Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

A potential market of $10 billion annually in the U.S. alone is keeping companies in the race to develop better drugs.

Propelled by a highly lucrative potential market and new pharmacologic approaches, pharma companies continue to pursue deals to develop a successful antiobesity drug. On November 2, Japanese company Takeda Pharmaceutical took a leap of faith based on Phase II results and acquired worldwide rights to Amylin Pharmaceuticals’ obesity candidates, pramlintide/metreleptin and davintide. The development partnership also included compounds from both companies’ research programs. Takeda paid Amylin $75 million up front and agreed to as much as $1 billion in development and milestone payments.

The pay-off potential for a safe and effective antiobesity drug is so compelling—an estimated $10 billion annually in the U.S. alone—that companies with previously failed drug are staying in the game by acquiring molecules with novel mechanisms of action. Pfizer CEO, Jeff Kindler, said last year that the firm would continue to pursue obesity treatments through internal R&D and licensing deals. Pfizer acquired Thiakis’ early-stage drug, a novel, long-acting synthetic peptide analog of oxyntomodulin, through its $62 billion Wyeth takeover, which was completed in October.

Previously, though, in November 2008, the company terminated a Phase III weight-management program with CP-945,598, a selective CB1 receptor inhibitor, due to a “changing regulatory perspective on the risk/benefit of the CB1 class and likely new regulatory requirements for approval.”

Merck & Co.’s selective CB1 receptor blocker, taranabant, also got the ax last year after Phase III studies revealed CNS side effects, chiefly depression and anxiety. Sanofi-aventis also yanked its candidate, rimonabant, a reverse CB1 inhibitor in the same year.

Underwhelming Antiobesity Candidates

Based on these past failures as well as the less than stellar efficacy results and questionable safety findings reported for current drugs at the 27th annual meeting of the Obesity Society held in October, Takeda’s $1 billion investment in Amylin’s pipeline may prove to be the best bet at this time. Pramlintide is a synthetic analog of amylin, a peptide hormone released along with insulin from pancreatic islet cells. Pramlintide, branded as Symlin, remains the only FDA-approved drug for type 1 diabetes besides insulin.

Amylin bought the rights to leptin in 2006 from Amgen, which discontinued development after Phase II studies showed that most obese patients did not lose weight compared with a placebo. Amylin hopes that putting metreleptin, a recombinant human leptin, together with pramlintide will provide a winning combination for weight-loss and obesity management.

Results from company’s 28-week, dose-ranging study of the metreleptin/pramlintide therapy, “successfully characterized patients who responded best to treatment and also provided important information about informed dose selection,” according to Amylin. The 149 patients with an initial BMI of less than 35 kg/m2 and treated with the highest pramlintide/metreleptin doses lost significantly more weight on average (11%, or 22 pounds) than those receiving placebo (1.8%, or 4 pounds) or either agent alone (approximately 5%, or 10 pounds).

FDA guidelines for antiobesity drugs require that individuals treated with the drug show a 5% greater weight loss after a year than those receiving a placebo or that at least 35% of patients on the drug achieve a 5% weight loss. The company reported that the most common side effects included mild-to-moderate nausea and that no cardiovascular or neuropsychiatric safety signals were observed.

Efficacy results and side effects of other drugs like Vivus’ Qnexa and Arena Pharmaceuticals’ Locaserin fueled doubts about their respective deal potential. Vivus actually reported positive Phase III data from two 56-week studies evaluating Qnexa’s safety and efficacy in more than 3,750 patients. The studies met all primary endpoints, showing statistically significant weight loss with Qnexa compared to placebo. Patients taking the drug showed significant improvements in cardiovascular and metabolic risk factors including blood pressure, lipid levels, and type 2 diabetes.

The company’s stock fell 15%, however, after Cowen and Co. issued a note saying that Vivus hid the extent to which central nervous system (CNS) side effects of its weight-loss drug Qnexa had forced patients to withdraw from two Phase III studies. “We believe adverse events such as disturbance in attention, memory impairment, amnesia, aphasia, and cognitive disorder—even if relatively rare—will prove to be serious regulatory hurdles for a weight-loss drug,” Cowen stated. “Therefore, we now have reduced conviction in the approvability of Qnexa, and partnering prospects also may be reduced.”

Qnexa combines phentermine, an amphetamine-like appetite suppressant, and topiramate, a marketed antiseizure medication. Both drugs have significant side effects. Phentermine was part of the Fen-Phen duo, a weight-loss drug that also contained fenfluramine, an appetite suppressant. The combination drug was taken by 18 million Americans until it was removed from the market in 1997 after 24 cases of heart-valve disease, shown to be associated with fenfluramine, occurred.  A similar amphetamine-like drug, dexfenfluramine, marketed under the trade name Redux, was also removed from the market that year. Later studies showed that nearly 30% of people taking fenfluramine or dexfenfluramine had indications of heart-valve abnormalities.

The FDA did not ask manufacturers to remove phentermine from the market; but its CNS side effects limit its use to a short-term regimen in combination with exercise, behavioral modifications, and caloric intake restrictions.

Arena’s results with Lorcaserin, a selective serotonin 2C receptor agonist, led Cowen’s Phil Nadeau to comment that “If this was a field goal, it would have hit the upright and bounced through.” Data barely met FDA efficacy guidelines and was consistent with results from the earlier BLOOM study, which showed that 47.5% of Lorcaserin patients versus 20.3% of placebo patients lost more than 5% of their weight. Data from the BLOSSOM trial also showed that a quartile of Lorcaserin patients with the greatest weight loss at week 52 lost an average of 35.1 pounds, or 16.3% of their body weight. Even with underwhelming results, analysts noted that the trial data suggested the drug was safe, which could mean that the therapy may be effective in conjunction with other diet medicines.

Physician Expectations

These results may not produce much enthusiasm among physicians, who say that already-marketed obesity drugs have too many side effects to justify their limited benefits. Roche’s Xenical and Abbott Laboratories’ Meridia cause multiple side effects including potential loss of bowel control.

Additionally, neither work well enough to effect significant weight loss. “Drug therapy has been disappointing, with weight loss over a year of just a few pounds for the average patient,” noted Paul Shekelle, M.D., an internist involved in establishing the current American College of Physicians obesity treatment guidelines. “That’s not going to get someone 30 to 40 pounds overweight interested.” Dr. Shekelle told GEN that an updated set of obesity treatment guidelines should be issued in about 18 months.

Nadeau also told GEN that “the direction our consultant physicians want to see obesity drugs go toward is centrally acting agents. They look at obesity as an addiction to food, at least in a good number of people. Ideal is what Amylin has referred to as an integrated neurohormonal approach, combining locally acting agents like GLP-1 to enhance satiety and centrally acting agents to control cravings would be ideal.

“However,” Nadeau continued, “at the same time, doctors have almost no tolerance for serious adverse side effects like mood alteration and increases in suicidal tendencies. They want something that’s completely safe.”

Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].

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