The diabetes landscape is a tad riskier for drugs in development that have a safety glitch or two, and the bottom line could mean higher costs.
New FDA draft guidance calls for more patients and lengthier trials for companies with certain safety issues, but the rules are no different from what is expected in drug development for other chronic conditions, the agency has said.
In general, the FDA wants companies to exceed previous expectations considering the growing diabetes population and the increased complexity of treatments, but it will be an absolute stickler with those drugs exhibiting serious side effects. Specifically, it wants a Phase III trial to include at least 2,500 subjects, with 1,300 of them exposed to the drug for a year or more, and 300 exposed for 18 months or more. Certain diabetes drugs on the market, such as Januvia (sitagliptin; Merck & Co. Inc.) and Byetta (exenatide; Amylin Pharma-ceuticals Inc. and Eli Lilly and Co.) were approved based on trials that didn't go beyond a year.
Some companies with early stage diabetes products say the new rules are in line with what was already planned for development. Sirtris Pharmaceuticals Inc., for instance, is working on SRT501, an oral small molecule formulation of resveratrol that activates Sirt1. It is in five Phase Ib trials.
"The draft guidelines will not impact our timetables," said John Lacey, associate director of corporate communications at the Cambridge, Mass.-based company, who added that its programs were "already meeting the draft guideline recommendations."
It is unclear, however, how the changes might affect later-stage compounds. Analyst Matthew Osborne of Lazard Capital Markets stated in a research note earlier this month his concern that they might delay a new drug application filing for Amylin's long-acting version of Byetta (exenatide LAR). The company is in the middle of enrolling Phase III trials for the compound and a regulatory submission is expected for the second quarter of 2009.
But Osborne fears that date could shift as the result of the draft guidance. He downgraded the company's stock (NASDAQ:AMLN) to hold from buy.
"We are moving to the sidelines pending further evidence that safety does not appear to be a concern for exenatide LAR," he wrote.
The issue with Amylin's product is whether its nonstop activation of the GLP-1 receptor would cause a different physiologic response in a subset of patients. A serious safety concern - even if it affects a very small number of patients - could bump up the approval requirements.
But Amylin spokeswoman Alice Bahner Izzo said her company is confident the current development program for exenatide LAR is adequate for submission because the FDA has worked with the company all along "and their thinking would have been reflected from the guideline update that they were clearly working on.
"The nice thing about the guidance," she added, "is that it does recognize that diabetes is multi-faceted and it mentions the post-prandial glucose contribution to a once-a-week control," an important part for understanding Amylin's and other innovative diabetes therapies.
In November, the FDA added to an existing black box warning of the diabetes drug Avandia (rosiglitazone, GlaxoSmithKline plc) that Type II diabetes patients, particularly those with underlying heart disease, are at an increased risk for heart attack. The FDA has denied that its new draft guidance is in response to Avandia's potential side effects, but it does suggest trials even longer than 18 months in some circumstances.
Companies developing peroxisome proliferator-activated receptor (PPAR) agonists, like Avandia, are urged to conduct two-year carinogenicity evaluations. The agency also may require data of up to two years to describe immunogenic potential in products with certain safety signals "cardiovascular or otherwise."
Longer trials could be a huge burden on a young company like InteKrin Therapeutics Inc., which licensed in January an oral PPAR gamma-selective modulator and partial agonist, INT131, from Amgen Inc. But the company has stressed that INT131 does not agonize the full receptor and therefore does not turn on the genes associated with weight gain and edema, as seen with Avandia and Actos. Other companies working on PPAR agonists include Metabolex Inc. and Plexxikon Inc. InteKrin raised $23 million in its first round in January to fund Phase IIb trials of INT131.
Jim Reddoch, an analyst with Friedman, Billings, Ramsey, reiterated his outperform rating for Amylin, prompting the stock to climb mid-month, based on projected peak annual sales of $2 billion for Byetta and its long-acting version. He didn't believe the draft guidance would adversely effect exenatide LAR's timeline because it seems to focus more on heart safety.
Some followers of the diabetes market breathed a sigh of relief when the new guidance emerged, since it appeared that the FDA stood by the age-old surrogate endpoint of improvement in HbA1c. Many had feared the agency might require costlier outcome trials with an emphasis on cardiovascular events or mortality. And it still might. Earlier this month, Sen. Chuck Grassley (R-Iowa) announced an investigation into the use of surrogate endpoints to approve drugs such as Avandia.
Safety Is Not The Only Challenge
For the time being, it appears that companies with solid safety profiles of their drugs have nothing to worry about. And some analysts, like Aileen Salares of Leerink Swann & Co., stand by long-acting Byetta. She issued her own note a few weeks ago saying that the drug's small pivotal trial "is not viewed as an impediment to a timely approval." She believes Amylin can use extensive post-market data on the twice-daily version of Byetta to prove the long-acting version's safety. Byetta was approved for Type II diabetes in 2005.
In any case, she said, "reduced GI discomfort such as nausea may be a sufficient signal to alleviate safety concerns with the LAR formulation."
Likewise, Salares didn't think the new guidance would affect other companies she covers, such as Biodel Inc., which is in Phase III trials with 800 patients to test its injectable rapid acting insulin VIAject, or MannKind Corp., which is developing the inhaled Technosphere Insulin, a product that could show an advantage over the currently marketed inhaled product, Exubera, because of its reduced antigenicity and a lower hypoglycemia risk.
But an inhaled product making it to market does not necessarily mean a windfall for MannKind, as Exubera's developer Nektar Therapeutics Inc. discovered. Analysts originally expected the product to reach $2 billion in sales five years after launch, eventually cannibalizing injectable insulin, but patient adoption of the new technology has been slow and sales were about $274 million in 2007, with 69 percent going to Nektar, leaving partner Pfizer Inc. with little to show for its efforts. The pharmaceutical company backed out of its deal last fall.
Indicating a trend by pharma to step away from non-injectable therapies, two other pharmaceutical companies, Eli Lilly & Co. and Novo Nordisk A/S dropped support of inhaled diabetes therapies AIR, from Alkermes Inc., and AERx iDMS, from Aradigm Corp. As a result, Generex Biotechnology Corp. has watched its stock decline by more than 30 percent to under $1.
That company issued a press release in mid-March reiterating its belief that pharma's rejection of inhaled diabetes therapies only gives Generex a competitive edge with its own oral insulin flagship product, Generex Oral-Lyn, which is in Phase III studies and was approved in India last October.
Navdeep Jaikaria, an analyst with Rodman & Renshaw, said in a research report, which seemed to boost the company's stock (NASDAQ:GNBT) slightly, that negative news of companies developing inhalable insulin has placed "unwarranted pressure on the shares of Generex." If anything, he said, their loss is Generex's gain, as safety issues with inhalable insulin only pave the way for an oral therapy as a viable alternative to injectables.
It is unclear whether any of the inhalable insulin companies would face costlier trials to get their products approved because the FDA's draft guidance is vague in referring to "safety issues." There are observations, however, that inhaled insulins lead to a decline in lung function, and there are formulation problems, Jaikaria said, with converting insulin into an inhalable powder. Oral-Lyn delivers insulin through the oral cavity and leaves no deposit in the lungs, the company has said.
Another diabetes therapy in limbo is Novartis AG's drug Galvus (vildagliptin), a DPP-4 inhibitor, which is on hold in the U.S. It was approved in Europe in February with a revised label due to an imbalance in liver enzyme levels seen in patients taking the higher dose. Januvia (Merck & Co. Inc.) is the only DPP-4 inhibitor on the market, but several companies, such as AstraZeneca plc, Bristol-Myers Squibb & Co. and Takeda Pharmaceuticals, are working in the space.