients out there that don\'t see a quality
> of life improvement even though the more severe do. It is just a
> comment that sometimes the more severe can see little improvements so
> much better than the less severe, so how compliant are they going to
> be about taking the drug?
>
> DR. PARSONS: Dr. Meyer?
>
> DR. MEYER: I just wanted to address Dr. Apter\'s question to us about
> the long-term data. There are a couple of pathways. Part (a) of this
> question is, if not, what further efficacy data should be obtained?
> So, the committee could, in theory, recommend that the drug not be
> approved until longer-term data are obtained.
>
> Another pathway, as I think you were getting to, is that the drug
> could be approved with what is called a Phase IV commitment, which is
> a commitment on their part to do a longer-term study. Or, it could be
> approved without such but the long-term study could be done otherwise.
>
> DR. APTER: We can propose a number of studies postmarketing. Right?
> For adverse effects, for long-term follow-up, for different doses?
>
> DR. MEYER: I think the intent of question 1(a) would be to have the
> committee give us their opinion as to what further efficacy data would
> be obtained the way the question is posed, that is particularly if you
> feel like there are not sufficient data currently, but I think we
> would be happy to receive that kind of input in any case.
>
> DR. PARSONS: Dr. Meyer, can you clarify for the committee in terms of
> Phase IV trials ongoing. In the past we have discussed them and they
> have generally been discussed for safety issues as opposed to efficacy
> issues. Is that not the case?
>
> DR. MEYER: They can be for either. In fact, for certain classes of
> drugs it is common to approve them for surrogate markers, for instance
> AIDS drugs, drugs for HIV will be approved based on biomarkers. Then,
> the Phase IV studies, in addition to getting more safety data, are
> actually to prove the efficacy on clinical endpoints such as mortality
> and progression to AIDS, and things like that. So, Phase IV studies
> are not just for safety. They can be for many, many reasons.
>
> On the other hand, obviously if the committee were to feel there were
> not sufficient data now one might argue that you should then do the
> study before approval. So.
>
> DR. PARSONS: Before we vote on this question, are there other
> committee members that have items for discussion or comments? Dr.
> Kercsmar?
>
> DR. KERCSMAR: The situation I have some experience with is another
> disease, cystic fibrosis, and one of the goals of they there for
> patients is to also slow the rate of progression and decline in FEV1.
> A number of the trials there with therapies have been much longer
> term, a four-year study for ibuprofen that showed significant slowing
> in the rate in decline of FEV1 as opposed to improvement. There have
> been some similar data here, a brief rise and then a decline over
> time, and what looks like in some of the extension studies here, a
> regression to the mean in both groups.
>
> So, I would agree that a longer-term study might give you a better
> idea if the current indication for approval of maintenance of FEV1 is
> true or not.
>
> DR. PARSONS: I think the other factor we might want to consider as a
> group is, indeed, some of the data that was presented in terms of how
> many patients there are in the United States and in the world who fit
> the definition of COPD that is not responsive or COPD.
>
> Also, although the average life expectancy varies with FEV1, for the
> majority of patients in the trial the average age was 60 such that
> they still have many years to live. I think others would verify that
> just in terms of information to put on the table. Dr. Joad?
>
> DR. JOAD: The design of the study seemed fine to me. I think if they
> do another study, a longer study, they would want to do lung volumes
> because they made a cogent argument but it was not part of their
> pivotal studies and I think it should be.
>
> DR. PARSONS: Additional discussion? I am going to ask the FDA one
> question before we start to vote on question number one. If we vote on
> question number one, if the vote is, yes, it is efficacious, do you
> want us to go on to 1(a)?
>
> DR. CHOWDHURY: The way the question is written, if the answer the
> question is that it is, yes, it is efficacious, then 1(a) would not
> apply. If the answer is no, then really what we are asking for is what
> should be required for approving the drug.
>
> DR. PARSONS: I just wanted to clarify that before we asked the
> question and voted on it. A vote of yes to question number one means
> question 1(a) does not go back on the table. Correct?
>
> DR. CHOWDHURY: Yes.
>
> DR. PARSONS: Any further discussion before we vote on question number
> one? Dr. Apter?
>
> DR. APTER: I would like to be able to say yes but with postmarketing
> recommendations.
>
> DR. CHOWDHURY: I missed the question. Is it a question to us?
>
> DR. APTER: I guess so. Given the alternatives you just gave us, I
> wanted another alternative, yes, but with these postmarketing
> recommendations.
>
> DR. CHOWDHURY: I mean, that can be something which you can put out as
> a discussion and as a comment that we take, but the voting is really
> as it is. Am I clear on that?
>
> DR. PARSONS: Anybody on the committee have further discussion? I have
> tried to encourage it to make sure we haven\'t cut anything up and
> truncated things. Dr. Meyer?
>
> DR. MEYER: I was just going to suggest why don\'t we go through the
> voting and if the vote comes out that the committee is on balance
> recommending approval, then, since we are ahead of schedule, after the
> formal voting is done there would be plenty of time to add thoughts
> about what other studies might be recommended even in light of
> recommended approval.
>
> DR. PARSONS: So, if there is no further discussion, I will read
> question number one again and then we are going to vote. I am going to
> ask that we actually ask on this side with committee members that have
> been on the committee for more than their very first time having to
> vote initially. So, we will start with Dr. Morris, but let me read the
> question again.
>
> The question on the table is has cilomilast at a dose of 15 mg twice
> daily shown a magnitude and consistency of efficacy that is sufficient
> to support approval for the maintenance of lung function, FEV1, in
> patients with COPD? Dr. Morris?
>
> DR. MORRIS: My answer is no, and the answer to 1(a) would be that
> long-term follow-up type studies that would include quality of life,
> that did look at drug use, that did look at hospitalizations and used
> those as parameters to say this drug had efficacy. Since we are
> targeting a population that might not have a lot of mobility in the
> FEV1, I would use those other parameters as efficacy.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: My answer is maybe but I have to decide which way to go.
> Can I pass for now and listen to other comments as we go around the
> table?
>
> DR. PARSONS: I am going to have to ask somebody how we do that
> procedurally. Yes, we can let you pass, but not everybody can pass.
>
> \[Laughter\]
>
> Ms. Schell?
>
> MS. SCHELL: My answer is no. Are we answering (a) now too? I would
> recommend further or longer studies including greater populations.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: My answer is no to question one.
>
> DR. PARSONS: My answer is no. I think there is potential but I would
> like to see different studies done. Dr. Apter?
>
> DR. APTER: My answer is yes, but there have to be postmarketing
> studies to follow those patients long term for safety, efficacy, a
> more diverse patient population, and other endpoints of physical
> functioning than COPD.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: My answer is also no for many of the same reasons that we
> have heard here already. I will come back and comment later when we
> get to 1(a).
>
> DR. JOAD: No.
>
> DR. KERCSMAR: My answer is no for the same reasons and I would like to
> see some other studies done.
>
> DR. PARSONS: I made an error. Dr. Surawicz, you are a voting member of
> the committee today. I apologize.
>
> DR. SURAWICZ: I vote yes, and I am swayed by the magnitude of the
> disease, the lack of other options, the notion that there may be
> additional benefits long term. That is it.
>
> DR. PARSONS: Dr. Cross, we are back to you.
>
> DR. CROSS: Yes, I am going to go with yes. I am impressed with the
> volume changes, the symptom relief in the sickest of the patients, and
> I am satisfied on the safety. I don\'t think it is necessarily going
> to be great but I think it needs further study and I think it will get
> further study if it is approved.
>
> DR. PARSONS: All the committee members have voted. The final vote is
> yes, three votes; no, seven votes. We are going to go on to question
> 1(a) for those that didn\'t answer it. I am going to go around the
> room again. We will start with Dr. Morris and go in the same direction
> for 1(a). What additional studies would you like to see?
>
> DR. MORRIS: I think for this particular population a longer study
> period of time would be beneficial, and with the other parameters we
> discussed that might give light to this agent. The trends possibly are
> there but it wasn\'t sufficient enough to convince me that it is ready
> at this point. But looking at the secondary parameters presented here
> in more detail, looking at quality of life and the use of medications
> to supplement exacerbations would be useful in helping to determine
> efficacy.
>
> DR. PARSONS: Dr. Cross, you voted yes but do you have additional
> comments?
>
> DR. CROSS: Yes, I want to see further studies done. I don\'t think in
> this country we are going to get away from doing them the way they did
> their first studies because people are taking Combivent. I think that
> is a tough one because it is sort of almost a standard of care in COPD
> to use both. I question the whole business of reversibility. If you
> have somebody on an anticholinergic you would have to pull them out of
> an anticholinergic and wash it out and then say they were
> irreversible. So, I have problems with the definition of irreversible
> disease that is being forwarded here, and would call for
> qualifications of that and say that irreversible is defined as
> somebody on effective cholinergics who also is having to show a
> significant effect to a beta sympathometic that was being given
> because I think you would have to look at those two groups differently
> because the response to an anticholinergic in the literature is better
> than the response to a sympathomatic and I don\'t think you can call
> it irreversible because we don\'t know what it was without the
> anticholinergic. I agree with other comments, there are a lot of Phase
> IV studies that should be done on this drug.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: As I stated earlier, I would like to see a greater
> diversity in populations including older people and more
> non-Caucasian, and also I would like to see the quality of life issue
> maybe studied more for those patients.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: Yes, I believe that longer-term studies are necessary,
> but then I question whether or not it is ethical to use placebo in a
> longer-term study in this type of disease. The company may need to
> consider a non-inferiority type of design where there is some active
> control instead of placebo.
>
> DR. PARSONS: I think what I would like to see, because of the
> magnitude of the disease and the duration that patients are likely to
> be on this medication, is a trial clearly designed to now address the
> question that we have been asked to approve the drug for, which is
> does this drug, indeed, stabilize FEV1 or lung function and quality of
> life, and ask that in a specific prospective, randomized design trial
> to specifically answer that question which, unfortunately, is going to
> be a long-term study, longer than 24 weeks I suspect. It is going to
> be expensive. There are a lot of issues with it. But I don\'t think
> that the current trial has actually specifically answered the question
> that we have been asked to answer. Dr. Apter?
>
> DR. APTER: I agree, long-term because I am concerned about the
> endpoint. We haven\'t really answered the question. Other populations,
> as I have already mentioned. Other doses.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: Just adding to what I agree with, and I agree with
> everything I have heard here so far, I think that there is an
> opportunity to also include people who are not only older but also who
> may have somewhat more severe disease.
>
> I think the other thing that I would encourage people to attend to is
> the precision and repeatability of the baseline measure because, if
> everything is going to peg off that baseline, I think we want to have
> a great deal of confidence going forward from that baseline that we
> know where people started before the initiation of the trial.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Yes, it is repeating what others have said, longer, a more
> diverse patient population, include lung volumes in the study.
>
> The other thing I would add is that I think once it is released people
> are going to want to use it for everybody, which means a big
> population of COPD that does have reversibility. So, especially with
> their preliminary data showing that reversibility may be more
> successful in patients who have reversible airways disease, at the
> time of this study they should just go ahead and address that issue so
> people would know who to apply it to.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: The beauty of going at the end is you can agree with
> what everybody else has said, which I do. A couple of points I think
> bear greater emphasis. I would agree with Dr. Chinchilli about if you
> are going to do a long-term study, perhaps not using a placebo design,
> and also the measurement of lung volumes might be very, very useful
> and should be included.
>
> DR. PARSONS: Dr. Surawicz?
>
> DR. SURAWICZ: I have no additional comments.
>
> DR. PARSONS: We can move on to question number two unless the FDA has
> further issues regarding question number one, further comments or
> questions.
>
> I will read question number two and then we will open it up for
> discussion. Question number two, is the safety database for
> cilomilast, aside from the concern about vasculitis, for the
> maintenance of lung function, FEV1, in patients with COPD sufficient
> to support approval? If not, what further safety data should be
> obtained?
>
> I will open it up for discussion. So, this is safety database for all
> side effects, not vasculitis. Comments from the committee? Dr. Morris?
>
> DR. MORRIS: I think overall the data presented appears very clean. I
> think the design of the study allowed for patients to be seen often
> and for people going through the trial there was a minimum of adverse
> side effects. So, in that light, I think for those people who were
> stable there was not, in my mind, a concern.
>
> However, I think there was a great area of potential safety concerns
> that we did not have an opportunity to see or to evaluate and that is
> when people do become ill with the COPD exacerbation and do become ill
> enough to go to a hospital, I would think that we are going to see
> toxicities. Now, because the number of those in this particular study
> is small, we didn\'t have the opportunity to see it very often, but in
> considering moving this agent out to a more ill population of COPD
> patients who do go into the hospital often we have to have more data
> on what does this look like when people get sick; when they are in the
> hospital; when they have new liver dysfunction or renal dysfunction,
> what does that do; and they have hypoxemia that is severe. What does
> that do to the arrythmogenicity? I am not sure but I do have concerns.
>
> So, in the sense of what we saw and the data that was presented, I do
> think it is clean and I have no safety concerns there but I would say
> there is a caveat. I think there is an area of study that has not been
> evaluated that should be evaluated more carefully, and that is when
> people do get sick. Then we could have a better recommendation to say
> do we continue this drug during acute exacerbation or not.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: I echo all of Dr. Morris\' comments. I think the studies
> would need to be done in Phase IV with those with cardiac disease, and
> I am also concerned about hypoxia and arrhythmogenicity and cardiac
> manifestations, including Holter monitors done on patients that
> weren\'t excluded because they had coexistent active heart disease.
>
> DR. PARSONS: Additional comments regarding the safety? If there are no
> additional comments we will vote on this one. We are going to start
> with the initial question and then we will go to 2(a). I think that
> would be the best way to do this.
>
> Question number two again, is the safety database for cilomilast,
> aside from the concern for vasculitis, for the maintenance of lung
> function, specifically FEV1, in patients with COPD sufficient to
> support approval?
>
> This time I will go in the correct order; I apologize. Dr. Surawicz?
>
> DR. SURAWICZ: Yes.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: No.
>
> DR. CROSS: Yes.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: Yes.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: Yes.
>
> DR. PARSONS: For myself, the answer is yes.
>
> DR. APTER: yes.
>
> DR. NEWMAN: Yes.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Yes.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: Yes.
>
> DR. PARSONS: The vote on question number two is nine yes and one no.
> In light of the one no, I think we should just go through the group
> and address \"if not, what further safety data should be obtained.\"
> Dr. Surawicz?
>
> DR. SURAWICZ: I pass.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I would just reiterate I think dealing with people who
> have more critical illness so we could have recommendations as to what
> to do when they become more severely ill.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: Ditto.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: I agree with Dr. Morris.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: Nothing to add.
>
> DR. PARSONS: I have nothing to add. Dr. Apter?
>
> DR. APTER: Nothing to add.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: If the study design in the future were to be broadened out
> to include somewhat more severe patients, then I think Dr. Morris\'
> point would be especially important. I think it is important already
> but it would be even more important because you could expect that
> there would be more admissions to the hospital and you would want to
> track those data.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: All of the GI side effects that they had were not
> particularly safety concerns but they certainly were very annoying and
> people had to drop out based on them. I don\'t know if the company has
> done this but, certainly, when we used to use theophylline all the
> time if you started low and worked the dose up slowly, then there were
> many, many fewer GI side effects and it became a tolerable condition.
> So, if the company hasn\'t really considered this or looked into it
> for this phosphodiesterase inhibitor then they should consider that in
> a future study.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: Nothing else to add.
>
> DR. PARSONS: We are going to question number three. Question three for
> the committee is do you feel that the concern about mesenteric
> arteritis has been adequately studied to be dismissed as a safety
> concern in humans? Then 3(a), if not, what further data should be
> obtained?
>
> I am going to open this up for discussion. I think for many of us, our
> eyes are on Dr. Surawicz.
>
> DR. SURAWICZ: Do you want me to make a comment?
>
> DR. PARSONS: Yes.
>
> DR. SURAWICZ: All right. I think that I am satisfied that the drug is
> safe, however given the experience that we had with lotronex a couple
> of years ago, I think it would be really important to monitor after
> the drug is marketed to make sure that nothing comes up. Certainly in
> that case there were some clues but it became really widely apparent
> when the drug was released and used widely, and sometimes in
> inappropriate patients. So, it is something I would keep an eye on but
> I am not worried and I would recommend yes as an answer to the
> question, for myself.
>
> DR. PARSONS: Other additional comments from the committee? Further
> discussion regarding this issue?
>
> DR. JOAD: Are we going to get to talk about what further data can be
> obtained? I think autopsies on people who die, their vessels should be
> looked at. I think that is a really important omission.
>
> Then the other thing is it seemed like what they were trying to do
> with colonoscopy seemed cumbersome and a lot of effort for not a very
> definitive answer.
>
> DR. SURAWICZ: But look at all those polyps that were removed and that
> cancer that was diagnosed! Everyone needs a colonoscopy after age 50.
>
> DR. PARSONS: That would certainly make our clinical trials easier in
> the future if we just do colonoscopy routine on everybody and then
> start trials. Dr. Newman?
>
> DR. NEWMAN: I guess I have a question for the members of the
> committee, especially for our GI consultant. Do we think that if they
> had been more successful in performing more colonoscopies and if there
> had been an inspection of vessels as available that we would know
> more? Would we have greater confidence?
>
> DR. SURAWICZ: Are you asking about the quality of the colonoscopies?
> Because we don\'t really look at vessels but we look at the mucosa as
> a result of whether the vessels are abnormal. I think the quality of
> the colonoscopies was probably quite good. I know there was one
> comment in one of the briefings that perhaps the transverse colon
> wasn\'t looked at appropriately, but most colonoscopists, I am pretty
> sure, would look at everything; they would look at absolutely
> everything because we don\'t want to miss a little polyp or a little
> lesion. So, I think if there was anything there mucosally, I think it
> would have been found.
>
> DR. NEWMAN: Not just quality but quantity. Not that many people
> actually ended up getting the procedure done.
>
> DR. SURAWICZ: No, but they were the highest risk people because they
> had blood in their stools or they had symptoms. So, I think it is
> unlikely you would have found anything in the asymptomatic people so I
> think it certainly made sense, what they were doing. There was nothing
> in any of these colonoscopy reports that bothered me at all. They were
> all findings that you would expect to see that had nothing to do with
> this drug whatsoever.
>
> DR. PARSONS: We know from experience that when drugs get approved for
> a patient population that was studied, it is frequent that we, as
> physicians, broaden out those indications to older people, people that
> are sicker, and people that have different FEV1s and maybe even have
> some of the exclusion criteria. That is not uncommon practice for all
> of us. Is there any reason to believe that in a patient population
> that is a little bit sicker that we would like to be giving this drug
> to, because there aren\'t really good drugs for COPD, that they would
> be more likely to be at risk for mesenteric vasculitis? Is there a
> specific patient population that you can describe to the committee who
> are actually at more risk to start with and that might be included in
> a different COPD population?
>
> DR. SURAWICZ: Not really. They already were studying old, sick people
> in this study\--not old but relatively old, older, sicker people in
> this study and with age you are more at risk to get mesenteric
> ischemia but we don\'t have any way to pick out a particular
> population. So, I think the best way to do it would be to approve the
> drug, postmarketing look for ischemia, follow people in the hospital
> to make sure that that is not what they develop because often for
> mesenteric ischemia you pick up the diagnosis after the patient has
> been in the hospital a few days; you don\'t tumble to it on diagnosis
> all the time. I think that would be reasonable so that if there is a
> problem it would show up that way. I think it is unlikely.
>
> DR. PARSONS: Further discussion or comments from the committee
> regarding this question?
>
> DR. CROSS: Were the animal studies oral dosing? They were? Then, there
> were deliberations on this committee with this same company 20 years
> ago on the most common drug we use for obstructive airway disease,
> salbutamol or albuterol, which caused tumors in the mesovarian ducts
> of rats and that probably held up approval a significant period of
> time, and we decided that we couldn\'t translate that easily to
> humans. I find great difficulty here. I mean, the older population is
> going to have atherosclerosis of these vessels and they are going to
> have a higher incidence, because they smoke, of ischemia of bowel
> vessels. But with this thing here we have absolutely no mechanism to
> propose because the rat didn\'t have atherosclerosis. I just have to
> take the data that is there and say that the rat doesn\'t translate to
> people and we don\'t have any clue of a mechanism of why one vessel
> bed that really isn\'t getting a higher dose of drug because it is the
> artery is susceptible to inflammation when we administer an
> anti-inflammatory drug.
>
> DR. PARSONS: Additional comments? We are ready to vote on question
> number three then. The question on the table is do you feel that the
> concern about mesenteric arteritis has been adequately studied to be
> dismissed as a safety concern in humans? We selective start with Dr.
> Surawicz.
>
> DR. SURAWICZ: Well, if I read the question carefully I vote yes but to
> be followed. Is that clear? I mean, I wouldn\'t dismiss it entirely.
> So, I don\'t think it is a concern now but I can\'t promise that it
> isn\'t going to be a concern in the future so it is something that
> needs to be watched. Is that unambiguous enough?
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I viewed it as something that would not be asymptomatic
> and it did not seem like these people were symptomatic with this
> particular illness. So, I think it has been addressed.
>
> DR. CROSS: I vote yes, and I do think I would do a certain amount of
> autopsies, carefully looked at for arteritis in the mesenteric
> vessels. This population has a large number dying off from different
> diseases so it should be no problem to get a certain amount of
> autopsies performed on a patient population that has been on this
> drug.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: Yes, with continued monitoring.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: Yes, I agree, yes, with continued monitoring.
>
> DR. PARSONS: I would vote yes as well, although I just realized
> something I should have asked before, which is the two safety
> questions are actually worded very differently. The one we voted on
> before says is the safety database sufficient to support approval, and
> this is have the concerns been adequately studied enough to be
> dismissed. So, the word \"dismissed\" is bothersome to me for the same
> reason I think maybe they are for other people on the committee. So,
> my answer is definitely yes but I certainly would continue to watch.
>
> DR. APTER: I share the reservations of my previous colleagues, yes,
> but watch.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: The way I read the question I think everyone\'s answer
> should be no with the caveats, but to go along with what I have heard
> here so far I would say yes, with the stipulation that there be the
> kind of follow-up that Dr. Surawicz and Dr. Cross both mentioned.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Maybe we could restate the thing so we don\'t go on record
> as saying it should be dismissed because I would like to vote yes
> also, but I don\'t really think it should be dismissed. My concern is
> not enough to affect approval, or something. That is the way I would
> prefer to vote on that.
>
> DR. MEYER: The discussion is captured in the public record. That will
> be part of the transcript.
>
> DR. JOAD: Okay. So, I will say yes, but like everyone else.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: Yes, and I agree with all the previous comments.
>
> DR. PARSONS: So the vote on question number three is ten yes and none
> no. That means we won\'t specifically go on to 3(a). I think it is
> important that most of the committee members did indicate that the
> dismissal is not what they voted on and that continued observation
> would be important. Does that capture the discussion? Is everybody on
> the committee comfortable with that?
>
> We are going to go on to question number four, do the efficacy and
> safety data provide substantial and convincing evidence that support
> the approval of cilomilast at a dose of 15 mg twice daily for the
> maintenance of lung function, FEV1, in patients with COPD?
>
> So, this question combines both the efficacy and safety questions. I
> am going to open it up for discussion.
>
> DR. CROSS: Just a question, we have already voted on one. I just
> wonder what in the world we need to vote on for four because it is
> 10-0 on safety.
>
> DR. PARSONS: I can ask the FDA to address that. My impression would be
> we should vote on it because it is the combined. There were people who
> voted yes for efficacy and some who voted no.
>
> DR. CHOWDHURY: Question number one is on efficacy, whereas question
> number four is efficacy, safety and indication. So, the whole picture
> comes together here. Based on the data that we have on efficacy, the
> data that we have on safety and the indication which we have heard a
> couple of times, does the whole picture come together for you to vote
> yes or no?
>
> DR. PARSONS: I just want to clarify the question one more time. This
> is not the exact indication that is in our brochure. The indication in
> our brochure is for patients with COPD not responsive to albuterol.
>
> DR. CHOWDHURY: The question is shortened but it is meant to be the
> full indication that the company has asked to obtain approval for,
> which is COPD which is not reversible to albuterol.
>
> DR. PARSONS: So, not the patient population that we may all end up
> treating but the actual indication is what we are voting on. We are
> going to open that for discussion. Dr. Newman?
>
> DR. NEWMAN: I think that when you have a disease that affects as many
> people as this does, if you take a public health perspective it is
> possible, with longer-term studies, that even a small effect could end
> up as a net benefiting a lot of people a little. From a public health
> perspective, that would in the long-term be beneficial to all of us.
>
> Likewise, I want to just go on the record of complimenting the company
> for the thoroughness with which much of the safety data has been
> addressed because, again, you are looking at a large population being
> potentially placed at risk given how common COPD is. I think reflected
> in the vote so far has been the sense that there has been good
> attention paid to most of the safety issues. I know where I am going
> to come down. It is based on the efficacy issue that has to be proved
> with longer-term studies.
>
> DR. PARSONS: Additional comments and discussion? Dr. Surawicz?
>
> DR. SURAWICZ: I agree with that and also what sways me is that it is a
> new type of drug and often the first may not be as efficacious as the
> others, but the others may not follow if the first is held up. Then
> the final point is that apparently there isn\'t anything else for
> these folks. So, that is a huge plus. I mean, even if you are just
> going to enhance the placebo effect, you know, it is sending a message
> to patients that things may come along.
>
> DR. PARSONS: We may want to have some discussion. There already has
> been the issue raised by Dr. Cross, who probably wants to jump in
> here, regarding that there are other treatments available for these
> patients. Dr. Cross?
>
> DR. CROSS: I just want to say that there is a lot of emerging
> literature on inhalation steroids in COPD and you have to call that
> anti-inflammatory. We will probably also run into problems with an
> older population with absorption and osteoporosis and all the problems
> we see in younger people that get inhaled steroids. But, certainly,
> that is pending.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: Well, I would argue that if committee members felt it should
> not be approved based on efficacy, then this has to be a decision not
> to approve it when you weigh the risks, for instance, and the
> benefits. There are no convincing benefits. Even if we hope there are
> going to be, I can\'t see how you could approve the two together if
> you don\'t approve effectiveness in the first place.
>
> DR. PARSONS: Additional comments? No further discussion? Yes, please,
> Mr. Kennedy?
>
> MR. KENNEDY: I am sitting here and I am trying to get a handle on what
> your thoughts are, and the thing that is coming to mind is I keep
> hearing postmarketing commitments of Phase IV commitments; and we are
> hearing a long-term study; we are hearing a study designed to show
> stabilization of FEV; and we are talking about this longer-term study
> that would include a more diverse population. We haven\'t heard from
> the agency whether that would be one study or two studies, and that
> may present something that would be a commitment on the part of the
> company of five or six years. With the safety profile that the drug is
> exhibiting now, would you be disappointed with your decision of this
> marginally positive efficacy if they declined to undertake that five-
> or six-year obligation? Or, is it a part of your assumption that they
> would automatically do it?
>
> DR. PARSONS: I did not necessarily make an assumption that the studies
> would get done. For me, the efficacy is small and the patient
> population that would likely have this drug prescribed is huge and I
> would like to see a better study to show that it really is
> efficacious, that it really does have a significant clinical
> difference, such that when the drug is available to patients and they
> are going to be taking it for years we can feel confident that,
> indeed, they are going to have a benefit. But I would like to hear
> other committee members. Dr. Newman?
>
> DR. NEWMAN: Likewise, I didn\'t make any assumption that a study would
> be done. I think we all would like to have a medication to treat our
> patients with COPD but I just would reinforce that I was underwhelmed
> by the efficacy data.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: Looking from the patient\'s perspective and the
> possibility of a large number of patients being treated with this
> medication, I would hope to see better results for them so that they
> don\'t have a false hope that this drug is going to help them, and we
> don\'t see a lot of improvement with it. So, just from the patient
> perspective, I think right now I would like to see more data that
> supports the drug.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: Yes, I think the long-term data is critical. I mean, these
> patients will lose 35 ml a year from just getting older every year and
> with the average COPD patient it is over 100. In the general 20
> million that have COPD it may be closer to 60. The company has done a
> half-year study and shown 30. I have more confidence in my colleagues,
> in the increased money, NIH is paying on COPD, the organization of the
> COPD Society, and I suspect there is going to be a large number of
> COPD clinical studies that are going to be done from unbiased
> viewpoints in the next few years. I take the comment that these are
> very expensive studies to do. They will be over prolonged time. I,
> myself, would like to see an inhaled steroid versus this drug done and
> this company is not going to do it; it is going to be somebody else.
> Those are my reasons for wanting it to go ahead with a lot of provisos
> on postmarketing surveillance by the company, but I also have
> confidence that our respiratory medicine community and the COPD
> societies and government funding will also look at this issue in some
> detail.
>
> DR. PARSONS: Dr. Apter?
>
> DR. APTER: I understand that we can recommend and the company may not
> want to take on the commitment, but I am hoping that our comments on
> the record will make a very strong case that this happen.
>
> DR. PARSONS: Additional comments and discussion?
>
> DR. CROSS: I wish this had said volume change as well as FEV1 because
> I agree with the comment that the volume change is very symptomatic in
> terms of the quality of life issue. When we think of how much
> reduction surgery is done and how equivocal that is and how much it
> costs and the fact that it is not maintained for the duration, that
> the rate of loss is equal at the end of a year. I have to say that I
> am as impressed with the volume change as the FEV1.
>
> DR. PARSONS: Further comments or discussion? Anybody need further
> clarification of the question? No? Then I will read the question and
> we will vote. Question four is do the efficacy and safety data provide
> substantial and convincing evidence that support the approval of
> cilomilast at a dose of 15 mg twice daily for the maintenance of lung
> function, FEV1, in patients with COPD?
>
> We are going to vote and we are going to start with Dr. Surawicz.
>
> DR. SURAWICZ: Yes.
>
> DR. PARSONS: Dr. Morris?
>
> DR. MORRIS: I vote no, briefly to explain it, based on what we saw as
> not having the consistent trends in the primary and secondary
> endpoints in the four pivotal studies. That is the majority of my
> answer and a minor aspect of it is the safety concerns I previously
> mentioned.
>
> DR. PARSONS: Dr. Cross?
>
> DR. CROSS: It is not very convincing and it is hard to go zero versus
> 1 on this issue, but I have to vote yes.
>
> DR. PARSONS: Ms. Schell?
>
> MS. SCHELL: No.
>
> DR. PARSONS: Dr. Chinchilli?
>
> DR. CHINCHILLI: No.
>
> DR. PARSONS: My vote is no for the issues I described before. Dr.
> Apter?
>
> DR. APTER: My vote is yes, I agree with Dr. Cross and if the drug is
> approved I strongly recommend postmarketing studies.
>
> DR. PARSONS: Dr. Newman?
>
> DR. NEWMAN: No.
>
> DR. PARSONS: Dr. Joad?
>
> DR. JOAD: No, and I would encourage the company to do the longer
> study.
>
> DR. PARSONS: Dr. Kercsmar?
>
> DR. KERCSMAR: No.
>
> DR. PARSONS: I am going to ask at this point if the FDA has further
> questions for the panel, not limited just to the four.
>
> DR. CHOWDHURY: No.
>
> DR. PARSONS: I am sorry, I forgot to announce the result of the last
> vote. I apologize. On question number four we have three votes for yes
> and seven votes that are no. Any additional questions from the FDA?
>
> DR. CHOWDHURY: No.
>
> DR. PARSONS: Any final comments from the committee? I think then that
> concludes the meeting. I would like to thank everybody for being here.
>
> \[Whereupon, at 2:40 p.m., the proceedings were adjourned.\]
>
> \- - -