Can Vivus Get Away Without Outcomes Study Of Obesity Drug Qsymia?

Fixed-dose combination of phentermine and topiramate is FDA-approved for chronic, long-term use, but the average duration in the real world is only about 2.1 months, which is reassuring for Qsymia’s cardiovascular safety, according to a new retrospective claims study.

Vivus Inc. is discussing results from a retrospective study of claims data for its obesity drug Qsymia with the US FDA, in hopes that the results may be incorporated into labeling and "reduce or modify the need for a cardiovascular outcomes study," the company said Jan. 14.

Approved by the FDA in 2012, Qsymia (phentermine/extended release topiramate) is cleared for use with diet and exercise for chronic weight management in adults with a body mass index of 30 kg/m² or more or 27 kg/m² or more and at least one weight-related comorbidity, such as hypertension or diabetes.

The limitations of use section of labeling advises that the effect of Qsymia on cardiovascular morbidity and mortality has not been established and that the safety and effectiveness of Qsymia in combination with other products intended for weight loss, including prescription and over the-counter drugs and herbal preparations, have not been established.

A study of medical claims data that the company says supports Qsymia's safety profile in people taking the combination compared with those who were former users will be printed in the February issue of the Journal of Clinical Endocrinology & Metabolism; initial results were published online earlier.

Vivus submitted a request in early 2017 for a labeling change to focus on short-term rather than chronic use, but a user date of Nov. 28 for the supplemental filing passed with no action.

“We intend to include these findings in our ongoing discussions with the U.S. Food and Drug Administration related to our requested label modification for Qsymia. The requested modification would allow for the safe and effective short-term use of Qsymia and could potentially reduce or modify the need for a cardiovascular outcomes study," the company said in its Jan. 14 announcement about the results.

In clinical studies, an elevation in heart rate had been detected for patients on the combination compared with patients on placebo, but the company suggested that the beneficial effects on weight, blood pressure, lipids and glycemic measures offset that effect.

The elevation in heart rate raised concerns during a meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee in 2012. However, panelists reviewing the drug were reassured that a post-approval cardiovascular outcomes study would be mandated and gave the drug the go-ahead.  (Also see "Panel Favors Qnexa Approval, Given Strong Efficacy, Certainty Of Post-Approval CV Study" - Pink Sheet, 22 Feb, 2012.) A long-term outcomes study to assess the risk for cardiovascular events was one of 10 post-marketing requirements attached to the approval.

Upon approval in 2012, the agency issued a statement advising against the use of the drug in patients who recently had unstable heart disease or stroke and regular monitoring of heart rate. (Also see "FDA Approves Vivus’ Obesity Drug, Recommends Against Use In High-Risk Heart Patients" - Pink Sheet, 17 Jul, 2012.) A long-term outcomes study was never started.

No Definitive Conclusions In Retrospective Claims Study

The retrospective study examined the records of more than 500,000 patients, comparing risk for major adverse cardiovascular events (MACE) of current users to those who stopped taking the medication, using records from Truven Health MarketScan Databases, which include commercial and Medicare claims. The study was funded by Vivus and carried out by RTI Health Solutions. Researchers looked at phentermine (PHEN) with topiramate (TPM) as separate components taken together, the PHEN/TPM fixed combination (Qsymia), and PHEN and TPM individually.

They used discharge status and medical billing codes to evaluate the rates of MACE, defined as hospitalization for acute myocardial infarction or stroke or in-hospital cardiovascular-related death, between 2012 and 2015.

"Most patients initiating PHEN/TPM (76%) were fixed PHEN/TPM users. Compared with the unexposed cohort, patients initiating PHEN/TPM were older and more likely to have a recorded history of obesity. In addition, patients initiating PHEN/TPM were more likely than the unexposed cohort to have hypertension, hyperlipidemia, diabetes, and sleep apnea," the article noted.

Researchers reported that the MACE rates among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users, whereas the rate of MACE among current users of TPM was greater than among unexposed former users.

There were fewer than 10 events in total for those on phentermine/topiramate or formerly on this regimen, so the results are difficult to interpret.

Phentermine/topiramate was not associated with a higher cardiovascular risk, but because there were so few MACE events during 3,245 person-years of follow-up, it is not possible to "draw a definitive conclusion from the data," the company reported.

However, the agency tends to be fastidious about cardiovascular outcomes trials (CVOTs). Furthermore, Vivus’ statement includes a comment from co-author Peter Kowey, Jefferson Medical College in Philadelphia, that “the confidence intervals for this observation were broad, indicating that the data were imprecise and compatible with a considerable range of possible effects.”

Investors appear encouraged, however. The company's stock price opened at $3.31 and closed at $4.45 on Jan. 14. On Jan. 15, it closed up by 2.9% at $4.58.

Sales Still Very Low

Vivus' Qsymia has struggled with slow sales from the get-go and the company has long floated the idea of less expensive safety studies as an alternative to an outcomes study. (Also see "Is Vivus worth saving?" - Scrip, 31 Jul, 2015.) Vivus reported only $9.7m in sales for Qsymia for the third quarter, down from $9.9m in the year-ago period.

When Qsymia was first launched, a number of Wall Street analysts thought the product was going to be worth up to $2.5bn, but obesity drugs have failed to gain traction.

The federal government views obesity as a lifestyle disease and this has influenced reimbursement. Consequently, it's largely a cash pay drug, CEO John Amos explained during a Jan. 9 presentation at the Biotech Showcase, held in San Francisco in parallel with the J.P. Morgan Healthcare Conference. Vivus is selling the drug for about $100 per month, which market research suggests is appropriate for an out-of-pocket expense for obesity, he added.

Cardiovascular outcomes trials are required for all new obesity drugs and diabetes drugs.

Eisai Co. Ltd. and partner Arena Pharmaceuticals Inc. reported in August that their obesity drug Belviq (lorcaserin HCl), a 5-hydroxytryptamine serotonin 2C receptor agonist that also was approved in 2012, was not associated with a higher risk of cardiovascular events in the CAMELLIA-TIMI 61 CV outcomes study. (Also see "CAMELLIA Adds To Belviq’s CV Confidence But ‘Caution’ Still Needed " - Scrip, 28 Aug, 2018.)

Although a randomized, prospective outcomes study was requested for regulatory purposes, usage of the fixed-dose combination of phentermine and topiramate is low and "performance of a randomized study of medications in a post-market setting is difficult, especially for CV event outcomes," Ritchie and colleagues said in the article about the retrospective study.

"With low drug uptake and rare outcomes, a retrospective observational database study is an efficient method to generate information on the safety of fixed-PHEN/TPM in usual clinical practice in a much shorter time than would be possible with a prospective study," the article states.

The FDA has acknowledged that observational studies using databases are effective for gathering safety information in clinical practice in a much shorter time frame, the article notes.

"The present study was also prespecified via protocol and conducted in accordance with both regulatory and international society guidelines for observational database studies," Ritchie and colleagues said.

"It included outcome measures previously validated within claims data. In an era in which regulators are calling for increased use of real-world evidence for regulatory decision-making, the present database analysis has provided timely data on a large number of patients in a manner that is actionable," in the sense of ruling out the doubling of MACE risk for patients on phentermine with topiramate.

"Furthermore, the insights gained from the present study were obtained within several months, rather than over several years," the authors said.

The article also notes that while the fixed-dose combination is approved for chronic long-term use, the average duration of use for current users in the study was only 2.1 months, similar to the amount of time phentermine and topiramate are used individually.

"These durations of use were shorter than those in the premarket clinical trials but presumably reflect actual clinical patterns of use and might further decrease any concerns about the risk of CV outcomes," the article says.

In an interview, CEO Amos explained that in the real world patients go through cycles where they use the drug for a period, lose weight and then go off it, believing they are able to maintain a new healthier lifestyle, including good eating habits, but then they may find they need to use a pharmaceutical again.

The efficacy reflected on the label is "pretty tremendous," and the company is trying to identify better ways to utilize the product to help deal with the obesity epidemic, the exec said.

Even though the just-published claims data are not definitive, Vivus believes a long-term outcomes study is not necessary. In addition to studies evaluating use for up to two years showing no harm, the company has been monitoring safety closely through a Risk Evaluation and Mitigation Strategy (REMS) and there has been no safety signal.

"This is a safe product – it is not a new chemical entity, it's phentermine and topiramate and both of those products have been available on the market from well before the '90s. There is a body of evidence and body of safety data out there regarding these products," Chief Medical Officer Santosh Varghese told Scrip.

Biomedtracker analysts are skeptical about prospects for a label change and an improved commercial outlook.

"While avoidance of a full-length CVOT could avoid a large expense, it seems unlikely that the label change for the drug would at this point lead to dramatic changes in use of the beleaguered drug, though it could help some. Since phentermine is approved for short term use, those who use Qsymia may already figure it is OK for that," the analysts said.