It was a mixed day for Acorda Therapeutics Inc., which said Fampridine-SR missed its endpoints in two pivotal Phase III trials in spinal cord injury (SCI), but also said the drug showed positive trends in a Phase II multiple sclerosis (MS) trial.
Acorda plans to pursue the MS indication, conducting either another Phase II trial or a Phase III trial depending on what comes out of upcoming meetings with the FDA.
Those meetings also will determine whether the company will continue development in the SCI indication.
"I think the critical features are that in spinal cord injury, one of the trials at least did give us a strong signal of what we were looking for, which is the spasticity," said Ron Cohen, Acorda's president and CEO. "And the other one didn't, and we don't know why. It's a disappointment and a surprise."
Fampridine-SR came close to meeting its endpoint in the MS study - improvement in walking speed, as measured by a timed 25-foot walk. Despite the miss, the strong trends on the timed walk and the significantly improved muscle strength may be enough for the company to move directly into a Phase III MS trial.
The primary endpoints in the SCI studies were the reduction of spasticity as measured by the Ashworth score and improvement of patients Subject Global Impression (SGI) rating.
Acorda, of Hawthorne, N.Y., will meet with the FDA to discuss a potential Phase III trial of Fampridine-SR in MS, as well as to determine whether it will further develop or file a new drug application for the product to treat SCI.
"Based on what we're seeing now, we are going to aggressively push forward the MS program because we believe we have excellent indications of potential efficacy in strength and walking," Cohen told BioWorld Today.
He declined to make guesses as to whether the company could move into a Phase III MS trial following talks with the FDA. The company might need to do another Phase II trial, he said. A decision will be made following further analysis of the trials within the next few months, and after the company meets with the FDA.
Acorda had planned to file an NDA in SCI by the end of this year, but Cohen said it is unlikely that the company would be able to keep that schedule.
In the two SCI trials (301 and 302), the Ashworth score and the SGI rating measured the patients' spasticity - the involuntary tension, stiffness or contraction of muscles - and the patients' own assessment of how well the drug affected them.
"We did see a progressive improvement in the Ashworth score in both studies," Cohen said. "The difference was in one of the studies the placebo group also showed a sustained progressive improvement throughout the study that came close to matching the drug group."
While the placebo group in the 301 study demonstrated a higher-than-expected reduction in the Ashworth score, the drug reached statistical significance in the 302 study when analyzed based on the patients' last observation carried forward. When analyzed based on all observations, it came close to meeting the primary endpoint.
"There's some anomaly there, but frankly, the overall p' value, if you average all the visits, was 0.069," Cohen said. "I think anyone would call that a very strong trend. It didn't miss significance by much."
Acorda is continuing to analyze the secondary endpoints in both trials of improvement in bowel, bladder or sexual function. And the company wants to find out what went wrong with the 301 study. The results not only differed drastically from the 302 study, but they also differed from all of the previous Phase II studies in spinal cord injury.
"You wind up scratching your head a bit, then delving into the data in a much more detailed way to figure out where there were clinical differences," Cohen said.
The two SCI trials began in the summer of 2002. (See BioWorld Today, July 2, 2002.)
Despite the failure to meet the endpoint in the MS trial, researchers did see a strong positive trend in improvement of walking speed and a significant improvement in leg muscle strength, a secondary endpoint.
"We had a statistically significant improvement in leg muscle strength across at least two of the drug groups," Cohen said.
Data from the MS trial are consistent with data from earlier double-blind trials that involved fewer subjects and shorter treatment periods. The timed 25-foot walk often is used to assess MS patients' functional status, as most people with MS experience impairment in walking ability and weakened muscles. The Lower Extremity Manual Muscle Test (LEMMT) also is used to assess leg muscle strength.
No current therapies are approved to improve walking and weakness in MS patients, Cohen said.
Showing consistency with prior studies, Fampridine-SR demonstrated adverse events of insomnia, paresthesias, dizziness and nausea in both the MS and SCI trials. Cohen declined to give a financial outlook for Fampridine-SR if approved, but he did say the drug would target about 250,000 people with chronic spinal cord injury and between 300,000 and 350,000 with multiple sclerosis in the U.S.
Fampridine-SR, an oral, sustained-release formulation of fampridine, is a selective neuronal potassium-channel blocker that restores nerve conduction. It blocks exposed potassium channels in damaged nerve fibers that have lost their insulating sheath of myelin, allowing the nerve fibers to transmit impulses again. The drug is dosed twice daily.
Acorda is developing Fampridine-SR under a license from Dublin, Ireland-based Elan Corp. plc. In October, Acorda gained exclusive, worldwide rights to the product for all indications in an expanded agreement with Elan. Acorda is responsible for clinical development, registration and potential commercialization, while Elan would be responsible for formulation development and manufacturing.
Aside from Fampridine-SR, Acorda is studying valrocemide to treat epilepsy and bipolar disorder with its partner Jerusalem-based Teva Pharmaceuticals Industries Ltd. Teva gained co-development and co-promotion rights to the drug last September in a deal that also gave it first negotiation rights to Fampridine-SR. (See BioWorld Today, Sept. 25, 2003.)
Valrocemide is expected to enter clinical development later this year.
Acorda filed for a $75 million initial public offering last October, only to withdraw it four months later so that it could raise private funds. It subsequently raised $11.5 million in a private round last month. (See BioWorld Today, Oct. 1, 2003, and March 5, 2004.)