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Class of once-weekly diabetes drugs poised for approval
  Nature Medicine 06 December 2011

The announcement last month that drugmakers Amylin Pharmaceuticals and Eli Lilly were parting ways is only the latest twist in their more than two-year quest for regulatory approval of their once-weekly injectable diabetes medication, Bydureon. The companies first filed for approval with the US Food and Drug Administration (FDA) in May 2009, and in the intervening period they have had to deal with two complete response letters for manufacturing issues and potential heart problems. But with new trial data in the bank and Bydureon's European approval in June, things are looking up, and a decision is expected from the FDA by 28 January.

"I think that the FDA will very likely approve Bydureon," says senior biotechnology analyst Thomas Wei of the investment firm Jefferies in New York. "And a big part of the reason I think that this will be successful is that the efficacy looks very good."

Bydureon, a reformulation of the company's already approved twice-daily injectable, Byetta (exenatide), is just one of several diabetes drugs in the pipeline that mimic the gut hormone glucagon-like peptide-1 (GLP-1) to lower overall blood sugar by stimulating insulin and inhibiting the hormone glucagon. And GLP-1 mimics have an edge over other drugs that act further upstream: they not only lower blood sugar but also cause weight loss. In a phase 3, 456-person trial, people taking Bydureon lost 2.6 kilograms (5.7 pounds) on average over a 26-week span-significantly more than those on insulin alone, who had an average gain of 1.4 kilograms (Lancet 375, 2234-2243, 2010). (Similar effects have been reported for other GLP-1 analogs.) This extra benefit of the drug against obesity, which often accompanies type 2 diabetes, could help it beat out its competition.

"To finally have a diabetes drug that not only lowers your glucose but also tackles your weight at the same time-that's a real breakthrough for patients and doctors," says Daniel Drucker, a diabetes researcher at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, who led phase 3 trials for Bydureon.

San Diego-based Amylin will receive custody of Bydureon in the split, but, even if approved, the drug faces competition down the road. British drug giant GlaxoSmithKline and New York-based Eli Lilly each have their own long-acting versions of GLP-1 analogs in phase 3 trials. Meanwhile, Denmark's Novo Nordisk has a pair of once-weekly GLP-1-like drugs in the works: one, currently in phase 2 testing, is a novel molecule called semaglutide, and the other is a reformulation of Victoza (liraglutide), the company's bestselling daily injectable diabetes drug, which is in phase 1 development.

Experts say that the clinical data published so far have not produced a runaway winner among these new drugs. "There aren't huge differences in efficacy or potency in regards to how they work," says Drucker. The driving factor may come down to how much weight people lose in comparative trials. The different GLP-1 analogs vary in size, so some of the drugs may be less able to cross the blood-brain barrier than others. "A question that all of us have is: how important is it for these drugs to access regions in the brain that control appetite and body weight?" Drucker says.

Another unknown is the long-term effect of each drug on morbidity and mortality- although Amylin and Novo Nordisk both have ongoing long-term trials which should produce results in 2016 if not before. But, until the long-term effects are known, it may not be reasonable to ask patients to pay more for these drugs, despite their convenience, says Nicole Pinelli, a clinical pharmacy specialist at Wayne State University in Detroit. "If there's nothing to say that these drugs reduce cardiovascular morbidity or mortality, it's hard to justify using them above and beyond the generic drugs that are currently on the market," she says.


The FDA twice sent the developers of Bydureon complete response letters in 2010, but the companies have turned a corner this year with a European green light for the long-acting diabetes drug and data that address heart safety concerns about the treatment. Yet the court struggles between the two lead developers of the drug, Eli Lilly ($LLY) and Amylin ($AMLN), have added a sour twist to the story.

The success of Bydureon, a long-acting version of the Amylin and Lilly diabetes drug Byetta, has implications for the companies' position in the increasingly competitive market for a class of drugs known as the GLP-1 receptor agonists. Novo Nordisk has been eating into the companies' Byetta business with its rival GLP-1 drug Victoza.

Yet Bydureon could be the first FDA-approved drug from this class that is injected once per week. The FDA is expected to complete its review of Bydureon by Jan. 28, and an approval could help Lilly and Amylin regain some lost ground in the GLP-1 market because of the dosing advantages over the existing meds. Alkermes ($ALKS), the drug-delivery specialist, provides the tech to prolong the availability of the drug in patients' systems, and it is due royalties on sales of Bydureon.

While Bydureon has made progress this year, Amylin and Lilly have feuded in court over Lilly's deal with Boehringer Ingelheim to promote the latter company's diabetes drug linagliptin. Yet the case also shows just how much is at stake for these companies in the blockbuster market for diabetes drugs.


Amylin sues Lilly over diabetes partnership

Mon May 16, 2011 3:44pm EDT

* Chides Lilly plan to help sell rival Boehringer drug

* Lilly, Amylin sell Byetta diabetes medicine

* Amylin shares fall 4.5 pct, Lilly edges up 0.7 pct (Adds analyst comment, byline)

By Lewis Krauskopf

NEW YORK, May 16 (Reuters) - Amylin Pharmaceuticals Inc (AMLN.O) sued longtime diabetes-drug partner Eli Lilly & Co (LLY.N) over its plans to help market a rival product with another company.

Lilly helps the smaller Amylin sell the Byetta diabetes medicine. Byetta, which is also known as exenatide, is Amylin's main product.

Shares of Amylin fell 4.5 percent after it announced the lawsuit on Monday. Analysts said the disagreement could mean Lilly has a weaker outlook for sales of the Byetta franchise, while the dispute also brings into question any potential acquisition of Amylin by Lilly.

Earlier this year, Lilly struck an agreement to develop five diabetes drugs with Germany's Boehringer Ingelheim. That alliance includes a Boehringer drug, known as linagliptin, that Amylin said is set to be a potential competitor to Byetta.

Linagliptin won U.S. approval earlier this month under the brand name Tradjenta.

Amylin wants to stop Lilly from using the same sales force to sell both products, the company said in a statement announcing the lawsuit.

"Obviously, there are disagreements currently as it stands, whether it's commercialization or their concern about Lilly's commitment to future growth of the exenatide franchise," Collins Stewart analyst Salveen Richter said. "That's one concern when you think about the outlook for sales.

"Then you've got the other question: Are they interested enough to acquire these guys or is this a potential acquirer that maybe is not going to pan out?" Richter said.

Lilly has been long seen as a potential acquirer of Amylin, should it desire full control of the Byetta franchise.

Amylin said the lawsuit, filed in U.S. District Court for the Southern District of California, alleges Lilly was engaging in anti-competitive activity and breaching its agreement to maximize commercialization of exenatide.

"Amylin selected Lilly as a partner to promote development and maximize sales of Amylin's exenatide products," Amylin said. "We are disappointed that we could not resolve this matter amicably and that we were forced to bring legal action to protect our rights, our products and our shareholders."

Amylin said it would still collaborate with Lilly on exenatide products, despite the litigation.

In a response, Lilly said it was committed to its obligations under the exenatide agreement and that it believed the lawsuit was without merit.

Lilly and Amylin began their alliance in 2002. Byetta was approved in the United States about six years ago. A longer-acting version, called Bydureon, was recommended for approval in Europe in April, but has faced repeated delays in the United States.

In January, Lilly announced the drug-development alliance with Boehringer. Indianapolis-based Lilly is trying to develop new medicines as it faces impending generic competition to its big-selling Zyprexa schizophrenia medicine.


Amylin waging legal war with Lilly over blockbuster Boehringer pact

May 16, 2011

When Eli Lilly and Boehringer Ingelheim announced early this year that they would join forces to advance new treatments to fight diabetes, the news evidently stirred considerable passion at Amylin, which has been struggling alongside Lilly to push Bydureon to an approval at the FDA. Today Amylin went public with its objections, filing suit claiming that the ambitious deal violated its own long-standing partnership with the pharma giant on the blockbuster Byetta.

Amylin's primary objection is focused on Boehringer's program for linagliptin, which Amylin sees as a big threat to Byetta. Bydureon--widely tapped as a likely blockbuster--is designed as the next-gen follow-up diabetes treatment to Byetta, and both rely on exenatide as the active ingredient. Amylin's suit seeks to stop Lilly from using the same sales force to promote linagliptin as the one now dedicated to Byetta. But at the same time Amylin wants to continue to develop new products with Lilly.

"Amylin selected Lilly as a partner to promote development and maximize sales of Amylin's exenatide products," says the company. "We are disappointed that we could not resolve this matter amicably and that we were forced to bring legal action to protect our rights, our products and our shareholders. Amylin is committed to exenatide, a franchise that we believe provides important treatment options for the millions of patients around the world with type 2 diabetes. Notwithstanding this litigation, we intend to continue to collaborate with Lilly in the development and commercialization of exenatide products."

Lilly wasted little time this morning in firing back its response to its longtime partner. "We believe the lawsuit is without merit and will vigorously defend our position," said Enrique Conterno, president of Lilly Diabetes, in a statement. "Our mission as a company is to bring needed therapeutic solutions to patients. Significant unmet need exists among patients with diabetes, and the condition's prevalence and complications from it are projected to rise sharply as we look to the future. Lilly has a strong heritage of bringing new diabetes innovations to the market and we know that patients and health care professionals want choices to treat this complex disease throughout its progression."

The deal between Lilly and Boehringer matched two powerhouses actively developing new treatments for diabetes. Lilly agreed to make an initial one-time payment to Boehringer Ingelheim of 300 million, adding 625 million in success-based regulatory milestones for linagliptin and BI10773. Lilly became eligible to receive up to $650 million in regulatory milestones on its two basal analogue insulins. And if Boehringer opted in to the Phase III development and potential commercialization of the antibody, Lilly would be eligible for up to $525 million in opt-in and success-based regulatory milestone payments. The companies agreed to share ongoing development costs equally.

- here's the Amylin release - here's Lilly's response - read the Reuters story

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