Cladribine
This is another drug used in chemotherapy. It has been effective in the treatment of certain leukaemias and lymphomas. Again, it is likely to be of benefit in MS by suppressing the immune system. It was tried in MS because it is relatively less toxic than some of the other anti-cancer agents. The first major study in the literature was performed in California and published in 1996.1 Fifty-one people were treated in a placebo-controlled RCT. The design was a bit unusual in that patients were crossed over from the placebo to the cladribine treatment group after one year in the study, and patients getting the cladribine first were then given placebo. The drug was given as a weekly course of injections every few months. The study again showed a favourable effect on progression of disability, with patients on cladribine tending to improve while those on placebo deteriorated.
Concerns were raised about side effects, particularly bone marrow suppression, but a more recent study of severely affected people with MS showed that the drug was well tolerated, and that these effects could be diminished by decreasing the dosage.2 A Californian RCT of 52 people over eighteen months with relapsing-remitting MS showed significant benefits for those treated with cladribine. Patients improved in terms of frequency and severity of relapses and the number of MRI lesions.3 In fact, by the sixth month of treatment, there were no new lesions at all in the cladribine treated group. The cladribine was given as a five-day course of injections every six months.
Side effects of cladribine are relatively mild considering the class of drug. Bone marrow suppression, decreased platelet count and decreased white cell count have been recorded. Shingles may also occur, as with other immunosuppressant therapies. Overall, these studies are again extremely encouraging for people with MS which is difficult to control with the standard therapies discussed earlier in this book. An advantage I see is that a course of therapy is needed only once every six months, and disease progression is likely to be very significantly slowed. The price in terms of side effects is probably acceptable if the MS is very active.
In January 2005, a large pharmaceutical company announced that it was beginning large-scale trials of an oral formulation of cladribine.4 1326 people with MS were randomised to receive either cladribine orally for a total of 8-20 days per year or placebo.5 The cladribine group had roughly 50% lower annualised relapse rate compared to the placebo group, with similar MRI benefit, although with a high rate of reduced blood count of immune cells in the cladribine group, and a number of herpes infections. This study, the CLARITY study, was a 96-week RCT enrolling 1326 patients with relapsing-remitting MS. A low dose and high dose of cladribine were tested against placebo. The cladribine tablets were taken in two or four treatment four- to five-day courses in the first year, so patients took cladribine tablets for only eight to 20 days in the year. In the second year, all participants took two treatment courses. The relapse rate in the placebo group was 0.33 per year on average; this fell to 0.14 per year in the low dose group, a 58 per cent reduction (p<0.001), and 0.15 in the high dose group, a 55 per cent reduction (p<0.001).
The drug was well tolerated with more patients in the treatment groups finishing the study than those in the placebo groups, and relatively mild side effects according to data released by the drug company. Longer term studies are under way looking at longer term safety, but as a chemotherapy agent there are likely to be some downsides to long-term treatment, especially related to bone marrow suppression and infections. The good news with this study is that the lower dose worked so well, at least as well as the higher dose, and that people tolerated the drug so well and stayed in the study. This compares very favourably to the interferon studies where there was a very high drop-out rate. The other really positive aspect is that the drug is taken orally, and only for a few days each year. It has the potential to really make a difference to the lives of people with MS if it proves in the longer term to be safe, and if it actually makes a difference to disease progression. The drug company is submitting cladribine for approval in mid 2009 in the United States and Europe. It has been granted fast-track status by the Food and Drug Authority.
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Side effects of cladribine are relatively mild considering the class of drug. Bone marrow suppression, decreased platelet count and decreased white cell count have been recorded. Shingles may also occur, as with other immunosuppressant therapies. Overall, these studies are again extremely encouraging for people with MS which is difficult to control with the standard therapies discussed earlier in this book. An advantage I see is that a course of therapy is needed only once every six months, and disease progression is likely to be very significantly slowed. The price in terms of side effects is probably acceptable if the MS is very active.
In January 2005, a large pharmaceutical company announced that it was beginning large-scale trials of an oral formulation of cladribine.4 1326 people with MS were randomised to receive either cladribine orally for a total of 8-20 days per year or placebo.5 The cladribine group had roughly 50% lower annualised relapse rate compared to the placebo group, with similar MRI benefit, although with a high rate of reduced blood count of immune cells in the cladribine group, and a number of herpes infections. This study, the CLARITY study, was a 96-week RCT enrolling 1326 patients with relapsing-remitting MS. A low dose and high dose of cladribine were tested against placebo. The cladribine tablets were taken in two or four treatment four- to five-day courses in the first year, so patients took cladribine tablets for only eight to 20 days in the year. In the second year, all participants took two treatment courses. The relapse rate in the placebo group was 0.33 per year on average; this fell to 0.14 per year in the low dose group, a 58 per cent reduction (p<0.001), and 0.15 in the high dose group, a 55 per cent reduction (p<0.001).
The drug was well tolerated with more patients in the treatment groups finishing the study than those in the placebo groups, and relatively mild side effects according to data released by the drug company. Longer term studies are under way looking at longer term safety, but as a chemotherapy agent there are likely to be some downsides to long-term treatment, especially related to bone marrow suppression and infections. The good news with this study is that the lower dose worked so well, at least as well as the higher dose, and that people tolerated the drug so well and stayed in the study. This compares very favourably to the interferon studies where there was a very high drop-out rate. The other really positive aspect is that the drug is taken orally, and only for a few days each year. It has the potential to really make a difference to the lives of people with MS if it proves in the longer term to be safe, and if it actually makes a difference to disease progression. The drug company is submitting cladribine for approval in mid 2009 in the United States and Europe. It has been granted fast-track status by the Food and Drug Authority.
- Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996; 93:1716-20
- Selby R, Brandwein J, O’Connor P. Safety and tolerability of subcutaneous cladribine therapy in progressive multiple sclerosis. Can J Neurol Sci 1998; 25:295-9
- Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999; 111:35-44
- Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005; 5:721-7
- Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med; 362:416-426
- Beutler E, Sipe JC, Romine JS, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996; 93:1716-20
- Selby R, Brandwein J, O’Connor P. Safety and tolerability of subcutaneous cladribine therapy in progressive multiple sclerosis. Can J Neurol Sci 1998; 25:295-9
- Romine JS, Sipe JC, Koziol JA, et al. A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis. Proc Assoc Am Physicians 1999; 111:35-44
- Sipe JC. Cladribine for multiple sclerosis: review and current status. Expert Rev Neurother 2005; 5:721-7
- Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med; 362:416-426