Sep 30, 2009
Sponsor applies to FDA for approval of oral Cladribine for relapsing MS – approval would mean first oral disease-modifying therapy for MS (UPDATED)
UPDATED 10/29/09
EMD Serono has announced that it has applied to the U.S. Food and Drug Administration seeking approval to market cladribine as the first oral disease-modifying therapy for relapsing forms of MS. In a large-scale phase 3 clinical trial, cladribine tablets significantly reduced relapse rates and other disease activity in people with relapsing-remitting MS. According to company spokespersons, the FDA has not yet made a decision about whether this drug will receive a priority review, which would expedite the time the agency has to make an approval decision.
Background/Trial Results: Cladribine is a chemotherapy that kills immune T cells and B cells, both of which are thought to be involved in immune attacks in MS. Injectable cladribine is used to treat hairy cell leukemia.
The large-scale phase 3 study that formed the basis of the application was the two-year “CLARITY” study, which was financed by the sponsor. During its first year, 1,326 participants were randomly assigned to receive a low dose of cladribine (two treatment cycles per year, each cycle consisting of one tablet per day for four to five consecutive days), a high dose (four cycles) of cladribine, or inactive placebo. In the second year, both treatment groups received a low dose of cladribine.
The primary endpoint was the drug’s effect on relapse rate at two years compared with placebo. The results, announced in a press release and in subsequent medical meetings, showed that relapse rates were reduced significantly more than placebo in both treatment groups (by 58% in the low-dose group and by 55% in the high-dose group). Those on placebo had an average of 0.33 relapses per year, versus 0.14 or 0.15 for those on therapy.
Cladribine tablets also reduced disease activity detected with MRI brain scans, including reductions in the volume of brain lesions (areas of damage) and in the number of active lesions. A greater proportion of those with no new disease activity were on active treatment (44.3% on a higher dose, 43% on a lower dose) versus those on inactive placebo (16%), and the drug also reduced the risk of disease progression by about 32% relative to placebo.
UPDATED: In terms of safety, 8.7% of those on cladribine experienced serious adverse events, versus 6.4% of those on placebo. There were 3 cases of different types of cancer among the 889 people who were on active therapy, 1 additional case that occurred during a 6-month monitoring period after the trial ended, and one case of a pre-cancerous cervical lesion. One of the main side effects experienced by those on active therapy was deficiency of white blood cells (lymphopenia), which might be expected from this type of agent and which would probably require monitoring if the drug becomes an approved therapy.
In addition to the completed CLARITY study, other ongoing studies of oral cladribine funded by EMD Serono include:
• The ONWARD study, an investigation of the safety and effectiveness of adding high or low doses of oral cladribine to interferons in a trial recruiting 260 people with relapsing forms of MS (this study is currently recruiting participants); and
• The ORACLE MS study, designed to evaluate the safety and effectiveness of oral cladribine in people who have experienced a neurological episode that puts them at risk for developing MS (this study is currently recruiting participants).
Comment: “If the FDA’s review of oral cladribine finds it to be safe and effective for people with relapsing MS, it would represent a major treatment breakthrough – hopefully the first of many successful oral therapies in the pipeline,” said John R. Richert, MD, Executive Vice President of Research and Clinical Programs at the National MS Society.