FDA Panel To Weigh Relevance Of Liraglutide’s Diabetes Experience In Obesity

Agency will ask external advisors Sept. 11 how the GLP-1 agonist’s safety in type 2 diabetes, approved as Victoza in 2010, informs the safety profile in obesity, where Novo Nordisk is seeking a higher dose and a different name.

FDA is seeking the Endocrinologic and Metabolic Drugs Advisory Committee’s input on the extent to which the safety of Novo Nordisk AS’ liraglutide can be extrapolated from its approval in type 2 diabetes to a new use in obesity.

In particular, FDA seeks the panel’s views on allowing liraglutide to be used in the first-line setting for weight management and whether an ongoing cardiovascular outcomes trial in diabetes would be sufficient to assess safety of the glucagon-like peptide-1 receptor agonist in obesity.

At the Sept. 11 meeting, FDA will ask the panel to discuss the safety database for liraglutide 3 mg per day – the dose to be marketed for obesity under the trade name Saxenda – given the extent of clinical trial and post-marketing experience with liraglutide doses of up to 1.8 mg for diabetes, where the drug has been marketed as Victoza since 2010.

The necessity for separate neoplasm epidemiology and CV safety studies specific to the obesity population will be up for discussion.

“How does the experience with liraglutide for diabetes mellitus inform the safety profile of liraglutide 3 mg per day for chronic weight management, given the different patient populations and doses,” FDA asks in draft questions released Sept. 9.

The agency also seeks the committee’s views on the adequacy of the efficacy data and various safety concerns, including neoplasms and gallbladder-related events. FDA poses one voting question: whether the overall risk/benefit assessment supports a chronic weight management indication.

Moving From Diabetes To Obesity

Novo Nordisk submitted an NDA in December 2013 seeking an obesity indication for liraglutide (Also see "Liraglutide’s FDA Panel For Weight Loss Is Test Of Diabetes Experience" - Pink Sheet, 1 Aug, 2014.). The proposed indication includes several limitations of use (see box).

The company believes its portfolio in the diabetes category makes it well-positioned for entry into the obesity market, a therapeutic area that has proven commercially challenging for two recent products: Vivus Inc.’s Qsymia (phentermine/topiramate ER) and Eisai Inc. and Arena Pharmaceuticals Inc.’s Belviq (lorcaserin) (Also see "Novo Nordisk Lays Out Obesity Commercial Strategy, Ahead of Liraglutide FDA Submission" - Pink Sheet, 4 Dec, 2013.).

Saxenda’s Proposed Indication

Saxenda is indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m² or greater (obese), or 27 kg/m² or greater (overweight) in the presence of at least one weight related comorbidity such as hypertension, dysglycemia (prediabetes and type 2 diabetes mellitus), dyslipidemia or obstructive sleep apnea.

Limitations of Use:

• In clinical trials of Saxenda, there were more cases of pancreatitis with Saxenda than with comparators. Based on spontaneous post-marketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with liraglutide marketed as Victoza. Saxenda has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Saxenda.
• The effects of Saxenda on cardiovascular morbidity and mortality has not been established.
• The safety and effectiveness of Saxenda in combination with other prescription and over the counter drugs intended for weight loss has not been established.

In an ironic twist of timing, FDA’s external advisors will convene to consider liraglutide’s efficacy and safety on the same day the agency is expected to take action on Orexigen Therapeutics Inc. and Takeda Pharmaceutical Co. Ltd.’s NDA for the obesity drug Contrave (naltrexone sustained-release/bupropion sustained-release) (Also see "Orexigen’s Big Plans On Hold As FDA Hashes Out Post-Marketing Requirements" - Pink Sheet, 11 Jun, 2014.).

FDA’s review of liraglutide for weight management does not appear to raise any major concerns about efficacy, although a statistical review that accounted for drop-outs in a different fashion did reduce the magnitude of estimated treatment effects seen in the primary analysis.

Using the prespecified analysis, a statistically significantly greater proportion of liraglutide-treated patients compared to those given placebo achieved at least 5% and 10% weight loss from baseline in five trials, clinical reviewer Julie Golden said. “In addition, all trials met the categorical efficacy standard (proportion of 5% responders in active-treatment group is at least 35% and approximately twice the proportion in the placebo-treatment group) as outlined” in FDA’s 2007 draft guidance on weight management drugs.

Neoplasms And CV Safety

If FDA’s questions to the panel are any indication, safety issues will be the major focus of attention at the meeting.

FDA’s 2010 approval of Victoza as a once-daily injectable treatment for type 2 diabetes came with a boxed warning about thyroid C-cell tumors observed in rodent studies, a Risk Evaluation and Mitigation Strategy and post-marketing study requirements that included a CV safety outcomes trial and an epidemiological study to evaluate thyroid cancer risks (Also see "FDA Clears Victoza, But Warnings And More Studies Pose Hurdles" - Pink Sheet, 26 Jan, 2010.).

In its questions to the committee, FDA notes that Victoza is not recommended as first-line therapy for those who have inadequate glycemic control with diet and exercise because of the thyroid C-cell tumor findings in rodents.

“If the current application were approved as proposed, it would be presumed that there would be no recommendation against using liraglutide 3 mg per day as initial therapy, for weight management, for patients with diabetes mellitus with BMI 27 kg/m² or greater,” FDA’s draft questions state. “Discuss the implication of this overlap in population and any concerns it may raise.”

The four Phase III weight-management trials were tracked for neoplasms. “Overall, adjudicated malignancies occurred at a similar rate in liraglutide- and placebo-treated groups,” Golden said. “A numerical imbalance favoring placebo was noted for breast cancer.”

There were five adjudicated thyroid neoplasm events reported during the main treatment period in the liraglutide group compared to one in the placebo arm, Golden said.

Division of Epidemiology reviewer Christian Hampp said thyroid cancers occurred somewhat more frequently in the liraglutide clinical program than would be expected in an age- and sex-standardized U.S. population.

Hampp noted that a post-marketing observational study is currently ongoing to determine the incidence of thyroid cancer among patients with type 2 diabetes exposed to liraglutide. “Conduct of a separate study focused on a weight-loss indication may be challenging due to limited ability to detect the indication in electronic health care data, despite different doses of the drug and different product names used for diabetes and proposed for weight loss. Should liraglutide be approved for weight loss, I do not recommend a separate observational study for cancer with the use of liraglutide as a weight-loss agent.”

However Hampp said that if a separate CV outcomes trial is being considered for liraglutide as a weight-loss agent, such a study should include adjudication and analysis of malignant neoplasms.

FDA is asking the advisory committee whether a second CV outcomes trial would be needed.

In the ongoing CV safety trial for Victoza, the maximum dose used is 1.8 mg per day. “Discuss whether this trial would be sufficient to characterize the CV risk of liraglutide 3 mg per day for weight management,” FDA said in a question to the committee.

In an analysis of CV event data from Phase II and III studies in weight management, liraglutide was associated with a non-statistically significant 60% reduction in the risk of major adverse cardiovascular events (comprising nonfatal myocardial infarction, nonfatal stroke and CV death), with the upper bound of the 95% confidence interval of 1.05. However, this was based on just 17 events.

“Point estimates for the hazard ratios of the MACE components were consistent with the composite. An on-study analysis (19 events), and an analysis that combined events from weight management and T2DM trials (66 events), were consistent with the primary analysis,” Golden said.

Golden’s review notes, however, that liraglutide was associated with an increase in resting heart rate at study visit in clinical trials, and this increase became more pronounced with continuous heart rate monitoring in a clinical pharmacology trial.

Liraglutide also was associated with an imbalance in gallbladder events in the weight-management trials, an effect which is not currently a labeled adverse reaction for Victoza.