# Presentation: 010686

## Industry Pipeline:Smoking Cessation ProductsSRNTNew OrleansFebruary 19, 2003

**Charles Grudzinskas, PhD**
**Drug Development Consultant**
**Annapolis**

## With the help of...

**Steve Arneric**
**Pharmacia**
**Doug Cary**
**Cary Pharmaceuticals**
**Will Dere**
**Lilly **
**Mark Epping-Jordan**
**Addex**

**Barbara Fox**
**Recovery Pharmaceuticals **
**Jed Rose**
**Duke University**
**Ed Sellers**
**Nicogen**
**Joel Sutton**
**GSK **
**Fred Walker**
**Pfizer**

## Charles GrudzinskasConflict of Interest Statement

**SAB ADDEX**
**SAB Cary Pharmaceutical**
**SAB Recovery (ATI)**
**NIDA Workshops & IRGs**
**NIAAA Workshops**

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## Pharmacological Agents for Smoking Cessation

**Indications**
**Acute withdrawal**
**1-More days**
**Initiate abstinence**
**7 to 14-Days**
**Maintain abstinence**
**??-Weeks**
**Sustained reduction in use/risk**
***Metric for clinical outcome/benefit***

**NIDA-NCI-NIAAA Transitional Working Group**
**October 9-10, 2002**

## Pharmacological Agents for Smoking Cessation

**Discovery**
**Development**
**Phase 0—Pre FIH**
**Phase 1—Safety & POM**
**Phase 2—Safety, activity & POC**
**Phase 3—Evidence of safety & ****	****	****	****effectiveness**
**Delivery**** **

**GW468818**
**GSK**
**TD nicotine & mecamylamine**
**Elan**
**SR141716**
**Sanofi-Synthelabo**

***From PhRMA Website***

## The Pipeline

**Nicotine reduced cigarette**
**NRT**
**Vaccines**
**Nicotine partial agonists**
**Combinations**
**Bupropion-mecamylamine oral**
**Nicotine-mecamylamine TD**
**MAO Inhibitors**
**Canabinoid antagonist**
**Gylcine receptor antagonist**
**mGluR2 agonist**
**CYP-2A6 inhibitors**

## Nicotine-Reduced Cigarette

## Nicotine-Reduced Cigarette

**Vector tobacco—”Quest”**
**Not marketed as a smoking cessation product**
**Designed to allow smokers to cut back on nicotine (to become nicotine free)**
**Quest 1: 17% less nicotine**
**Quest 2: 58% less nicotine**
**Quest 3: virtually nicotine free**

**www.vectortobacco.com**

## NicotineReplacement Therapy (NRT)

## Nicotine Replacement

**Marketed**
**Gum (2 & 4 mg) **
**Patch (7, 14, 21 & 42 mg)**
**Nasal (0.5mg/nostril) **
**8-40 doses/day**
**Inhaler (4mg; 2mg absorbed)**
**6-16 doses/day**
**Lozenge (2 & 4 mg)**

## Oral Nicotine Replacement

**The StrawTM**
**8 mg**
**Recovery Pharmaceuticals**
**Phase 3**

**www.recoverypharma.com**

## The StrawTM Targets

**Oral delivery**
**An individual sips any beverage through The StrawTM and swallows the nicotine beads**
**The entire dose of nicotine is delivered in the first sip**
**Manual stimuli**
**Increased compliance**
**Behavioral component**

## The StrawTM Status

**Phase 1 & 2 completed (1/02)**
**“****The trial established that The StrawTM generated plasma levels of nicotine comparable to or higher than those seen with marketed nicotine replacement therapy products”**
**Preparing for a pivotal Phase 3 trial**

## Nicotine Vaccines

## Nicotine Vaccines 

**Xenova **
**TA-NIC**
**Cantab (ImmunoLogic)**** **
**Phase 1**
**NicVax**
**Nabi Biopharmaceuticals**
**Phase 3 **

## TA-NIC Vaccine

**Xenova**** **
**Phase 1**
**The active ingredient of the TA-NIC vaccine is a protein conjugate**
**Nicotine derivative coupled to recombinant cholera toxin B (rCTB)**

**http://www.xenova.co.uk/dc_ta_nic.html**

## TA-NIC Vaccine

**Phase 1 clinical testing of TA-NIC began in 9/01 and the results of these trials were announced in 6/02**
**Well-tolerated both systemically and locally**
**Shown to generate a specific anti-nicotine response**

## TA-NIC Vaccine

**The double-blind, randomized, placebo-controlled study **
**Safety, tolerability and immunogenicity of TA-NIC**
**Both smokers and non-smokers **
**Intra-muscular injection**
**Two different dose levels**
**Variety of dosing regimens**

## NicVax Vaccine

**Nabi Biopharmaceuticals**
**Phase I safety trial reported 10/02**
**Demonstrated that a single injection of NicVAXTM resulted in a rapid immune response**
**Generated **_**substantial amounts**_** of nicotine specific antibodies**
**Associated with only mild to moderate local reactions**

## NicVax Vaccine

**Reduced nicotine levels in the brain by up to 64%**
**Prevented nicotine-induced blood pressure increases**
**Attenuated hyperactivity induced by nicotine injections**
**Blocked the effects of nicotine in nicotine-addicted animals**
**Reduced the incidence of seizures caused by high doses of nicotine**

## Slide 24

## NicVax Vaccine

**The company plans to initiate additional clinical trials of NicVAXTM in smokers and ex-smokers in 2002 and 2003**

## Nicotine Partial Agonists

## CP-526,555  Smoking Cessation

**CP-526,555  ****Smoking Cessation**

*An Orally Effective Nicotinic Partial Agonist for Smoking Cessation*

## CP-526,555

**Orally-active drug**
**Nicotinic receptor partial agonist **
**First non-nicotine therapy in development specifically designed for smoking cessation**
**As a partial agonist it reduces the severity of nicotine withdrawal symptoms & nicotine craving experienced upon cessation of smoking **

## CP-526,555

**By binding to the nicotine receptors, this compound reduces the satisfaction associated with smoking thereby decreasing the likelihood of relapse **

**www.rotman.utoronto.ca/~norli/tch/mgt431-2002/ **
**Announcement_Pfizer_SVP.doc **

## CP-526,555

**“****Excellent efficacy for CP-526,555 for smoking cessation has been demonstrated in a Phase II double-blind parallel study which compared three different doses of this compound with an active control, Zyban®, and placebo.”**

## CP-526,555Continuous Quit Rate

**CP-526,555****Continuous Quit Rate**

**35/126 (28%)**

**47/126 (37%)**

**60/125 (48%)**

**42/126 (33%)**

**20/123 (16%)**

**®**

## CP-526,555

**The primary endpoint was a 4-week continuous quit rate observed during treatment**
**A dose dependent increase in continuous quit rate was seen as one goes from 0.3 mg once-a-day, to 1 mg once-a-day to 1 mg given twice daily with almost half of the smokers quitting at the high dose**
** **

## CP-526,555

**“****Zyban® at 150 mg given BID, afforded a continuous 4-week quit rate of 33%**
**At one year with short term dosing the CP-526,555 quit rate is 17%**
**CP-526,555 has proven to be well tolerated**

## CP-526,555

**“****Also seeing a significant reduction in nicotine craving”**
**“...****exciting results have propelled this agent into a full development program.”**
**“...****includes longer dosing intervals as well as PRN dosing after the treatment interval to prevent relapse.”**
**“...****also performing clinical studies using dose titration.****”**

## Combination ProductsNicotine

**Nicotine-Mecamylamine-TD**

## Mecamylamine/Nicotine TD

**In 1996, Sano completed a 260-patient Phase II study with its combination nicotine-mecamylamine patch which identified the therapeutic dose range **
**Elan Corp.**
**Still in Phase 3**

## Mecamylamine/Nicotine TD

**48 Volunteers**
**Combination of mecamylamine plus nicotine patch was more effective than nicotine patch alone**
**Abstinence rate at one year 37.5% vs 4.2% **

**www.update-software.com/abstracts/ab001009.htm**

## Mecamylamine/Nicotine TD

**Second study**
**80 Volunteers**
**Treated for four weeks **_**prior**_** to cessation with one of four treatments: **
**1. Nicotine patch plus mecamylamine capsules**
**2. Nicotine alone**
**3. Mecamylamine alone**
**4. No active drug**

## Mecamylamine/Nicotine TD

**In the doses used, mecamylamine was well tolerated, although up to 40% of subjects required reductions in dose, usually because of constipation.**

## Combination ProductsNon-Nicotine

**Oral Bupropion/Mecamylamine**

## Oral Bupropion/Mecamylamine

**Cary Pharmaceuticals**
**Daily doses expected to be less than either single product**
**Completed Phase 1 open-label study testing the following combination of**
**Bupropion 150 mg b.i.d.**
**Mecamylamine 2.5 mg b.i.d**
**Nicotine patch 14 mg/24 hr**

## Oral Bupropion/Mecamylamine

**Subjects (n = 28)**
**3-Weeks of meds**
**High desire to quit (>74/100 scale)**
**Low desire to quit  (<26/100 scale)**
**In general, the combination was well tolerated and there were significant changes in smoking-related measures for both groups**

## MAO-A InhibitorsMOA-B Inhibitors

## MAO-A Inhibitors

**Befloxatone **
**Sanofi-Synthelabo**
**Phase 3**
**Befloxatone was dropped from development for depression and moved into Phase 3 trials for smoking cessation**

## Befloxatone (1999)

**Comparison of the Efficacy & Safety of 3 Oral Doses of Befloxatone **
**2.5 mg/day, 5 mg/day & 10 mg/day vs. Placebo**
**Aid to Smoking Cessation in Smokers**
**A Randomized, Double-Blind, 6-Month Multi-Center Phase II Trial 10-Week Active Treatment**
**3.5-Month Follow-Up**

**www.hsc.wvu.edu/som/bmed/apmr/1996 **

## MAO-B Inhibitors

**SL 251188 **
**Sanofi-Synthelabo**
**Phase 1**

## Canabinoid Antagonist

## Canabinoid Antagonist

**SR 141716 **
**Sanofi-Synthelabo**
**Phase 2**

## Gylcine Receptor Antagonist

## Gylcine Receptor Antagonists

**GW468816**** **
**GSK**
**Phase 1?**
**Launch 2006?**

## mGluR2 Agonist

## mGluR2 agonists

**Lilly**
**Tested in nicotine withdrawal in animals ****	**
**Attenuation of nicotine withdrawal**
**Potentiation of acoustic startle in rats**** **

## Inhibition of Normal Metabolism of Nicotine CYP-2A6 Inhibitors 

## CYP-2A6 Inhibitor

**Nicogen, Inc. **
**Nicotine is metabolized by CYP2A6**
**Variations in CYP2A6 activity account for variations in need for and pattern of nicotine intake **

## CYP-2A6 inhibitor 

**CYP2A6 is genetically variable**
**Hypothesis:**
**Decreases in activity result in decreased likelihood of being a smoker**
**Decreased smoking intensity**
**Decreased risk of lung cancer**
**Decreased likelihood of having Ras oncogene mutations**
**Increased likelihood of being able to stop smoking **

## CYP-2A6 inhibitor

**Mimic these genetic defects to achieve cessation or exposure reduction**
**Decrease enzyme activity**
**Chemical inhibition**
**Decrease expression**
**Decrease translation**
**Enhance bioavailability of NRT**
**Oral/patch or other NRT nicotine**
**Increase efficacy of existing NRT products****  **

## CYP-2A6 inhibitor

**Use drugs that:**
**Act only in the liver or **
**Ones that have CNS activities and both inhibit CYP2A6 and affect smoking in other ways****  **

## CYP-2A6 inhibitor

**Methoxsalen (a prototypic CYP2A6 inhibitor) in combination with NRT**
**AUC nicotine (gum) increase 50% compared to placebo**
**AUC nicotine (patch) increase 25% compared to placebo**
**Additional studies have been done with tranylcypromine and show similar results**

## CYP-2A6 inhibitor

**Smokers given methoxsalen showed a significant increase in shunting of NNK to NNAL (NNK is activated by CYP2A6) indicating a decrease in body burden of activated NNK carcinogens **

## Two studies of methoxsalen's effect on nicotine. 
Study 1:
17 Regular smokers with normal CYP2A6 metabolism received methoxsalen (3.5, 10, or 30 mg tablets) or placebo in combination with oral nicotine replacement (4 mg capsules)

**Study 1:**
**17 Regular smokers with normal CYP2A6 metabolism received methoxsalen (3.5, 10, or 30 mg tablets) or placebo in combination with oral nicotine replacement (4 mg**** capsules)**

**CYP-2A6 inhibitor**

## Study 1:
Blood levels of nicotine at 30-minute intervals for three hours
10 mg or 30 mg doses of methoxsalen = 2X nicotine levels vs. placebo or 3.5 mg methoxsalen 
Higher methoxsalen dose subjects reported far less desire to smoke 

**Blood levels of nicotine at 30-minute intervals for three hours**
**10 mg or 30 mg doses of methoxsalen = 2X nicotine levels vs. placebo or 3.5 mg methoxsalen **
**Higher methoxsalen dose subjects reported far less desire to smoke **

**CYP-2A6 inhibitor**

## Study 2:
Methoxsalen (30 mg) or placebo in combination with nicotine or placebo
After 60-minute abstinence were allowed to smoke at will for 90 minutes
Smokers who received methoxsalen plus nicotine
Fewer cigarettes
Longer intervals between cigarettes
Fewer puffs on each cigarette 

**Methoxsalen (30 mg) or placebo in combination with nicotine or placebo**
**After 60-minute abstinence were allowed to smoke at will for 90 minutes**
**Smokers who received methoxsalen plus nicotine**
**Fewer cigarettes**
**Longer intervals between cigarettes**
**Fewer puffs on each cigarette **

**CYP-2A6 inhibitor**

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## Befloxatone 

**CP-526,555**

**Nic-Mec TD**

**Befloxatone **

## Befloxatone 

**The StrawTM**

**NicVAC**

**CP-526,555**

**Nic-Mec TD**

**Befloxatone **

**CYP450-2A6**

**SR 141716**

## Befloxatone 

**The StrawTM**

**NicVAC**

**CP-526,555**

**Nic-Mec TD**

**TA-NIC**

**Bup-Mec**

**SL 25,1188**

**GW468816**

**CYP450-2A6**

**Befloxatone **

**SR 141716**

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## Slide 68

## GW 320659 (1555U88)

**Mixed noradrenergic and dopaminergic uptake inhibitor **

## GW 320659 (1555U88)

**1998 - Glaxo Wellcome, "A Multi-Center, Double-Blind, Double-Dummy, Placebo-Controlled, Randomized, Parallel Group, Dose Response Evaluation of 1555U88 (2.5mg/day, 5mg/day, 10mg/day, 15mg/day) and ZybanTM (bupropion hydrochloride) Sustained Release (300mg/day) versus Placebo As Aids to Smoking Cessation."**

**www.hsc.wvu.edu/som/bmed/apmr/1996 **