Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

High clinical trial costs and slower FDA approvals are among the hurdles to obesity drug approval.

The FDA resembled a longtime dieter splurging on a hearty meal over the summer when, within 20 days, it approved the first two new obesity treatments in more than a decade.

Vivus has targeted the fourth quarter to launch Qsymia (phentermine and topiramate extended-release), approved July 17. By early 2013, first sales are expected for Belviq (lorcaserin hydrochloride), to be made by Arena Pharmaceuticals and distributed by Japan’s Eisai, following June 27 approval. Both drugs must complete postmarketing studies assessing their risk for major adverse cardiac events, and win scheduling from the Drug Enforcement Administration.

Also next year, Orexigen Therapeutics plans to release interim data on a post-Phase III clinical trial assessing cardiovascular (CV) risks for experimental weight-loss drug Contrave. If interim results show less than a doubling of CV risks, the company will resubmit to FDA a New Drug Application (NDA) to market Contrave through partner Takeda, which holds North American rights. The agency rejected Orexigen’s previous NDA in 2011, insisting it conduct another trial to rule out excess CV risk.

Safety Issues

FDA and drugmakers hope the new treatments avoid the side effects of obesity medicines developed since Roche’s 1999 approval for lipase inhibitor Xenical (orlistat), followed in 2007 by an over-the-counter version (Alli) sold by GlaxoSmithKline. That year, an FDA panel recommended against Sanofi’s Zimulti following the suicide of three patients in trials. In 2010, Abbott Laboratories withdrew at FDA’s request Meridia (sibutramine), after a six-year post-marketing study requested by European regulators found increased risk of heart attacks and strokes compared with placebo—though Abbott noted most of that study’s 10,000 patients had underlying CV disease and could not receive the drug.

Meridian was approved in 1997. That same year, two other drug companies withdrew obesity treatments—dexfenfluramine (Redux), and fenfluramine (Pondimin), which when combined with phentermine resulted in Fen-Phen. Pfizer predecessor Wyeth set aside some $21.1 billion to pay patient claims for heart damage linked to the drug.

Intent on avoiding another Fen-Phen, FDA tightened its scrutiny of experimental obesity drugs. In 2007, the agency issued draft guidance insisting on safety benchmarks of one-year trials with a minimum 4,500 patients—about 3,000 randomized to treatment, at least 1,500 to placebo.

“The safety profile for any drug for chronic use must be squeaky clean, particularly so when it has not been shown to have significant clinical benefit (i.e., reduced morbidity/mortality). This can only be shown with extensive clinical trials, which are significant in terms of financial and time investment,” Deborah Toscano, life sciences senior industry analyst with Frost & Sullivan, told GEN. “It is a high hurdle to demonstrate significant weight loss in controlled clinical trials and is inherently difficult (partially due to a oftentimes significant placebo effect confounding the results) therefore often not worth the investment due to high risk of failure and loss of millions of dollars invested.”

Clinical Trials

The bottom line explains the paucity of obesity drug development as much as red tape. Average Phase III trial costs for obesity drugs were $253.6 million, well below the $5.57 million average for the rare disease drugs studied—though a bargain compared to the $2.855 billion average spent for heart drugs, according to an April report by the Manhattan Institute for Policy Research.

That report also linked slower FDA approvals for drugs against obesity and three other disorders to the high cost of Phase III clinical trials. They accounted for 90% or more of development costs for nine of 12 drugs studied—including Belviq, Contrave, and Qsymia.

The Belviq and Qsymia approvals reflect a shift by FDA away from viewing obesity treatments as cosmetics and more as drugs for a growing health problem. Some 75 million Americans (about one-quarter of the U.S. population) are obese, according to American Heart Association.

“You don’t need to make the drugs excessively expensive to be able to make a very significant amount of money, just simply because of the pure market size,” Henrik Rasmussen, M.D., Ph.D., president and CEO of Rasmussen Biotech & Pharma, told GEN. “Depending on the competition, it’s fair to say this area has blockbuster potential.”

While tighter trial regulation remains a challenge, industry sees a silver lining in greater certainty that should yield more drugs entering the market. “I don’t know it I would call it an explosion, but you will certainly see much more activity in the field of developing new obesity drugs,” Dr. Rasmussen said.

Dr. Rasmussen is also clinical affairs consultant for Unigene Laboratories, which is preparing for FDA an Investigational New Drug Application of its lead anorexigenic peptide for morbid obesity UGP281. Unigene is seeking a partner with which it can start Phase I clinical testing in the first half of 2013, Roxanne Tavakkol, vp, global regulatory affairs & quality assurance for Unigene, told GEN.

In May, Unigene reported preclinical results in rats and dogs for UGP281—namely a 10–15% dose-related body weight decrease over seven days of treatment. While the preclinical drug was injected, Unigene said, commercialization plans call for an oral dose manufactured recombinantly through the company’s Peptelligence™ technology platform.

A key challenge for obesity drugmakers is the steep dropout rate for trials reported at 30% to 50%, resulting in longer times and steeper costs slowing down development. It could get slower still. In March, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the agency require new obesity drugs to undergo clinical trials focused on CV risks.

Regulations like these have sparked criticism by industry-friendly groups including Manhattan Institute as well as the California Healthcare Institute (CHI) and The Boston Consulting Group (BCG). In May, CHI-BCG compared FDA’s standards for obesity drugs with those for cancer, where the agency has promoted speedier reviews.

Among obesity drug developers, Zafgen is under way with a Phase II trial for its selective methionine aminopeptidase 2 (MetAP2) inhibitor beloranib, with patients being recruited and the first doses set for this month. In June, the company reported Phase I data from two studies in severely obese women showing improved weight loss and triglycerides, LDL cholesterol, waist circumference, and diastolic blood pressure.

“People who are obese have a double problem: They are overproducing fat from calories that they take in from their diet. And secondly, they are less able to utilize that fat-stored energy as energy for their metabolism,” Thomas E. Hughes, Ph.D., Zafgen’s president and CEO, told GEN. “Our drug focuses on restoring that balance to fat metabolism.”

He said Zafgen sees beloranib “potentially as a six- to nine-month treatment,” though given the disease’s chronic nature, “We’re not ruling out the possibility that the drug would be used for quite a long period of time in order to keep people at a healthy weight.”

Another preclinical drug developer, Ember Therapeutics, has licensed from Dana-Farber Cancer Institute its hormone irisin, which targets “brown fat” cells—especially “beige fat” cells produced from white fat depots when triggered by conditions such as exercise and cold. In July, Bruce Spiegelman, Ph.D., of Dana-Farber and Harvard Medical School—one of Ember’s scientific cofounders—published a first description of the cells’ genetic profile in the journal Cell.

According to Ember, the beige fat discovery provides additional scientific validation of irisin and its impact, but does not change its development program for an irisin-based drug candidate. What this discovery provides, according to the company, is a better understanding of what fat cell types to use for the purposes of drug screening and optimization. The company also says it is working on several preclinical programs that are advancing rapidly toward the clinic, but has not yet provided specific clinical timelines.

Encouraging as they appear, the initial results by drugmakers will require years of additional trials and millions of additional dollars, with no guarantee of success. But with the U.S. and the Western world increasingly overweight, companies that succeed at reversing obesity will, sooner rather than later, find themselves in Fat City.

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