番茄社区

BARCELONA -- Disability progression, brain atrophy, and relapses all remained significantly reduced in patients with relapsing-remitting multiple sclerosis for 3 years after completing two courses of alemtuzumab (Lemtrada) therapy, researchers said here.

Most patients in the drug's pivotal trials who remained in an extension study did not require repeat treatments since the initial two courses given during the first year, there has been no increase in the annualized relapse rate among those remaining in the CARE-MS I extension study, said , of Charles University in Prague. She also noted that patients with strong initial responses to the treatment maintained those responses through the follow-up period, which now extends to 5 years from patients' initial enrollment.

Other extension-phase analyses reported here at the annual meeting showed that the drug's benefits persisted in a wide range of efficacy measures, including effects on brain atrophy and MRI lesion burden.

For example, , of VU University Medical Centre in Amsterdam, and colleagues reported that rates of brain volume loss remained low throughout the 5-year period -- with an almost negligible 0.07% rate of loss in the final year of follow-up.

Another analysis led by , of the University of British Columbia, found that, among patients not receiving booster doses of alemtuzumab, about two-thirds showed no evidence of MRI lesion activity in year five, and 65% had no evidence of any kind of disease activity -- clinical or MRI-detected -- during the last follow-up year.

, of OhioHealth Physician Group in Columbus, Ohio -- a site investigator in the CARE-MS program, but not an author of any of the current reports -- told 番茄社区 that the follow-up data "looks the same or better in many cases" than what was reported from the main trials.

He noted that among all patients in the extensions, 40% were still showing no evidence of disease activity (NEDA). "We've never seen this before," Boster said.

Alemtuzumab differs from other MS therapies in several ways. An anti-CD52 antibody, it initiates a profound and, in many individuals, an apparently permanent shift in immune responsiveness in a way that limits development of MS relapses. It is delivered in two infusion courses given a year apart, and unless patients show a resumption of significant disease activity, no further dosing is given.

It was approved in late 2014 on the basis of two pivotal trials, CARE-MS I and II, the first of which tested the drug as first-line therapy for relapsing-remitting MS while the second recruited patients who had used other disease-modifying drugs. Both trials used interferon-beta as the control, and were unblinded because the sponsor, Genzyme-Sanofi, believed a double-blind design was impractical given alemtuzumab's unusual dosing schedule.

The drug performed very well, with annualized relapse rates of 0.18 and 0.26 in CARE-MS I and II, respectively, both of which were about half the rates seen with interferon, and with similarly impressive effects on MRI measures.

But the unanswered question was how long the effects would last. The data reported here appear to supply that answer: at least 5 years.

Patients completing the randomized phase were invited to participate in the extensions, and nearly all did so. The current reports focused on those who were assigned to alemtuzumab in the randomized phase: the extensions enrolled 349 from CARE-MS I (95% of those eligible) and 393 from CARE-MS II (93% of those eligible). Retention through the subsequent 3 years of follow-up was also high, with about 10% lost to follow-up by year five.

Havrdova, in her platform presentation, reported that 32% of patients in the CARE-MS I extension received one or more additional courses of alemtuzumab, and another 2% received another disease-modifying therapy. About half of these retreatments were because patients showed relapses, and 26% were because MRI scans revealed new lesion activity; 23% involved both.

Annualized relapse rates remained very close to the 0.18 seen in the randomized phase, ranging from 0.14 to 0.19 during the 3 years of the extension. And rates of NEDA did as well: ranging from 60% to 62% during the extension, compared with 68% during the second year of the randomized phase.

When Havrdova and colleagues restricted their analysis to participants with NEDA during year two of the randomized phase, more than 90% of them remained free of clinical disease activity and about 80% showed no resumption in MRI lesion activity. NEDA was maintained in a total of 77% of those who had NEDA during the randomized phase.

A separate analysis of the CARE-MS II extension, reported by , of Central Texas Neurology Consultants in Round Rock, Texas, as a poster, yielded generally similar results.

But adverse events remain a concern with alemtuzumab. The clinical trials showed that infections and new autoimmune diseases -- especially involving the thyroid -- were increased with the drug.

Havrdova reported that all autoimmune events occurred within 2 years of the last dose among the 349 CARE-MS I extension participants, meaning that the risk continued in patients who took retreatments. The incidence of thyroid autoimmune events peaked at 20% in the first year of the extension (treatment year three) and declined thereafter.

Immune thrombocytopenia, another worrisome side effect, was relatively rare at 1.1% during the entire 5-year study. Autoimmune nephropathy was also rare with just a single event occurring in year 3.

Infections, however, were common and remained so during the extension. Some 56% of alemtuzumab-treated patients developed infections during the main study's first year; in year five, 40% developed infections.

Fox told 番茄社区 that the infection risk was not particularly worrisome and that the new data, overall, just confirmed what was already known about alemtuzumab's safety profile.

He also pointed out the drug came with a risk evaluation and management strategy that includes regular monitoring for autoimmune effects, and that these -- especially those affecting the thyroid -- don't pose particularly difficult management issues.