New Drug Ampyra Approved by FDA for Multiple Sclerosis Patients
Late Friday afternoon, January 22, 2010, the Food and Drug Administration (FDA) announced that they approved AMPYRA™ (dalfampridine, formerly known as fampridine-SR) as a treatment to improve walking in multiple sclerosis patients. Developed by Acorda Therapeutics in partnership with Elan Corp, AMPYRA™ is a proprietary slow-release formulation of the compounded drug 4-aminopyridine (4-AP).
Although the name AMPYRA™ only hit the internet on Friday, the drug and its predecessor 4-aminopyridine have a long history. Researchers have been looking into the effects of demyelination on nerve conduction for many decades. The first studies looking into the effect of 4-AP on nerve fibers were published in 1980. See Nature. 1980 Feb 7;283(5747):570-2.
[Agriculturally, 4-aminopyridine chloride, sold under the brand name Avitrol, is used as an extremely effective bird repellant since it works on the central nervous system of baited birds whose behavior then frightens other birds of the flock.]
Please keep in mind that AMPYRA™ (dalfampridine) is an oral symptomatic treatment of multiple sclerosis. It is NOT an immunomodulator which would replace drugs like Avonex, Copaxone, etc. It is a potassium channel blocker which helps electrical impulses travel over demyelinated nerves and should NOT be used by people with a history of seizures or who have moderate to severe kidney disease.
If you’d like to skip the history portion of this article and go straight to the personal stories, continue reading on page 3.
Early research out of London (1969-1983) included published papers related to conduction, demyelination, ion channels, 4-AP and multiple sclerosis. The first clinical study of 4-AP and visual function in MS was published in 1983. See J Neurol Sci. 1983 Aug-Sep;60(3):353-62. Early research from Yale and Brown Universities (1977-1994) include several studies of demyelination and aminopyridine in multiple sclerosis and spinal cord injuries.
Research in Chicago (1974-1991) focused on the use of 4-AP in treatment of MS symptoms. Three small clinical trials performed at Rush Multiple Sclerosis Medical Center in Chicago were published between 1987-1991 in which researchers observed clinical benefits while also comparing oral vs. intravenous delivery of the compound. See Ann Neurol. 1987 Jan;21(1):71-7. See Ann Neurol. 1990 Feb;27(2):186-92. See Neurology. 1991 Sep;41(9):1344-8.
In 1990, Elan Corporation obtained the Know-How related to fampridine (4-aminopyridine) for symptomatic treatment of multiple sclerosis from Rush-Presbyterian Hospital in Chicago. Research continued in Amsterdam (1990-1996) where several clinical studies were conducted including the first large trials of 4-AP in MS looking at its broad effects on disability (EDSS) and long-term safety and efficacy (during one trial two patients had seizures and one developed hepatitis). See Ann Neurol. 1992 Aug;32(2):123-30. See Clin Neuropharmacol. 1993 Jun;16(3):195-204. See Arch Neurol. 1994 Mar;51(3):292-6.
In 1994 and 1996, Elan obtained the patents to the sustained-released technology for Fampridine-SR (slow-release fampridine/4-aminopyridine) which had been developed by Joseph Masterson and Michael Myers. Elan also sponsored clinical research at the University of Maryland, Baltimore (1990-97) as well as the very first clinical trials of Fampridine-SR in multiple sclerosis. See Neurology. 1997 Apr;48(4):817-21.
In March 1995, Dr. Ron Cohen founded Acorda Therapeutics, Inc. to develop therapeutic products for spinal cord injury and other central nervous system disorders. Immediately, Acorda obtained the rights to develop fampridine for therapeutic use in spinal cord injury from the Canadian Spinal Research Organization (CSRO). In January 1997, Acorda entered into another licensing agreement, this one with Elan, to develop fampridine-SR for treatment of spinal cord injury.
In April 1998, Acorda and Elan entered a joint venture and formed the MS Research & Development Corp (MSRD). MSRD turned around and licensed research and development technology from Elan to develop Elan's proprietary oral sustained release formulation of fampridine for the treatment of multiple sclerosis. MSRD was permanently terminated in September 2003 when Acorda entered into agreements with Rush and Elan, terminating the Rush license to Elan with mutual releases. In the process Rush granted Acorda worldwide license to the Know-How and Orphan Drug Designation to fampridine for treatment in MS.
In December 2000, Accorda had announced they would initiate a Phase II trial of Fampridine-SR in MS (MS-F201). Results of that dose-ranging study were presented at the Sept 2002 ECTRIMS meeting but weren't fully published until 2007. See Mult Scler. 2007 Apr;13(3):357-68. Epub 2007 Jan 29. In April 2004, Acorda announced that Phase III clinical studies of Fampridine-SR in spinal cord injury did not produce the desired statistically-significant results, but that positive data from a second Phase II trial in MS (MS-F202) confirmed results from previous Phase II trials.
Acorda Therapeutics turned to developing Fampridine-SR for use in MS announcing in May 2005 that they had worked out a Special Protocol Assessment (SPA) with the FDA for their phase III trial design. On April 7, 2006, Acorda’s President and CEO Ron Cohen rang the opening bell on Wall Street to celebrate their successful IPO launch. In September 2006, Acorda announced positive Phase III results (MS-F203) which were later presented at the AAN meeting in May 2007 and the ACTRIMS meeting in Washington, DC in June 2007. Results from this 1st Phase III trial were finally published in The Lancet in February 2009. See Lancet 2009; 373: 732–38.
In January 2008, Acorda announced positive data from a successful QT safety study which is required by the FDA for all new drugs seeking regulatory approval. In June 2008, Acorda announced positive results from the 2nd Phase III study of Fampridine-SR in MS (MS-F204). Results from this second Phase III trial have yet to be published.
In March 2008, Acorda announced the results from a commissioned survey focused on Mobility and Quality of Life. Also in the spring of 2008, Acorda sponsored several MS Walks throughout the country. Walk MS is one of the larger fundraisers for the NMSS. In conjunction, Acorda launched the non-branded outreach website titled “I Walk Because” which features videos and profiles of MS patients and Walk MS participants.
In January 2009, Acorda submitted their New Drug Application (NDA) to the FDA for approval of Fampridine-SR (which is now called AMPYRA). The FDA Central Nervous System Advisory Committee held a meeting on October 14, 2009 to evaluate the clinical significance of AMPYRA (referred to as Amaya or Ampriva at the time) for improving walking ability in MS patients. Detail regarding the various clinical trials and data leading up to this approval can be found in the 177-page document (pdf) prepared for the FDA Committee meeting.
Data from the Phase III trials suggest that only some patients may derive a clear benefit and selectivity in responsiveness might be related to the proposed mechanism of action where only some patients would be expected to have axons (nerves) susceptible to the drug effects at any given time.
The FDA Committee voted 12 to 1 that clinical data on Fampridine-SR 10 mg twice daily demonstrated substantial evidence of effectiveness as a treatment to improve walking in people with multiple sclerosis (MS) and voted 10 to 2 (1 abstention) that it is clinically meaningful and can be safe for use. But due to the increased risk of seizures associated with the drug and concerns about the use of Fampridine-SR in patients with renal impairment, the Committee also recommended by a vote of 12 to 1 that Acorda be required to evaluate the effects of doses lower than 10 mg twice daily, but by a 10 to 2 vote (1 abstention) that these studies not be required prior to approval. Lower doses are not expected to be available for at least two or three years, if at all.
On January 22, 2010, FDA announced that they had awarded marketing approval for AMPYRA™ (dalfampridine, 10mg extended release tablet taken twice daily) as a treatment to improve walking in MS patients. AMPYRA™ will be marketed in the United States by Acorda Therapeutics and out of the US by Biogen Idec who purchased those rights last June 2009.
Since I have no personal experience with either AMPYRA™ or 4-AP, I asked a couple of MS friends to share their stories. Please meet Connie and Melissa.
Diagnosed with MS in 1999, Connie quickly learned that she has the primary progressive form of MS. Her initial symptoms include numbness in hands and feet, tingling in arms and legs, extreme fatigue and weakness. She was still walking unassisted in 2002 but by the end of 2005 needed hand controls for her vehicle and began using a walker, even after four courses of Novantrone.
At the time Connie first learned of 4-aminopyridine in August 2008, she was treating her MS with only the Swank Diet and Low-dose Naltrexone. Connie found a neurologist who was willing to prescribe 4-AP which has to be made by a compound pharmacist. She started with a low dose of 5mg immediate release capsule, gradually reaching a daily total of 20mg. After a few months, she switched to a slow-release formulation the compound pharmacist provided.
“My initial reaction to 4-AP was wonderful! I was able to walk 8-9 steps without the walker, and without holding on to anything at all. I also had greatly improved leg strength and stamina, which enabled me to stand at the sink during canning season for long periods of time, among other feats of endurance. My typing accuracy and speed also improved immensely. Sadly, that is no longer the case. However, if I am late with a dose I can REALLY tell it, as my foot drop becomes very bad, and I can barely lift either leg.”
Connie reports that although 4-AP is still somewhat effective for her, she is eager to switch to AMPYRA™. She fears the price is going to be exhorbitant and plans to seek out financial assistance as she cannot afford to purchase Medicare Part D coverage.
Experiencing her first symptoms in 1988, Melissa didn’t have a significant exacerbation until 1998 when she found herself unable to walk. She regained the ability to walk with a noticeable gait impairment and was finally diagnosed with MS in 1999. Melissa’s symptoms over the years have included tingling, numbness, fatigue, weakness, loss of fine motor skills, heat sensitivity, spasticity, impaired balance, incontinence, and cognitive difficulties. Needing a cane daily and a wheelchair on long excursions, a trip to the grocery store qualified as a long excursion.
In 2005, Melissa’s neurologist asked her if she would be interested in participating in a phase III clinical trial for ‘this new drug’ in development. She said sure. The trial was double-blinded which means that neither the patient nor the trial physician would know whether the participant was receiving drug or placebo. Melissa reports that her journey with AMPYRA began from that very first pill.
“Within about 3 hours I had what can only be described as ‘unusual’ sensation. It sort of felt like a little spark, like the lights went on or a mini burst deep inside of energy that I had not enjoyed for years. It was my body remembering. I truly believe my body was reactivated that very same day. Every day became so exciting. I gained back one thing after the other. It did NOT repair or FIX me 100% (important to make clear) but the benefits to my quality of life were undeniable.”
Melissa reports that even after four years on study drug she continues to enjoy benefits and has never experienced any adverse side effects. She no longer experiences foot drop, fatigue, or spasticity. She is no longer heat sensitive, but cold still bothers her. Melissa laughs that her balance isn’t all that great, but she only uses a cane outside. Of course her MS is still progressing but Melissa believes that without AMPYRA™, she would need 24/7 assistance.
I know that Melissa has been very excited for the greater MS community to gain access to this medication so I asked her to tell me from personal experience and in her lay opinion whom she believes would benefit most from AMPYRA™. “I believe this drug will help all people in every category of MS, just like it helped them to varying degrees as has been published in the trial results.” The clinical trial which Melissa participated in was published in The Lancet last winter. See Lancet 2009; 373: 732–38.
I really want to thank Connie and Melissa for sharing their stories with us. If you have stories to share of your own, please do so in the comment section. Remember that AMPYRA™ is a symptomatic treatment of MS. It is not an immunomodulator which would replace Avonex, Copaxone, etc. It is a potassium channel blocker which works to help the electrical impulses travel over portions of demyelinated nerves.
Two Phase III clinical trials of AMPYRA™ showed that 34.8% vs 8.3% and 42.9% vs 9.3% (treatment group vs placebo group, respectively) of patients experienced, on average, a consistent improvement in their walking speed, increasing it by 25.2% vs 4.7% and 24.7% vs 7.7%. According to the National Multiple Sclerosis Society, even a modest improvement in walking ability could mean that thousands of people could benefit from the drug.
Dr. John Richert, executive vice president of Research & Clinical Programs at the National MS Society, says approval means patients can now skip the compounding pharmacy and get a consistent, exact dosage in a guaranteed time-released formula, which would lower the risk of getting a toxic dose instead of a therapeutic dose.
"It's likely that further study and clinical practice may help to determine the extent to which the drug may impact other functions, and may also provide hints as to which patients are most likely to respond positively to the therapy," Richert said. He added that the drug would not help nerves that have been destroyed and emphasized that people should try the drug to see if it works for them.
Side effects reported during the two Phase III clinical trials include: falls (15.8% vs 15.3%; 11.7% vs 16.8%), urinary tract infection (13.6% vs 13.9%; 17.5% vs 8.4%), dizziness (8.3% vs 5.6%; 8.3% vs 0.8%), insomnia (8.3% vs 4.2%; 10.0% vs 1.7%), fatigue (6.1% vs 2.8%), nausea (6.1% vs 4.2%; 8.3% vs 0.8%), upper respiratory tract infection (6.1% vs 9.7%; 5.8% vs 6.7%), asthenia (5.7% vs 6.9%; 8.3% vs 4.2%), back pain (5.7% vs 0%; 5.8% vs 2.5%), balance disorder (5.7% vs 2.8%; 5.8% vs 1.7%), headache (5.7% vs 5.6%; 9.2% vs 0.8%), arthralgia (5.0% vs 4.2%), nasopharyngitis (5.0% vs 4.2%) and paraesthesia (5.0% vs 1.7%).
Elan Corporation will continue to manufacture AMPYRA™ for Acorda Therapeutics and Biogen Idec who purchased the rights to develop and commercial Fampridine-SR in markets outside of the United States in June 2009. AMPYRA™, anticipated to be available in the US in March 2010, will be distributed through a network of specialty pharmacies and coordinated by a team providing support services to facilitate access to the drug for patients and healthcare providers. As of yet, Acorda has not released information regarding the price or further details on the prescription assistance program which they plan to offer, although analysts estimate an annual price tag of $5,000-$10,000.
Acorda has established a phone line that individuals may call for information: 1-888-881-1918. The full label with prescribing and patient information guide is now available on the FDA’s Website (.pdf)
Also visit AMPYRA™ (am-PEER-ah)'s website for more information. I feel confident that plenty of MS patients and neurologists will be eager to give AMPYRA a try.
However, I did recently come across a small study which suggests that 4-aminopyridine can prevent remyelination as it seems to inhibit oligodendroglial regeneration. See Glia. 2004 Nov 1;48(2):156-65. This is a good question to ask the scientists, especially since myelin repair is also an important aspect of living with this disease.
Sanofi-Aventis has an investigational drug in Phase II trials, Nerispirdine (HP184), which blocks both potassium and sodium ion channels. Nerispirdine is an analogue of 4-aminopyridine but has shown not to be a convulsant in in-vitro studies. See Clin Exp Pharmacol Physiol. 2009 Nov;36(11):1104-9. Epub 2009 Apr 27.