Full results of the Cladribine Tablets Treating MS Orally (CLARITY) trial of oral cladribine (Leustatin, Ortho Biotech) in patients with relapsing-remitting multiple sclerosis (MS) showed a greater-than-50% reduction in annualized relapse rates with both low- and high-dose regimens vs placebo.

“In my personal opinion, oral short-course treatment with cladribine tablets demonstrates substantial benefit in patients with relapsing-remitting MS,” principal investigator Gavin Giovannoni, MBBCh, PhD, chair of neurology at the Institute of Cell and Molecular Science at Barts and the London School of Medicine and Dentistry, in the United Kingdom, told attendees here.

Cladribine is already approved for treatment of leukemias and lymphomas. The short-course regimens used in this trial mean that patients with MS would be treated for “5 days, twice a year, or 10 days of therapy a year,” Dr. Giovannoni noted.

Adverse event rates were consistent with those seen previously with the drug, and 90% of patients in each group were able to complete treatment.

Top-line results of the CLARITY trial were released in January by Merck Serono (Geneva, Switzerland), and reported by Medscape Neurology & Neurosurgery at that time. Full results were presented here at the American Academy of Neurology 61st Annual Meeting in the late-breaking science session to a packed audience. The study was funded by Merck Serono.

CLARITY in Results

Cladribine is a synthetic purine nucleoside analog prodrug, Dr. Giovannoni explained. It accumulates and incorporates into the DNA of lymphocytes and causes selective induction of apoptosis in both dividing and nondividing types of lymphocytes.

“The properties of the compound that are important for MS is that it targets both CD4+ and CD8+ lymphocytes as well as B cells and has relatively transient effects on neutrophils and monocytes,” he said. In addition, cladribine reduces levels of proinflammatory chemokines and crosses the blood-brain barrier.

The CLARITY study was a randomized, double-blind, placebo-controlled trial. A total of 1326 patients with relapsing-remitting MS according to revised McDonald criteria were randomized in a 1:1:1 ratio to receive placebo or 1 of 2 dose regimens of cladribine. All had an Expanded Disability Status Scale (EDSS) score of less than 6 at baseline.

Patients in the low-dose group received 2 short treatment courses in the first year, with each course consisting of once-daily administration for 4 to 5 consecutive days at a dose of 3.5 mg/kg. The high-dose group received 4 treatment courses in the first year at a dose of 5.25 mg/kg. In the second year, both treatment groups were given 2 treatment courses at the assigned dose.

Rescue therapy with interferon-beta1a was available to the patients, but only after 24 weeks, he noted.

The primary end point was the relapse rate at 96 weeks. Secondary analyses included magnetic-resonance-imaging (MRI) end points, the proportion of subjects who remained relapse-free, and disability progression at 96 weeks.

Of treated patients, 90% completed the study (92% in the lower-dose group and 89% in the higher-dose group), compared with 87% in the placebo group.

At 96 weeks, there was a statistically significant reduction in the annualized relapse rate with both the high- and low-dose regimens compared with placebo, Dr. Giovannoni said. “We were quite surprised, despite having a relatively low event rate in the placebo arm, that there was a robust and highly significant impact on relapse rates in both study arms,” he noted.

CLARITY: Primary End Point

Dose Group	Relative Reduction in Annualized Relapse Rate vs Placebo (%)	Annualized Relapse Rate for Cladribine	Annualized Relapse Rate for Placebo	P
3.5 mg/kg	57.6	0.14	0.33	< .001
5.25 mg/kg	54.5	0.15	0.33	< .001

Secondary end points were also met, he noted; the odds ratio of remaining relapse-free were was twice as high with treatment as without.

CLARITY: Relapse-Free Patients by Treatment Group

Dose Group	Placebo (%)	Cladribine (%)	Odds Ratio	P
3.5 mg/kg	60.9	79.7	2.53	< .001
5.25 mg/kg	60.9	78.9	2.43	< .001

Disability progression, defined as a sustained progression based on the baseline EDSS score, another secondary end point, was also significantly reduced by 33% and 31%, respectively, in the 3.5- and 5.25-mg/kg cladribine groups vs placebo.

CLARITY: Disability Progression With Cladribine vs Placebo

Dose Group	Hazard Ratio	95% CI	P
3.5 mg/kg	0.67	0.48 – 0.93	.018
5.25 mg/kg	0.69	0.49 – 0.96	.026

Finally, there was also a significant reduction in MRI activity, including T1 gadolinium lesions, active T2 lesions, and the composite of unique active lesions, with reductions of between 73% and 88% across these end points with treatment, he said.

Adverse Events

Adverse event rates were comparable between treatment groups and consistent with the mechanisms of action. “What is coming out of this appears to be a higher rate of adverse events in the higher dose compared with the low dose,” he noted.

CLARITY: Adverse Events

End Point	Placebo (%)	Cladribine 3.5 (%)	Cladribine 5.25 (%)	Cladribine Total (%)
Any treatment-emergent adverse event	73.3	80.7	83.9	82.4
Serious adverse events	6.4	8.4	9.0	8.7

Two patients in the placebo group died, and 2 in each of the cladribine groups. Causes of death in cladribine patients included 1 acute myocardial infarction and 1 pancreatic carcinoma in the low-dose group; in the high-dose group, there was 1 cardiorespiratory arrest on the background of pancytopenia pneumonia in a patient found subsequently to have tuberculosis, and 1 patient drowned.

Lymphopenia and leukopenia occurred more frequently in the cladribine-treated groups than the placebo group, 26.7% vs 1.8%, and 7.1% vs 0.5%, respectively, not unexpected given the presumed mechanism of the drug, he noted. There were 4 malignancies, all in the cladribine groups, all in different organ systems. Herpes zoster occurred only in the cladribine groups, Dr. Giovannoni noted, but he added, “They were all dermatomal, and none of them were generalized and complicated.”

“Based on successful completion of the CLARITY study, we plan to submit cladribine tablets for registration to the European Medicines Agency and to the Food and Drug Administration for mid-2009,” Elmar Schnee, president of the company, said in a press release issued with the top-line results in January.

Expanding Options

Jeffrey Cohen, MD, from the Mellen Center at the Cleveland Clinic Foundation, in Ohio, presented new data here on another drug being evaluated for the treatment of MS, fingolimod, a still-investigational oral medication. Asked for comment on the CLARITY findings, he said, “As a neurologist who cares for people with MS, having more options is exciting. On the good side, [cladribine] showed benefit compared with placebo, and it’s an oral medication, which is attractive to patients. On the negative side, it also has some safety issues that will have to be addressed.”

In general, the flurry of results with new treatments such as cladribine, fingolimod, laquinimod, and a number of other drugs now being investigated in MS leaves this field “in a very exciting place,” Dr. Cohen added. “We’re going to hopefully soon have a number of new choices to offer patients with MS. Deciding which shows the optimal benefit and risk profile will depend on further experience, but I think most likely we’ll end up using different drugs in different settings.”

The study was funded by Merck Serono in Geneva, Switzerland, an affiliate of Merck in Darmstadt, Germany. Dr. Giovannoni reports that he has received personal compensation for activities with Biogen Idec, Merck-Serono, Teva-Aventis, and Bayer-Schering Pharma as a consultant, scientific advisory board member, or speaker. He has also received research support from Teva-Aventis, Biogen Idec, and Bayer-Schering Healthcare. Disclosures for coauthors are published with the abstract.