A Review of Rimonabant – A Novel Cannabinoid Type CB1 Receptor Antagonist
Bradley Allen Fremming, Pharm D., Captain, USAF, BSC; Steven Thomas Boyd, Pharm D., BCPS, CDE, CDM1 Chief Inpatient Pharmacy Services, 55th MDG Ehrling Bergquist Hospital 55MDSS/SGSAP, Offutt AFB and 1Creighton University, School of Pharmacy and Health Professions, Department of Pharmacy Practice, California St. Omaha
OBJECTIVE: To review the pharmacology, pharmacodynamics, pharmacokinetics, clinical efficacy and safety profile of Acomplia™ (rimonabant), a new cannabinoid type CB1 receptor antagonist. DATA SOURCES: Primary literature and review articles were obtained via a Medline search and additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles pertinent to rimonabant and the endocannabinoid system were reviewed for data relevant to this article. DATA SYNTHESIS: Rimonabant is the first in a new class of drugs that selectively antagonizes the cannabinoid type CB1 receptor. This antagonism has been shown to have beneficial effects in the treatment of obesity. In humans, rimonabant has demonstrated a role in achieving significant weight loss, while leading to positive improvements in metabolic parameters and cardiovascular risk factors. To date, the safety and tolerability of rimonabant has been encouraging, with the most common adverse effect being nausea. CONCLUSION: Ongoing clinical trials are demonstrating that rimonabant appears to be a novel and effective approach to treating obesity. Rimonabant is the first in a new class of drugs called selective cannabinoid CB1 receptor antagonists. Upon the completion of clinical trials, the drug may be approved for the treatment of obesity in late 2005. (Klinik und Forschung 2005;11:13-16) KEY WORDS: endocannabinoid, obesity, rimonabant, SR141716, SR141716A
Referred to as the global epidemic by the World Health Organization, obesity is becoming a leading preventable and modifiable metabolic disease across the world.1 Obesity is related to serious health conditions such as stroke, diabetes, insulin resistance, hypertension, dyslipidemia, and cardiovascular disease.2 Along with being a chief health concern, obesity is also poising to become a major economic problem with huge monetary consequences.3 The NIH National Heart, Lung, and Blood Institute evidence based guidelines provide recommendations and treatment options for the management of obesity.4 Current agents available for the management of obesity have unfortunate side effects. This article reviews a promising new and unique alternative in the management of the obesity epidemic currently in Phase III clinical trials called rimonabant (Acomplia™).
The discovery of the endocannabinoid (EC) system in the early 1990’s was due in large part to the specific action of marijuana’s psychoactive component tetrahydrocannabinol (THC). The system appears to act as a neuromodulatory system affecting several physiological functions not only in the central nervous system but also in the autonomic nervous system, the endocrine network, cardiovascular, gastrointestinal, reproductive, and the immune system.5 The homeostatic control of these physiological systems and the regulation of motivational behavior merits special attention because of its impact on human disease, including addiction and weight loss. Ongoing EC system research is yielding data suggesting inhibition of the EC system controls the motivation for appetite stimuli, including food and drugs.6 The EC system includes several endogenous ligands (endocannabinoids) from two families of lipid signaling molecules.7 The two main endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG), which play an intricate part in regulating the EC system. These lipid transmitters serve as natural ligands, or agonists, for the cannabinoid receptors. In contrast to classical neurotransmitters, endocannabinoids do not appear to be stored in the interior of synaptic vesicles, due to the high lipophilicity of these ligands.8 Instead they are produced and stored in phospholipid molecules within cellular membranes.9 When endocannabinoids are released from the phospholipid molecule of the postsynaptic target cell, they enter the extracellular space. There they active the cannabinoid receptors located on the presynaptic terminal, ultimately inhibiting the release of either the inhibitory neurotransmitter gama-amino-butyric acid (GABA) or the excitatory transmitter glutamate.10 This messaging process employed by endocannabinoids is called retrograde signaling. The endocannabinoids are then thought to be inactivated by a reuptake mechanism called the anandamide membrane transporter and hydrolyzed by a fatty acid amid hydrolase or monoglyceride lipase inside the neuron or astrocyte.5,8
Research into the mechanism of action of the endocannabinoid system has revealed two types of cannabinoid receptors which have been localized and pharmacologically characterized in mammalian models.11 They are referred to as CB1 and CB2 receptors, the names proposed by the IUPHAR Subcommittee on Cannabinoid Receptor Nomenclature and Classification.12 Cannabinoid receptors are included in the super family of G-protein coupled receptors where their signal transduction is mediated by the process of G-protein activation.13 In addition, CB1 receptors are also coupled to several calcium and potassium channels.14 Both discovered and cloned in the early 1990’s, CB1 and CB2 receptors exhibit 48% amino acid sequence identity and share only 44% overall identity.15 ,14 Across species, the sequence of CB1 receptors is almost identical.12 CB1 receptors are the most abundant G-protein coupled receptors in the brain, with densities being similar to that of GABA and glutamate ion channels.15,13 The presence of specific and saturable CB1 binding sites has been discovered in the CNS and in peripheral tissues.12 The highest density of CB1 type receptors are found in the basal ganglia, substantia nigra pars reticulate, and in the association and limbic cortices, suggesting an important role in motivational processing.13,16 The lowest concentrations are found within the brainstem. CB1 receptors play a role in pain relief, muscle relaxation, and other basic body functions.17 Agonists for the cannabinoid receptors include the arachadonic acid derivatives anandamide and 2-arichidonoylglycerol. Agonists are usually classified according to chemical structure into one of four groups: classical, nonclassical, aminoalkylindole, and eicasanoid.12 Several cannabinoid agonists are already utilized clinically for the treatment of nausea and vomiting provoked by cancer chemotherapy and against acquired immunodeficiency syndrome-related anorexia.12 Possible clinical uses for cannabinoid agonists under investigation include multiple sclerosis, spinal injury, and chronic pain management. Rimonabant (Acomplia™) is neurokinin-3 antagonist and highly selective cannabinoid type CB1 receptor antagonist.18 It is currently being researched and developed in Phase III trials by the France-based pharmaceutical manufacturer Sanofi-Aventis.19 The chemical name is n-Piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide. Please refer to Figure 1 for the chemical structure and molecular formula of rimonabant. Rimonabant specifically targets the endocannabinoid system where it shows discernible selectivity for the CB1 receptor while showing little affinity for CB2 receptors or other non-cannabinoid receptors.12 Specifically, rimonabant displays 1000 fold higher affinity for the CB1 receptor. Originally studied as an anti-marijuana agent, rimonabant is a selective, potent, and orally active cannabinoid antagonist with a long duration of action and shows high affinity for the centrally located cannabinoid receptors (Ki = 2 nM) and displays low affinity for the peripheral cannabinoid receptors (Ki > 1000 nM).16,20 Studies have shown that following oral administration of rimonabant, 50% of the brain cannabinoid receptors remained significantly occupied eight hours post, indicating that rimonabant is able to cross the blood-brain barrier, has a long duration of action, and is specific for the brain cannabinoid receptor.20 The mechanism by which rimonabant regulates food intake is thought to be centrally mediated, but recent results suggest a peripheral mechanism as well. Therefore, it seems likely that CB1 receptors located on adipocytes might be one of the pathways of rimonabant’s peripheral metabolic activity and benefit.21 Rimonabant is capable of blocking craving for food and drugs and is currently undergoing clinical trials for obesity, smoking cessation, and alcohol abuse. Essentially, its target is to silence signals in the brain, stomach, and fatty tissues that promote smoking and eating.22 Pharmacodynamic studies in rodents have shown that given alone, rimonabant was able to improve memory, suggesting a role for endocannabinoids in the neuronal functions associated with memory.11 Rimonabant is attesting to become a powerful tool in the treatment of obesity, as preliminary results of Phase III trials have demonstrated it to be a successful aid in weight loss because of its properties in altering the heightened pleasure associated with eating highly palatable foods.13
Currently, there is limited information regarding Phase I/II trials with rimonabant. Overall, Phase II clinical data has shown weight loss to be significant in obese patients treated with rimonabant. A randomized, double-blind, placebo-controlled, cross-over study in 20 male patients with body mass index (BMI) = 27 was conducted to assess the effect of 7-day repeated oral administration of rimonabant on hunger, feeling of fullness, food consumption, and body weight in overweight or obese subjects.23 The results showed that patients were less hungry when taking rimonabant and body weight over one week showed a substantial reduction compared to placebo (720 g less when compared to placebo, P = 0.008). Another study of 167 obese patients demonstrated that administration of rimonabant (5, 10 or 20 mg/daily) for 16 weeks significantly reduced weight compared with placebo. More importantly, this study revealed that the decrease in weight continued during the entire four month duration of the study.18 A further study conducted to assess the effect of rimonabant on body weight and waist circumference in 287 obese patients found that daily doses of rimonabant produced a dose-dependent weight loss and reduction of waist circumference.24 The 16-week trial resulted in a significant weight loss in two of three treatment groups versus placebo (p<0.001).
Rimonabant is currently undergoing rigorous Phase III Clinical Trial testing to determine its role in the management of the obesity epidemic. Sanofi-Aventis has developed the Acomplia™ Clinical Development Program which includes one arm clinically geared to the utilization of rimonabant in obesity. This arm of the program is referred to as the Rimonabant In Obesity (RIO) Trials. These trials include RIO-North America, RIO-Europe, RIO-Lipids, and RIO-Diabetes. The trials encompass more than 6600 patients worldwide and range from one to two years in length.25 ,26 They are all prospective, randomized, multi-center, double-blind, placebo-controlled trials.27 RIO-North America and RIO-Europe studied an obese or overweight population with or without co-morbidities, excluding diabetes. RIO-Lipids studied an obese or overweight population with untreated dyslipidemia while RIO-Diabetes examined an obese or overweight population with Type 2 Diabetes.28 The trials were initially scheduled to near finalization at the end of 2004 with results made available in 2005. To date, only early preliminary results are available for RIO-Lipids and RIO-North America, while one-year results from the RIO-Europe Trial were recently published in April, 2005. As mentioned, results of the RIO-Europe Trial were recently presented to the scientific community at the American College of Cardiology Scientific Sessions.21 The purpose of the trial was to examine the relationship between rimonabant and subsequent weight loss and improvement in cardiovascular risk factors in over 1500 overweight or obese patients. Furthermore, another key undertaking was to determine the role of rimonabant in aiding in weight loss maintenance after a period of treatment. This multinational, Phase III trial compared two fixed doses of rimonabant (5mg and 20mg daily) to placebo over a two-year period. Patients meeting the inclusion and exclusion criteria of the trial were randomized to double-blind treatment consisting of placebo (n=305), rimonabant 5mg/day (n=603), and rimonabant 20mg/day (n=599). Baseline characteristics among treatment groups were similar. Along with active placebo or medicinal treatment, subjects were asked to maintain a mild hypocaloric diet (600kcal/day deficit) and were visited with every 28 days where they received dietary and physical activity counseling.21 Results revealed a significant weight loss in subjects randomized to receive rimonabant treatment versus placebo. After one year, patients lost an average of 3.4kg with rimonabant 5mg/day (p=0.002 vs. placebo), and 6.6kg with rimonabant 20mg/day (p<0.001 vs. placebo). Those subjects randomized to placebo lost an average of only 1.8kg. Statistical analysis also revealed that a greater number of patients in the rimonabant groups were able to lose 5% or greater of their weight from baseline compared to the placebo group (p<0.001). However, rimonabant 20mg/day specifically yielded a greater likelihood of a 10% or greater weight loss from baseline versus placebo (p<0.001).21,29 Cardiovascular risk factor improvements were also assessed and found to be significant in the rimonabant groups versus placebo. Treatment with rimonabant was able to increase HDL-cholesterol and decrease triglycerides. Treatment with rimonabant 20mg/day produced a significant decrease in non-HDL cholesterol (4.3%, p<0.001) versus placebo while the lower dosed group did not produce this significant effect. This trial was not specifically designed to assess people with diabetes; however, subjects did exhibit improved insulin sensitivity following rimonabant administration. Finally, a key finding that illustrates real-life applicability of this trial was that the prevalence of the diagnosis of metabolic syndrome was reduced by more than half.21 This finding will certainly prove to have huge implications in the future medical management of cardiovascular disease and Type 2 Diabetes Mellitus. Early results of the RIO-Lipids Trial were presented for the first time to the scientific community at the American College of Cardiology Annual Meeting in March, 2004.30 This trial enrolled overweight or obese persons with dyslipidemia and randomized them to receive either a daily, fixed dose of rimonabant or placebo. The results demonstrated that patients were able to lose weight and improve their lipid and glucose profiles subsequent to rimonabant administration. Patients treated with the higher dose of rimonabant (20mg/day) lost significantly more weight (8.6kg) than those treated with placebo (2.3kg) (p<0.001). Over forty percent of treated patients were able to lose more than ten percent of their body weight as compared to placebo. The effect of rimonabant on cardiovascular risk factors was also assessed in the RIO-Lipids Trial. Results revealed that rimonabant administration was able to positively influence the lipid profile in subjects as well as improve insulin sensitivity. Most clinically significant was the finding that the number of subjects diagnosed as having metabolic syndrome at baseline was reduced by over half after treatment with rimonabant (p<0.001). RIO-North America is the largest of the RIO Trials and has enrolled over 3000 obese or overweight patients throughout the United States and Canada. Two-year results of this trial were first presented at the American Heart Association (AHA) Scientific Sessions in November 2004.31 RIO-North America compared two fixed-dose regimens of rimonabant with placebo. The results from this trial are consistent with what was demonstrated in the RIO-Lipids Trial as well as the RIO-Europe Trial, discussed above. It was established that following one year of treatment with rimonabant, patients lost significantly more weight in the treatment groups compared to the placebo group. Furthermore, waist circumference decreased, lipid profiles were positively influenced, and the prevalence of a diagnosis of metabolic syndrome was significantly reduced.32 Second-year outcomes demonstrated while patients randomized to placebo regained weight initially lost in the first year, those who remained on rimonabant were successful in maintaining their weight loss during the second year, further adding to the growing body of evidence supporting this drug’s effectiveness.31 These well-developed Rimonabant In Obesity (RIO) Trials were consistent in their findings and demonstrate the need for long-term outcome studies to further determine rimonabant’s role in weight loss, treatment of metabolic syndrome, and improvement in cardiovascular risk factors.
Toxicity and Safety
Generally, the safety profile of rimonabant was deemed encouraging early in Phase I/II trials. In one of the earliest trials, other than mild gastrointestinal effects observed with the highest dose of rimonabant administered, an excellent tolerability was demonstrated among subjects.27 In a smaller 7-day trial, patients were able to tolerate the administration of rimonabant well.23
The safety and tolerability profile of rimonabant has been evaluated in Phase III trials and results have been positive overall. Rimonabant was tolerated well in RIO-Lipids with the most commonly reported side effects being nausea, dizziness, and upper respiratory tract infections.26 RIO-North America was able to demonstrate a positive safety profile over a two-year period.33 While most observed side-effects were minor and transient, overall study discontinuation due to adverse events was less than 10% in the treatment groups compared to nearly 13% in the placebo group.31 This trial also revealed no impact on mental health, EKG, or heart changes. RIO-Europe results were very similar in regards to observations of adverse effects. This trial also demonstrated that side effects were mild and transient and were most likely to appear in the first year of treatment. The most common side effects noted in RIO-Europe were nausea, dizziness, and vomiting. While overall drop-out rates due to rimonabant administration were slightly higher in RIO-Europe, they were still low and rather comparable to placebo.21 Again, RIO-Europe confirmed the findings in RIO-Lipids and RIO-North America that rimonabant did not have a significant effect on EKG, blood pressure, or heart rate changes. While preliminary data surrounding the safety and tolerability profile of rimonabant are overwhelmingly positive, long-term safety data is still unknown.
Discovered over a decade ago, the understanding of the mechanism of the endocannabinoid system has greatly increased. This keen understanding has lead to the development of drugs specifically designed to modify the endocannabinoid system’s important role in the regulation of feeding.34 These drug developments are now being recognized as being largely efficacious in the treatment of obesity. These drugs are designed with the hope that they are safe, effective, selective in the targets producing as few adverse effects as possible, and easy to take. Rimonabant (Acomplia™) is proving to fulfill this hope. Rimonabant has been shown in human models to influence the activity of the endocannabinoid system by selectively antagonizing the cannabinoid type CB1 receptor centrally and peripherally. This action has led to positive outcomes such as decreased body weight with the ability to maintain that weight loss, improvements in metabolic parameters such a HDL-cholesterol and triglycerides, and improved insulin sensitivity.27 Furthermore, this compound has shown a remarkable role in its potential to ameliorate metabolic syndrome. These significant findings have been accompanied by an encouraging safety and tolerability profile, with most side effects being mild and transient. As obesity continues to increase in prevalence across the world, rimonabant may prove to be a unique and new alternative in the limited arsenal of options available to clinicians. Further research is certainly warranted and greatly anticipated into the development and utilization of this new compound.
1 Formiguera X, Canton A. Obesity: Epidemiology and Clinical Aspects. Best Practice and Research Clinical Gastroenterology 2004;18(6):1125-1146. 2 Webber LS, Bedimo-Rung AL. The Obesity Epidemic: Incidence and Prevalence. Journal of the Lousiana State Medical Society 2005;157(1):S3-11. 3 Finkelstein EA, Ruhm CJ, Kosa KM. Economic Causes and Consequences of Obesity. Annual Review of Public Health 2005;26(1):239-258. 4 National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: the Evidence Report. Bethesda, MD: National Institutes of Health, 1998. 5 Cota D, Marsicano G. Endogenous Cannabinoid System as a Modulator of Food Intake. International Journal of Obesity 2003;27:289-301. 6 Rodriguez De Fonseca F. The Endocannabinoid System: Physiology and Pharmacology. Alcohol and Alcoholism 2005;40(6):2-14. 7 Di Marzo V, Bisogno T, De Petrocellis L. Cannabimimetic Fatty Acids Derivatives: The Anandamide Family and Other Endocannabinoids. Current Medicinal Chemistry 1999;6:721-744. 8 Di Marzo V, Melck D, Bisogno T. Endocannabinoids: Endogenous Cannabinoid Receptor Ligands and Neuromodulatory Action. Trends in Neuroscience 1998;21:521-528. 9 Di Marzo V, Fontana A, Cadas H. Formation and Inactivation of Endogenous Cannabinoid Anandamide in Central Neurons. Nature 1994;372:686-691. 10 Alger B. Endocannabinoids: Getting the Message Across. PNAS 2004;101:8512-8513. 11 Howlett AC. The Cannabinoid Receptors. Prostaglandins and Other Lipid Mediators 2002;68-69:619-631. 12 Pertwee RG. Pharmacology of Cannabinoid CB1 and CB2 Receptors. Pharmacology and Therapeutics 1997;74(2):129-180. 13 Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid Physiology and Pharmacology: 30 Years of Progress. Neuro Pharmacology 2004;47:345-358. 14 Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacological Reviews 2002;54:161-202. 15 Shire D, Calandra B, Bouaboula M, Barth F, Rinaldi-Carmona M, Casellas P, et al. Cannabinoid Receptor Interactions with the Antagonists SR 141716A and SR 144528. Life Sciences 1999;65(6/7):627-635. 16 D’Souza DC, Kosten RT. Cannabinoid Antagonists: A Treatment in Search of an Illness. Archives of General Psychiatry 2001;58:330-331. 17 Vastag B. Experimental Drugs Take Aim at Obesity. JAMA 2003;289(14):1763-1764. 18 Rimonabnat. SR 141716a, SR 141716. Drugs RD 2002;3:65-66. 19 Halford JCG. Clinical Pharmacotherapy for Obesity: Current Drugs and Those in Advanced Development. Current Drug Targets 2004;5:637-646. 20 Carmona-Rinaldi M, Barth F, Heaulme M, Alonso R, Shire D, Congy C, et al. Biochemical and Pharmacological Characterisation of SR141716A, the First Potent and Selective Brain Cannabinoid Receptor Antagonist. Life Sciences 1995;56(23/24):1941-1947. 21 Van Gaal L, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the Cannabinoid-1 Receptor Blocker Rimonabant on Weight Reduction and Cardiovascular Risk Factors in Overweight Patients: 1-Year Experience from the RIO-Europe Study. The Lancet 2005;365:1389-1397. 22 Conti CR. Editor’s Note: Another Pill for Weight Reduction. Clinical Cardiology 2005;28:59-60. 23 Heshmati HM, Caplain H, Bellisle F, Mosse M, Fauveau C, Le Fur G. SR141716, a Selective Cannabinoid CB1 Receptor Antagonist, Reduces Hunger, Caloric Intake, and Body Weight in Overweight or Obese Men. Obesity Research 2001;9(3):70S. 24 Jensen M, Abu-Lebdeh H, Geohas J, Brazg R, Block M, Noveck R, et al. The Selective CB1-Receptor Antagonist Rimonabant Reduces Body Weight and Waist Circumference in Obese Subjects. International Journal of Obesity 2004;28(Supp 1):S27. 25 Molecule of the Month: Rimonabant Hydrochloride. Drug News and Perspectives 2004;17(6):403. 26 Cleland, JGF, Ghosh J, Freemantle N, Kaye GC, Nasir M, Clark AL, et al. Clinical Trials Update and Cumulative Meta-Analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-LIPIDS and Cardiac Resynchronisation Therapy in Heart Failure. The European Journal of Heart Failure 2004;6:501-508. 27 Boyd ST, Fremming BA. Rimonabant – A Selective CB1 Antagonist. The Annals of Pharmacotherapy 2005;39:684-690 28 Cluzel M. Acomplia (Rimonabant) – A New Foundation for the Management of Cardiovascular Risk Factors. Sanofi Aventis 2005. 29 Van Gaal L. Press Release: Improvement in Cardiovascular Risk Factors with Rimonbant Demonstrated in Two-Year Study. RIO Steering Committee 2005. 30 Carnois N, Podvin J. Press Release: Two Pivotal Studies Indicate Acomplia (Rimonabant) Offers a Novel Approach to Cardiovascular Risk Management in Overweight/Obese People and Smokers. Sanofi-Synthelabo 2004. 31 Pi-Sunyer X. Press Announcement: Long-Term Benefits of Rimonabant Confirmed in Two-Year Study. RIO Steering Committee 2004. 32 Pi-Sunyer X. RIO-NA: Rimonabant in Obesity – North America. Amercan Heart Association 2004 Annual Scientific Sessions. 33 New Diet Drug Stirs High Hopes. Heart Advisor February 2005. 34 Vickers SP, Kennett GA. Cannabinoids and the Regulation of Ingestive Behavior. Current Drug Targets 2005;6:215-223.
Bradley Allen Fremming, Pharm D, Captain, USAF, BSC 55th MDG Ehrling Bergquist Hospital 55MDSS/SGSAP 2501 Capehart Road, Offutt AFB, NE 68113 firstname.lastname@example.org