By Kim Coghill
The lengthy journey taken by Amylin Pharmaceuticals Inc. to introduce its lead diabetes drug, Symlin, entered the final leg Thursday when the San Diego-based company submitted a new drug application to the FDA.
The company is asking to market Symlin (pramlintide acetate) as an adjunctive therapy to insulin for the treatment of people with Type I or Type II diabetes. Symlin is a synthetic version of human amylin, a hormone secreted with insulin by the beta cells in the pancreas.
"This is a very large event for Amylin, obviously. Arguably this is the most significant event to date," said Mark Foletta, Amylin's chief financial officer. "We believe this drug should be approved and it's a good drug candidate for the treatment of insulin-using diabetics. This NDA represents over 13 years of research and development and 660,000 pages of material."
The FDA is expected to accept the application for review within 60 days, and Amylin hopes to have the product on the market by fourth quarter 2001.
Back in 1998, Amylin was developing Symlin through a partnership with Johnson & Johnson, of New Brunswick, N.J. But after investing $175 million and failing to produce a workable product, Johnson & Johnson pulled out of the deal, leaving the smaller company on its own. (See BioWorld Today, March 3, 1998.)
When asked whether Amylin would actively seek another partner, Foletta said, "We really had to buckle down and get through the last few years on our own. Now we find ourselves in an interesting spot. We don't have a partner and we've submitted an NDA. Not many companies our size have been in this position.
"We are considering partnering arrangements, but we also are looking at the market and we are starting to build a commercial function internally," Foletta said. "We are analyzing the market and how we can penetrate that market either with a partner or on our own. But the way the market looks, we feel it is possible for an organization our size to do this."
Foletta said there is no change in the drug submitted for approval vs. the product that was being developing with Johnson & Johnson. "The difference is the dose. The actual dose that was selected and the endpoint at the outset of the study is not the [lower] dose that we are using today."
The successful Phase III trials of Symlin demonstrated statistically significant improvements in blood glucose control without weight gain in insulin-using people with Type I or Type II diabetes. The reductions in blood glucose were achieved with no increase in severe hypoglycemic event rates compared to the control group. No major safety concerns were noted in the suggested therapeutic range during the development program in which more than 4,400 patients were exposed to Symlin.
"Symlin has had a rocky development, but Amylin overall conducted six Phase III clinical trials," said Fariba Ghodsian, managing director of health care research at Roth Capital Partners Inc. in Los Angeles.
"I think we can come to the conclusion that the drug is actually managing glucose levels, helping provide some weight loss to the patient, and the drug seems to provide better glucose management without leading to hypoglycemia."
Ghodsian has a "buy" rating on Amylin's stock (NASDAQ: AMLN), saying, "Diabetes is obviously a difficult disease and insulin obviously is the ultimate therapy and since its discovery, it has saved millions of lives. But there hasn't really been much innovation on the drug discovery part. We have innovation on the delivery of insulin, but there really hasn't been much on drug discovery for insulin-dependent patients."
There are an estimated 4.4 million people with diabetes who use insulin in the United States, of whom 3.7 million take multiple doses each day.
Amylin's stock closed Thursday at $10.812, up 18.75 cents.
Negative Results Part Of The Process
Amylin was faced with a number of setbacks in its quest to submit the NDA for Symlin.
The problems seemed to surface back in 1997 when Amylin and Johnson & Johnson determined that in an initial Phase III trial for Type II diabetes, the drug failed to lower glucose on an intent-to-treat basis after 12 months. (See BioWorld Today, Aug. 19, 1997.)
The companies forged ahead despite Amylin's 43 percent drop in stock following publication of the news.
And a year later, things got worse for Amylin. The company's stock dropped 77 percent in October 1998 when Amylin disclosed results from two European/Canadian Phase III studies in which pramlintide failed to show statistically significant results. In those studies, two dosing arms in the Type I study and one in Type II diabetic achieved statistical significance in reducing average blood glucose. However, statistical analysis methods required that the dose selected for regulatory purposes, 90 micrograms three times a day, show statistical significance, and the drugs failed in both studies. (See BioWorld Today, Oct. 22, 1998.)
Upon losing its partner, Amylin cut its work force by 75 percent, from 190 employees to 45.
But the company persevered and in October 1999 raised $18.5 million in a private sale of stock to finish Phase III trials and to pay for regulatory applications. (See BioWorld Today, Oct. 8, 1999.)
Amylin was back on track last November when it released results of a one-year pivotal trial for Type I diabetes that indicated Symlin produced a statistically significant lower primary glucose control endpoint. (See BioWorld Today, Nov. 10, 1999.)
The study showed when Symlin was added to a patient's insulin regimen, the primary glucose control endpoint (glycated hemoglobin, HbAIc) was significantly improved at six months, compared to those who took only insulin. For the Symlin 60 micrograms three-times-a-day group, HbAIc was reduced by 0.3 percent at six months, compared to those receiving insulin alone (p=0.008). (See BioWorld Today, Nov. 10, 1999.)
In February, Amylin raised about $100 million through the sale of 8.3 million shares at $12 each. Net proceeds were earmarked for continued development of Symlin and other products being researched by the company. (See BioWorld Today, Feb. 23, 2000.)
Other than Symlin, Amylin also has in development AC2993, another diabetes candidate, which is in Phase II evaluation for the treatment of Type II diabetes. A long-acting-release formulation, AC2993 LAR, is in preclinical development.
The company's third candidate, AC3056, is in Phase I evaluation as a potential treatment for metabolic disorders relating to cardiovascular disease.