Glatiramer Acetate May Be an Option for Clinically Isolated Syndrome

Allison Gandey

October 07, 2009

October 7, 2009 — Results from a phase 3 placebo-controlled trial suggest that early treatment with glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) may delay progression from clinically isolated syndrome to multiple sclerosis. However, the trial also shows that more than half of placebo-treated patients had no further clinical event. The findings, published October 7 in an early online release of The Lancet, have neurologists talking about when to treat and when to wait and see.

The parallel group study, known as the PRECISE trial, was undertaken in 16 countries at 80 sites. The work was paid for by Teva, and the company was involved in the study design, conduct, data analysis, and publication.

"This study establishes glatiramer acetate as an option for patients with clinically isolated syndrome who choose to start treatment early to improve control of the underlying disease process," report the investigators, led by Giancarlo Comi, MD, from the University Vita-Salute San Raffaele in Milan, Italy.

Glatiramer acetate is an immunomodulator that was approved in March by the US Food and Drug Administration for use in relapsing-remitting multiple sclerosis.

Similar to Beta Interferon

The new trial findings are similar to those of previous studies with beta interferon, in which investigators observed a delay in clinically definite multiple sclerosis.

In an accompanying comment article, Dr. David Miller and Dr. Siobhan Leary, from the University College London Institute of Neurology in the United Kingdom, point out that some neurologists will suggest that beta interferon or glatiramer acetate should be used for most patients with clinically isolated syndrome with magnetic resonance imaging results showing multifocal lesions.

Advocates will argue that prevention or delay of relapses is a worthwhile goal and that early immunomodulatory treatment, which prevents inflammatory white matter lesions and associated axonal damage, could improve long-term prognosis.

At the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis in September, researchers presented failed results from the largest study to date in secondary progressive multiple sclerosis.

After studying 600 patients with advanced disease, investigators concluded that Eli Lilly and BioMS Medical's dirucotide had no significant treatment effect. After the presentation of these MAESTRO-01 results, many clinicians emphasized the importance of early treatment.

During an interview, session cochair Gavin Giovannoni, MBBCh, PhD, from the Institute of Cell and Molecular Science at Barts and the London School of Medicine and Dentistry, in the United Kingdom, said, "Once degeneration has occurred, it can be difficult to modify the course of disease."

However, Dr. Giovannoni acknowledged the challenge of patient selection for early treatment — particularly when dealing with those without clinical symptoms.

Some neurologists will instead adopt a wait-and-see approach, arguing that many patients remain well for a long time. "More than half of placebo-treated individuals had no further clinical event during the PRECISE trial," the editorialists note.

Weighing the Evidence

Neurologists who choose to wait will argue there is a lack of evidence that early, rather than deferred, treatment alters risk for long-term disability and secondary progression or the pathology that underlies it.

Dr. Miller and Dr. Leary point out that either small or no effects of glatiramer acetate and beta interferon have been noted on disability outcomes. They also note that the long-term effects of these therapies are uncertain.

As previously reported by Medscape Neurology, trial findings were presented in April 2008 at the American Academy of Neurology annual meeting. Investigators showed that glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo.

The research team studied 481 patients with clinically isolated syndrome. Participants received either subcutaneous glatiramer acetate 20 mg per day or placebo for up to 36 months.

PRECISE Primary Endpoint

Endpoint Hazard Ratio 95% Confidence Interval P Value
Time to clinically definite multiple sclerosis 0.55 0.40 – 0.77 .0005

The most common adverse events in the glatiramer acetate group were injection-site reactions and immediate postinjection reactions.

Dr. Miller and Dr. Leary suggest that better predictors of the course of multiple sclerosis are needed to identify which patients need therapeutic intervention.

"The greatest unmet therapeutic need in multiple sclerosis is to identify treatments that delay, prevent, and even reverse progressive irreversible disability," the editorialists note. "Strategies focused on neuroprotection and repair — in addition to or instead of immunomodulation — might be needed to achieve this goal."

This study was paid for by Teva Pharmaceutical Industries. Lead author Dr. Giancarlo Comi reports that he has received compensation from the company.

Lancet. Published online October 7, 2009.

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