Susan Jeffrey

November 07, 2011

November 7, 2011 (Amsterdam, the Netherlands) — A new study suggests that natalizumab (Tysabri, Biogen Idec/Elan) may be an effective option for the treatment of active pediatric multiple sclerosis (MS).

The study, a cohort study of 35 pediatric patients treated out to 23 months with natalizumab, showed that the drug was safe and well-tolerated and was effective in suppressing disease activity in almost all patients.

"I think the message is that the pediatric patient is no different in their response," to natalizumab than adult patients, senior author Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, told Medscape Medical News. "So there is absolutely no reason not to treat pediatric patients."

Neurologists have not been used to treating patients with pediatric MS aggressively because there has not been a lot of experience in this population, Dr. Comi added. However, pediatric MS tends to have a more active presentation, "so it's better to have exactly the same attitude."

The results were presented by first author Angelo Ghezzi, MD, from Centro Studi Sclerosi Multipla dell'Ospedale di Gallarate in Lombardy, Italy, on behalf of the Italian Society of Neurology's MS Study Group here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Nonresponders

About 30% of children with pediatric MS have an inadequate response to first-line medications such as interferon beta-1a or glatiramer acetate, Dr. Ghezzi noted in his presentation. Natalizumab, which in phase 3 and phase 4 studies has shown strong suppression of clinical and magnetic resonance imaging (MRI) activity in adult patients with relapsing-remitting MS, has been shown in previous case reports and observational studies to be a "promising therapeutic option" for pediatric patients as well as adults, the authors say.

In this non–industry-sponsored observational study, 15 Italian centers enrolled pediatric patients (younger than 18 years) with definite MS to look at the long-term safety and effect on clinical evolution of the disease of natalizumab therapy. Natalizumab has been authorized in Italy for pediatric patients with MS who have a severe or aggressive evolution of disease and no other therapeutic option, the authors note.

Patients were treated with natalizumab if they had had at least 2 relapses in the previous 2 years and/or incomplete recovery despite treatment with interferon or glatiramer acetate; or had experienced a recent severe relapse with incomplete recovery.

The study included 35 patients (21 girls), 25 of whom had previously been treated with at least 1 disease-modifying agent, and 13 of whom had previously been treated with more than 1 agent. Patients received a standard dose of 300 mg natalizumab every 28 days.

Patients underwent clinical and laboratory evaluation on treatment days and had an MRI every 6 months. Follow-up was 23.8 months (standard deviation, 9.8 months), covering 24.7 infusions, and was more than a year in all cases.

The mean age at the start of natalizumab treatment was 15 years, and the mean disease duration pretreatment was 28 months (±20 months). The mean number of attacks for these patients was 4.6, and the mean number of attacks in the year previous to natalizumab treatment was 2.6. Patients had a mean of 5.8 gadolinium-enhancing lesions at baseline.

"We observed an impressive reduction of disease activity," the researchers note, with reductions seen in relapse rate, Extended Disability Status Scale scores, and active gadolinium-enhancing lesions on MRI compared with baseline.

Table. Outcomes Before and After Natalizumab Treatment in Pediatric MS

Endpoint Pretreatment Posttreatment
Relapse rate 2.6 0.1
Extended Disability Status Scale scores 2.6 1.8
Gadolinium-enhancing lesions 5.8 0.4

Only 1 clinical relapse occurred during treatment, with worsening of preexisting symptoms at the first infusion, the authors note. Thirteen patients (12%) had scans showing new T2 lesions during follow-up, and 4 patients (3.6%) had new gadolinium-enhancing lesions. Three quarters of patients, 26 (74%), remained free of new T2 or gadolinium-enhancing lesions during follow-up.

The drug was well-tolerated: 35 mild adverse events were seen in 15 cases, most commonly headache (9) and vertigo (4); nasal congestion faringitis or tonsillitis was seen in 4 cases; and herpes zoster was seen in 3 cases.

Patients were tested for the presence of anti–John Cunningham virus antibodies, which have been shown in adult patients to flag those at risk of developing progressive multifocal leukoencephalopathy (PML) with natalizumab therapy. Of the 35 patients, 12 were found to be positive for anti–John Cunningham virus antibodies.

Four patients stopped natalizumab for this reason, but 8 continued with therapy because of their excellent clinical response. Natalizumab was given every 2 months in these patients, and they were monitored with MRI every 3 months. No cases of PML have been seen.

Of the 4 patients positive for antibodies who stopped treatment, as well as 2 other patients who stopped for other reasons, 3 were treated with interferon or with glatiramer acetate. Two patients remained stable on those treatments, but 1 patient developed active lesions. Of the other 3 patients who stopped therapy, all restarted natalizumab because of the reappearance of clinical or MRI signs of disease activity. Natalizumab was given at an increased interval between administration and MRI every 3 months, instead of 6.

"Natalizumab is a promising and quite effective drug for pediatric MS cases with aggressive evolution and poor response to first line medications," the authors conclude. Data on anti–John Cunningham virus antibodies were "reassuring," they note, "and helpful to identify patients at risk of PML."

What's not clear at this point, Dr. Ghezzi and colleagues add, is how best to manage the withdrawal of natalizumab in pediatric patients.

Concern About Natalizumab as First-Line Therapy

Asked for comment on these findings, Emmanuelle Waubant, MD, PhD, associate professor of Neurology at the University of California, San Francisco, expressed concern that of the cohort, 10 of these pediatric patients had received no previous treatment with other immunomodulatory agents, but were de novo patients treated first-line with natalizumab.

"This is not at all the practice of pediatric MS centers usually," she said. "There is a limited amount of safety data in children, so we almost never do that, and when I say 'we,' I think I can speak for most of my colleagues of the Pediatric MS Network in the United States."

First-line choices usually include interferon beta or glatiramer acetate, again based on good long-term safety data not only in adults but also in children. Although they are not specifically approved for children, she noted, these drugs have been used in that population for more than a decade.

Although natalizumab is sometimes used in pediatric MS, she said, "in 99% of the cases, patients on natalizumab have been on a first-line disease-modifying therapy for at least 6 to 12 months before that."

"I could understand if it was 1 in 35 patients, but 10 in 35 patients means someone in the group uses Tysabri very often as a first-line treatment. I'm not saying if it's good or bad, I'm just saying that in terms of the long-term data for safety, we just don't have it, and for children, the consequences in the long-term may be bigger than when we treat adults."

Moreover, the mean follow-up in this report is still relatively short. "In the short term I'm not concerned, but 4 or 5 years down the line, what's the safety for my pediatric patient?"

Lessons From Pediatric MS

At the meeting, Dr. Waubant, who specializes in pediatric MS, also gave a talk on what the study of pediatric patients can teach neurologists about how to approach their adult MS patients.

"Pediatric MS gives us a unique window of opportunity to study the effect of age on immune and neurologic maturation that may improve our understanding of adult-onset MS," Dr. Waubant noted.

"When we are looking at young patients we are touching on phenomena such as maturation of the central nervous system [and] maturation of the immune system, and it gives us a better understanding of what the respective role these 2 have on the course of the disease," she told Medscape Medical News. "We can learn from that to extrapolate the understanding to adult MS, and possibly come up with new strategies to treat patients better."

Studying pediatric cases of MS also provides an opportunity to study risk factors for the disease much closer to disease onset, perhaps mitigating the confounding factors that might mask these relationships.

"Patients are closer to the exposures for the risk factors, and their parents can give us a lot of information about those possible risk factors," she added. "If we're thinking about infections, or diet, or toxins, or stress — what happened during the pregnancy or just after the pregnancy — all these are important to consider, and it's hard to get to that when we're studying MS in adults."

Because of the current overlap of risk factors in pediatric and adult-onset MS, "newly identified risk factors in pediatric MS are expected to apply to adult MS as well," she said.

Dr. Waubant is principal investigator of a new case-control study that aims to examine these kinds of exposures. The study, called Genetic and Environmental Risk Factors for Pediatric MS and Interactions, is funded by the National Institutes of Health and is now ongoing at 10 centers in the United States. They have a recruitment target of 640 cases of pediatric MS within 2 years of onset, and 1280 matched control patients.

"We hope to have exciting data in the next 4 years from now," she said.

The study was not sponsored by any pharmaceutical company. Dr. Ghezzi received honoraria for speaking from Bayer-Schering, Biogen-Dompè, Merck-Serono, and Novartis; honoraria for consultancy from Actelion, Merck-Serono, and Novartis; and support for participation in national and international congresses from Bayer-Schering, Biogen-Dompè, Merck-Serono, Novartis, and sanofi-aventis. Dr. Comi received personal compensation form Bayer-Schering, Serono Symposia International Foundation, Merck-Serono International, TEVA Pharmaceutical Industries Ltd, sanofi-aventis, and Biogen-Dompè for consulting services and received personal compensation from TEVA Pharmaceutical Industries Ltd, sanofi-aventis, Serono Symposia International Foundation, Biogen-Dompè, and Bayer-Schering for speaking activities. TEVA Pharmaceutical Industries Ltd, sanofi-aventis, Serono Symposia International Foundation, Biogen-Dompè, and Bayer-Schering have given Dr. Comi supported for the costs of travelling and lodging related to speaking activities. Disclosures for the other coauthors are published in the abstract. Dr. Waubant has disclosed no relevant financial relationships.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstract 61. Presented October 20, 2011.

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