Cladribine effective in early MS, but safety fears persist

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.

The oral immunosuppressant drug cladribine delays conversion to clinically definite multiple sclerosis in patients with a demyelinating event, according to results from a randomized controlled trial.

Cladribine, also used as a chemotherapy agent, was shown in a previous trial to be effective in relapsing MS (N. Engl. J. Med. 2010;362:416-26). However, regulators’ concerns about cladribine’s long-term safety risks – particularly prolonged lymphopenia, infections, and malignancies – caused its manufacturer, Merck, to withdraw its U.S. and European bids for approval as a multiple sclerosis (MS) treatment in 2011. The current trial, called ORACLE MS, led by Dr. Thomas Leist of Thomas Jefferson University, Philadelphia, was stopped the same year with about 60% of patients completing the full 96 weeks, although follow-up continued for 24 weeks after the final dose.

With several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile, cautioned Dr. Cameron and Dr. Bourdette.Dr. Leist and his colleagues randomized 617 patients with MRI evidence of a demyelinating event to cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, or placebo. Cladribine was seen associated with a significant risk reduction for time to conversion to clinically definite MS, compared with placebo: The hazard ratios were 0.38 for the 5.25-mg/kg dose and 0.33 for the 3.5-mg/kg dose. Lymphopenia was reported in 5% of patients in the higher-dose group and 2% of patients in the lower-dose group. The investigators concluded that cladribine had potential benefit as an induction agent for people in the early stages of MS (Lancet Neurol. 2014;13:257-67) .

In an editorial accompanying the study, Dr. Michelle H. Cameron and Dr. Dennis Bourdette of Oregon Health and Science University in Portland, cautioned that with several better-studied agents to choose from, clinicians should not put the convenience of oral dosing above an uncertain safety profile. "When treating MS, a disease that is rarely fatal, has a highly variable course, and lasts decades after diagnosis, the wisdom of accepting serious risks such as opportunistic infections and malignancies is questionable," they wrote. First-generation MS treatments such as beta-interferons and glatiramer acetate, they noted, "are inconvenient since they require self-injections." However, these are efficacious "and have proven to be safe for more than 20 years. We have not been so fortunate with some subsequent therapies," Dr. Cameron and Dr. Bourdette added, citing mitoxantrone and natalizumab as two whose risks became clear after marketing approval (Lancet Neurol. 2014;13:235-7).

Dr. Leist and his colleagues’ study was funded by Merck; Dr. Leist and his coauthors disclosed financial relationships with Merck and/or other manufacturers. Two were employees of a Merck subsidiary, EMD Serono, at the time the study was submitted. Dr. Cameron disclosed prior support from Acorda Therapeutics, and Dr. Bourdette disclosed funding from Teva, Biogen Idec, Elan, and Genzyme.