Amylin's Pramlintide/Metreleptin Combo Becomes The Latest Obesity Casualty

Discontinuation is unrelated to prior safety suspension, say Amylin and Takeda, who acknowledge that "this is a difficult time for innovators and regulators."

Development of a once-promising combination of pramlintide and metreleptin for obesity has been discontinued after a "commercial reassessment," Amylin Pharmaceuticals Inc. and Takeda Pharmaceutical Company Limited announced Aug. 4.

Marketed for type 2 diabetes as Symlin, pramlintide is a synthetic analog of the natural hormone amylin, while metreleptin is an analog of the natural hormone leptin. The combination once looked very promising. In a proof-of-concept study released in 2008, after 24 weeks of treatment patients lost 12.7% of their body weight, or 25 pounds on average.

The combination was in Phase II as a twice-daily injectable. Most of the late-stage obesity candidates are oral formulations.

In a statement, the companies say they jointly made the decision to discontinue, based on a "revised development plan" as well as "evolving dynamics within the obesity therapeutic area."

Those "evolving dynamics" almost certainly reflect the regulatory climate - which is perceived as quite challenging.

All three drugs that have been reviewed in the past year by FDA received "complete response" letters from the agency, including Orexigen Therapeutics/Takeda's Contrave (buproprion/naltrexone) Vivus' Qnexa (phentermine/topiramate) and Arena Pharmaceuticals/Eisai's novel lorcaserin. In June, Orexigen announced that any agreements with the agency regarding its Contrave application could be subject to change, as FDA has decided to hold another advisory committee meeting on obesity drugs in early 2012 .

Asked if regulatory factors played a role in the decision, Amylin and Takeda responded that "with regard to the overall regulatory environment, undoubtedly this is a difficult time for innovators and regulators."

"While we remain disciplined about only advancing those candidates with the strongest potential for success, Amylin and Takeda will continue to evaluate other assets as potential candidates for the treatment of obesity and related indications under the terms of the existing collaboration agreement."

In 2009, Takeda paid $75 million upfront plus development and sales milestones as part of a deal to develop a number of obesity candidates, including the hormone combination and the amylin-mimetic peptide davalintide (Also see "Amylin And Takeda Team Up In Obesity" - Pink Sheet, 2 Nov, 2009.). Davalintide was dropped in 2010 in light of disappointing trial results.

Amylin also clarified that the decision to drop the pramlintide/metreleptin program was not related to a suspension of development announced in March.

Development of the combination was suspended after the discovery that two patients developed antibodies with potential neutralizing activity to metreleptin (Also see "More Obesity Setbacks For Amylin And Takeda" - Pink Sheet, 16 Mar, 2011.). At the time, the companies said that the move was a precaution to protect patient safety.

Working On More Frequent Dosing

Though in theory, obesity promises a vast, lucrative market, R&D in the space is littered with failures, notably with the withdrawal of GlaxoSmithKline PLC's cannabinoid-receptor 1 agonist Acomplia (rimonabant), which led to a pipeline purge as many Big Pharmas dropped their same-class candidates. Aside from the three recently rejected drugs, few candidates are in late-stage development (Also see "Late-Stage Obesity Pipeline Is Stuffed With Mix Of Mechanisms" - Pink Sheet, 1 Apr, 2011.)

Given that many of the failures have been centrally-acting agents that have had non-localized side effects, developers have believed that drugs targeting the gut, including peptide hormones, could stand a better chance (Also see "Obesity Drug Developers Go With The Gut: R&D Hopes Focus On Locally Acting Agents" - Pink Sheet, 1 Apr, 2011.).

But peptide hormones are hard to make and hard to deliver - they generally have to be injected and in combination to achieve sufficient efficacy.

In the statement announcing the pramlintide/metreleptin discontinuation, the companies noted that the "interplay of hormonal signals, such as amylin and leptin, plays a crucial role in the regulation of body weight." Advances in peptide engineering and delivery may enable the development of a therapy with less frequent dosing, the statement said.

Pipeline Gap

Following the discontinuation of the combination, Amylin's pipeline is left with a range of formulations of the type 2 diabetes treatment Byetta (exenatide), including once-weekly Bydureon, which was resubmitted to FDA at the end of July.

Amylin also has metreleptin in Phase III for lipodystrophy, a group of rare diseases characterized by loss of fat tissue. Setbacks for metreleptin/pramlintide will not affect the lipodystrophy program, according to the company. Patients with this condition have depressed levels of leptin, so development of leptin-neutralizing antibodies wouldn't worsen their condition.

During a July 26 earnings call, Amylin said it plans to complete a BLA for the lipodystrophy indication by the end of this year and the drug could reach the market by the end of 2012.

Prior to submission, the company is working on understanding the epidemiology related to rare forms of lipodystrophy, which it says afflicts around 1,200 patients in the U.S. and 3,000 globally.

"We've actually got a lot of activities under way at the moment. We're specifically working with key thought leaders in the area and identifying patients at this time," Amylin CEO Daniel Bradbury said during the call.

As for Takeda, the discontinuation of the combination leaves a gap when it comes to obesity compounds.

The company has the lipase inhibitor cetilistat in Phase III in partnership with Norgine BV. But prospects for this compound were somewhat dimmed by safety issues - notably liver injury- cropping up for Roche Holding AG's marketed lipase inhibitor Xenical. GlaxoSmithKline recently announced plans to sell off alli, the over-the-counter version of orlistat.

-Emily Hayes ([email protected])