The completion of the second advisory committee review for Arena Pharmaceuticals Inc.’s lorcaserin marks the end of an intense period of debate over regulatory requirements for obesity therapies – and with five new drug reviews, a post-market safety review (and withdrawal) and a two-day meeting on regulatory expectations, sponsors are beginning to get a clearer picture of how FDA and its expert advisers will handle obesity drugs going forward.

The perceived lack of clarity over regulatory expectations for obesity therapies has cast a cloud over the field. Despite FDA’s issuance of a draft guidance on development standards for drugs for weight management in 2007, there has been considerable confusion over the appropriateness of both the efficacy and safety metrics – a drama that has played out at meetings of the Endocrinologic and Metabolic Drugs Advisory Committee.

The issues were made murkier when FDA took action on the three obesity drug applications that had been reviewed by the panel in the past two years – issuing “complete response” letters for all three, despite a positive advisory committee vote for one.

FDA has acknowledged that its obesity policies need to be revised, both for efficacy and safety. Efficacy metrics are presumably part of a project on treatment goals for obesity therapy hosted by George Washington Univesity that has featured participation by high-ranking FDA officials Also see "Weighty Issues: GW Obesity Outcomes Project Tests Model For Patient Input In Drug Development" - Pink Sheet, 14 May, 2012.. The furthest progress has been made on cardiovascular safety standards. The historic Achilles heel of obesity therapies, with some signals in the clinical trials of the novel agents, one of the key regulatory issues has been the necessity of cardiovascular risk assessment.

The topic has been featured at all of the advisory committee reviews, and was the subject of a two day meeting of its own in March Also see "Obesity Drugs’ CV Risk Assessment Needs Hard Endpoints, Panel Tells FDA" - Pink Sheet, 2 April, 2012..

But in the recent re-reviews of Qnexa and lorcaserin, it appears that FDA and the expert panel are getting more in line on what constitutes a CV safety signal and whether it warrants an outcomes trial before approval.

A post-market study proved the undoing of Abbott Laboratories Inc.’s Meridia (sibutramine). The company pulled the drug from the market after the Sibutramine Cardiovascular Outcomes Trial found a slightly higher rate of cardiovascular events, including heart attack, stroke, resuscitated cardiac arrest or death with the drug compared to placebo and the company failed to show an offsetting benefit Also see "REMS Cannot Save Abbott's Obesity Drug Meridia In Face Of Cardiovascular Issues" - Pink Sheet, 8 October, 2010..

The lorcaserin session was the third time this year the panel discussed CV safety in weight-loss drugs. This most immediately impacts the pending NDAs for Vivus Inc.’s Qnexa (phentermine/topiramate) and Orexigen Therapeutics Inc.’s Contrave (naltrexone/bupropion), as well as the Arena therapy.

Going into the two-day session devoted solely to CV risk, FDA said drugs with an identified CV signal must be studied in an outcomes trial before going to market. The committee then recommended that even for drugs without a signal, a specific degree of risk should be ruled out pre-approval, with a tighter risk standard ruled out post-marketing Also see "CV Risk Assessment For All Obesity Drugs Seems Inevitable Pre-Approval Requirement" - Pink Sheet, 30 March, 2012..

That approach is taken in guidance for diabetes drugs Also see "FDA’s Diabetes Guidance On CV Risk Will Get First Test With Pending NDAs" - Pink Sheet, 22 December, 2008.. In the diabetes space, sponsors must rule out an 80% increase in CV risk pre-approval and a 30% increase post-approval.

Lorcaserin CV Data Scant But Reassuring

In the case of lorcaserin, which the committee supported approving 18-4 (one abstention), panel members said post-market studies of heart safety would be sufficient Also see "Lorcaserin Safety Questions Can Be Answered In Post-Market Study, Panel Tells FDA" - Pink Sheet, 11 May, 2012.

The CV study requirement had been in question because lorcaserin’s development program was designed before pre-approval CV risk-assessment became an issue and the clinical trials accrued minimal data on the medication’s risk for major adverse cardiovascular events.

To provide an assessment despite the data shortcomings, Arena did a post hoc analysis of events identified through searches using Medical Dictionary for Regulatory Activities terms. A broad search for hemorrhagic cerebrovascular conditions, ischemic cerebrovascular conditions and ischemic heart disease found 25 events in the arm receiving 10 mg twice a day, the dose proposed for marketing, and 23 in the placebo arm, producing a point estimate of 1.08 (95% CI, 0.81, 1.91). A narrow search for ischemic cerebrovascular conditions and myocardial infarction found 15 events in the treatment arm and 19 in the placebo arm, producing a point estimate of 0.78 (95% CI, 0.40, 1.54).

Adjudication by a cardiovascular clinical events committee lowered the number of relevant events to five in those receiving lorcaserin and six in those receiving placebo, producing a point estimate of 0.85 (95% CI, 0.25, 2.73).

Arena also reported favorable movement in cardiometabolic parameters, including systolic and diastolic blood pressure and heart rate, for those receiving lorcaserin.

The panel found the limited information reassuring. A look at the broad search finds the point estimate is close to null and the upper bound is 1.9, Sanjay Kaul, Cedars-Sinai, pointed out. The adjudicated events also have a reassuring point estimate, he said. “It’s going in the right direction.” The upper bound is 2.73, but that is influenced by the number of events, he pointed out. Requiring CV studies prior to approval would be moving the goal posts, he contended.

William Hiatt, University of Colorado, said: “If you just take these numbers alone out of context, the point estimates are fine, the upper bounds don’t quite get it.” But, he added, the absence of adverse effect on blood pressure and other parameters make a post-approval study appropriate.

FDA is amenable to using a post hoc review of CV events to look for a CV signal for drugs with a pending application, similar to how it handled pending diabetes drugs when it changed policy to require pre-market CV outcomes trials.

Office of Drug Evaluation II Director Curtis Rosebraugh indicated FDA is amenable to a post hoc review of CV events as a suitable method of looking for a signal for drugs with pending applications. The agency took a similar approach with diabetes drug applications that were pending when FDA issued its guidance, which the advisory committee supported, he said.

When FDA brought Bristol-Myers Squibb Co.’s Onglyza (saxagliptin) to the advisory committee, he pointed out, “there was a lot of discussion with the panel that of course it probably was not what we would want to see prospectively, but it kind of fulfilled the spirit of what had been recommended by the panel, and so they felt that using those sort of terms for applications that were in-house, not the ones that would be coming in in the future, was probably okay.”

Erica Brittain, a statistician at the National Institute of Allergy and Infectious Diseases, voiced concern about whether a trial could be conducted with a placebo arm once the drug reaches the market.

It is doable, Rosebraugh reassured her. “We have another obesity drug that’s going to be doing a trial. … The designs are a lot different than with the diabetes drugs, but I think it is feasible to do one.”

Qnexa Study Post-Approval

Earlier in the year, the panel endorsed Qnexa approval after its second look at the drug, with the understanding that a CV study would be conducted post-marketing Also see "Panel Favors Qnexa Approval, Given Strong Efficacy, Certainty Of Post-Approval CV Study" - Pink Sheet, 22 February, 2012..

FDA has not yet taken action on that application, but Vivus has submitted a Risk Evaluation and Mitigation Strategy, which usually is one of the last things to come up in NDA discussions.

With Qnexa, the panel again was confronted with a clinical program that produced scant information on CV events. Data on cardiovascular parameters was mixed. While data on blood pressure was positive, the heart rate of some patients increased. In this case, strong efficacy played a role.

“Of all the obesity drugs, this drug has the highest efficacy in terms of weight loss. So that somehow shifts the balance more in favor of requiring a post-approval study, rather than a pre-approval study,” Kaul concluded.

Pre-Approval Study For Contrave

Contrave is the one drug among the three pending weight-loss medications facing a pre-approval cardiovascular outcomes trial. The advisory committee recommended approval with a post-marketing CV trial for Contrave during its first-cycle look at the drug, even though the product failed to provide the improved blood pressure and pulse levels typically associated with weight loss Also see "Panel Continues To Push For Obesity CV Guidance As It Backs Contrave Approval" - Pink Sheet, 13 December, 2010..

FDA, however, decided the study should be conducted pre-approval and Orexigen has committed to a trial with 10,000 obese or overweight (with at least one co-morbidity) patients. If an interim analysis excludes a doubling of the CV risk, the company could resubmit its NDA as early as 2014 Also see "Orexigen Agreement On Contrave CV Trial Hints At FDA’s Thinking On Obesity" - Pink Sheet, 26 September, 2011..

In terms of identifying a CV signal upfront, Division of Metabolism and Endocrinology Products Deputy Director Eric Colman said during the March meeting it could come from animal studies or the clinical program.

Ellen Seeley, Harvard Medical School, protested that sponsors could not design studies to pick up a signal unless they know what to look for.

The agency looks at the traditional risk factors, Colman responded. “We look at blood pressure. We look at pulse. We look at all the various lipid parameters, glucose, insulin sensitivity. We would have that data by the end of the Phase II study. So we have a group of factors that we look at and that would allow us to get some sense of whether or not we needed to have a discussion with the company along the lines of, ‘this may require future study and an outcomes trial.’”

Whatever the findings of the Contrave trial, the resubmission will necessitate another review by the Endocrine and Metabolic Drugs Advisory Committee – and offer another opportunity to revisit FDA’s emerging requirements for obesity drugs.

Recent Round Of Obesity Reviews Suggests CV Safety Standards Have Come Into Focus

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