# Presentation: 238630

## FDA Medical Imaging Drugs Advisory Committee

**July 10, 2000**
**BLA 99-1407**
**LeuTech****®****  **
**Palatin Technologies, Inc.**

- CP000.02

## CP001.01

## Palatin Presenters

- Charles Putnam	Chief Operating Officer	Palatin Technologies, Inc.
- Terry Smith, Ph.D.	Executive Director of 		Product Development		Palatin Technologies, Inc.
- Eric Rypins, M.D.	Department of Surgery		Tri-City Medical Center
- Samuel Kipper, M.D.	Director of Nuclear Medicine		Tri-City Medical Center
- Karen McElvany, Ph.D.	Director of Clinical Affairs		Certus International, Inc.

- CP002.01

## Additional Palatin Consultants

- Robert Carretta, M.D.	Sutter-Roseville Medical Center	Roseville, California
- Christopher Palestro, M.D.	Long Island Jewish Medical Center
- 		New Hyde Park, New York
- Mathew Thakur, Ph.D. 	Thomas Jefferson University
- 		Philadelphia, Pennsylvania
- M.B. Khazaeli, Ph.D.	Univ. of Alabama
- 		Wallace Tumor Institute
- 		Birmingham, Alabama
- Kathleen Madsen, Ph.D. 	Certus International, Inc.	Chesterfield, Missouri

- CP012.02

## LeuTech®MIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- CP003.01

## Palatin Technologies, Inc.

- Biopharmaceutical company, established in 1996
- Two products currently under development
- PT-141 cyclic melanocortin peptide for treatment of erectile dysfunction
- LeuTech radioimaging agent for equivocal appendicitis

- CP004.01

## LeuTech

- Murine IgM monoclonal antibody specific to the CD-15 antigen found on the surface of human neutrophils
- Potential utility as a white blood cell imaging agent with advantages relative to existing WBC agents
- In-vivo labeling
- No blood handling
- Fast Results
- No opportunity for reinjection errors

- CP015.01

## Development History

- Developed by Dr. Mathew Thakur in 1989
- First human clinical use in 1990
- Proof of concept in various infections
- Physician sponsored IND
- Palatin sponsored IND submitted 1997
- Initial indication: appendicitis with equivocal signs and symptoms
- Commonly occurring condition
- Need for additional diagnostic information
- Rapid and certain confirmation of diagnosis (histopathology)
- Biologics License Application submitted in November 1999

- CP016.01

## LeuTech - Additional Studies

- Osteomyelitis - prosthetic joint infections
- Osteomyelitis - diabetic foot ulcers
- Post-surgical infection
- Inflammatory bowel disease

- CP008.01

## LeuTech - Proposed Indication

- 	Scintigraphy with Technetium Tc 99m Anti-CD15 Antibody is indicated for the diagnosis of appendicitis in patients with equivocal signs and symptoms.  It is useful to rule out appendicitis in patients presenting with equivocal diagnostic evidence.

- CP006.01

## LeuTech

- Accurate in patients presenting with equivocal signs and symptoms of appendicitis
- Safe - no significant adverse reactions
- Improves patient management

- CP009.02

**Notes:**
 High sensitivity is important to confidently rule out disease and forego surgery without risk of disease progression.  In pooled results from Phase 2/3 clinical trials the evaluations by unblinded  site investigators was 82% and the pooled site investigators’ sensitivity was 93 %.
  A high Negative Predictive Value provides clinicians with confidence in appropriate patient discharge, avoiding unnecessary surgery or hospitalization for observation.  In the pooled results from the phase 2/3, the aggregate blind-read NPV was 89% and the site investigatiors’s NPV was 96%.
 High specificity is critical to avoid unnecessary surgery.  Pooled phase 2/3 results showed 92 % specificity among blinded readers and 85% specificity for site investigators.
  No deaths, serious adverse events or any other significant adverse events occurred in any subject enrolled in any of the trials.  No subjects discointinued particiaption due to AEs.  
Potential economic benefits: 1) no blood handling thereby eliminating risks to lab personnel, 2)  easily and rapidly prepared thereby reducing procedure time, 3) High specificity (low  number of false positives) reduces unnecessary surgery, and 4) high sensitivity reduces risk of emergency surgery and fatalities

## LeuTechMIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- CP010.01

##  Characteristics of LeuTech

- LeuTech is a Tc 99m labeled antibody which binds* in vivo* to
- human neutrophils and is useful for imaging infection.
- Specific to CD15 antigens
- Binds avidly  (Kd = 10-11 M)
- Abundant binding sites  (~ 5.1 x 105 antigens per PMN)
- No change in chemotaxis, phagocytosis, or adherence of neutrophils at indicated dosage

- TS001.02

## Properties of LeuTech

- Pentameric IgM monoclonal antibody
- Produced in cell culture from hybridoma cell line
- Molecular weight 970,000 Daltons
- Distribution T1/2 of 18 minutes and elimination T1/2 of 8 hours
- 14% to 50% of circulating radioactivity is bound to PMNs.

- TS004.01

## Contents of LeuTech Kit

- Vial, containing 250 μg of lyophilized antibody
- Maltose, monohydrate
- Succinic Acid, ACS
- Sodium Potassium Tartrate, tetrahydrate, USP
- Glycine, USP
- Disodium EDTA, dihydrate, ACS
- Stannous Tartrate
- Ampoule of ascorbic acid solution

- TS002.02

## Preparation of LeuTech

- Add 20 - 40 mCi of pertechnetate to lyophilized antibody
- Incubate 30 minutes at 37° C
- Add ascorbic acid solution
- Labeling efficiency > 90%
- Tested by ITLC
- Mean labeling efficiency = 96.9%

- TS003.03

## LeuTechMIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- TS006.01

## Demographics of Appendicitis CDC Division of Bacterial Diseases Center for Infectious Disease (1990 CDC Report)

- Most common cause of abdominal pain requiring surgery.
- Excluding trauma, most frequently encountered condition requiring emergency surgery in both adults and children
- 250,000 new cases of appendicitis per year
- Peak incidence in second and third decades of life
- Lifetime risk of appendicitis is 7%
- Negative laparotomy rates range from 10% to 30%
- Higher in certain populations (geriatric, pediatric)

- ER001.02

**Notes:**
*Am J Epidemiol 1990 Nov;132(5):910-25 The epidemiology of appendicitis and appendectomy in the United States. Addiss DG, Shaffer N, Fowler BS, Tauxe RV 

## Statement of the Problem

- The classical picture of appendicitis is a young person with central abdominal pain that localizes to the right lower quadrant with guarding, anorexia, and leukocytosis.
- Up to 50% of patients with appendicitis present to the Emergency Department without classical signs and symptoms.
- Accurate and timely diagnosis is particularly difficult  in
- Early appendicitis
- Reproductive age females
- Pregnancy
- Extremes of age

- ER002.01

## Statement of the Problem

- Surgeons traditionally have three choices:
- Send home: wrong for positive cases
- Immediate surgery: wrong for negative cases
- Admit and observe: not ideal for any case
- In equivocal cases, admission and observation is often the practice, with the following clinical consequences:
- Unnecessary admission in patients without appendicitis
- Delay in treatment in patients with appendicitis

- ER003.03

## Statement of the ProblemPatients without Appendicitis

- Unnecessary admission
- Unnecessary surgery

- ER008.01

## Statement of the ProblemPatients with Appendicitis

- Delay in treatment of appendicitis can lead to perforation and/or sepsis.
- If patients are sent home in error, they almost invariably return with perforated appendicitis.
- Perforation frequently results in increased morbidity and prolonged hospitalization.

- ER004.02

## Current Imaging Modalities

- Ultrasonography
- Highly operator-dependent
- Diagnostic accuracy is highly variable
- Low sensitivity (~50%) with perforation
- Helical Computed Tomography
- High accuracy is possible
- Optimal technique not  standardized
- Intravenous/oral contrast vs. contrast enema vs. no contrast
- Lengthy or uncomfortable preparation may be required
- All existing modalities require morphological changes to make a diagnosis of appendicitis

- ER005.02

## Conclusions

- Management of appendicitis remains a problem
- Current modalities have limitations
- LeuTech has the potential to improve the management of these difficult patients

- ER009.01

## LeuTechMIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- ER007.01

## LeuTech Imaging

- LeuTech imaging techniques were developed during the course of Phase 2 and implemented in the Phase 3 study in equivocal appendicitis patients
- No patient preparation required
- Supine patient position on imaging table
- Gamma camera above abdomen and pelvis
- Intravenous administration followed by immediate imaging
- Sedation was not required in adults or children

- SK001.02

## LeuTech Biodistribution

- Blood pool clearance is rapid but variable
- RE system: liver, spleen & bone marrow
- Urinary excretion: kidneys & bladder
- No intestinal or biliary excretion

- Anterior

- Posterior

- Phase 3 Patient A-33: 14 y.o. male

- SK002.02

- 2 Hours

## LeuTech InterpretationAppendicitis Zone

- Phase 3 Patient J-22: 15 y.o. male

**LeuTech Interpretation****Appendicitis Zone**

- Anterior Static 72 min

- SK007.01

## LeuTech InterpretationCriteria for Appendicitis

- Location: abnormal uptake of any intensity level with any distribution within the appendicitis zone
- Asymmetry: uptake on the right side is greater than that on the left
- Persistence: abnormal uptake does not disappear with time or positional changes

- SK006.01

## LeuTech InterpretationCriteria for Negative Scan

- Absence of abnormal persistent LeuTech accumulation within the “appendicitis zone”
- Presence of abnormal persistent LeuTech accumulation outside of the appendicitis zone was considered negative for appendicitis but positive for “other infection”

- SK003.02

## Typical Dynamic Image SequenceNegative Scan

- Phase 3 Patient A-03: 8 y.o. female

- 11 min

- 15 min

- 19 min

- 23 min

- 27 min

- 31 min

- 35 min

- 39 min

- 43 min

- 47 min

- SK004.02

## Typical Static Image SequenceNegative Scan

**Typical Static Image Sequence****Negative Scan**

- Phase 3 Patient A-03: 8 y.o. female

- Anterior
- 59 min

- Posterior
- 59 min

- Right Anterior
- Oblique
- 67 min

- Left Anterior
- Oblique
- 76 min

- SK005.02

## Positive LeuTech ScanFocal Uptake Pattern

- Dynamic Series 11 - 47 minutes

**Positive LeuTech Scan****Focal Uptake Pattern**

- Phase 3 Patient A-8: 43 y.o. female

- SK009.02

## Positive LeuTech ScanFocal Uptake Pattern 

- Phase 3 Patient A-8: 43 y.o. female, perforated appendix

- Anterior Static
- 61 minutes

- SK008.02

## Positive LeuTech ScanLinear Uptake Pattern

- Phase 2 Patient A-32: 17 y.o. male, retrocecal appendix

- Anterior Static 48 minutes

- SK010.02

## Positive LeuTech ScanDiffuse Uptake Pattern

- Phase 3 Patient H-14: 61 y.o. female, appendicitis with phlegmon

- Dynamic Series 4 - 32 minutes

- SK011.02

## Positive LeuTech ScanPerforated Appendix with Pelvic Abscess

- Phase 2 Patient A-01: 34 y.o. female

- Anterior Static 51 minutes

- SK012.02

## Case Study 1

- Phase 3 Patient A-9: 26 y.o. female
- Initial plan: immediate surgery
- LeuTech scan: negative for appendicitis
- Post-scan plan: discharge home
- Final diagnosis: negative for appendicitis

- Anterior Standing Static
- 57 minutes

- SK016.01

## Case Study 2

- Phase 2 patient A-26: 26 y.o. male
- Initial plan: send home
- LeuTech scan: positive for appendicitis
- Surgical findings: mesenteric adenopathy, normal appendix
- Pathology report: appendicitis and reactive nodal hyperplasia

- Anterior
- Dynamic
- 4 min

- Anterior
- Dynamic
- 40 min

- Anterior
- Dynamic
- 20 min

- Appendix
- Specimen

- Lymph Node
- Specimen

- SK013.02

## False Positive LeuTech Scan

- Phase 3 Patient C-3: 34 y.o. male
- LeuTech: Positive for appendicitis
- Surgery: Crohn’s Disease of Terminal       Ileum with Obstruction

- Anterior 61 minutes

- SK021.01

## LeuTech Imaging Observations

- Simple to perform
- Safe and does not require blood handling
- Easy to interpret
- Provides rapid diagnostic results in a difficult, equivocal patient population
- Improves overall patient management
- Surgeons and ER physicians continue to request LeuTech studies

- SK018.02

## LeuTechMIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- SK019.02

## LeuTech Clinical Experience

- Phase 1 - Biodistribution/Dosimetry	N = 10
- Phase 2 - Appendicitis			N = 56
- Phase 3 - Appendicitis			N = 203
- Other	Investigator IND Pilot Studies	N = 69*	Investigator IND HAMA Study	N = 30*	European Study			N = 17*	Phase 2 Osteomyelitis		N = 24	Repeat-Dose HAMA Study		N = 30
- 				TOTAL	N =439
- *not conducted under Palatin IND

- KM001.01

## Phase 1 Study

- Evaluated safety, biodistribution, pharmacokinetics and radiation dosimetry
- 10 healthy volunteers, single site
- 6 female, 4 male
- 20 to 46 years
- No adverse events reported
- No clinically significant changes in vital signs or clinical laboratory measurements related to LeuTech

- KM002.02

## Phase 1 Study (cont’d)

- Radioactivity excreted primarily via urine
- 45% of radioactive injected dose is in the liver at 1 hour post-injection
- Highest radiation absorbed doses:
-  spleen (0.23 rad/mCi)
-  kidneys (0.19 rad/mCi)
-  liver (0.18 rad/mCi)
-  bladder wall (0.12 rad/mCi)
- Effective dose equivalent = 0.068 rem/mCi

- KM003.02

## Equivocal Appendicitis StudiesPhase 2 and Phase 3 Studies

- Phase 2 Study
- 56 patients with equivocal appendicitis
- 2 sites in U.S.
- “gold standard” was final institutional diagnosis (surgery/pathology report or 1 month follow-up)
- Phase 3 Pivotal Study
- 203 patients with equivocal appendicitis
- multicenter - 10 sites  in U.S.
- “gold standard” was final institutional diagnosis (surgery/pathology report or 2-week follow-up)
- Similar study design for both studies

- KM004.02

## Inclusion CriteriaPhase 2 and Phase 3 Studies

- Males and females
- Pediatric, adult and geriatric patients
-  8 years for Phase 2
-  5 years for Phase 3
- RLQ pain and equivocal presentation of acute appendicitis
- Absence of typical signs, symptoms or history

- KM006.02

## Equivocal Signs and Symptoms Phase 2 and Phase 3 Studies 

- Atypical history/symptoms
- absence of periumbilical pain migrating to RLQ
- no gradual onset of pain
- no increasing intensity of pain over time
- pain not aggravated by movement and coughing
- Atypical physical examination
- absence of McBurney’s point tenderness
- absence of referred tenderness to RLQ with palpation in other quadrants
- absence of abdominal muscular spasm with RLQ tenderness
- Temperature less than 101° F
- WBC count less than 10,500/mm3

- KM007.01

## Major Exclusion CriteriaPhase 2 and Phase 3 Studies 

- Phase 2
- Pregnant and nursing women
- Phase 3
- Pregnant and nursing women
- Diagnosis of Pelvic Inflammatory Disease (PID)
- Patients with 2 or more hospital admissions for abdominal pain of unknown etiology in past 6 months
- Patients who had already undergone CT for work-up of current episode of RLQ abdominal pain

- KM008.02

## Clinical Trial DesignPhase 3 Study

- Primary Efficacy Indicators
- Sensitivity and specificity of Blinded Readers’ evaluations
- Statistical evaluation:  95% one-sided Confidence Intervals
- Secondary Efficacy Indicators
- Accuracy, PPV and NPV of Blinded Readers’ evaluations
- Site Investigator evaluations
- Intended clinical management and likelihood of appendicitis

- KM005.01

## LeuTech DosagePhase 2 and Phase 3 Studies 

- Adult Dose
- 10 mCi - 20 mCi Tc 99m LeuTech(containing 75 - 125  μg anti-CD15 antibody)
- Pediatric Dose (5 - 17 years)
- 0.21 mCi per kg body weight with maximum of 20 mCi

- KM009.01

## Image AcquisitionPhase 2 and Phase 3 Studies 

- Imaging of lower abdomen with LFOV camera
- low-energy, parallel-hole, high resolution collimator
- photopeak at 140 keV  10%
- Dynamic image acquisition
- immediately post-injection for ten 4-minute frames
- Static supine anterior, posterior, 20° - 25° RAO and LAO planar images
- Standing anterior image
- Additional images and SPECT imaging optional

- KM010.01

## Image EvaluationPhase 2 and Phase 3 Studies 

- Images read by site investigators and Blinded Readers
- Images read as “negative for infection” or“positive for infection”
- no indeterminate reads
- “positive for infection” scans classified as “appendicitis” or “other infection”
- Time of first positive image was recorded in Phase 3

- KM011.02

## Blinded Reader EvaluationsPhase 2 and Phase 3 Studies 

- Managed by independent core laboratory
- 3 Blinded Readers (not otherwise participating in study)
- No clinical history or symptoms provided (Phase 3)
- Demographic information provided
- age, sex, height, weight
- Images presented on computer monitors
- dynamic images evaluated as endless loop cine display

- KM049.01

## Patient Management PlanPhase 2 and Phase 3 Studies 

- Surgeons completed questionnaires before imaging, indicating:
- likelihood of appendicitis on a five point scale
- treatment plan
- surgery
- admit for observation
- send home
- Same questionnaire was completed after imaging, prior to further treatment or testing.

- KM012.02

## Demographics Phase 2 Study

- 56 patients enrolled at 2 sites
- 31 female, 25 male
- 9 to 77 years (15 patients < 18 years)
- 28 (50%) acute appendicitis
- 9 perforated appendix
- 28 (50%) no appendicitis
- 7 “other infection”

- KM013.01

## Efficacy Results Phase 2 Study

- Accuracy	79	88
- Sensitivity	89	96
- Specificity	68	79
- PPV	74	82
- NPV	86	96
- Total Patients	56	56
- 	Positive	28	28
- 	Negative	28	28
- *Aggregate results

- 		 Blinded Read* 	 Site Investigator

- KM014.01

## Demographics Phase 3 Study

- 203 patients enrolled at 10 sites
- 200 evaluable patients
- Six sites enrolled between 19 and 39 patients
- 60% female, 40% male
- 5 to 86 years (49 patients < 18 yrs)
- 59 (30%) acute appendicitis
- 13 perforated appendix
- 141 (70%) no appendicitis
- 23 “other infections”

- KM015.02

## Equivocal Population Phase 3 Study

- Absence of classic signs and symptoms
- Surgeons’ assessment of the likelihood of appendicitis
- Prevalence of “admit for observation” as surgeons’ intended management plan

- KM016.02

## Equivocal Presentation of AppendicitisPhase 3 Study

- 92% with _>_ 2 equivocal signs/symptoms
- 65% with _>_ 3 equivocal signs/symptoms

- 8%

- 27%

- 34%

- 31%

- KM017.01

## Pre-Scan Likelihood of Appendicitis Phase 3 Study

- 12%

- 31%

- 32%

- 4%

- 22%

- KM018.01

## Pre-Scan Intended Clinical ManagementPhase 3 Study

- 23%

- 60%

- 17%

- KM019.02

## Age Distribution Phase 3 Study 

- KM020.02

## LeuTech Imaging Phase 3 Study 

- Simple planar imaging
- standard high resolution collimator
- SPECT not required
- optional in protocol
- only 9 of 203 patients had SPECT (8 at one site)
- SPECT images not included in Blinded Read

- KM021.02

## Time to First Positive Image Phase 3 Patients with Appendicitis

- KM022.03

## Efficacy Results Phase 3 Study

- Accuracy	88	87
- Sensitivity	75	91
- Specificity	93	86
- PPV	82	73
- NPV	90	96
- Total Patients	200	182
- 	Positive	59	54
- 	Negative	141	128
- *Aggregate results, Concordance 88% to 90%, Kappa 0.54 to 0.55

- 		 Blinded Read* 	 Site Investigator

- KM023.03

## Likelihood RatiosPhase 3 Study

- Blinded Reader 1	6.75	0.21
- Blinded Reader 2	6.66	0.38
- Blinded Reader 3	13.44	0.25
- Aggregate	10.52	0.27
- Site Investigators	6.45	0.11
- Odds that reader correctly diagnosed appendicitis with LeuTech were 6 to 13 times greater than the pre-test odds of appendicitis.
- Odds that reader missed a diagnosis of appendicitis with LeuTech was reduced 1/9 to 1/3 times the pre-test odds of appendicitis.

- 		LR(+)	LR(-)

- KM052.02

## Blinded Read Results* Phase 2 and Phase 3 Studies

- Accuracy	79	88
- Sensitivity	89	75
- Specificity	68	93
- PPV	74	82
- NPV	86	90
- Total Patients	56	200
- 	Positive	28	59
- 	Negative	28	141
- *Aggregate results

- 		 Phase 2 	 Phase 3

- KM025.02

## Site Investigator Results Phase 2 and Phase 3 Studies

- Accuracy	88	87
- Sensitivity	96	91
- Specificity	79	86
- PPV	82	73
- NPV	96	96
- Total Patients	56	182
- 	Positive	28	54
- 	Negative	28	128

- 		 Phase 2 	 Phase 3

- KM026.02

## Likelihood of AppendicitisPhase 3 Patients with Appendicitis 

- KM027.02

## Likelihood of Appendicitis Phase 3 Patients without Appendicitis

- KM028.02

## ROC Curve Analysis Likelihood of Appendicitis – Phase 3

- KM030.02

**FPF (1-Specificity)**

**TPF (Sensitivity)**

- 0.0

- 0.2

- 0.5

- 0.8

- 1.0

- 0.0

- 0.2

- 0.5

- 0.8

- 1.0

- Post-LeuTech Scan
- Area = 0.95

- Pre-LeuTech Scan
- Area = 0.81

- p<0.0001

## Intended Clinical Management Phase 3 Patients with Appendicitis

- KM032.02

- *

- *One patient had a positive LeuTech scan

**Notes:**
3 patients shifted from “Send home” to “Surgery”
25 patients shifted from “Admit for observation” to “Surgery”

## Intended Clinical ManagementPhase 3 Patients without Appendicitis

- KM033.02

- *

- *4 of 13 patients had other disease requiring surgery

**Notes:**

  5 patients shifted from “Surgery” to “Send Home”
 39 patients shifted from “Admit for Observation” to “Send  
  Home”
  2 patients shifted from “Send Home” to “Surgery” and 6 
   patients shifted from “Admit for Observation” to “Surgery”
 4 of 13 surgery patients required surgery for other conditions

## Intended Clinical Management PlansPhase 3 Study

- LeuTech favorably impacts patient management
- 74 of 189 patients (39%) had favorable shifts
- 25 patients with appendicitis shifted from ‘admit for observation’ to ‘surgery’
- 0 patients with appendicitis shifted away from ‘surgery’
- 39 patients without appendicitis shifted from ‘admit for observation’ to ‘send home’
- Difference between pre- and post-scan management was statistically significant (p<0.00001)

- KM034.02

## Overall LeuTech Safety Data

- Safety measurements included
- Adverse Events
- Clinical Laboratory Measurements
- Vital Signs
- HAMA Measurements
- Overall summary of safety for 439 subjects
- includes all subjects injected  (Palatin IND studies and other studies)
- 393 subjects included in original BLA filing
- 46 subjects summarized in 120-Day Safety Update to BLA

- KM035.01

## Overall Safety Population All Subjects

- 439 subjects
- 202 males, 237 females
- Mean age 34.1 years (5.2 yr to 91.4 yr)
- Mean anti-CD15 IgM antibody dose 120.1 g
- Mean radioactive dose 14.5 mCi

- KM036.02

## Age Distribution All Subjects

- KM037.02

## Adverse Events Overall Incidence (N = 439)

- 30 subjects experienced 39 AEs
- No serious adverse events
- Single “moderate-severe” AE (injection site pain)

- KM038.02

## Adverse Events Overall Incidence (N = 439)

- Vasodilatation (flushing), 11 subjects (2.5%)
- Dyspnea, 4 subjects (0.9%)
- All others < 0.7%
- headache
- pain (injection site, abdomen, 		chest)
- asthenia
- malaise
- syncope
- diarrhea

- ecchymosis
- joint disorder
- dizziness
- paresthesia
- pharyngitis
- rhinitis

- KM039.02

## Adverse Events Drug Related

- 20 AEs in 14 subjects classified as “possibly or probably related” to LeuTech
- headache 	1	( 0.2%)
- injection site reaction 	1	(0.2%)
- chest pain 	1	(0.2%)
- injection site pain 	1	(0.2%)
- vasodilatation/flushing 	11 	(2.5%)
- ecchymosis 	1	(0.2%)
- dizziness 	1	(0.2%)
- paresthesia 	1	(0.2%)
- dyspnea 	2	(0.5%)

- KM050.01

## Clinical Laboratory Measurements

- Clinical laboratory measurements obtained in 4 of 8 clinical trials (N = 242 subjects)
- Investigators assessed clinical significance of changes in clinical laboratory measurements
- 7 clinically significant changes in 4 subjects (1.7%)
- lab error in one subject
- disease-related in 2 patients
- possibly related to LeuTech in one subject
- elevated LDH and AST resolved without treatment

- KM040.01

## Vital Signs

- Vital signs measured in 6 of 8 clinical trials (N = 383)
- pulse rate
- blood pressure
- oral body temperature
- Mean vital sign changes from baseline
- several statistically significant changes noted
- mean changes were very small in magnitude, with no clinical importance.

- KM041.01

## Vital Signs (cont’d)

- Clinically significant changes defined in protocol
- systolic BP > 35 mm Hg
- diastolic BP > 25 mm Hg
- pulse rate > 20 beats per minute
- Clinically significant changes noted in 20 subjects
- decrease in pulse in 7 subjects  (1.8%)
- increase in pulse in 5 subjects (1.3%)
- decrease in BP in 3 subjects (0.8%)
- increase in BP in 5 subjects (1.3%)
- No vital sign changes attributed to LeuTech

- KM042.02

## HAMA Response Single Injection

- HAMA response to a single injection of LeuTech was evaluated in 3 of 8 studies (N = 54)
- 30 normal volunteers (HAMA study)
- 20 patients (Phase 3 appendicitis study)
- 4 patients (Investigator IND study)
- HAMA levels measured at baseline and 3-4 weeks post-injection
- No positive responses in any of the 54 subjects

- KM043.02

## Summary of Efficacy

- LeuTech was found to be effective in two clinical trials for diagnosing and ruling out appendicitis.
- Results in pivotal Phase 3 trial corroborated earlier Phase 2 trial.
- Accuracy of blinded readers (83% - 89%) was consistent with site investigators (87%).
- LeuTech scan had a favorable impact on intended clinical management.

- KM045.01

## Summary of Safety

- No serious side effects.
- Only 30 of 439 subjects experienced AEs (39 events).
- No serious AEs
- 20 AEs in 14 subjects considered possibly related to LeuTech
- Vasodilatation (flushing) reported by 11 (2.5%) subjects
- No other AEs with incidence over 1%
- Minimal incidence of clinically significant changes in vital signs and clinical laboratory measurements
- No HAMA response following single injection

- KM046.02

## Conclusion

-     LeuTech has been shown to be a safe and effective diagnostic agent for diagnosing and ruling out appendicitis in patients presenting with equivocal signs and symptoms.

- KM047.01

## LeuTechMIDAC Meeting Agenda

- Introduction 	C. Putnam
- Description of LeuTech 	T. Smith, Ph.D.
- Equivocal Appendicitis	E. Rypins, M.D.
- Imaging Techniques and Interpretation	S. Kipper, M.D.
- Clinical Development Program	K. McElvany, Ph.D.
- Conclusion	C. Putnam

- KM048.02

## LeuTech

- Accurate (87%) in patients presenting with equivocal signs and symptoms of appendicitis
- Useful to rule out appendicitis (NPV 96%)
- Safe - no significant adverse events in 439 patients
- Improves patient management by facilitating earlier surgery in patients with appendicitis and earlier discharge in patients without appendicitis.

- CP009.02

**Notes:**
 High sensitivity is important to confidently rule out disease and forego surgery without risk of disease progression.  In pooled results from Phase 2/3 clinical trials the evaluations by unblinded  site investigators was 82% and the pooled site investigators’ sensitivity was 93 %.
  A high Negative Predictive Value provides clinicians with confidence in appropriate patient discharge, avoiding unnecessary surgery or hospitalization for observation.  In the pooled results from the phase 2/3, the aggregate blind-read NPV was 89% and the site investigatiors’s NPV was 96%.
 High specificity is critical to avoid unnecessary surgery.  Pooled phase 2/3 results showed 92 % specificity among blinded readers and 85% specificity for site investigators.
  No deaths, serious adverse events or any other significant adverse events occurred in any subject enrolled in any of the trials.  No subjects discointinued particiaption due to AEs.  
Potential economic benefits: 1) no blood handling thereby eliminating risks to lab personnel, 2)  easily and rapidly prepared thereby reducing procedure time, 3) High specificity (low  number of false positives) reduces unnecessary surgery, and 4) high sensitivity reduces risk of emergency surgery and fatalities

## LeuTech - Proposed Indication

- 	Scintigraphy with Technetium Tc 99m Anti-CD15 Antibody is indicated for the diagnosis of appendicitis in patients with equivocal signs and symptoms.  It is useful to rule out appendicitis in patients presenting with equivocal diagnostic evidence.

- CP006.01

## CP013.01