Drug may offer MS turnaround

A disease thought to be incurable is now a step closer to losing that dispiriting reputation. Multiple sclerosis, the disabling neuromuscular disease that has resisted effective drug therapy, eases off in some people given a drug normally prescribed for leukemia, researchers report in the Oct. 23 New England Journal of Medicine.

“More than half the patients in this study actually improved a significant amount” when taking the drug alemtuzumab, says study coauthor David Margolin, a neurologist at Genzyme Corp. in Cambridge, Mass., which teamed with an international team of researchers in conducting the trial. “We think this is something very special.”

That optimism is tempered by worrisome side effects that showed up in MS patients taking the drug. Two more large-scale trials of MS patients are now getting under way to address those issues and confirm the positive findings.

In MS, the body’s own immune cells orchestrate an attack on myelin, the fatty sheaths that insulate nerve fibers in the central nervous system. The origins of this mutiny remain a medical mystery, but the disaster that follows is well documented: A torrent of inflammation robs the nerves of their protective myelin, disrupting nerve signals and resulting in the motor control losses that mark MS. In the early stages, MS attacks often come and go in relapsing-and-remitting fashion. In the worst case scenario, the autoimmune assault becomes chronic, leading to irreparable nerve damage and permanent disability.

Enter alemtuzumab, also called Campath. This drug targets a compound called CD52, which appears on T cells and B cells, the prime movers of the immune system. Alemtuzumab works well, killing off nearly all the T and B cells, and thus wiping out a huge portion of a person’s immune system. That’s a good thing if your immune cells are running amok, as in autoimmune disease or leukemia. But it can leave a person vulnerable to infection.

Fortunately, this housecleaning is temporary. Since nascent T and B cells don’t make CD52, they escape the purge and go on to repopulate the immune system anew. That takes a few months for B cells but years for T cells, says study coauthor Alasdair Coles, a neurologist at the University of Cambridge in England.

While the drug has helped patients fight chronic lymphocytic leukemia, testing against MS progressed slowly in the 1990s as researchers mainly tested alemtuzumab in advanced-stage, mostly middle-aged MS patients, with little success.

That approach changed in 2002 when an international team of researchers began testing the drug on younger, less-advanced-stage MS patients over the course of a three-year trial. The scientists enrolled people mainly in their 20s and 30s with MS that was diagnosed only 1.3 years earlier, on average, and who hadn’t been treated for the condition yet.

The researchers randomly assigned 111 to get interferon beta 1a, a standard MS drug given as three injections per week. Another 223 patients received alemtuzumab, delivered in a series of intravenous infusions over five days once a year. Most volunteers getting alemtuzumab got two series of infusions, one at the outset and another after 12 months; 46 received a third course a year after that.

The interferon group was slated to receive regular injections during the three-year trial, but two-fifths stopped taking the drug at some point, most complaining of side effects or lack of effectiveness. All patients were monitored for three years.

Clinical testing showed that disabilities for people on interferon rose on average during the trial but fell in those getting alemtuzumab, a first for a large trial, the authors point out.

Overall, 57 percent of those on alemtuzumab improved during the study, while roughly one-fifth worsened and the others held steady. Of those getting interferon, one-third improved, 41 percent declined and the rest held even.

Over the three years, only 20 percent of the alemtuzumab patients had a relapse, compared with 48 percent of the interferon patients.

What’s more, magnetic resonance imaging, or MRI, of the patients’ brains showed less inflammation in those getting alemtuzumab. The brain can wither in MS patients. Between months 12 and 36 in this study, interferon patients experienced a slight loss of brain volume on average whereas alemtuzumab patients added volume.

Combined, these findings suggest that the drug is somehow promoting brain repair in MS patients. “This is unprecedented. It hasn’t been seen before,” says Coles. “Up until now, no one would have thought this would happen.” He was particularly surprised by the MRI data. “Between 12 and 36 months,” he says, patients getting alemtuzumab “were actually acquiring new tissue in the brain.”

The most common side effect from alemtuzumab concerns the thyroid gland, and 23 percent of patients getting the drug in this trial developed thyroid problems. In some people, the gland becomes overactive; in others, it became underactive. Of those getting inferferon, 3 percent developed thyroid problems.

Immunologist Bibiana Bielekova of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., says these thyroid problems are not always easy to treat. Plus, many patients with early-stage MS and mild symptoms might not relish the risk of developing a new problem, particularly when there are several other options available for treating their MS at that stage.

On the other hand, Margolin says, thyroid problems, if manageable, “might be a fair trade off” since they aren’t as serious as MS.

A dangerous bleeding disorder called ITP, or idiopathic thrombocytopenic purpura, showed up in 3 percent of alemtuzumab patients and 1 percent of interferon patients. ITP patients’ immune cells attack their own blood-clotting platelets, risking hemorrhage. One person on alemtuzumab died from the disorder.

“We are quite aware of how incredibly effective this drug is,” Bielekova says. “But everybody is scared to death of those side effects.”

Margolin says physicians will closely monitor patients’ platelet counts in the two upcoming trials of alemtuzumab.

Previous studies had gauged alemtuzumab’s effects against MS largely in patients who had late-stage disease. The drug showed promise, but patients still went downhill, Bielekova says.

Margolin suggests that using alemtuzumab to treat early-stage MS patients “who are still walking around” yields benefits because temporarily knocking out T cells and B cells quells the immune system’s ability to generate inflammation, an early-stage event in MS. “That seems to give the body a chance to recover,” he says.

The new findings are “remarkable,” says Stephen Hauser, a neurologist at the University of California, San Francisco, writing in the same NEJM issue. This and previous work pitting alemtuzumab against MS represent “thoughtful clinical investigations [that] have advanced the field substantially,” he says. But only long-term testing will establish alemtuzumab’s place in the anti-MS armamentarium, he says.