On February 1st Orexigen(R) Therapeutics, Inc. and Takeda Pharmaceutical Company Limited (Takeda) announced that the FDA issued a complete response letter dated January 31, 2011 regarding the New Drug Application for Contrave® (naltrexone HCl/bupropion HCl) extended-release tablets for the treatment of obesity, including weight loss and maintenance of weight loss (http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1522207&highlight=). In the letter, FDA noted concern about the cardiovascular safety profile of naltrexone/bupropion when used long-term in a population of overweight and obese subjects, stating “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.” This decision came against a backdrop of a positive recommendation from the FDA December 7, 2010 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, which voted 13 to 7 that available data demonstrate an adequate risk:benefit ratio to support approval. The Committee also voted 11 to 8 that a study of cardiovascular safety, as measured by the incidence of major cardiac adverse events (MACE) should be conducted as a post-approval, versus pre-approval, requirement.
To put this somewhat surprising decision into a larger context, a good place to start is with the information on cardiovascular effects of bupropion contained in the approved product labeling and the briefing materials provided for the Advisory Committee meeting (Contrave AdCom Briefing Document). Bupropion (Welbutrin®, Zyban®) has weak sympathomimetic activity as a result of its inhibition of norepinephrine re-uptake. The approved labeling for contains the following statement regarding cardiovascular effects. “In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.”
In clinical trials of Contrave, no overall effect on mean systolic and diastolic blood pressure (SBP, DBP) was observed. But analysis of treatment-emergent increases in S/DBP (patients experiencing â‰¥ 2 values of systolic/diastolic blood pressure â‰¥ 140/â‰¥ 90 mm Hg) revealed an approximately 2-3 fold increase in Contrave-treated patients (see Table 29, page 120 of the briefing document). This same pattern was observed in both non-diabetic and, importantly, diabetic patients. Finally, there was a small, non-significant, increase in the incidence of MACE in treated patients (2 vs. 5 in the placebo vs. Contrave group; Table 36 of the briefing document). However, the overall incidence of events was too low to draw any definitive conclusions regarding the impact of Contrave on ischemic cardiovascular events.
Against a background of recent controversies surrounding the cardiovascular risk of other new weight loss (e.g. Meridia®) and anti-diabetic (e.g. Avandia®) products, what’s a regulator to do? The answer seems to be increasingly clear, starting with the Draft Guidance Developing Products for Weight Management (Development of Weight Management Products ucm071612.pdf). But additional insight can be gained by examining recent presentations by Mary H. Parks, M.D., Director, Division of Metabolism and Endocrinology Products (DMEP), ODE II, OND, CDER, FDA. The first of these was presented in the context of evaluation of cardiovascular risk for novel therapies for type 2 diabetes (MH Parks CV Risk T2DM Presentation ). This presentation outlines the recommendations in the Draft Guidance mentioned above: a comparison of cardiovascular event rates with the new agent by conducting a meta-analysis of phase 2 and 3 trials and conducting a single, large safety trial (slide 13). How large? Large enough to demonstrate that the upper bound of the 95% confidence interval for the cardiovascular risk ratio is at least less than 1.8. How large is that? If the annual event rate in the drug group is 2% and in the comparator group is 1.75%, this would require a study of 2,800 subjects for 5 years (see slide 16). This would yield a cumulative duration of exposure of 14,000 patient-years (2800 pts x 5 years). In a lower risk population (ie. non-diabetics) event rates are lower (see above) so trials need to be correspondingly larger and/or longer. The Contrave clinical program achieved only 2,313 patient-years of cumulative exposure, with only 1,661 patients treated for 1 year or more. Viewed in this context, the FDA action appears less surprising, given the appearance of a potential hypertension ‘signal’, and an ambiguous answer regarding cardiovascular risk based on duration of exposure. It’s also not surprising that at this point the clinical programs to support approval of novel therapies for obesity and type 2 diabetes are beginning to develop as much overlap as the conditions themselves.
This posting was prepared by Tim O’Neill, Ph.D., one of Camargo’s research scientists who specializes in cardiovascular pharmacology.