Cladribine May Delay Conversion to MS and Reduce Lesions

By Lorraine L. Janeczko

NEW YORK - Oral cladribine may delay conversion to multiple sclerosis (MS) and reduce lesions in patients with a first clinical demyelinating event, a new phase III trial shows.

Treatment at the time of the first event is known to delay the onset of MS, and early treatment in general might reduce the likelihood of later progression, the authors wrote online February 4 in Lancet Neurology.

In their ORACLE MS trial, cladribine significantly delayed the time to conversion to MS compared with placebo using both the Poser and the 2005 McDonald criteria. Cladribine also significantly reduced patients' magnetic resonance imaging (MRI) lesion counts compared with placebo.

"Our trial sets a new benchmark for what is achievable in early MS treatment," lead author Dr. Thomas P. Leist, from Thomas Jefferson University in Philadelphia, Pennsylvania, told Reuters Health.

"This is the first study of clinically-isolated syndrome patients that shows an effect on progression to clinical MS of over 60%. It showed unequivocally that we can get very high efficacy in these early patients with this medication. The size of the biological effect surprised me because it was above and beyond what was seen in other trials in clinically isolated syndrome," he said.

As to whether the drug should be the standard of care, co-author Dr. Patrick Vermersch, of the University of Lille-Nord de France in Lille, advised in an email that it should not, but that "oral cladribine could be considered as an induction therapy with two courses of treatment if clinically isolated syndrome is severe with sequelae and with a high T2 lesions load on brain or spinal cord MRI."

However, Dr. Leist noted that the trial's sponsors have decided not to continue pursuing cladribine.

He and his colleagues conducted a double-blind, randomized, three-arm phase III study in 160 medical centers in 34 countries.

They recruited patients 18 through 55 years of age who had a first clinical demyelinating event 75 days or fewer before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower.

Of the 903 patients the researchers assessed for eligibility, they enrolled 616 and randomly assigned 204 patients to receive 5.25 mg/kg of cladribine, 206 patients to receive 3.5 mg/kg of cladribine, and 206 to receive placebo. The study lasted 96 weeks.

Cladribine significantly delayed the time to conversion to clinically definite MS according to the Poser and the 2005 McDonald criteria at both doses compared with placebo (p<0.0001 for both).

Cladribine also significantly decreased the number of new or persisting T1 gadolinium-enhancing lesions, new or enlarging T2 lesions, and combined unique active lesions compared with placebo (p<0.0001).

Adverse events occurred in 165 (81%) patients in the 5.25 mg/kg group, in 168 (82%) patients in the 3.5 mg/kg group, and in 162 (79%) patients in the placebo group. The risk of adverse events with active treatment did not increase compared with placebo, except for lymphopenia, which was severe in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

"Cladribine is a very interesting medication," Dr. Leist said. "It is relatively quickly cleared from body, so its biological effect persists in the absence of actual medication, allowing a person to be treated intermittently, with absence of medication for much of the year. This may potentially be an important consideration since many patients are on polypharmacy."

"I am most encouraged by the results but also disappointed that the companies that sponsored the trial, Merck Serono in Europe and EMD Serono in the US, have decided not to pursue further commercialization of this medication," he added.

"Unless somebody else picks this up, we probably won't learn much more. As an MS physician, I am disappointed that cladribine may not be a medication available to my patients," he said.

Dr. Dennis Bourdette of Oregon Health and Science University in Portland co-wrote an accompanying editorial. He told Reuters Health in an email, "Any treatment that reduces the chances of having a relapse in MS should increase the time to conversion to clinically definite MS after the first demyelinating event. If anything, this new trial provides added evidence that cladribine is effective in relapsing MS."

Dr. Bourdette agreed with Dr. Vermersch that the drug should not be the standard of care.

"There are serious safety concerns about the use of cladribine in MS, which are the primary reason that it was not approved by the FDA to treat MS. There are much safer drugs, such as glatiramer acetate and the recombinant beta interferons, that are effective in controlling relapsing MS and in delaying time to conversion to clinically definite MS after a first demyelinating event, and these should remain the standard of care," he said.

"Physicians should not be prescribing cladribine off-label to treat MS because the long-term risks of treatment are uncertain," he said.

Dr. Leist and all other study authors have received funds from Serono, and two authors were Serono employees at the time of the study's submission.

SOURCES: https://bit.ly/N7VhKy and https://bit.ly/1mJ2yjK

Lancet Neurol 2014.

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