Caroline Helwick

June 01, 2017

NEW ORLEANS — A drug once thought out of the running as a new oral agent in multiple sclerosis (MS) treatment may be gaining new legs.

Post hoc analysis of two trials of cladribine tablets showed that, depending on cumulative dose, up to 90% of patients were free of new lesions on MRI and up to 81% remained relapse-free after 4 years. Especially important for this agent, the analysis raised no long-term safety concerns.

"We compared the results from two 2-year studies to further understand the duration of efficacy of cladribine tablets," said Kottil Rammohan, MD, director of the Multiple Sclerosis Center at the University of Miami in Florida. "The overall rates of new clinical and MRI disease activity-free status were consistently high across all subsets of MS patients for the duration in both trials.…The effect was extremely robust."

The findings were presented here at the Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting.

The post hoc analysis, which was led by Gavin Giovannoni, MBBCh, PhD, from Queen Mary University of London, United Kingdom, came from the 867 patients in the CLARITY Extension (EXT) study, drawn from 1184 patients who first completed CLARITY. There was a treatment gap between the two studies (median duration, 43 weeks [range, 4 weeks to 6 years]).

CLARITY EXT compared the safety and efficacy of 2 years of additional cladribine vs no additional treatment. The current analysis of the CLARITY EXT study aimed to provide insights into the proportions of patients remaining free from various markers of disease activity.

Cladribine is a chemotherapeutic agent that targets white blood cells and is used to treat certain hematologic malignancies. The findings could support the efforts of EMD Serono Inc (a business of Merck KGaA) to gain drug approval for relapsing-remitting MS.

A new drug application for MS was rejected by European regulators in 2010 and by the US Food and Drug Administration in 2011.

The agencies were concerned about an increase in malignancies in patients taking the drug. Since that time, however, several agents with comparable adverse event profiles have been approved, suggesting that the thinking about the risk-to-benefit ratio of new MS agents may have shifted. The current study found no increase in risk for malignancy.  

CLARITY EXT Post Hoc Analysis Design

In CLARITY EXT, patients who received placebo in CLARITY were assigned to cladribine tablets 3.5 mg/kg body weight, and those who received cladribine (3.5 or 5.25 mg/kg) were re-randomly assigned 2:1 to cladribine tablets 3.5 mg/kg or placebo. 

This resulted in five groups, based on the treatment patients received in the CLARITY and CLARITY EXT (dose is cumulative over 4 years):

  1. Placebo/cladribine (PC) 3.5: placebo in CLARITY and cladribine 3.5 mg/kg in CLARITY EXT (n = 244)

  2. Cladribine/placebo (CP) 3.5: cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY EXT (n = 98)

  3. Cladribine/cladribine (CC) 7.0: cladribine 3.5 mg/kg in CLARITY and cladribine 3.5 mg/kg in CLARITY EXT (n = 186)

  4. Cladribine/placebo (CP) 5.25: cladribine tablets 5.25 mg/kg in CLARITY and placebo in CLARITY EXT (n = 92)

  5. Cladribine/cladribine (CC) 8.75: cladribine 5.25 mg/ kg in CLARITY and cladribine 3.5 mg/kg in CLARITY EXT (n = 186)

Results were presented for the proportions of patients qualifying as relapse-free, with no confirmed disability progression at 3 months and no new T1 gadolinium-positive (Gd+) or combined unique lesions, after 2 years of the extension study.

Consistent Benefit Observed

The analysis showed that 73% to 90% of patients receiving cladribine in the two studies remained free of new T1 Gd+ lesions, and 75% to 81% remained relapse-free.

Table. Outcomes After CLARITY EXTENSION Study (Years 3 to 4)

Treatment Group Free From Relapse (%) Without 12-Week Confirmed Disability Progression (%) No New T1 Gd+ Lesions (%)
PC 3.5 (n = 244) 79.6 75.8 85.1
CP 3.5 (n = 98) 75.6 72.4 73.0
CC 7.0 (n = 186) 81.2 77.4 88.9
CP 5.25 (n = 92) 75.3 78.3 80.2
CC 8.75 (n = 186) 76.7 76.3 89.9


By treatment group, there were no statistically significant differences in percentage of patients relapse-free or in proportion without 12-week confirmed disability progression. In an exploratory analysis, however, the proportion of patients with no new T1 Gd+ lesions was significantly lower in groups that received placebo in the extension study. The annualized relapse rate overall was 0.13, similar to that in CLARITY, Dr Rammohan said.

Also, in patients treated with cladribine 3.5 mg/kg in CLARITY and placebo in CLARITY EXT, a shorter gap between the two studies resulted in a higher proportion of patients with no new T1 Gd+ lesions (87.5% when gap was 4 weeks or less), compared with patients with a longer treatment gap (64.6% to 77.3%).

"The drug seems to have a durable clinical effect," he said, pointing to no additional benefit for greater cumulative dosing.  But he acknowledged that "you do see MRI breakthrough activity when you move from cladribine to placebo, though no increase in clinical relapse or disability."

Safety Profile

The most commonly reported adverse event in patients treated with cladribine tablets was lymphopenia, and the incidence varied by treatment group. The highest incidence (40.9%) was observed with CC 8.75, while the lowest (7.6%) was with CP 5.25.

Lymphopenia leading to treatment discontinuation was highest with CC 8.75 (12.4%) and CC 7.0 (11.8%).

Dr Rammohan commented that lymphopenia could be "long-lasting" as "it takes patients longer than a year to reach pre-treatment CD4 levels." However, he felt this did not compromise the drug's good tolerability profile.

The incidence of infections was fairly consistent, ranging from 45.1% with PC 3.5 to 49.0% with CP 3.5. Only about 2% of these were considered serious.

In an integrated safety analysis of infections and neoplasms in the CLARITY, CLARITY EXT, ORACLE-MS, ONWARD, and PREMIER trials of cladribine, the adjusted incidence of adverse events  per 100 patient-years for neoplasms (benign, malignant, unspecified) was 1.14 with cladribine tablets 3.5 mg/kg and 1.01 with placebo. 

"In more than 1900 patients treated with cladribine, we saw no increase in cancer…. Concerns raised about this after CLARITY may have been unwarranted," Dr Rammohan said.

"Reassuring" Safety Data

David E. Jones, MD, assistant professor of neurology at the James Q. Miller MS Clinic of the University of Virginia Health System, Charlottesville, told Medscape Medical News, "It's reassuring to have more safety data on cladribine."

"In the initial study, there were four cancers and I think one precancerous condition, and one of the concerns was they were mostly gynecologic cancers. So it was concerning that there seemed to be a predilection for certain kinds of cancers with this drug," he explained.

"Also, in hairy cell leukemia [for which cladribine is used] there's been a risk of cancer, but this is in older individuals who probably have more risk factors," he said. "Still, with 30 being the average age of MS diagnosis, we may wonder what the long-term effects will be, especially in lymphopenic patients whose cell counts have not recovered by a year."

"Certainly, the efficacy looks good and it's an oral agent, which is exciting," Dr Jones continued. "But since the CLARITY trial we have seen approval of lots of new agents, including three oral agents and the highly effective alemtuzumab and ocrelizumab. I am a little suspicious that they may have missed their opportunity."

The study was supported by EMD Serono Inc USA and Merck Serono SA, Geneva, Switzerland. Dr Rammohan has received honoraria for lectures and steering committee meetings from EMD Serono, Biogen, Sanofi-Aventis, Genzyme, Novartis, Teva Neurosciences, Acorda, and Roche/Genentech. Dr Jones has consulted for Biogen-Idec and Genzyme.

Consortium of Multiple Sclerosis Centers (CMSC) 2017 Annual Meeting. Abstract DX04. Presented March 26, 2017.

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