Steinman warned of drug's risk prior to FDA approval

Regulators’ decision to pull M.S. medication from market shows difficulty of deciding when to fast-track new drugs

Larry Steinman

The news last week that the federal Food and Drug Administration was pulling the multiple sclerosis drug Tysabri from the market stunned many in the medical profession, but neurology professor Larry Steinman, MD, who developed the drug, wasn't among them.

Steinman had raised the possibility of problems more than a decade ago.

The FDA withdrew the drug after reports that one M.S. patient had died of a rare neurological infection and a second had become ill with the same condition, known as progressive multifocal leukoencephalopathy, or PML. The FDA had approved the drug just three months ago under a fast-track system designed to get drugs quickly into the hands of patients afflicted with serious diseases.

The Tysabri case illustrates the difficulty of balancing the need for adequate drug testing with the urgency of getting drugs quickly to patients with serious ailments.

Steinman said he predicted early in the drug's development that patients might suffer immunological side effects from Tysabri, which works by preventing lymphocytes, white blood cells of the immune system, from entering the brain and damaging the sheath that protects nerve cells. As the nerve cells misfire, patients suffer progressive loss of motor control and ultimately, paralysis.

Steinman and collaborators at Athena Neuroscience (later bought by Elan, the maker of the drug) had first described this novel approach in a 1992 paper in the journal Nature. They soon learned, however, that the drug was not as specific as they had hoped; it not only prevented migration of lymphocytes to the brain, but to other organs as well, such as the gut and the pancreas. With an immobilized immune system, the body would be unable to fight off disease, Steinman said.

"I was right there at the beginning, and I had a worry then because we learned that the molecule we were targeting was not a unique zip code to gain entry to the brain," said Steinman, who heads the doctoral program in immunology.

He said his biggest concern was that patients would become vulnerable to opportunistic infections. Indeed, PML is an opportunistic infection that most often affects AIDS patients, whose immune systems are compromised.

Despite the concern, the drug did progress to clinical trials, with spectacular results. In one trial, researchers found the drug reduced the frequency of patient relapses by 66 percent, compared with a placebo.

In a second trial, patients took Tysabri in combination with the interferon beta drug Avonex; at the end of a year, those on this combination treatment had a significant reduction in relapses.

The trial results showed a "hint" of increased incidence of infection, Steinman said, with some patients in the phase-II trials developing an upper respiratory tract infection known as pharyngitis. But it was in a "comfort zone" in which doctors and patients would be willing to take a risk, he said.

Steinman said he was thrilled with the trial results and began to question his own predictive powers regarding the drug's potential side effects. Nonetheless, he continued to voice his concerns at medical meetings and in scientific journals.

In June 2004 review article in Science magazine, he wrote that this approach to treatment carried "at least a theoretical concern that recipients of the therapy would become generally compromised in their ability to fight infection."

Still, the FDA was so impressed with the trial results that it approved the drug in November 2004 under an accelerated process. Analysts predicted the drug—the first new drug for M.S. in eight years—would have a $2 billion market within two years.

At the time of the drug's approval, it had only been tested in a few thousand patients, Steinman noted.

"I worried that when it becomes the blockbuster everyone expected, what would happen when we had 50,000 patient-years of experience?" he asked. "And sure enough, after only a few thousand patient-years of experience, the drug gets pulled because it causes two people to develop a horrendous disease, and one is already dead."

Still, Steinman said he believes the FDA acted appropriately.

"I think basically the FDA did an adequate job," he remarked. "I tilt in favor of getting things into the hands of physicians earlier, rather than later." If untoward events then occur, he added, the drug could be pulled from the market.

The company has indicated that it might reintroduce Tysabri later as a stand-alone therapy. The two patients affected by the rare infection were both part of the combination treatment trial, using Tysabri with an interferon beta drug.

But Steinman said he doesn't believe taking Tysabri now would be worth the risk, given that there are other treatments available for the roughly 400,000 M.S. patients in this country.

"There are alternatives," Steinman said. "It would be hard to justify putting someone at risk for such a potentially lethal complication."

He and his colleagues now are working on the development of two other M.S. drugs that have a different mechanism of action and that they hope will be more targeted than Tysabri.

He has co-founded two companies, Neurocrine Bioscience in San Diego, and Bayhill Therapeutics in Palo Alto, to spearhead development of the drugs, both now in clinical trials.