The future of endocannabinoid-oriented clinical research after CB1 antagonists
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- Le Foll, B., Gorelick, D.A. & Goldberg, S.R. Psychopharmacology (2009) 205: 171. doi:10.1007/s00213-009-1506-7
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Great interest has been shown by the medical community and the public in the cannabinoid CB1 receptor antagonists, such as rimonabant, for treatment of obesity, metabolic syndrome, and possibly drug addiction.
This novel class of drug has therapeutic potential for other disorders, as the endocannabinoid system is involved in various health conditions. However, rimonabant, the first clinically available member of this class of drugs, has been linked to increased risk of anxiety, depression, and suicidality. Due to those risks, the European Medicines Agency called for its withdrawal from the market in October, 2008. Shortly after this decision, several pharmaceutical companies (Sanofi-aventis, Merck, Pfizer, Solvay) announced that they would stop further clinical research on this class of drug. Here, we provide an overview of those events and make several suggestions for continuing such clinical research, while safeguarding the safety of patients and clinical trial subjects.
KeywordsRimonabantCB1 receptor antagonistPharmacotherapySafetyDrug dependenceAddictionObesity
Possible therapeutic indications for cannabinoid CB1 antagonists/inverse agonists
– Diabetes (Rosenstock et al. 2008)
– Hypotension/shock (Batkai et al. 2004)
– Liver disease (Izzo and Camilleri 2008)
– Gastrointestinal disease (Izzo and Camilleri 2008)
– Reproductive health (e.g., miscarriage; Habayeb et al. 2008)
– Arthritis (Richardson et al. 2008)
As one example, CB1 receptor antagonists show promise in treating drug addiction (De Vries and Schoffelmeer 2005; Le Foll et al. 2008; Le Foll and Goldberg 2005; Wiskerke et al. 2008), for which there is a need for more effective treatments (Le Foll and George 2007; Reuter and Pollack 2006). Blocking CB1 receptors reduces motivation for Δ9-tetrahydrocannabinol, the active ingredient of cannabis, in a nonhuman primate model (Justinova et al. 2008; Tanda et al. 2000) and partially blocks the psychological and cardiovascular effects of smoking a cannabis cigarette in humans (Huestis et al. 2007). Clinically validating these promises would be of value to the field of drug addiction.
Rimonabant (Acomplia®, Sanofi-aventis) was the first selective CB1 ligand introduced into clinical practice. This CB1 receptor antagonist (with inverse agonist action) has been shown efficacious as a treatment for obesity (Despres et al. 2008; Hampp et al. 2008) and for improving dyslipidemias, diabetes, and metabolic syndrome (Despres et al. 2005; Scheen 2008; Van Gaal et al. 2005). It had been approved as an obesity treatment in more than 50 countries worldwide, including the European Union (EU). Rimonabant was also being developed for smoking cessation, with statistically significant, albeit modest, evidence for efficacy (Cahill and Ussher 2007; Le Foll et al. 2008; Rigotti et al. 2009), especially in minimizing weight gain often associated with smoking cessation.
Tempering this promise has been a growing concern about the psychiatric safety of CB1 receptor antagonists (Christensen et al. 2007; Food and Drug Administration Endocrinologic and Metabolic Advisory June 13, 2007; Rucker et al. 2007), notably increased rates of depression, anxiety, and suicidality related to drug use. These psychiatric concerns led to the October, 2008 decision by the European Medicines Agency to suspend marketing of rimonabant in the EU. Following this decision, the drug-maker Sanofi-aventis announced on November 5, 2008, its decision to withdraw rimonabant from the market worldwide and to discontinue its ongoing rimonabant clinical development program for all indications (Sanofi Aventis 2008). Around the same time, several other CB1 receptor antagonists/inverse agonists not yet approved for marketing were withdrawn from clinical development by their developers, including taranabant (Merck) and otenabant (Pfizer), both in phase 3, and ibipinabant (Solvay/Bristol-Myers Squibb) and surinabant (Sanofi-aventis) in phase 2 (Jones 2008; Merck 2008).
It should be noted that rimonabant was eventually withdrawn from marketing in the EU because its clinical use was not following the criteria established to maximize its benefit/risk ratio, i.e., community clinicians were prescribing it to patients at high risk for depression and suicidality and many patients were not taking it long enough to achieve the potential benefits. We agree that the public should be protected from medications with unfavorable benefit–risk ratios.
However, the unfavorable conditions that existed with rimonabant prescriptions in the community do not exist in the clinical research environment, where subjects are rigorously screened for eligibility and drug administration must adhere to the protocol schedule. We consider it premature to stop further clinical research on cannabinoid antagonists in important human diseases as a result of the termination of clinical development of currently available CB1 receptor antagonists/inverse agonists. It is possible that several conditions which currently have no treatment may benefit from the use of such a class of drugs (Table 1). Cannabinoid CB1 receptor antagonists/inverse agonists and other ligands modulating endocannabinoid transmission may have a very positive benefit–risk ratio for other indications. We therefore make several suggestions for continuing such important clinical research, while safeguarding the safety of patients and clinical trial subjects.
First, we suggest that rimonabant and similar compounds remain available for clinical research under strictly controlled circumstances that maximize safety, such as single-dose studies, inpatient studies, or short-term outpatient studies with rigorously screened subjects under close monitoring. This would allow researchers to perform “proof of principle” or “proof of concept” clinical trials. In this regard, full and transparent disclosure of all safety data from clinical trials would advance our understanding of the risks associated with this class of compounds and hopefully improve the design of future clinical trials.
Second, we suggest continued development of more selective CB1 receptor ligands. It is possible that the observed psychiatric adverse events were due, at least in part, either to inverse agonism properties or to excessive blockade of CB1 receptors. Both rimonabant and taranabant showed evidence of inverse agonist activity in preclinical studies. It is possible that “cleaner” compounds that are neutral (so-called pure) CB1 antagonists or inverse agonists with little antagonism may have a more favorable pharmacological profile. For example, in animal studies, both CB1 receptor neutral antagonists and inverse agonist/antagonists reduce food intake and food-reinforced behavior, while only the former cause nausea and vomiting (Salamone et al. 2007). Whether this dissociation between desired effects and side effects holds for human psychiatric indications remains to be evaluated.
Another approach is development of CB1 receptor antagonists/inverse agonists that do not act in the central nervous system and so presumably would be devoid of psychiatric side effects. Although such novel ligands might be ineffective for central nervous system-mediated disorders such as drug addiction, there is evidence that a peripheral antagonist can reduce feeding and weight gain in animals (Pavon et al. 2008). Other indications, such as coronary artery disease (Nissen et al. 2008; Sugamura et al. 2009), liver and pancreatic disease (Izzo and Camilleri 2008), inflammatory bowel disorders (Izzo and Camilleri 2008), and arthritis (Richardson et al. 2008) may also benefit from peripheral CB1 antagonism.
Third, we suggest continued research on pharmacological approaches that bypass the CB1 receptor and modulate the endocannabinoid system by different means. Targeting the enzyme fatty acid amide hydrolase (Gobbi et al. 2005; Kathuria et al. 2003; Scherma et al. 2008a), which breaks down endocannabinoids or the endocannabinoid membrane transporter system (Beltramo et al. 1997), may have therapeutic utility, notably for nicotine addiction (Scherma et al. 2008b), while avoiding psychiatric side effects.
In conclusion, there is increasing evidence that the endocannabinoid system plays a significant role in various human illnesses. It is important to continue clinical research in this area and to evaluate promising preclinical findings. The recent termination of clinical development of one class of compounds should not deter continued work in this field, which holds the promise for meaningful clinical benefits.
Drs. Gorelick and Goldberg are supported by the Intramural Research Program, NIH, National Institute on Drug Abuse. Dr. Gorelick was an investigator in clinical trials of rimonabant at NIDA sponsored by Sanofi. He did not personally receive any funding from Sanofi. Drs. Le Foll and Goldberg report no competing interests.