When Hillel Panitch, MD, decided last summer to accept an invitation to make a presentation on the status of multiple sclerosis (MS) clinical trials at the annual meeting of the American Society for NeuroTherapeutics (ASENT), he did not realize just how timely his presentation would be. "This turned out to be a little more topical than I thought it would be, because of the news over the last few days," he told attendees of the session on March 4 in Washington, DC. "The news," of course, was the withdrawal from the market of natalizumab (Tysabri, Elan Corporation/Biogen Idec), a newly approved drug for MS, and the discontinuation of clinical trials after 1 fatality and an occurrence of another serious disorder in one of the trials.
When Hillel Panitch, MD, decided last summer to accept an invitation to make a presentation on the status of multiple sclerosis (MS) clinical trials at the annual meeting of the American Society for NeuroTherapeutics (ASENT), he did not realize just how timely his presentation would be. "This turned out to be a little more topical than I thought it would be, because of the news over the last few days," he told attendees of the session on March 4 in Washington, DC. "The news," of course, was the withdrawal from the market of natalizumab (Tysabri, Elan Corporation/Biogen Idec), a newly approved drug for MS, and the discontinuation of clinical trials after 1 fatality and an occurrence of another serious disorder in one of the trials.Biogen Idec and Elan announced on February 28 that they were voluntarily withdrawing natalizumab from the market and halting the clinical trials involving the drug. In one of the MS trials, natalizumab was being tested as a monotherapy against placebo. In another trial, natalizumab was being used in conjunction with interferon beta 1a, another Biogen Idec MS drug marketed as Avonex.The companies cited 1 death and another illness that resulted from progressive multifocal leukoencephalopathy (PML) in the combination trial as the reason for the suspension. The FDA approved natalizumab just last November after reviewing 1 year of data from the 2-year trials.On March 30, the companies announced that their ongoing safety evaluation of natalizumab led to the discovery of a third case of PML that resulted in the death of the patient. That patient was a participant in an open-label clinical trial evaluating natalizumab as a treatment for Crohn disease. The original diagnosis for the patient was malignant astrocytoma; however, the diagnosis was later determined to be PML.The companies continue to analyze data on approximately 3000 patients who were participating in clinical trials of the drug for MS, Crohn disease, and rheumatoid arthritis. "The results of this safety evaluation will be discussed with regulatory agencies to determine the appropriate path forward for Tysabri," said Amy Brockelman, spokesperson for Biogen Idec.Panitch, a professor of neurology and director of the Clinical Trials Unit at the University of Vermont College of Medicine-and a veteran of about 30 clinical trials himself-was one of the investigators in the combination trial. At the ASENT meeting, he outlined some of the main problems with MS clinical trials since the first ones began in the late 1960s: "We have too many drugs to test . . . everything from immunomodulators, the neuroprotective drugs, the symptomatic agents. And there are not enough patients. Probably about half the patients suitable for therapy are already on treatment, so they're not available. Another 25% or so wouldn't be caught dead in a clinical trial. A few more don't want to give themselves injections of any kind, so they're waiting for an oral drug to come along."Another major problem, he added, is duration of the MS trials. "Duration is a particular issue in MS-and long-term follow-up-because you can't do short trials in MS. We're dealing with a disease that lasts 30 or 40 years and trying to treat it on the basis of trials that go on for 2 years or less," he told the session attendees.Still, he told Applied Neurology later in March, "We're much better off than we were 12 years ago when there was nothing approved for the treatment of MS other than corticosteroids for acute attacks. Now we have 5 different drugs on the market, 4 of which are appropriate for relapsing remitting MS and 1 of which is used in a more advanced progressive MS. Tysabri would've been number 6 but probably the most effective of the [drugs] for relapsing MS."WHAT'S AVAILABLE NOWCurrently approved MS disease-modifying drugs include 2 interferon beta 1a products (Avonex from Biogen Idec and Rebif from Serono and Pfizer); 1 interferon beta 1b agent (Betaseron from Berlex); 1 glatiramer acetate drug (Copaxone from Teva Neuroscience); and 1 chemotherapy agent, mitoxantrone (Novantrone from Serono).A review in Neurology describes the disease-modifying therapies for MS.1 In a head-to-head comparison study of Avonex and Rebif, Panitch was first author.2 In that same issue of Neurology, 2 editorials discuss the marketing versus the scientific aspects of the study, which led the FDA to overturn orphan drug status for Avonex and to approve Rebif.3,4As MS clinical trials go, Panitch said, the natalizumab trials were well designed and two of the largest ever for MS. The monotherapy trial included 942 patients and the combination trial included 1171 patients. "Both showed very dramatic reductions in relapse rate," he added. (See Applied Neurology, Mental Notes, January and March 2005). However, he said the negative outcome of the natalizumab combination trial will have a major impact on testing of all immune-suppressing drugs for MS.ONGOING EDUCATION AND FOLLOW-UPPanitch said Biogen Idec and Elan have contacted the investigators in the natalizumab trials and are following up on the patients. "Of course, the treatment has stopped, but the follow-up will continue every 3 months," he said. "Then we have several thousand patients out there who received anywhere from 1 to 3 doses by prescription. Some of them will go back to one of the other drugs. Many of them were treated with Tysabri after it was approved because they had already failed at least a couple of the other drugs, so they're kind of left hanging. However, I don't believe they're at any significant risk for complications like PML. Most of them were treated with monotherapy."In a "Dear Healthcare Professional" letter published on February 28, Biogen Idec and Elan recommended that physicians evaluate appropriate patients for signs and symptoms of PML and report any potential cases to the companies or to the FDA's MedWatch Web site at www.fda.gov/medwatch. In a follow-up letter on March 18, the companies reported that their panel of experts who reviewed the first 2 PML cases concluded that cerebrospinal fluid analysis for JC virus (the virus that causes PML) was the best test to confirm the diagnosis of PML in patients for whom clinical examination findings and MRI scans show signs of PML. Both letters are posted on www.tysabri.com.Panitch said that the third case of PML, reported March 30, was a "very complicated case not as clearly related to Tysabri as the others," because of the combination of therapies the patient had been taking. In the Elan/Biogen Idec announcement, the companies said that the patient had received 8 doses of natalizumab over 18 months and previously had received multiple immunosuppressive medications.So what does Panitch think needs to happen now? "What we need is to be able to get Tysabri back or identify another agent that is equivalent in effectiveness but is safer to use," he said. "I think there's a chance it could come back if there is no more than a handful of [PML] cases. It could come back with a black box warning as a last-ditch therapy," he added, for patients who haven't responded to other medications.REFERENCES1. Goodin DS, Frohman EM, Garmany GP, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines [published correction appears in Neurology. 2002;59:480]. Neurology. 2002;58:169-178.2. Panitch H, Goodin DS, Francis G, et al; EVIDENCE Study Group; University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506.3. Lublin FD. When marketing and science intersect: do patients with MS benefit? Neurology. 2002;59:1480-1481.4. Kieburtz K, McDermott M. Needed in MS: evidence, not EVIDENCE. Neurology. 2002;59:1482-1483.---Sidebar-Background on PMLProgressive multifocal leukoencephalopathy, or PML, has existed in the medical literature since 1958, when it was first described in the journal Brain.1 Its cause, the JC virus, was described in 1971 in a Lancet article2; the virus got its name from the initials of the affected patient, according to an editorial in Neurology by Kenneth M. Tyler, MD.3 Once rare, PML is now highly associated with AIDS; affected patients account for about 85% of PML cases, Tyler wrote.According to the National Institute of Neurological Disorders and Stroke, no cure or current effective treatment exists for PML, and although some patients have lived with the disease for months or years, death most often occurs within 1 to 4 months. No current PML clinical trials are open for recruitment, but 6 are listed as being complete or no longer recruiting on the FDA Web site athttp://www.clinicaltrials.gov/search/term=Progressive Multifocal Leukoencephalopathy.1. Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain. 1958;81:93-111.2. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet. 1971;1:1257-1260.3. Tyler KL. The uninvited guest: JC virus infection of neurons in PML. Neurology. 2003;61:734-735.