FDA Extends the Review Period for Oral Cladribine

Cladribine is an investigational oral drug being studied for the long-term treatment of relapsing forms of multiple sclerosis (MS). It was submitted to the United States Food and Drug Administration (FDA) for approval earlier this year, receiving Fast Track status in July 2010. Fast Track status reduces the FDA’s review time from 10 months down to six – and a decision was expected by November 28, 2010. However, the agency has extended the review time by three months, with a decision now anticipated by February 28, 2011.

According to a press release from the company developing the drug, EMD Serono (an affiliate of Merck KGaA, based in Germany ), "The FDA extended the review period to provide additional time for a full review of additional information provided under the new drug application (NDA)." EMD Serono also notes that it continues to work closely with the FDA during the review process of oral cladribine, referred to as "Cladribine Tablets."

While oral cladribine was approved earlier this year in Australia and Russia, European regulators issued a negative opinion in regard to whether the benefits outweigh the risks. Merck Serono (a division of Merck KGaA) plans to appeal this negative decision, which came from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency. This rejection was issued in September, prior to the FDA extending its review period of the drug.
Additional Information on Cladribine

Cladribine is currently used in an injectible form to treat leukemia. The oral form, presently being studied for the treatment of relapsing forms of MS, is given in one or two courses per year, depending on the study regimen.
The main risk of a side effect with cladribine is the potential for developing infections, most commonly Herpes infections. A prolonged decrease in white blood cells has also been seen in some patients. The FDA will further evaluate other side effects and risks, including its safety in pregnancy as well as any potential risk of cancer.

Earlier studies of injectible cladribine (mentioned in the last section of this article) showed an average 90-percent reduction in gadolinium-enhancing lesions and a marked reduction in relapse rate. For this reason, the orally administered form was designated by the FDA as a Fast Track product for relapsing forms of MS, for potentially quick approval.

This drug predominantly affects peripheral blood lymphocytes, with relative preservation of other cell types and components. It causes a preferential and sustained depletion of certain T cells in the immune system, as well as a decrease in B cells. (T and B cells are two types of lymphocytes, which help to keep the body free of infections and cancer.) Cladribine also seems to directly influence the overall T-cell response. In a large-scale Phase III clinical trial, cladribine significantly reduced relapse rates and other disease activity in people with relapsing-remitting MS.

Recent and Ongoing Studies
The two-year Phase III CLARITY trial of two levels of cladribine versus placebo involved 1,326 patients with RRMS. Each course consisted of once daily administration for four to five consecutive days, and study participants took cladribine for a total of eight to 20 days of treatment during the year. It met its primary endpoint, showing 55- to 58-percent reductions in annualized relapse rates, a 31- to 33-percent reduction in disability progression, and a substantial reduction in lesion burden. No clinical relapses were seen in 79 to 80 percent of the treated group, as compared to 61 percent in the placebo group. In the ongoing two-year extension study, all participants will receive cladribine; it will continue to assess safety, tolerability and effect on progression of disability.

Detailed study data were released in the spring of 2010 at the American Academy of Neurology and Consortium of MS Centers meetings. Conclusions included that treatment with cladribine resulted in an early onset of effect in MRI and clinical outcomes. MRI evidence of disease activity was reduced by both cladribine regimens. The MRI findings were accompanied by significant improvements in clinical outcomes and a favorable safety profile. Additionally, a substantial proportion of patients achieved a disease activity-free status over 96 weeks. Study results were also published in the February 4, 2010 issue of The New England Journal of Medicine (vol. 362: pages 416-426).

The long-term safety of cladribine will be tested in the eight-year PREMIERE registry. It will provide long-term active safety and risk-benefit information.
Some patients with aggressive MS failed to respond clinically and by MRI after two short courses of cladribine. A reduction of T- or B-lymphocyte counts was not seen in these patients. It may be that some patients with aggressive MS disease are resistant to cladribine, may require additional courses to reduce relapses or MRI activity, or may require additional courses to cause a reduction of lymphocyte count which may be tied to the efficacy of the drug. A larger cohort of patients with aggressive MS is being followed to expand these findings.

The 200 participants in the ongoing ONWARD Phase II study are all individuals who have experienced at least one relapse while taking Rebif (interferon beta-1b). This study combines oral cladribine with Rebif, to determine whether the combination is more effective than Rebif alone.
The Phase III ORACLE MS study is ongoing, and will assess whether cladribine can delay the time to a second clinical demyelinating attack in 600 individuals who have had a first clinical demyelinating event, also referred to as a clinically isolated syndrome (CIS). The study will be completed in October 2012.
(Please note that much of the preceding information appears in the Summer/Fall 2010 issue of MSAA’s magazine, The Motivator, in our annual "Multiple Sclerosis Research Update." Written by Diana M. Schneider, PhD and Jack Burks, MD, this article may be accessed at www.mymsaa.org/publications/motivator/summer-fall10/cover-story/ .)

The Transition from Injectable to Oral Cladribine
Several years ago, Phase II and Phase III clinical trials of injectable cladribine demonstrated some effects in people with MS. In these trials, new lesion development was reduced in the brain as seen on MRI scans, although total lesion volume did not appear to be affected.
Individuals with relapsing-remitting MS also experienced clinical benefits (with an exacerbation rate approximately half of the rate experienced by individuals taking a placebo). Disability in terms of EDSS was not affected. The results of these studies, however, were considered to be mixed and could not be replicated in a follow-up phase III study (which may be due to participants having more advanced MS than in previous studies).

Researchers determined that further studies were needed, employing participants who have MS in earlier stages. But in these later trials, investigators were able to use an oral formulation rather than giving the drug through injections. Medications in drug trials are frequently administered via injection, as this method can deliver higher amounts into the blood system as opposed to drugs taken orally. However, the oral formulation of cladribine was able to reach the desired level in the blood. For this reason, investigators are now able to conduct trials with the oral version, which is both painless and more convenient for the participants.

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Written by Susan Wells Courtney, MSAA Senior Writer & Creative Director
Reviewed by Dr. Jack Burks, MSAA Chief Medical Officer