I am often asked about 505(b)(2) drug development failures. After all, 505(b)(2) is a regulatory pathway that is chosen because it is lower cost and has lower risk than a 505(b)(1). The lower risk is attributable to the reliance on the known safety and efficacy of the reference drug product. Indeed, one of the strategies employed in 505(b)(2) drug development is to improve the safety and/or efficacy of a known marketed product. We don’t know if the following product will not be approved, but the prospects are grim based on an unfavorable Advisory Committee vote.
Vivus, Inc. submitted an NDA for Qnexa, a fixed dose combination of phentermine and topiramate for aid in weight management (“weight loss”). Phentermine was approved in 1959 for short-term treatment of obesity. The originator product was discontinued and replaced by numerous generics. Phentermine acts to release norepinephrine which has an appetite-suppressing effect. Topiramate was approved in 1996 for the treatment of epilepsy and approved in 2004 for migraine prophylaxis and hyperammonemia. It is not known what causes topiramine to suppress appetite. According to Vivus, there were over 6 million prescriptions for phentermine and over 9 million prescriptions for topiramate in 2009. Vivus has developed a controlled release capsule formulation containing lower-than-currently-marketed doses (1/8 to 1/2 of phentermine and 1/16 to 1/4 of topiramate). The development rationale was that by combining the two drugs, the doses of each component might be lower than the monotherapy and thus allow for long-term treatment of obesity. Indeed, the combination was shown to be more efficacious than the total weight loss of each component alone.
On July 15 of this year, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met to review the NDA application. The FDA and Vivus briefing information is here. FDA’s position was clear — there was no issue with the efficacy but there were concerns about safety, specifically psychiatric adverse events including suicidality, neurocognitive adverse events, cardiovascular safety (readers may remember the controversy around the anti-obesity drugs fen-phen — an ad hoc prescribing of the combination of fenfluramine and phentermine. Fenfluramine was removed from the market in 1997 due to cardiac valvulopathy), incidence of metabolic acidosis, and teratogenicity. Of these, the FDA appeared to have the most concern about the teratogenicity. Topiramate is a known teratogen in several animal species. The FDA summarized the human evidence:
“Human pregnancy outcomes with topiramate exposure have been tracked in several pregnancy registries including the North American Antiepileptic Pregnancy Registry and UK Epilepsy and Pregnancy Registry. Topiramate monotherapy-exposed pregnancies in the North American registry had a higher prevalence of malformations (4.1%, 95% CI: 1.9, 7.6) compared to controls (1.6%, 95% CI: 1.5, 1.7). The UK registry reported a major congenital malformation rate of 4.8% (95% CI: 1.7, 13.3) from 70 pregnancies exposed to topiramate monotherapy of 200 mg and higher.”
Despite contraceptive counseling and monthly pregnancy checks, 34 pregnancies were experienced on Qnexa clinical studies. Though no malformations were observed in the resulting newborns, the FDA was clearly concerned that Qnexa would be used chronically by pregnant women. Vivus’ briefing information was nearly silent on this issue — maybe they didn’t see it coming? They were well prepared in their commentary at the Advisory Committee meeting. The company consultant, Dr. Gideon Koren, a University of Toronto professor with extensive experience in evaluating the risk of drugs on pregnancy outcomes and founder of Motherisk at the Hospital for Sick Children at the University of Toronto, said that if he counseled a “woman with topiramate — I will reassure her that if she took the drug into pregnancy, she is not likely to have an increased risk for malformations [meeting transcript (PDF), page 80, line 17]. He also argued that the proposed dose of Qnexa is lower and because the women are obese, the dose is “per kilo body weight less than half of what women with typically in epilepsy receive”[ibid, page 79, line 5].
The Committee voted 9 against approval, 7 for approval and no abstentions. During member commentaries on their vote, one member, Dr. Capuzzi said he meant a ‘no’ vote. But several members indicated that their ‘yes’ vote carried with it a proviso that additional studies should be conducted prior to approval. None of the member questioned the efficacy of the product. In fact, most stressed that it was likely to be an outstanding drug to reduce obesity. Rather, they were concerned with safety. In general, they were concerned that anti-obesity drugs would be used for a long time (the clinical trial duration was 1 year, per current Guidance). Dr. Abraham Thomas of Henry Ford seemed to sum up the sentiments of many of the ‘no’ voters as well as some of the concerns of the ‘yes’ voters [ibid., pages:356-7 line 7]
Cardiovascular concerns: “we should start a cardiovascular trial to look at outcomes in a higher risk population before release so we have the data within two to three years of release of the medication. ”
Bone health: “This medication, because of the acidosis, could affect both spectrums of bone health, peak bone mass in the younger generation — because peak bone mass is developed through the mid-20s — and then osteoporosis or fracture risk in the older subjects.”
“We do need more information about suicide risk.”
Dr. Cragan added: “I couldn’t really justify widespread use with the reproductive outcomes concerns that we have. And as I listened to the panel members discuss the other adverse events, it actually raised my level of concern rather than lessening it.” [ibid, page 366, line 17]
Of course, the FDA is not bound by its Advisory Committee votes. Vivus can also submit additional data. The PDUFA date is October 2010.