What’s Next in Obesity Treatment?
QNEXA® (Vivus, Inc.) looks promising. QNEXA is a once-daily weight loss therapy that contains a combination of immediate-release phentermine hydrochloride (PHEN) and extended-release topiramate (TPM). These two agents suppress appetite through complementary mechanisms (decreased hunger and increased satiety), leading to greater weight loss than with either agent alone. Both PHEN and TPM are FDA approved at higher doses than those contained in QNEXA. The Endocrinologic and Metabolic Drugs Advisory Committee voted 20 to 2 to recommend FDA approval on 2/22/12 and the FDA is expected to release a decision in April. The FDA is waiting for Vivus, Inc. to provide assessment of topiramate’s and phentermine/topiramate’s teratogenic potential and a detailed plan and strategy to evaluate and mitigate any potential teratogenic risks in women of childbearing potential (WOCBP) and evidence that QNEXA-associated elevations in heart rate (mean increase of 1.6 bpm on the highest dose) do not increase the risk for major adverse cardiovascular events.
Currently phentermine is restricted to short-term management of obesity. Topiramate is approved for treatment of seizure disorders. The prescription use of these drugs spans more than 52 years for phentermine and more than 15 years for topiramate.
At present, approved pharmacotherapies for obesity are generally associated with <5% weight loss and are often poorly tolerated. The only treatment demonstrated to reliably produce more than 10% sustained weight loss for obesity is bariatric surgery, but is associated with surgical risks, nutritional deficiencies and infections.
From the FDA Advisory Committee briefing document below: The study population evaluated in the QNEXA pivotal clinical development program included a range of adult subjects, from overweight (BMI >27 kg/m2) to severely obese (BMI >60 kg/m2), with a range of obesity-related comorbidities, including type 2 diabetes, hypertension, and hypertriglyceridemia. Within a total of 3807 patients in the one-year cohort, 752 subjects (19.8%) fell into the “low” cardiovascular risk category , 2498 (65.6%) into “moderate” risk, and 557 (14.6%) into the “high” risk group. Thus, the QNEXA clinical sample of patients represents a broad spectrum of cardiovascular risk, and one that represents the range of patients likely to use QNEXA, if approved.
Two trials and an extension of the second trial [1,2,3] and other data [see link at bottom] comprise evidence provided to the FDA by Vivus. [We have not performed any critical appraisals, FYI.] The two trials reported that a phentermine/topiramate 15 mg/92 mg combination produced a magnitude of weight loss (~10%) that exceeded levels associated with current pharmacotherapies which produce <5% weight loss. Adverse events on the highest dose include paresethesias ~20%, dry mouth ~17%, constipation ~14%, dizziness ~6% to 10%, dysgeusia ~10%, depression ~5% to 8% and irritability ~3% to 5%. Only 1% to 2% discontinued treatment due to adverse events. It appears likely that many will conclude that benefits outweigh harms.
For more information and details of the Phase 3 studies presented to the FDA, go to http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials
1: Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY, Troupin B, Day WW. Controlled-Release Phentermine/Topiramate in Severely Obese Adults: A Randomized Controlled Trial (EQUIP). Obesity (Silver Spring). 2012 Feb;20(2):330-42. doi: 10.1038/oby.2011.330. Epub 2011 Nov 3. PubMed PMID: 22051941.
2. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Apr 16;377(9774):1341-52. Epub 2011 Apr 8. Erratum in: Lancet. 2011 Apr 30;377(9776):1494. PubMed PMID: 21481449.
3. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012 Feb;95(2):297-308. Epub 2011 Dec 7. PubMed PMID: 22158731.
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