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Home > MSAA Publications > The Motivator > The Motivator: Winter/Spring 2009 > Research News
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Research News

Oral Cladribine Meets Primary Endpoint in Phase III Trial

Written by Susan Wells Courtney
Reviewed by Dr. Jack Burks

In January 2009, Merck Serono (Geneva Switzerland) announced results of their Phase III CLARITY trial. According to the release, cladribine tablets met the two-year endpoint of reducing the relapse rate in patients with relapsing-remitting MS (RRMS). More than 1300 patients with RRMS participated in the CLARITY study, which was a 96-week, randomized, double-blind, placebo-controlled, international trial.

Two different dose regimens were compared to placebo, and those taking the lower total dose had a 58-percent relative reduction in annualized relapse rate (ARR) versus those given a placebo. Patients given the higher dose experienced a 55-percent decrease in ARR versus placebo. Secondary endpoints included reductions in lesion activity, proportion of patients who were relapse-free, and progression of disability. All of these secondary endpoints were met as well.

Study participants received low-dose or high-dose active drug, or placebo. These were given in two or four treatment courses during the first year, followed by two treatment courses during the second year. A treatment course consisted of one oral tablet taken daily for four to five consecutive days. Lymphopenia, which is a decrease in the number of lymphocytes (white blood cells) in the blood, occurred more often in the treated group. This was expected given cladribine 's presumed mechanism of action. Both the treated and the placebo groups reported headaches and nasopharyngitis (nose and throat irritation) as the most frequent adverse events.

Oral cladribine is the first oral therapy for MS to have Phase III trial data reported to the FDA. This drug reduces the number of certain T-lymphocytes, which are believed to be involved with the inflammation and damage that occurs in MS. Merck Serono plans to submit an application for the approval of oral cladribine to the FDA in mid-2009.

Results Announced from Study of Dirucotide (MBP8298) in RRMS Patients

Dirucotide, previously known as MBP8298, has been in clinical trials primarily for the treatment of secondary-progressive multiple sclerosis (SPMS), but also for relapsing-remitting multiple sclerosis (RRMS). On January 30, 2009, dirucotide 's developer (BioMS Medical Corp.), announced the results of MINDSET-01, an exploratory phase II clinical trial designed to evaluate the effectiveness and safety of dirucotide in patients with RRMS.

MINDSET-01 enrolled 218 patients with RRMS at 24 sites in Europe. While the treatment did not meet its primary endpoint of reducing annualized relapse rates or reducing associated secondary MRI endpoints, it did meet certain secondary endpoints relating to the progression of MS. Changes in progression were measured using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) score.

In this 15-month study, dirucotide (or placebo) was given via three single intravenous injections at zero, three, and nine months. Dirucotide was generally well tolerated and no patients withdrew from the study due to side effects - the most common of which were redness and burning sensation at the injection site.

Measuring progression according to the EDSS and MSFC scores are the primary and secondary outcomes in the ongoing SPMS trials, all of which are fully enrolled. These include the MAESTRO-01 (a pivotal phase III study taking place in Canada and Europe with 611 patients), the MASESTRO-02 (an open-label follow-up study with patients who have successfully completed the MAESTRO-01 trial), and the MAESTRO-03 (a pivotal phase III study taking place in the United States with 510 patients).

Dirucotide (a peptide) is a synthetic fragment of myelin basic protein (MBP). It replicates the site on the MBP molecule that is believed to be a target of attack by cells of the immune system - in 65 to 75 percent of all people with MS. This treatment is believed to induce or restore immunologic tolerance to attack.

Oral BG-12 Reduces Brain Lesions in Patients with MS

According to the data from a Phase IIb study, Biogen Idec's oral compound BG-12 (BG00012, dimethyl fumarate) reduced the number of new gadolinium enhancing (Gd+) lesions by 69 percent in patients with RRMS, compared to placebo. This data was published in the October 25, 2008 issue of The Lancet. Data also showed a 53-percent reduction in the mean number of T1-hypointense lesions and a 44-percent reduction in cumulative new Gd+ lesions in patients taking BG-12 versus those on placebo.

The presence of Gd+ lesions is thought to indicate continuing inflammatory activity within the central nervous system (CNS), while T1-hypointense lesions (also known as "black holes") are associated with significant damage and loss of brain tissue. According to Biogen Idec, an ad hoc analysis conducted during the study showed that Gd+ lesions were less likely to evolve into T1-hypointense lesions in patients taking BG-12 versus placebo.

These data suggest that BG-12 may have neuroprotective as well as anti-inflammatory effects. Inflammation and damage to the myelin and nerves within the CNS play an important role in the MS process, particularly for those with the relapsing-remitting form of the disease. BG-12 has also been shown to activate the "Nrf2 transcriptional pathway." This pathway helps defend against the destruction of nerves, protects the blood-brain barrier, and supports the integrity of myelin within the CNS.

In the Phase IIb study, the treatment arms included two dose levels of BG-12 given one to three times daily, or placebo. The drug was administered orally (by mouth) for 24 weeks. BG-12 met all of the study endpoints when given at the higher (240 mg) dose level, three times daily. Adverse events in the group receiving active treatment included flushing, headache, nausea, diarrhea, upper abdominal pain, hot flush, and [lower] abdominal pain. Many of these side effects decreased over time. Frequency of infection was low and did not differ between the active-treatment and placebo groups.

The United States' Food and Drug Administration (FDA) granted Fast Track designation for BG-12 in 2008. "DEFINE" and "CONFIRM" are two Phase III studies for BG-12, which will include more than 2,000 patients in North America, Europe, and worldwide. Individuals with relapsing-remitting MS who are interested in enrolling may visit www.clinicaltrials.gov and search for "BG-12" for more information.

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Last Updated on Friday, 14 September 2012 13:36