Daniel M. Keller, PhD

June 12, 2014

ISTANBUL, Turkey — A recent study suggests that treatment with natalizumab (Tysabri, Biogen Idec) beyond 2 years compared with switching to other drugs can control relapsing-remitting multiple sclerosis (RRMS) with adequate safety.

The longer a patient with RRMS is treated with natalizumab, the greater the risk of developing progressive multifocal leukoencephalopathy (PML), especially in patients who are infected with JC virus after 2 years of monthly treatments.

"Our study provides evidence to support the choice of continuing treatment with natalizumab after the 24th administration," Luca Durelli, MD, from the Department of Clinical and Biological Sciences at the University of Torino and the San Luigi Gonzaga University Hospital in Obassano, Italy, reported here at the 24th Meeting of the European Neurological Society (ENS).

Between 2005 and May 2014, among 125,800 patients with MS treated in the postmarketing setting, 462 cases of PML have been reported, of which 23% were fatal, for an incidence of 3.6 cases/1000 treated. The highest prevalence has been in patients receiving natalizumab for 2 to 3 years.

In this present prospective, multicenter, observational Tysabri discontinuation study after the 24th natalizumab administration (TY-STOP), 130 adult patients with clinically and radiologically stable RRMS were stratified according to their choices of treatment after the 24th dose of natalizumab, 300 mg every 28 days, and observed every 3 months for 1 year.

Treatment options presented to the patients after the 24th natalizumab dose were to continue receiving natalizumab ("continuers"), to start treatment with a different therapy ("switchers"), or to stop any disease-modifying therapy ("quitters").

First-line therapy options were interferon β-1a, interferon β-1b, or glatiramer acetate. Second-line options were fingolimod (since December 2011), natalizumab, or mitoxantrone (only 2 patients).

Of the 130 patients, Professor Durelli reported on 124 (95.4%) who had completed the entire 1-year follow-up, which consisted of 43 (35%) who continued natalizumab and 81 (65%) who interrupted it.

Table. Effects of Therapy Choices on MS Outcomes at 1 Year

Outcome Total (n = 124) Continuers (n = 35) Quitters (n = 73) Switchers (n = 16) P Value
Expanded Disability Status Scale score 3.59 ± 1.77 3.16 ± 1.69 3.79 ± 1.82 4.03 ± 1.76 .144
Annualized relapse rate 0.56 ± 0.78 0.17 ± 0.38 (Reference) 0.75 ± 0.86 (RR, 4.40) 0.56 ± 0.73 (RR, 3.28) .003
Presence of MRI activity, n (%) 50 (40.3) 10 (28.6) (Reference) 36 (49.3) (OR, 2.81) 4 (25.0) (OR, 1.00) .029

OR, odds ratio; RR, relative risk.

 

The following baseline characteristics did not significantly differ between the patients who continued natalizumab and those who did not: age, body mass index, age at disease onset, sex, disease duration at baseline, disability scores, annual relapse rates, MRI activity, and disease-modifying therapies before natalizumab initiation.

The as-treated population consisted of 73 (59%) quitters, 16 (13%) switchers, and 35 (28%) continuers.

For the intention-to-treat population, after 1 year of observation following the decision to stay on natalizumab or not, there was no significant difference in the mean Expanded Disability Status Scale scores, but the annualized relapse rate had tripled (0.24 ± 0.48 for those remaining on natalizumab vs 0.73 ± 0.85 for those not; P = .004) and the presence of MRI activity in the previous year had doubled (26.8% vs 51.3%, respectively; P = .018).

Results were similar for the as-treated population, with no significant differences in disability scores but a higher annualized relapse rate among quitters and switchers compared with continuers. MRI activity during the follow-up year was higher among quitters but not among switchers compared with continuers.

Professor Durelli said that in the as-treated population, the overall frequency of adverse effects was similar among the patients treated with the different therapies, and "during the period of observation no new safety issues emerged."

Among the continuers, there was 1 case of pyelonephritis and 1 acute myocardial infarction. Among switchers, 1 case of PML occurred in a patient who had been receiving natalizumab for 28 months. The patient made a full recovery after being treated with plasma exchange and mirtazapine.

In no patient who stopped natalizumab did disease activity return worse than it had been before natalizumab therapy.

 
Our study provides evidence to support the choice of continuing treatment with natalizumab after the 24th administration. Dr. Luca Durelli
 

Professor Durelli concluded that in patients with relapsing-remitting MS, "interruption of treatment with natalizumab after the first 24 courses exposes [patients] to an increased risk of clinical and/or MRI MS disease activity." He added the study results can support a choice of continuing natalizumab beyond 24 months.

Relapse Activity Increase

Session chairman Kjell-Morten Myhr, MD, PhD, professor of neurology at the University of Bergen, Norway, told Medscape Medical News that the study "very well showed the efficacy of Tysabri. When stopping Tysabri and starting them on a less potent treatment, the relapse activity will increase."

Infection with JC virus is a major risk factor for PML in patients treated with natalizumab, and 60% to 80% of adults in the United States and Europe are positive for antibodies to it, indicating exposure. "Of course, it would be best for the treatment of the disease itself continuing with the Tysabri, but it's a difficult issue with the risk of PML," he said.

He commented that he had the impression that the study patients had not been screened for JC virus before natalizumab initiation, probably because screening was not yet available.

"For those that are JC virus negative, there is no reason to stop after 24 months. They should continue," he said. "These patients that could be considered for stopping or switching are JC virus positive after 24 months." In keeping with usual practice, he recommended that JC virus–negative patients be tested every 6 months because they can become infected at any time.

Dr. Myhr said in his experience, when the risks of PML are explained to patients and they elect to continue natalizumab, sometimes they come back in a few months and have decided to switch to another drug because they say that they are continuously thinking about the risk.

"It's difficult for patients to make decisions, and I think they need time to make their decisions. So we really need good biomarkers to differentiate the risk for this serious complication," he said, noting that the JC virus index will be 1 biomarker "to identify those with a low risk but still a risk but lower than those with a high index."

Professor Durelli had no disclosures. Dr. Myhr has received honoraria for lecturing; participation in advisory boards or pharmaceutical company–sponsored clinical trials; and travel support from Allergan, Almiral, Bayer Schering, Biogen Idec, Novartis, Merck-Serono, Roche, and Sanofi-Aventis.

24th Meeting of the European Neurological Society (ENS). Abstract OS1115. Presented May 31, 2014.

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