Thanks Fred. I have copied the text of your link below. I am traveling but if I have some time before the Adv Meeting this month, I will try to do a point by point kind of post about the issues outlined in this article.
-------------------------------------------------------
Acorda Therapeutics’ Fampridine-SR likely to receive FDA approval with REMS/black box label
By Kimberly Ha and Elizabeth Krutoholow
Published: October 2 2009 16:16 | Last updated: October 2 2009 16:16
This article is provided to FT.com readers by Pharmawire—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.pharmawire.com
--------------------------------------------------------------------------------------------------------
Acorda Therapeutics’ (NASDAQ:ACOR) Fampridine-SR, a drug that is designed to improve walking ability in patients with multiple sclerosis, will likely receive FDA approval later this month, despite its increased risk for seizures, neurologists and a source close to the situation told Pharmawire.
FDA briefing documents will be available on 12 October. The company is expecting an FDA decision on 22 October.
But according to risk management consultants who previously worked at the FDA, the drug will likely receive a strict risk management (REMS) procedure and a black box warning for seizure risk.
Patients with multiple sclerosis will ultimately face difficulties with walking, as their disease progresses. In clinical trials, Fampridine-SR has been found to improve impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged.
Repeated calls to Acorda were not returned.
Fampridine-SR (4-AP) is an investigational oral, sustained-release tablet formulation of 4-aminopyridine, which is available in compounding pharmacies. A compounding pharmacy makes drugs from ingredients that physicians prescribe, but are not regulated by the FDA from a safety standpoint. There have been cases of accidental compounding error, which has lead to seizure and hospitalization in certain patients on 4-AP.
A key criticism of Acorda’s drug is that less than half of the patients actually respond. In the first Phase III trial, there was a 25% improvement in walking speed after 14 weeks in 34.8% of patients taking Fampridine-SR compared to 8.3% on placebo.
A source, who has been involved with the drug’s development since its initial stages at Elan (NYSE:ELN) a number of years ago, said although a few patients respond to this drug, there have been individuals that demonstrated dramatic responses, which have encouraged further development of the agent. The source further noted that pilot studies at Elan sought to determine which patients would respond, but response proved difficult to predict.
Neurologists and investigators have pushed for continued development of Fampridine-SR in order to standardize the formulation of a drug that has been sometimes shown to improve walking ability, according to the source. ”We would prefer to have 4-AP formulated correctly because if patients have a seizure, at least you know it wasn’t because of a local compounding pharmacy error,” he said.
But there will need to be a lot of patient education with Fampridine-SR to prevent patients from overdosing, since the seizures are dose-dependent, the source added. Although he has not run into any problems so far in terms of seizures with 4-AP, he noted that he only has a small number of patients on this agent.
Dr David Brandes, medical director of the Northridge Multiple Sclerosis Center and assistant clinical professor of neurology at UCLA, who has been using 4-AP in patients for 20 years, said there have been some seizures in Acorda’s trials, and one overdose that led to brain damage. While seizures are certainly a risk, it is not one that neurologists are afraid of, he said. The benefit is so great and this is a low dose of Fampridine, so the risk is remote, he noted.
Dr Daniel Kantor, assistant professor of neurology and Director of the Comprehensive Multiple Sclerosis Center at the University of Florida, said he believes Fampridine-SR will definitely be approved with a REMS, and probably receive a boxed warning for seizure risk. The key issue now is on adoption, and if neurologists will choose to switch patients who are currently on 4-AP onto Acorda’s formulated drug, or just prescribe it to new patients.
Kantor, who has prescribed 4-AP to a number of his patients on a selective basis, said after two months, patients will know whether or not they are a responder. The drug may make the most sense in patients who are heat-sensitive, since 4-AP helps the conduction of the nerves work better. From his experience, the response rate so far in his clinic has been much more than one-third of his patients. “I don’t know exactly how many, but at least half. I’m very happy with it. I’m not starting everyone on it, but I’m choosing who I’m starting on,” he said.
Pricing will be key to adoption
One main issue in terms of adoption, will ultimately be pricing, since the active ingredient in Fampridine-SR, the compounded agent 4-AP is much cheaper, neurologists noted. “Fampridine-SR is probably going to cost USD 10,000/year, since there’s no competition or pricing war, until Sanofi comes out with their competing agent, nerispirdine,” Kantor said.
Acorda management have not stated an official price for Fampridine-SR yet, but industry analysts have modeled potential pricing in the range of USD 7000-10,000 annually. “Patients will have to pay a lot less from the compounding pharmacy, since 4-AP costs USD 70 per month. That’s USD 840 a year, versus paying USD 10,000,” Kantor said.
Sanofi-Aventis’ nerispirdine, a drug that potentially helps improve walking ability in MS patients, is currently in Phase II trials, according to clinicaltrials.gov. Kantor said Sanofi is currently in the process of recruiting patients for their Phase III nerispirdine trials, and is in the process of adding additional clinical sites.
Patients with heat sensitivity - or Uhthoff’s phenomenon - may benefit the most from Fampridine-SR, noted Dr Robert Lisak, chairman of neurology at Wayne State University School of Medicine and an investigator on the trial. Uhthoff’s phenomenon, which is common, is the appearance or worsening of neurological symptoms when body heat is elevated.
Dr Michael Racke, professor and chairman of neurology at the Ohio State University Medical Center, said the agent creates a selective advantage for conduction along demyelinated neurons, so physicians would use oculography to diagnose patient improvements on double vision. However, most physicians won’t have this test as a resource, he said.
The neurology community is optimistic for approval but there are price concerns, Lisak said. Dr David Mattson, professor of neurology and vice chairman for clinical practice at Indiana University School of Medicine, agreed that he was optimistic for the agent’s approval.
Cost concerns remain since the safety data on Fampridine-SR compared to 4-AP has never been confirmed in a clinical, head-to-head study, Lisak said. Those patients with significant deficits, but who are still ambulatory and looking to walk faster, are likely candidates for Fampridine-SR, Lisak speculated. The agent has potential in selected patients, he added.
REMS procedure
A REMS consultant, who previously worked at the FDA, said Biogen Idec’s and Elan’s risk management program for its leading multiple sclerosis drug Tysabri is the example the FDA uses as the gold standard for REMS. Biogen has obtained ex-US rights to Fampridine-SR and Elan receives seven percent of royalties on the drug.
To minimize the number of seizures that may occur with Fampridine-SR, the company may need to have patient specific procedures in place to prevent things like overdose, a second REMS consultant noted.
The REMS procedure will have to be extremely vigilant about warning patients regarding overdose; the therapeutic window is narrow, and seizures are dose dependent, one industry observer noted. Insurance companies may also ask for proof of response. The onus will be on neurologists to explain the risks of overdose to their patients - which may make it more difficult to sell the drug, and ultimately hurt sales, he said.
Dr Norman Kachuck, chief of the Multiple Sclerosis and Neuroimmunology Division of the Department of Neurology, and Director of the University of Southern California MS Comprehensive Care Center, noted that there are an overwhelming number of patients who have symptoms that could be remediated with Fampridine-SR. It will require a receptive neurologist and an efficient patient relationship to determine who is responding to the agent, he said.
Dr Hillel Panitch, a primary investigator for Acorda and professor of neurology and director of the multiple sclerosis clinic at the University of Vermont College of Medicine and Fletcher Allen Health Care, said the agent has a place in people who have trouble walking with secondary and primary progressive MS with spastic paralysis. “I’ve been following this for a while and I am glad to see someone finally has a good enough result for approval,” he said.
Panitch said he would not treat everyone with Fampridine-SR, but would reserve the agent for patients with limited walking, spasticity and weakness. It will be a useful addition for patients who could use an extra boost to leg strength and walking ability. Some patients have had remarkable responses, Panitch agreed, adding that the agent can make a big difference. |
