Allison Gandey

October 27, 2010

October 26, 2010 (Gothenburg, Sweden) — New 5-year data from the PRECISE trial show early treatment with glatiramer acetate delays progression from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS).

Presenting here at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, investigators report a 41% reduced risk of conversion compared with placebo. The hazard ratio is 0.59 with a P value of .0005.

"Glatiramer acetate was well tolerated with only 33% overall withdrawals over 5 years," report the researchers headed by Giancarlo Comi, MD, from the University Vita-Salute San Raffaele in Milan, Italy.

The drug is marketed by Teva Pharmaceutical Industries under the brand name Copaxone. It is an immunomodulator that was approved in March last year by the US Food and Drug Administration for relapsing-remitting MS.

Magnetic resonance imaging findings at 5 years.

The original phase 3 placebo-controlled trial known as PRECISE was funded by Teva, and the company was involved in the study design, conduct, data analysis, and publication. The trial was undertaken in 16 countries at 80 sites.

Investigators evaluated 481 patients with T2 lesions and a first clinical event. Patients were randomized to receive either 20 mg daily of glatiramer acetate or placebo subcutaneously for 36 months.

The objective of this prospectively planned analysis 5 years after randomization was to determine whether early treatment with glatiramer acetate reduces disease activity and brain atrophy on magnetic resonance imaging in patients with a first clinical event.

The researchers compared the effects of early glatiramer acetate with those of delayed treatment initiated after diagnosis of clinically definite MS or after 3 years in the trial. Most of the patients, 85%, entered the open-label phase of the study and 60% completed an average of 4.3 years of follow-up.

The primary efficacy outcome was time to clinically definite MS. "As you can see — and I think this is a very important result — after about 5 years we still have a quite significant and relevant advantage for those who received immediate treatment compared to those who had a delay of treatment in terms of risk to convert," Dr. Comi told delegates here.

The conversion rate at the end of follow-up was 32.9% in the initial active treatment group and 49.6% in the original placebo group.

Very few conversions occurred during the extension phase, after the first 6 months, he noted. "Again, this is an interesting phenomenon to keep in mind, that in CIS patients, the very strong risk to convert in the first 6 months," after the first symptoms, that became very low over time.

The conversion rate in the double-blind phase was 85% based on MacDonald criteria, he noted.

Relapse rates were 23% lower for those receiving immediate vs delayed treatment, even taking into account the difference in time exposed to treatment.

Investigators also found that patients receiving early treatment with glatiramer acetate experienced a significant reduction in the cumulative number of new T2-weighted lesions and volume. T2 lesion volume accumulation in the immediate treatment group was less than 50% that in the delayed treatment group.

The percentage of brain volume change during the entire observation period was significantly lower in patients treated early. They were "shocked" by this effect on atrophy, he said, an effect that has not been seen in previous studies.

"I think this long-term follow-up of the PRECISE study is particularly informative because it is confirming the key importance of early treatment and the importance not to lose time, not to delay the intervention in order to protect, in the best way, our patients," Dr. Comi said.

Moderator Alan Thompson, MD, from the University College London Institute of Neurology in the United Kingdom, called this a "very positive study" and asked Dr. Comi whether this effect would be expected from other disease-modifying therapies. He called this a difficult question but said based on what is known about the mechanism of action, glatiramer acetate targets MS pathophysiology so would be expected to provide early benefit.

"We anticipated that the 3-year results would be confirmed at 5 years," second study author Maria Rocca, MD, from the Scientific Institute and University of Ospedale San Raffaele in Milan, Italy, told Medscape Medical News."We would certainly stress the importance of early treatment to clinicians."

Comparing Beta Interferon

Dr. Comi noted during his presentation that other trials, such as BENEFIT with interferon beta-1a, have also shown an advantage with early treatment.

However, although PRECISE suggests a benefit with glatiramer acetate, the trial also shows that many placebo-treated patients had no further clinical event. These earlier findings, published last October in an early online release of The Lancet, had neurologists talking about when to treat and when to wait and see.

More than half of placebo-treated individuals had no further clinical event during the PRECISE trial.

In a comment article accompanying that publication, Dr. David Miller and Dr. Siobhan Leary, from the University College London Institute of Neurology in the United Kingdom, pointed out that either small or no effects of glatiramer acetate and interferon beta have been noted on disability outcomes. They also noted that the long-term effects of these therapies are uncertain.

Still, the editorialists said they anticipated that some neurologists will suggest that interferon beta or glatiramer acetate should be used for most patients with CIS 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.

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 condition that underlies it. Many patients remain well for a long time.

"More than half of placebo-treated individuals," the editorialists noted, "had no further clinical event during the PRECISE trial."

This study was funded by Teva Pharmaceutical Industries. The presenters have received compensation from the company.

26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): Parallel Session 10 and Poster 986. Presented October 15 and 16, 2010.

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