Class: Purine antimetabolites
Name: Cladribine (Mavenclad®)
General Dosage: Oral chemotherapy medication with two treatment cycles over a little more than one year.
Mechanism of Action: Inhibits pro-inflammatory lymphocytes. Temporarily reduces the number of both T and B lymphocytes.
Effectiveness: Compared to placebo, decreases relapse rate by 58%; modest positive effect on disability progression and rate of brain volume loss.
Possible Side Effects: Boxed warnings* for risk of cancers and birth defects if used in pregnant woman. Approved by FDA for rescue use only.
Cladribine, an FDA approved chemotherapy treatment, is a small molecule that can both kill and alter the function of certain white blood cells. This is significant in the treatment of MS in that two types of white blood cells, T and B lymphocytes, are thought to play key roles in disease progression. To date, cladribine is most often used to treat leukemia and lymphoma.
A study on cladribine which involved 1,326 patients, looked at the rate of relapse between patients on cladribine compared to placebo. Study participants either received cladribine in a 3.5 mg or 5.25 mg dose, or placebo. Of the three groups, patients on cladribine demonstrated significantly lower annualized rates of relapse (0.14 and 0.15) than those on placebo (0.33). As in previous studies, adverse events among the cladribine groups included lymphocytopenia (type of cancer) and herpes zoster.
The safety profile of cladribine has been reported as acceptable and a great deal is known about the agent as a treatment for other diseases, particularly certain types of cancer. Cladribine, a chemotherapy and immunosuppressive therapy, does pose significant risk of complications including toxic effects on organs such as the liver. The therapy reduces the number of white bloods cells in patients’ blood and bone marrow, which can make them more susceptible to infection.
In addition, the drug causes long term, if not permanent, changes in the white blood cells in the blood, the consequences of which are not fully understood. The drug may also cause a certain kind of cancer, most likely one of the blood such as leukemia or lymphoma. Further research is needed in order to evaluate the effects of long-term use and expand what is known about the safety profile.
* Boxed Warning: A black boxed warning is the FDA’s most stringent warning for drugs and medical devices on the market. Black box warnings, or boxed warnings, alert the public and health care providers to serious side effects, such as injury or death.
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The following was originally published in eMS News May 14, 2009:
Cladribine is an FDA approved chemotherapy treatment most often used to treat leukemia and lymphoma. By mid-2009, however, the therapy will likely head to the FDA and European EMEA for approval as an MS treatment; it has been designated for Fast Track and may possibly be – in 2010 – the first available oral treatment for MS.
Cladribine is a small molecule that can both kill and alter the function of certain white blood cells, particularly T and B lymphocytes, which are thought to play key roles in the progression of MS.
Detailed results of a phase III study, CLARITY, were released last week at the annual American Academy of Neurology meeting. The study monitored three groups of patients with relapsing-remitting MS: two cladribine – one low dose and the other a higher dose – and a placebo. Participants in the two Cladribine groups took the agent between 8 and 20 days a year.
The study demonstrated significant reduction in relapse rates: the participants who took cladribine experienced approximately 50% fewer relapses than those who took placebo. No significant difference in benefit was seen between the two doses – the lower 8-day dose resulted in reduction rates in relapse of 58%, which was essentially equal to the 55% reduction seen in higher dose participants.
Additionally, 80% of the patients treated with low-dose cladribine and 79% of the patients treated with the high-dose regimen experienced no clinical relapse, compared with 61% in the placebo group. Thus, the lower dose appears adequate to treat MS and may be safer than the higher dose. Those who took cladribine also exhibited a more than 30% reduction in the risk of disability progression compared to placebo over the two years of the study.
The therapy is now being studied in another Phase III study, ONWARD, with the purpose of measuring its effectiveness as an add-on therapy to an injectable interferon beta-1a therapy – Rebif, Avonex, or Betaseron. Cladribine may have a role in combination therapy. Study participants will be assigned to one of two treatment groups – cladribine or placebo – while remaining on their interferon therapy. Cladribine or placebo will be administered two to four times each year for four to five days.