Issue Date: March 15, 2010
Loyal Steward Of A Small Molecule
It is commonly estimated that it takes a successful drug 12 years to go from discovery to Food & Drug Administration approval and commercialization. That statistic is usually trotted out to make the point that drug development takes a long, long time.
Tell that to researchers at Rush University Medical Center, in Chicago. They began studying 4-aminopyridine as a treatment for multiple sclerosis (MS) in 1983. After years in their labs and a long sojourn at the Irish drugmaker Elan, the drug ended up with the biotech firm Acorda Therapeutics. In January, it finally won FDA approval under the name Ampyra.
A quarter-century after it started research, Rush maintains a commercial interest in the molecule, which is hailed as a breakthrough in MS treatment, one of the first to actually reverse the effects of nerve dysfunction rather than just slow damage caused by the disease.
A fourth player, however, has been involved with the molecule nearly the whole time: the custom chemical firm Regis Technologies, which began manufacturing 4-aminopyridine to FDA’s current Good Manufacturing Practices standards shortly after Rush began its work. Regis supplied both Elan and Acorda and is still the sole supplier of the active pharmaceutical ingredient (API).
It began with a phone call in 1983. “Rush looked us up in the phone book,” says Sean Bradley, business development director at Regis, noting that the company, based in Morton Grove, Ill., was likely the closest supplier to the Chicago hospital. Regis took the job, a small one, without much hope of it getting bigger. “To be honest, a request from a hospital was the longest of long shots back then,” he says. “At less than $20,000, it was a very small project.”
But it was an intriguing project, Bradley says, given the molecule, which garnered a great deal of interest in the late 1970s and early 1980s as a possible treatment for nerve damage and disease. “The most interesting thing about the program was that it was the smallest of small molecules,” he says. “Thirteen atoms in total. One ring. Most drugs are not that small.”
Dusan Stefoski, a neurologist and the director of Multiple Sclerosis Center at Rush, began work on 4-aminopyridine with colleague Floyd A. Davis in the early 1980s. He says the molecule’s size enables it to readily cross the blood-brain barrier. The compound has the ability to compensate for the deterioration of nerve cells’ myelin sheath, which results in a kind of short-circuiting of nerve impulses.
“We had specialized over the years in the electrophysiology of MS, and we knew the mechanisms of the disease,” Stefoski recalls. “It was known that manipulating nerve impulses by changing sodium and potassium channels in specific ways could force nerve impulses to travel through tissue damaged by MS.” The trick was to do this safely.
“Manipulating sodium channels is too dangerous,” Stefoski explains. “This is what venomous snakes and scorpions do to paralyze their prey.” But research at Duke University had already shown that 4-aminopyridine worked as a potassium channel blocker. “So it became apparent to our team at Rush that now there is a compound that selectively blocks potassium channels and that we could try to use it on MS.”
But potassium channel blockers also pose safety risks, as researchers at the National Hospital for Neurology & Neurosurgery, in England, found out the hard way. Approved by a hospital ethics committee, 4-aminopyridine was administered to patients in a trial that determined the drug is unfit for human use. “The cases were never published,” Stefoski says. “But the drug probably caused seizures.”
Rush worked on the compound for three years, attempting to find a safe dosage at which to test it. “One big thing was that the compound was not available at a high enough purity,” he says. “This is where Regis came in.” The contractor developed a proprietary synthesis route with multistep purification.
Rush began testing the molecule on patients. “Elan came in when they saw the results,” Stefoski says. Elan, which declined to be interviewed, licensed the drug and began moving it toward the clinic. There it hit its first roadblock, a multi-million-dollar clinical trial in 1993 that failed to prove efficacy.
In 1997, Acorda, with headquarters in Hawthorne, N.Y., began licensing 4-aminopyridine from Elan so it could do its own work on a therapy for spinal cord injury. Within a year, Acorda was working with Elan on a sustained-release dose of the drug, says Bill Dollard, Acorda’s senior director of technical operations.
According to Dollard, the sustained-release formula would be crucial to developing a safe dose of 4-aminopyridine. By the 1990s, the chemical was already in use—it could be prescribed by doctors and compounded by pharmacists, but no standard dosage-form drug had been approved by FDA. “Lots of people were taking it, but there was no guarantee it would work,” he says. “And it wasn’t covered by insurance.”
Elan’s challenges with developing the drug were compounded by other problems in its business. The company’s stock plummeted from a 2001 high of $62.85 per share to $1.05 per share in October 2002. Changes in Elan’s business model had already caused development of 4-aminopyridine to grind to a halt. As the company began off-loading assets, it transferred the license to the drug to Acorda in 2003.
Pushing forward on an MS therapy, Acorda faced a new challenge on the purity front as FDA raised its standards for required purity levels. Regis went to work on developing new analytical methods to prove that its 4-aminopyridine met the new standards.
Regis executives did this knowing that the manufacturing project was, and is, relatively small for a commercial drug. “When Elan came in, we started producing 20-kg batches,” Bradley says. “Over the course of working with Elan, we began producing a couple hundred kilograms, and even working with Acorda, we are producing less than a metric ton.”
Over the 20-plus years of working with the various stewards of the molecule, Regis at times thought production would stop altogether. Now that Ampyra has been approved, Regis enjoys a role as the sole supplier of API. It also holds the drug master file—a unique situation for a contract manufacturer, Bradley notes.
Managing multiple relationships over many years has been a struggle, Bradley says. But the entry of another player last July may mean good things for everyone involved, including Regis. Biogen Idec signed on last year to market the drug outside the U.S. The big biotech firm is likely to significantly boost sales of Ampyra, and thus production of the small small molecule 4-aminopyridine.
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