Transcript Slide 1
DEVELOPING MEDICATIONS TO TREAT SUBSTANCE USE DISORDERS: PITFALLS AND PROMISES
Phil Skolnick, Ph.D., D.Sc. (hon.) Director, Division of Pharmacotherapies and Medical Consequences of Drug Abuse
The Gains In Medications To Treat SUDs Are Incremental
Why Haven’t We Been More Successful At Developing Medications To Treat Addictions ?
It’s Not For Lack Of Putative Targets Identified In Preclinical Studies
-Kappa opioid receptor antagonists -Dopamine (D 3 ) receptor antagonists -5HT 2A receptor antagonists -5HT 2C receptor agonists -mGluR 5 receptor antagonists -CRH 1 antagonists -FAAH inhibitors -Orexin antagonists Compounds acting at these targets may be effective against multiple drugs of abuse
Why Haven’t We Been More Successful At Developing Medications To Treat Addictions ?
• Historically, big pharma has not embraced developing medications to treat addictions* (*with the exception of nicotine) Some of the factors often cited for this indifference : -Cost of developing an NCE (current estimates: a bit south of $2BB including cost of capital) -Perceived small market size (translates to return on investment) Suboxone sales (2009) of >$750,000,000 belie this perception -Difficulties in executing a clinical trial campaign using patients with SUDs (often many comorbid conditions + lifestyle issues) -Stigma associated with addiction to illegal substances
High Cost of Developing Drugs To Treat Neuropsychiatric Disorders Science, 329: 502-504,2010
The Drug Development Cycle Time Has Increased Dramatically Time from First Pharmacological Testing to New Drug Approval, 1963 - 1997 1960s 1970s 1980s 3.8
4.4
5.2
1.9
2.4
4.3
5.6
2.1
2.8
1990s 5.6
6.7
2.0
0.0
5.0
10.0
15.0
1st Pharm Testing to IND File IND File to NDA Subm NDA Subm to Approval
Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook, 2002/2003.
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Why Haven’t We Been More Successful At Developing Medications To Treat Addictions ?
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Recent mergers (e.g. Pfizer/Wyeth, Schering-Plough/Merck) have resulted in a consolidation (read: net loss) of programs, including CNS. -Several big pharmas (GSK, A/Z) have dropped discovery medicine programs in psychiatry . -Both a reduction in the number of potential partners AND lack of enthusiasm for drugs to treat psychiatric disorders dampens enthusiasm for investment in CNS based startups/biotechs, often the drivers of innovation.
The Current Probability of Success in Developing Drugs to Treat CNS Disorders Is Dismal Lead 3%
C.C.
8%
Ph. I 17%
Ph . II Ph. III 25%
59%
NDA 85%
Pharma Retrenchment Will Affect The SUD Pipeline -Most molecules that we explore are “repurposed” – with the cutback in psychiatry R&D, many promising early –mid stage molecules will not be developed. -The upside: there may be a bumper crop of mid-stage molecules in the near-intermediate term.
-The trend away psychiatry research in big pharma will have a negative, trickle-down effect on CNS focused biotech/small pharma, since there are fewer “end game” (licensing) partners. -Our new champions may be small/mid-size pharma: e.g. Alkermes, Titan, Catalyst, R/B But will these companies have the resources and infrastructure to develop truly innovative medicines?
THERAPEUTIC STRATEGIES TO TREAT SUDs
• • • Replacement/Substitution (e.g. methadone, buprenorphine, nicotine) Magic Bullets and Arrows (e.g. cocaine vaccine; nicotine vaccine; mAbs to methamphetamine; engineered cocaine esterases) New Age [targets developed because of a better understanding of the neuroscience of addiction] (e.g. mGluR5 antagonists, 5HT2C agonists, D3 antagonists)
Therapeutic Horizon For SUDs • • • • Near Term (≤3 y) NicVax Probuphine Vivitrol (for relapse prevention to opiates)
• • • • • •
Therapeutic Horizon for SUDs
Long Term (≥7 y) D3 antagonist (NCE, not buspirone) mGluR5 antagonist (fenobam) Vaccines (cocaine and others) mAbs (stimulants, opiates) κ antagonist (JDTic) PPAR-γ agonists (glitazones)
Probuphine
®
: An Implantable SR Formulation of Buprenorphine
Subcutaneous implant that delivers low, continuous, steady-state levels of buprenorphine for 6 months Strengths/Advantages • Reduces risk of diversion • Improves compliance – one good decision every 6 months • Reduces side-effects associated with fluctuating drug levels • Provides efficacious therapy while reducing overall drug exposure to the patient 12
13 20 18 16 14 12 10 8 4 2 0
Study 1: Difference in Mean % Negative Urines (Δ from placebo)
P = .0006
P = .0253
40% - 29% 28% - 9%
Weeks 1-16 Weeks 17-24
Study 1: Secondary Efficacy Outcomes
Outcome Measure (24 weeks) Treatment Retention Probuphine > Placebo
p
< .0001
Patient-Rated Opioid Withdrawal
p
= .0039
Clinician-rated Opioid Withdrawal Global Improvement of Opioid Addiction (Clinician-Rated)* Global Severity of Opioid Addiction (Clinician-Rated)* Opioid Craving Visual Analog Scale (VAS) * Responder Analysis 14
p
= .0004
p
< .0003
p
= .0086
p
= .0009
Probuphine
• • • Follow on Ph III trial initiated in Q2’10 Trial compares the effects of probuphine (100 patients), suboxone (100 patients) and placebo (50 patients) Enrollment completed Q’3 2010, results expected in Q2’11
NO ATTEMPT TO “OVERSMOKE” THE EFFECT OF NICVAX
STATUS OF NICVAX CLINICAL PROGRAM
• • • Multiple Phase III studies (each with ~1,000 patients) initiated under an “SPA” with the FDA. Primary endpoint is long term abstinence from smoking.
First trial initiated Q4’09 and enrollment completed Q3’10. Final data expected Q4’11.
Second trial initiated Q1’10 and enrollment is expected to be complete by Q1’12.
Bupropion
• • • A dual (DA/NE) uptake inhibitor Approved for the treatment of depression and smoking cessation No significant difference from placebo in a large trial treating methamphetamine dependence (Elkasheff, et al., 2007). Primary outcome measure: the proportion of participants having a methamphetamine-free week.
Bupropion Increases Abstinence In Methamphetamine Users (Success defined as ≥ 2 weeks of methamphetamine free urine lasting through the end of study) McCann and Li (2010) – reanalysis of Elkasheff, et al.,2008
Placebo Bupropion Bupropion vs. Methamphetamine Total Sample Abstinence During Last 3 Weeks Failures Successes 68 (94.4%) 65 (82.3%) 4 (5.56%) 14 (17.7%)
Reanalysis of data from Elkasheff, et al., 2008
3.2 x P = 0.02
(Chi-square test)
Bupropion Is Most Effective In Producing Abstinence In “Light-to-Moderate” Methamphentamine Users (success defined as ≥ 2 weeks of methamphetamine free urine lasting through the end of study) No measure of medication compliance was included in this study. Based on compliance data in other studies, these data may underestimate the efficacy of bupropion in producing ≥ 2 weeks of EOSA McCann and Li (2010) – reanalysis of Elkasheff, et al.,2008
Placebo Bupropion Bupropion vs. Methamphetamine “Low” Baseline Use (≤ 18 days) Abstinence During Last 3 Weeks Failures Successes 34 (97.1%) 27 (75.0%) 1 (2.86%) 9 (25.0%)
Reanalysis of data from Elkasheff, et al., 2008
8.7 x P = 0.007
(Chi-square test)
Is Bupropion Effective For The Treatment of Methamphetamine Abuse?
• Based on reanalysis of the Elkasheff, et al. (2007) report, a second trial was initiated.
• Multisite, double blind study comparing bupropion (150 mg b.i.d.) and control in methamphetamine. Last patient randomized January, 2011. Data expected Q2’11.
Therapeutic Horizon For SUDs • • • • Near Term (≤3 y) NicVax Probuphine Vivitrol (for opiate addiction) Bupropion • • • • Mid Term (4-6 y)
5HT2c agonist (lorcarserin)
Buspirone (D3 antagonist +) Bupropion/Naltrexone (Contrave) Vigabatrin
Lorcaserin, A 5HT2C Agonist, Is In Late Stage Development -Arena has completed phase III clinical testing of Lorcaserin for the primary indications of obesity and weight management. An NDA was submitted in December, 2009.
Lorcaserin is currently in phase III for the treatment of obese and overweight patients with type 2 diabetes. The results will be filed as a supplement to the NDA.
An advisory committee recommended against approval and in Q4’10 the FDA did not approve lorcarersin to treat obesity. The sponsor is currently conducting additional studies to address the FDA’s concerns.
Why Lorcaserin?
o Preclinical data suggest 5-HT 2C agonists may be effective for the treatment of nicotine, cocaine and other drugs of abuse. o Lorcaserin is appears to be safe and well tolerated in clinical trials. The most common side effect: headache o Lack of serious adverse effects in clinical studies: • No increased risk of depression or suicidal ideation • No cardiac valvular side effects
5-HT 2C receptor agonists: preclinical studies predict efficacy in multiple SUDs
Cue-induced Reinstatement of Nicotine Self-Administration
Zaniewska et al., 2007 Cunningham et al., 2011, in prep.
Ro 60-0175
Grottick et al., 2001
Reinstatement models Initiation Maintenance Extinction Reinstatement Cocaine priming - Footshock stress - Conditioned cue Cocaine Saline Session Adapted from Erb, Shaham and Stewart, 1996
5-HT 2C receptor agonists: preclinical studies predict efficacy in multiple SUDs
Cue-induced Reinstatement of Meth Seeking Drug-induced Reinstatement of Meth Seeking Lorcaserin Lorcaserin
Why Haven’t We Been More Successful At Developing Medications To Treat SUDs?
Clinical Trial Conduct/Execution • There are multiple reasons why clinical trials fail; while most often blamed, the failure of a mechanism/ validity of our models is only one potential source of failure.
• The three most important aspects of a successful clinical trial: COMPLIANCE, COMPLIANCE, AND COMPLIANCE
Medication Compliance Is Required For Adequate Testing Of A Hypothesis In The Clinic
Noncompliance May Have Spoiled Cocaine Dependence Drug Trial • SAN FRANCISCO (EGMN) - A trial of the anticonvulsant vigabatrin to treat cocaine dependence may have failed because the patients weren't taking it and not because the drug didn't work, an analysis of the study results suggests.
• A subsequent analysis of urine samples retained from the study showed that fewer than 40 percent of 53 patients in the vigabatrin arm who completed the 12-week study had urine drug levels that would indicate adherence to the medication regimen. The subsequent urinalyses suggested that at five of the 11 study sites, fewer than half of the patients had taken the medication as prescribed.
• Treatment adherence was rated at 85% using pill counts and patient self-reports to measure treatment adherence.
(headline from HEALTH DAILY NEWS)
VACSP/NIDA Study # 1026 Phase 2, Double-Blind, Placebo-Controlled Trial of Modafinil for Methamphetamine Dependence Placebo Modafinil 200 mg Modafinil 400 mg 68 72 70
An ICC of 0.21 indicates a very low agreement between measures
The Conduct Of Clinical Trials Is Unlikely To Change in The Short/Mid Term: How do we tackle the compliance problem?
• Electronic monitoring (e.g. MEMS) [easily gamed] • Measurement of drug/metabolite in a biological fluid should be incorporated into every SUD trial protocol. Use of “compliant” subjects in statistical evaluation.
• Recognition by regulatory authorities that a “snapshot of compliance” may be the only practical surrogate in a real world setting.
• Incorporation of riboflavin into formulations has been used as a means of detecting compliance in both placebo and drug groups. Alternatively, the use of “homeopathic” amounts of drug in the placebo, sufficient for detection in blood/urine, prevents subjects from “gaming” the trial.
Why Haven’t We Been More Successful At Developing Medications To Treat Addictions ?
Clinical Trial Issues (cont’d).: Are current outcome measures appropriate?
-Can we make a compelling argument that medication induced: 1) Reductions in drug use during the course of an 8 or 12 week trial 2) Changes in an instrument (or subscale) such as the ASI
Provide significant, long term benefit to the patient---
-Not only regulatory bodies (e.g. FDA) but 3 commercially successful.
rd party payers (insurance companies, formulary committees) must be convinced for a medication to be approved and