Russia Approves Oral Cladribine to Treat MS

Yael Waknine

July 22, 2010

July 22, 2010 — The Russian Federal Service on Surveillance in Healthcare and Social Development has become the first government agency to approve an oral formulation of cladribine (Movectro tablets; Merck KGaA) for the treatment of relapsing-remitting multiple sclerosis (MS). The product is expected to launch in early 2011.

Cladribine is the first oral disease-modifying drug to be approved for MS. Currently used disease-modifying drugs such as interferon beta-1a/1b, glatiramer acetate, mitoxantrone, and natilizumab require regular and frequent parenteral administration that limits long-term therapeutic compliance.

"I would hope that the appreciation of the importance of cladribine tablets by the Russian Federation is something that will quickly percolate to other regulatory authorities across the world," said Mark S. Freedman, MD, CSPQ, FAAN, FRCPC, in an interview with Medscape Medical News. "Cladribine tablets offer not only unprecedented MS disease control but...an oral formulation which only needs to be taken for a few days over a few weeks a year. There are numerous patients who stand to benefit greatly from this agent."

Dr. Freedman, an investigator in the clinical trial that supported the Russian approval, is senior scientist in neuroscience at the Ottawa Hospital Research Institute, professor of medicine at the University of Ottawa, and director of the Multiple Sclerosis Research Unit, Ottawa Hospital-General Campus in Ontario, Canada.

Cladribine is a purine nucleoside analog that hinders the action and proliferation of lymphocyte subtypes involved in the pathologic process of MS.

Study Findings

Russian approval was supported by data from the phase 3 CLAdRIbine Tablets Treating MS OrallY (CLARITY) study of 1326 patients who were randomly assigned in an approximate 1:1:1 ratio to receive either cladribine at 1 of 2 doses or placebo. In the first year, once-daily cladribine was administered in 2 (3.5 mg/kg total dose) or 4 (5.25 mg/kg total dose) treatment courses, each lasting 4 to 5 days depending on patient weight (total days, 8 - 20). During the second year, all patients received 2 treatment courses (total days, 8 - 10).

Results at 96 weeks showed that cumulative doses of 3.5 mg/kg and 5.25 mg/kg cladribine yielded statistically significant benefits over placebo in terms of relapses, disability, and magnetic resonance imaging outcomes. Cladribine therapy:

  • Significantly decreased the annualized relapse rate by 57.6% and 54.5%, respectively, relative to placebo (0.14 and 0.15 vs 0.33 for placebo; P < .001 for both comparisons), and yielded significantly more relapse-free patients at week 96 (79.7% and 78.9% vs 60.9% for placebo; P < .001 for both comparisons).

  • Significantly decreased the risk for 3-month sustained progression of disability by more than 30% (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.48 - 0.93; P = .02; and HR, 0.69; 95% CI, 0.49 - 0.96; P = .03).

  • Significantly decreased mean brain lesion count by up to 88% on 3 magnetic resonance imaging measures: gadolinium-enhancing T1-weighted lesions (0.12 and 0.11 vs 0.91; Δ, 85.7% and 87.9%), active T2-weighted lesions (0.38 and 0.33 vs 1.43; Δ, 73.4% and 76.9%), and combined unique lesions (0.43 and 0.38 vs 1.72; Δ, 74.4% and 77.9%; P < .001 vs placebo for all comparisons).

"[O]ral cladribine represents a potentially important improvement in tolerability over existing MS disease-modifying therapies that are parenterally administered," noted Bruce Cree, MD, PhD, in an interview with Medscape Medical News. "Without a doubt, the dosing regimen will be extremely well tolerated, [requiring only] 1 or 2 pills/day for 4 or 5 days per week for 2 weeks each year."

Dr. Cree is an assistant professor of clinical neurology at the University of California–San Francisco School of Medicine, attending physician at the University of California–San Francisco Medical Center, and a Sylvia Lawry fellow of the National Multiple Sclerosis Society.

As expected with the drug's mechanism of action, lymphocytopenia was the most commonly reported adverse event in patients receiving 3.5 mg/kg and 5.25 mg/kg cladribine (21.6% and 31.5% vs 1.8% for placebo) but was not generally linked to an increased risk for infection (47.4% and 48.9% vs 42.5% for placebo). Activation of latent herpes zoster occurred in 20 patients (vs 0 for placebo), and 1 cladribine-treated patient died following reactivation of latent tuberculosis.

Cancer occurred in 4 patients receiving cladribine therapy, with each case affecting a different organ — patients were diagnosed with melanoma, pancreatic cancer, ovarian cancer, and early-stage (0) cervical cancer. A choriocarcinoma was diagnosed in 1 patient receiving 5.25 mg/kg cladribine about 9 months after completion of the study. No malignancies were reported in the placebo group.

Other studies in the cladribine development program include the 2-year CLARITY extension study, the phase 3 Oral Cladribine in Early MS (ORACLE MS) 2-year study, and the phase 2 Oral Cladribine Added ON To Rebif (interferon beta-1a) New Formulation in Patients With Active Relapsing Disease (ONWARD) trial.

Approval in the United States

Cladribine was granted fast-track status by the US Food and Drug Administration (FDA) in 2006, but in November 2009 the agency denied a new drug application from EMD Serono, Inc (an affiliate of Merck KGaA), for reducing relapses in patients with relapsing forms of MS.

According to 1993 regulations posted on the FDA's Website, refusal to file (RTF) differs from refusal to approve an application after full review, in that it is generally "based on omissions or inadequacies so severe as to render the application incomplete on its face."

Historically, RTFs have been based on omission or haphazard presentation of a required new drug application section, clear failure to include evidence of efficacy compatible with regulations, or omission of critical data, information, or analyses required to evaluate safety and efficacy or provide adequate directions for use.

The FDA notes that RTF is "not a final determination" but is intended to offer the sponsor an early opportunity to develop a "reviewable and potentially approvable application." Minor omissions that would not interfere with or delay application review should not lead to RTF.

According to Bloomberg's article by Naomi Kresge, Merck drug unit head Elmar Schnee told investors at the January 11 JPMorgan healthcare conference that the FDA's concerns had to do with "tabulation," or how the data were counted, and with the documents Merck filed. More than 1 well-controlled study may be needed to satisfy the agency's proof-of-efficacy requirements.

Speculation also exists about whether long-term safety concerns are at issue — cladribine-associated immune suppression could leave patients with MS vulnerable to opportunistic infections and cancers. In November 2009, Merck began recruitment for a long-term 2-year safety study of 1000 patients previously exposed to cladribine in clinical trials.

"[T]here are important safety concerns with respect to use of this medication. Because cladribine is an immune-suppressing medication, there are adverse events including infections (herpes zoster reactivation and tuberculosis, for example), as well as neoplasms and myelodysplastic syndromes, that appear to be associated with the medication," Dr. Cree warned, noting also that long-term safety experience with cladribine use on an annual basis is not available. "Physicians and patients will need to be well-informed about the available data on cladribine before deciding to use this medication, when and if it becomes available in the United States."

According to Dr. Freedman, however, the speculation is just that — speculation. "Ongoing extension data will help to clarify whether one needs to continue yearly treatment; it is possible that a 2-year course might confer protection for a number of years before retreatment is necessary. Should this be the case, any 'speculation' regarding potential long-term toxicity will be rendered less of a concern.

"So far, 4 unrelated cancers have raised concern, but in a study of over 1000 patients, such numbers are not unexpected. They predicted all sorts of terrible things when interferon first surfaced, and here we are some 20 years later with not a single of the 'doomsday scenarios' panning out — instead, interferon has a safety record other agents could only wish for," Dr. Freedman added.

Although the company resubmitted its application for cladribine approval this month, the inherent delay could give rival drug fingolimod HCl (Gilenia; Novartis AG) a timing lead on US approval. In a June 10 meeting, FDA Peripheral and Central Nervous System Drugs advisory committee members voted unanimously that fingolimod capsules demonstrated substantial efficacy in treating MS and that the safety of the proposed 0.5-mg dose justified approval.

Cladribine tablets are also currently being evaluated for approval by the European Commission.

Cladribine injection (Leustatin; Ortho Biotech Products, LP) previously was approved by the FDA for the treatment of active hairy cell leukemia.

Dr. Freedman is on the steering committee for some of the ongoing trials with cladribine and served as an investigator in CLARITY study. Dr. Cree serves on the external steering committee for the ORACLE cladribine study.

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