Qnexa Proposed REMS Focuses On Registry, Web-Based Physician Education

FDA advisory committee will hear Vivus' proposal for a voluntary pregnancy registry that could calculate the risk of major birth defects from the obesity drug; potential cardiovascular problems would be assessed in large outcomes trial.

Vivus is proposing a voluntary pregnancy registry as part of a Risk Evaluation and Mitigation Strategy to address safety concerns about its obesity drug Qnexa , which FDA is taking to the Endocrinologic and Metabolic Drugs Advisory Committee July 15.

The registry is included as part of an assessment plan for the proposed Qnexa REMS, which would focus on educating prescribers and patients about the drug's risks through a Medication Guide and risk communication plan.

Safety has been a stumbling block for obesity drugs and both FDA and Vivus plan to address this issue during the committee meeting - the sponsor with its REMS and FDA with discussion questions that center on the potential for Qnexa to cause teratogenicity, psychiatric-related, cognitive-related and cardiovascular adverse events and metabolic acidosis.

Falling on the heels of the Avandia advisory committee (see (Also see "Avandia Day Two Might Be Same Old Song Even With Broken RECORD" - Pink Sheet, 13 Jul, 2010.) ), the Qnexa review will be a bellwether for how FDA and its outside advisors handle the safety issues surrounding obesity drugs, two more of which will also go before advisory committees before the end of the year. CDER Director Janet Woodcock recently called into question whether a pharmacological therapy for the condition can have tolerable toxicity (Also see "FDA's Woodcock On Obesity Drugs: It's Hard To Fight Mother Nature" - Pink Sheet, 28 Jun, 2010.).

Qnexa is a fixed-dose combination of phentermine hydrochloride and topiramate. Phentermine is used as monotherapy for short-term treatment of obesity; toparimate has been approved to treat seizures since 1996 and for migraine prophylaxis since 2004. Qnexa, or Phen/TPM, was assessed during the clinical program at three strengths: low, 3.75 mg PHEN/23 mg TPM; mid, 7.5 mg Phen/46 mg TPM; and high, 15 mg Phen/92 mg TPM, versus placebo.

FDA notes that much is unknown about Qnexa's risk. But it also points out that toparimate includes a warning about suidicality that is part of labeling for all antiepileptic drugs, while phentermine, because of its mechanism of action, is contraindicated for patients with advanced arteriosclerosis, cardiovascular disease or moderate to severe hypertension. The combination of phentermine and fenfluramine was withindrawn from the market in 1997 because of increased risk for cardiac valvulopathy. But FDA says current evidence indicates the threat was due to the fenfluramine.

Toparimate also is teratogenic in several species. So while 19 babies without congenital anomaly were born to women taking Qnexa during clinical trials, an FDA briefing memo points out that it is unknown if the doses of the compound in Qnexa appreciably increase the risk of congenital malformations.

In all, 34 pregnancies were reported during the Qnexa trials. This large number, given the controlled clinical program, in which enrollment required agreement to use birth control and a negative pregnancy test at each study visit, "underscores the large potential for pregnancy exposure" if Qnexa is approved for weight loss, FDA says.

FDA's Maternal Health Team recommended a registry as a means to collect observational data on exposure to the drug during pregnancy and on related pregnancy and infant outcomes.

Vivus' proposed REMS would address that concern. The firm says registry would estimate the risk of major birth defects and other adverse outcomes in women exposed to Qnexa, as well as other weight-loss treatments, at any time during pregnancy.

The comparison group will be pregnant women who are obese and not exposed to any weight-loss medications. Given the negative impact of obesity on pregnancy, such as hypertension, miscarriages and congenital malformations, the registry will enable Vivus to look for benefits with its drug, as well as safety issues.

Web-Based Prescriber Training

The education program would cover the potential for misuse and over-prescribing, appropriate dosing and titration, appropriate patient selection, as well as the risk of depression, anxiety, suicidality and changes in behavior/mood; the risk of cognitive events, such as concentration and memory difficulties; acute angle closure glaucoma, metabolic acidosis and the risks of pregnancy, with messages about contraception.

To assess prescriber and patient understanding of the REMS messages, Vivus plans to conduct knowledge, attitude and behavior surveys.

A web-based program would be made available to educate health care providers. While health care providers could prescribe Qnexa without the training, Vivus plans to cross-check the names of those participating in the program with prescriber data. This would enable the company to identify those who have not participated in training so they can be targeted to receive a reminder about the importance of the training in managing patients on the drug.

Vivus also plans to monitor for adverse events of special interest - depression, suicidality, changes in mood/behavior, cognition effects, acute angle closure glaucoma and pregnancy - and standardize the reports.

Large Cardiovascular Outcomes Trial

One safety issue raised by the FDA briefing documents and not covered by the REMS is cardiovascular safety. Vivus would address that in a large cardiovascular outcomes trial if the drug is approved. Early results from an outcome study in 10,000 patients led to a CV warning for Abbott's Meridia (sibutramine) (Also see "Will A CV Warning On Meridia Alter FDA Views On Obesity Drugs?" - Pink Sheet, 30 Nov, 2009.), and that product itself also expected to go before an advisory committee this year to address ongoing safety concerns.

Eleven of the 17 voting members on the Qnexa committee will come to the discussion following two days of meeting on the CV safety issues surrounding GlaxoSmithKline's diabetes drug Avandia (rosiglitazone), and one of the issues they will be considering is directly relevant to the long-term study that Vivus is proposing. Critics have questioned the ethics of continuing the Avandia TIDE trial, which aims to determine whether the product has CV risk compared to Actos , and the Institute of Medicine has issued a brief report to help guide the agency on how to conduct post-marketing safety studies (Also see "IoM Report On Postmarketing Study Ethics Could Drive Broad Overhaul Of Informed Consent" - Pink Sheet, 9 Jul, 2010.).

For Qnexa, FDA says the clinical significance of changes in vital signs associated with Qnexa are unknown. There were small to modest mean reductions in both systolic and diastolic blood pressure in patients receiving the drug versus those receiving placebo, while Qnexa patients had small mean increases in heart rate relative to placebo, FDA says. Palpitations comprised the majority of arrhythmia-related adverse events, occurring in 12 (8%) of placebo subjects and 27 (1.7%) of high-dose Qnexa patients.

Relatively few elderly individuals or those with a history of myocardial infarction or stroke were enrolled in the trials. Four myocardial infarctions were reported among Qnexa patients versus none in the placebo subjects; four cases of coronary artery disease were reported in placebo-treatment subjects versus none in the Qnexa patients.

Vivus is seeking approval of labeling that says "Phen/TPM is indicated for the treatment of obesity, both weight loss and maintenance of weight loss, and should be used in conjunction with diet and exercise. Phen/TPM is recommended for obese patients (BMI>30 kg/m) or overweight patients (BMI>27 kg/m) with weight-related co-morbidities, such as hypertension, type 2 diabetes, dyslipidemia, or central adiposity (abdominal obesity)." The mid-dose, once daily, is the recommended maintenance dose.

-Cathy Dombrowski ([email protected] )