New Paradigm Would Open More Avenues To Obesity Drug Approval

Assessments of obesity drugs should look at their effects in patients grouped by health status and FDA should expand the universe of secondary endpoints available to assess benefits, a group of stakeholders says.

A new paradigm for obesity drug approval envisioned by a group of stakeholders would broaden the opportunities for obesity drug development by targeting indications to patient subgroups with differing risk/benefit considerations and by expanding the spectrum of health improvements considered in the approval equation.

If FDA were to adopt the new framework, the agency and sponsors would target various obesity subpopulations, rather than the obesity population as a whole – so a drug found to have risks that could be deemed inappropriate for obese patients with few or no health problems could be approved for those with a high illness burden.

The panel of stakeholders convened by The George Washington University School of Public Health and Health Services outlines the approach in a consensus report “Obesity Drug Outcome Measures,” released Aug. 14. Four FDA officials, including Center for Drug Evaluation and Research Director Janet Woodcock and Office of New Drugs Director John Jenkins, participated in discussions leading up to the report, but were not asked to sign the document.

The stakeholders “recognized that if we can target [drug reviews] more directly to the true clinical presentation, … we may be able to open up more possibilities for drug approvals,” Jeff Levi, executive director for the Trust for America’s Health, explained during a webinar discussion of the report by several members of the stakeholder group.

Obesity Population Is Not Monolithic

An impetus for the framework was members’ agreement that the obesity population is not monolithic, but contains a spectrum of patients ranging from those who are well or have minor impairments to those who are very ill, and drug reviews should reflect this with a “patient-centered” approach to drug approval, he said.

“Different groups of people may have very different potential benefits of treatment as well as different levels of acceptable risk” for the therapy, pointed out Scott Kahan, of GW and Johns Hopkins University.

The group’s report comes as FDA recently broke the more than decade-long drought in entrants to the obesity space and approved two drugs with a general indication: chronic weight management in adults who are obese or who are overweight and have at least one weight-related co-morbidity.

FDA approved Arena Pharmaceuticals Inc.’s Belviq (lorcaserin) in June (Also see "What Belviq Labeling Means For Other Obesity Drug Sponsors" - Pink Sheet, 2 Jul, 2012.). Vivus Inc. received the go-ahead for Qsymia (phentermine/topiramate) in July (Also see "Qsymia Sales Reps Recruited For Experience With Metabolic Products" - Pink Sheet, 23 Jul, 2012.). Orexigen Therapeutics Inc. reports that it expects to reach the interim analysis point in the cardiovascular outcomes trial for Contrave in the second half of 2013, with possible approval as early as the first half of 2014. [Editor’s Note:This story was changed to clarify that Orexigen expects to reach the interim analysis point in the CV trial in the second half of 2013, not by mid-year]. Contrave(naltrexone/bupropion) is the third in the trio of obesity drugs that have been seeking FDA approval since the end of 2009 (Also see "Orexigen On Quicker-Than-Expected Pace To Obtain Data Needed To Re-File NDA For Contrave" - Pink Sheet, 7 Aug, 2012.).

Patients in clinical trials for those drugs were classified by whether they were overweight or obese, as measured by Body Mass Index, and whether they had a weight-related co-morbidity. But that assessment is too simplistic, according to the stakeholders.

Characterizing Obese Patients

The panel of stakeholders convened by The George Washington University suggests obese patients could be put in three categories, based on their health status, for purposes of assessing whether an obesity drug’s benefits outweigh its risks:

• Obese and Well – those who carry excess weight but who do not have any co-morbidities or risk factors for co-morbid conditions and are not impaired in daily feeling or functioning;
• Obese with Risk Factors – patients who carry excess weight and who have measurable risk factors for co-morbid conditions and/or impairments to their daily feeling or functioning; and
• Obese and Sick – those who carry excess weight and who have one or more obesity-attributable co-morbidities and impairments to their daily feeling or functioning.

Instead of BMI, the panel proposes FDA characterize obese patients’ by their health status and review drugs accordingly. One characterization option, the panel suggests, is a three-tiered characterization system based on health status. Another alternative, the panel says, is the Edmonton Obesity Staging System from Alberta Health Services and the University of Alberta.

Instead of being faced with an all or nothing situation, subcategorizing patients would allow FDA to approve a riskier drug for those who already have one or more co-morbidities, but eliminate healthy obese patients from the scope of its approval. “FDA could potentially make drugs with possible serious adverse side effects available to those with significant medical need while limiting or restricting use among other patients,” the report says, “without having to deny approval for the drug across the entire population.”

How To Limit Off-Label Prescribing?

A key to making this approach effective is eliminating off-label prescribing to inappropriate patients. The panel offers no silver bullet, but suggests FDA look at adapting a proposal from the Infectious Diseases Society of America to speed development of antibiotics for highly resistant bacteria by approving them with an indication for a limited population (Also see "Antibiotics Approval Changes GAINing Acceptance; PDUFA May Not Get LPADed Out" - Pink Sheet, 17 Apr, 2012.).

If FDA approved an obesity drug using this framework, the therapy could be indicated as “not to be prescribed off-label,” the group says, conceding that this approach “requires further data to determine if it would be effective.”

FDA can require a Risk Evaluation and Mitigation Strategy to minimize harm, an approach taken with Qsymia to address the teratogenic potential of the drug’s phentermine component (Also see "REMS For Qsymia Limits Distribution, But Vivus To Explore Expanding Access" - Pink Sheet, 23 Jul, 2012.). But, the panel notes, REMS were not intended to address off-label prescribing and may be inadequate for the task.

Obesity Drug Benefits Beyond CV

A second prong to the panel’s quest for more obesity drug approvals is for FDA to move beyond the current focus on weight loss and changes in cardiometabolic parameters and give greater consideration to secondary endpoints that reflect a patient’s feeling and functioning.

Alleviation of symptoms, such as joint pain and urinary incontinence, and functional limitations, such as decreased mobility, “in and of themselves might warrant approval,” the stakeholder report says.

Often, patients are most impacted by quality of life issues, such as mobility and pain, Joseph Nadglowski, CEO of the Obesity Action Coalition, pointed out, so measurement of hypertension and diabetes parameters do not give a complete picture of how weight loss improves an individual’s condition.

“If a drug induced a modest weight loss, perhaps not even meeting the current FDA threshold, but that same drug, concomitant with that modest weight loss, had a major effect on mobility,” adding those benefits to the risk/benefit equation “would work to the benefit of the patient and look at the totality of the effect of the agent,” contended Neil Gesundheit, Stanford University.

The report suggests FDA update its guidance “to include improvements in feeling and functioning domains, for which validated means of measuring such improvements exist, as appropriate and optional secondary endpoints” that would be part of the benefit/risk calculation. The stakeholders provide a list of potential secondary endpoints.

In the run up to the recent obesity drug approvals, FDA has acknowledged frustration with its existing obesity approval standards (Also see "Panel Continues To Push For Obesity CV Guidance As It Backs Contrave Approval" - Pink Sheet, 13 Dec, 2010.).

The agency and its advisory committee indicated they are searching for reasons why obesity drugs are clinically meaningful, Preston Klassen, head of global development at Orexigen, explained in an interview. FDA wants “to more fully understand the clinical meaningfulness of different amounts of weight loss and so these added benefits always add information that is useful to that broader risk/benefit equation,” he said.

Although FDA was only an observing participant in the stakeholder group, their contribution to the discussion was quite helpful in understanding the agency’s perspective, said Klassen, who participated in the stakeholder panel. “It was helpful to hear their comments about the types of measures and benefits that they think about, that they would love to see exhibited … so it’s pain and it’s mobility and it’s sleep apnea and it’s a number of things listed in the document.” However, he noted “many of them … are measures that are not yet ready for prime time in terms of quantifying benefit from a regulatory perspective.”

Validating Measurement Tools Up To Sponsors

Given the potential for the secondary endpoint data to reinforce the benefit side of the benefit/risk equation, Christine Ferguson, a professor at GW who heads the university’s obesity outcomes project, told “The Pink Sheet” she expects sponsors to step up the plate and do the validation work.

One reason to do so could be to obtain data to support a drug in the marketplace. “If you want to be able to talk about quality of life for a drug once it’s approved, you need to have a way of showing the agency, with an appropriately validated measure, that you’re actually improving quality of life, noted Klassen. “If the data are robust enough, you can get that in your label and you can actually talk about that.”

Other stakeholder recommendations call for labeling to “clearly specify that these are drugs with potentially serious adverse effects that are intended only for the clinical treatment of chronic obesity,” for pediatric and adolescent patients to be included in clinical trials once safety concerns have been addressed and for creation of a registry of children and adolescents who have been treated with obesity drugs for an extended period of time in order to assess long-term outcomes and side effects.

Industry participants who signed the report, in addition to Orexigen’s Klassen, were from Arena and Takeda Pharmaceutical USA Inc., which has North American rights to Contrave (Also see "Takeda Bulks Up In Obesity With Orexigen Deal" - Pink Sheet, 2 Sep, 2010.). The stakeholders participated in the project as individuals rather than as formal representatives of their organizations, the report notes. Unrestricted gifts from Orexigen, Takeda, Vivus, Eisai Co. Ltd., Novo Nordisk AS, and the Obesity Action Coalition supported the effort.

The obesity outcomes report is just one part of GW’s obesity initiative. The project also will look at the delivery system for obesity drugs and employing health information to monitor prescribing and use trends and to provide prescribers with information so they can be good stewards of the drugs, Ferguson said. “At the end of the day, there’s an interest in linking up the right drug to the right person at the right time in the right amount for the right length of time.”