“Lemons for Obesity” Or Sour Grapes? A Key Dissent on Qnexa, With a Twist of Avandia

NIH Cardiologist Michael Lauer takes a page out of the Cleveland Clinic playbook and rips an advisory committee for recommending approval of Vivus’ Qnexa for weight loss without demanding a pre-market outcomes study. But this is no Avandia: Cleveland Clinic cardiologist Michael Lincoff is on the other side of this debate.

When Vivus Inc. returned to the Endocrinologic & Metabolic Drugs Advisory Committee on February 22 to try to win a vote in favor of approval of the weight loss therapy Qnexa (phentermine/topiramate), the company had a very strong advocate on its side: Michael Lincoff, the current chair of the Cardiovascular & Renal Drugs Advisory Committee.

Lincoff gave a “cardiologist’s perspective” on the Qnexa application near the end of Vivus’ presentation. He tackled head-on one of the two key questions under consideration: should Vivus be required to do a pre-market cardiovascular outcomes study for Qnexa, or would a proposed post-market study suffice?

Lincoff offered his views for why the totality of the data for Qnexa suggest a very good cardiovascular profile, and specifically why—in his view—a modest increase in heart rate should not be interpreted as an indication of potential risk. Instead, he argued, the more relevant factor is the blood pressure/heart rate product, which suggests an overall beneficial effect of the drug.

Lincoff spoke up throughout the meeting on the feasibility of doing a post-approval outcomes study—and noted he had agreed to serve as the primary investigator. The vast majority of the committee was reassured; the vote in favor of approving Qnexa was an overwhelming 20-2. (Also see "Setting the Stage: Qnexa and the Power of REMS" - Pink Sheet, 1 Mar, 2012.)

Clearly, having the current chair of the Cardio-Renal Advisory Committee on your side surely helps any sponsor addressing a CV safety question.

But it isn’t just Lincoff’s chairmanship that made him a great choice for the sponsor. Lincoff’s day job is vice chair of the Department of Cardiovascular Medicine at the Cleveland Clinic. It is in that capacity that he will be conducting the outcomes trial on behalf of Vivus—and the value of an implied endorsement of the Cleveland Clinic for the sponsor’s plans cannot be overstated.

After all, the focus on CV outcomes for Qnexa (and for the weight loss category overall) is a direct result of the firestorm touched off by the Cleveland Clinic Cardiology Department Chair Steve Nissen in critiques of diabetes safety standards, first in a paper challenging the CV safety profile of Bristol-Myers Squibb Co.’s Pargluva (which cleared the E&M committee but was rejected by FDA) and then in a meta-analysis of the CV outcomes data for Avandia.

It is no exaggeration to say that the entire review of Qnexa has happened in the shadow of Avandia: the first E&M committee review of the weight loss application took place the day after a two-day marathon debate over the marketing status of the diabetes drug. (Also see "Weighing the Regulatory Climate: Qnexa and the New Approval Model" - Pink Sheet, 1 Sep, 2010.) And the re-review occurred just ahead of a two-day discussion in March of expanding the CV standards imposed on the diabetes class because of Avandia into the weight loss category. (Also see "The Inevitable Outcome: Diabetes Safety Model Expands to Weight Loss…and Beyond?" - Pink Sheet, 1 May, 2012.)

So the involvement of Cleveland Clinic in the Qnexa application tells FDA and especially the Endocrine & Metabolism Drugs Division that it will not face second-guessing from that center if it gives Qnexa a pass from the safety standard and approves it with a post-marketing requirement.

Unfortunately for FDA, that does not mean the agency can expect to be immune from criticism from a prominent cardiovascular clinical trial organization if it does indeed approve the drug. The Cleveland Clinic cardiology department may be aligned with the sponsors in this case, but not the head of the National Heart, Lung & Blood Institute Division of Cardiovascular Science, Michael Lauer.

An Important “No” Vote

Lauer was one of the two “no” votes on the panel, and—as one of the few cardiologists participating, it was a “no” that carried added weight.

Lauer raised two critical objections to allowing Qnexa on the market without outcomes data.

First, he refused to accept the reassurance offered by Lincoff about the heart rate increase, insisting that “heart rate is one of the best biomarkers we have.” While Lauer agreed that other surrogate markets (like blood pressure and lipids) look “reassuring,” that just means “we find ourselves in a very confusing place.”

Secondly, Lauer objected to the premise that a post-marketing study could be completed as quickly and easily as Lincoff suggested. Pointedly noting his status as head of a National Institutes of Health clinical trials unit, Lauer said that “we run a lot of clinical trials” and they “always run into problems enrolling subjects.” Those problems will only be enhanced by approving the agent, he said, since “people will interpret it to mean the drug is safe and effective” and will have no incentive to join a trial where they may be randomized to placebo.

Adding another layer of subtext to the differences between Lauer and Lincoff: the two used to be colleagues, with Lauer having been director of clinical research in the cardiology department at the Cleveland Clinic before joining NHLBI.

“The public health issue here is enormous,” Lauer emphasized. Qnexa will “likely be prescribed to millions or tens of millions” so the “consequences of making a mistake here are huge.” And, he added, alluding to the troubled history of weight loss drugs, “unfortunately, we have made a mistake before.”

Lauer’s arguments clearly did not carry the day. The majority view was reflected by Cedars-Sinai cardiologist Sanjay Kaul, who stressed that the significant efficacy of the drug and the lack of available therapies for the morbidly obese population outweigh the important need to rule out CV risks. Kaul supported a post-market study, but stressed that it would be reasonable for FDA to conclude that a pre-market study is in fact required.

Importantly, Kaul did not disagree with Lauer on the importance of heart rate as a signal; Kaul just sees the public health benefit from an effective weight loss agent as offsetting the public health risk if that signal translates into excess CV events.

That dialogue leaves open the possibility that FDA would overrule the panel as it did when the same committee explicitly voted that Orexigen Therapeutics Inc.’s Contrave (bupropion/naltrexone) does not need a pre-market CV outcomes study despite a small increase in blood pressure associated with the therapy. Nissen, in fact, is the primary investigator on the Contrave outcomesstudy.

However, there hasn’t been any indication of that so far. FDA did extend the Qnexa review by three months, setting a July 27 deadline for action. However, according to Vivus, that extension related to ongoing work to define a Risk Evaluation & Mitigation Strategy for the product. In addition, Lauer was not invited to the March 28-29 panel that discussed CV outcomes for weight loss—a notable absence given his point of view on the Qnexa panel.

Taking a Page From the Nissen Playbook

Lauer, however, isn’t letting his vote speak for itself. Instead, he took a page from the Cleveland Clinic playbook and published an article in the Annals of Internal Medicine entitled “Lemons for Obesity.” The article appeared online on April 9.

In the article, Lauer recounts his participation in the February 22 Qnexa review and argues that the weight loss category has a history of “lemons”—and that the only wise course is to demand that new drugs prove they are “peaches” before they can be approved.

In the case of Qnexa, Lauer notes the incredibly small number of cardiovascular events seen in clinical trials, and repeating his assertion that “it is impossible to draw any conclusions” about the drug’s CV profile based on that “tiny sample.”

“We cannot assume that an absence of excess cardiovascular events in small trials—trials that yielded only 12 outcome events—means that we can confidently conclude that Qnexa is safe,” Lauer wrote. Nor, he argues, can we ignore the prior history of weight loss drugs with adverse cardiovascular effects.

That means, Lauer wrote, “insisting on a large-scale, preapproval cardiovascular outcomes trial of Qnexa.”

“It would be too risky to rely on post-approval surveillance or to hope that a rigorous trial could be conducted in a timely manner,” he concluded. “If Qnexa prevents cardiovascular events, or at least doesn't increase the risk for them, in a preapproval trial, then we will all know that we have the peach we've been waiting for.”