Many treated patients were disease activity-free (DAF) as early as 24 weeks post treatment and sustained this status over the 96-week trial.

The German company’s US subsidiary EMD Serono has submitted a New Drug Application with the Food and Drug Administration for cladribine as a therapy for reducing relapses in people with MS. The drug was filed with the European Medicines Agency in July.

The filing is based on the two-year Phase III CLARITY trial, which revealed that 43% and 44% of patients with relapsing-remitting MS treated with cladribine, on a total dose of 3.5 mg/kg and 5.25 mg/kg respectively, had absence of disease activity, compared with 16% on placebo. Fereydoun Firouz, EMD Serono’s chief executive, said that if approved, short-course therapy with cladribine tablets “could transform the way people approach their treatment options, and meet an unmet need as an oral, disease-modifying drug”.

The company has not given any sales estimates for cladribine but analysts confidently predict blockbuster status for the compound which has been granted fast-track status by the FDA.

News of the filing came hours after Novartis had presented promising initial data from a two-year Phase III trial of its oral MS FTY720 (fingolimod). The Swiss company is planning regulatory submissions in the USA and Europe before the end of the year.

By Kevin Grogan

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These data show that over two years of study, 43% and 44% of patients treated with Cladribine Tablets (total dose of 3.5 mg/kg and 5.25 mg/kg respectively) had absence of disease activity, compared with 16% of patients who received placebo (p<0.001 for both Cladribine Tablets groups). Disease activity was assessed both clinically and radiologically and absence of disease activity was stringently defined as no relapses, no sustained disability progression, no T1 gadolinium-enhancing lesions and no active T2 lesions based on magnetic resonance imaging (MRI) during the study.
“Immune-mediated disorders such as relapsing forms of multiple sclerosis are characterized by periods of disease activity alternating with periods of remission, and a very important goal in treating such disorders is to help patients achieve and maintain disease remission for longer periods of time,” said Dr. Peter Rieckmann, Professor of Neurology, Director Department of Neurology, Bamberg Hospital, Germany, UBC Research Chair Vancouver/Canada and an investigator in the CLARITY study. “This CLARITY data analysis is very encouraging, based on the comparison between short-course oral treatment with Cladribine Tablets and placebo with respect to MS patients who had no disease activity, as assessed by both clinical and radiological measures over two years, with only 8-20 days of treatment in the first year of study and only 8-10 days of treatment in the second year of study.”

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In the 96-week phase 3, randomised, double-blind, placebo-controlled Cladribine Tablets Treating MS Orally (CLARITY) trial, cladribine tablets demonstrated significant efficacy in the treatment of patients with relapsing-remitting MS.

Vissia Viglietta, MD, Merck Serono, Inc., Rockland, Massachusetts, presented the safety results of the study at a poster presentation on June 22.

The trial assessed 2 dosing regimens of the immunomodulatory drug and compared them with placebo. A total of 1,326 patients were randomised to either cladribine 5.25 mg/kg total dose, cladribine 3.5 mg/kg total dose, or placebo.

As expected based on the mechanism of action of cladribine, lymphopenia occurred more frequently with active treatment. The association was dose related; patients in the highest-dose group showed the highest incidence (31.5% vs 21.6% and 1.8% in the 3.5-mg/kg and placebo groups, respectively).

“This finding was not associated with any clinical outcomes,” Dr. Viglietta emphasised. “Furthermore, the vast majority of patients recovered quickly during the 96-week period.”

Infections/infestations occurred with similar incidence across treatment groups (48.9%, 47.7%, and 42.5% with cladribine 5.25 mg/kg, cladribine 3.5 mg/kg, and placebo, respectively), suggesting that first-line immune defence mechanisms remained adequate.

In almost all cases in each group, infections were considered mild or moderate by the investigators.

“Three isolated solid malignancies occurred in the 3.5-mg/kg group,” Dr. Viglietta reported. “They were unrelated to the mechanism of action of cladribine.” One choriocarcinoma was noted in the highest-dosage group approximately 9 months after the completion of the study.

In the 5.25-mg/kg, 3.5-mg/kg, and placebo groups, 7.9%, 3.5%, and 2.1% of patients discontinued treatment because of adverse events (AEs). Lymphopenia was the reason for discontinuation in 2.0%, 0.5%, and 0%.

Apart from blood and lymphatic system disorders, AEs leading to treatment discontinuation were comparable across the treatment groups. In the same group order, 9.0%, 8.4%, and 6.4% of patients experienced serious AEs.

“We are acquiring more safety data with the 4-year extension trial,” Dr. Viglietta concluded. At the same time, a safety registry is being established. “Every patient who has been treated with cladribine even once will be followed for a total of 8 years.”

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Merck KGaA on Wednesday presented detailed results from a previously announced Phase III study of investigational oral multiple sclerosis drug cladribine at the American Academy of Neurology annual conference. The findings demonstrated that annual short-course treatment with cladribine significantly reduced the rate of clinical relapses, disability progression and brain lesions in patients with relapsing-remitting MS, and also led to a significant increase in the proportion of patients who remained relapse-free, the drugmaker said.

The CLARITY study involved 1326 patients who were randomised to receive one of two doses of cladribine or placebo. Results showed that patients treated with the low-dose regimen of cladribine experienced a 58-percent relative reduction in annualised relapse rates, compared with placebo, while those in the high-dose regimen group experienced a relative reduction of 55 percent. The company also stated that, over the two-year course of the study, treatment with cladribine also led to a more than 30-percent reduction in the risk of disability progression relative to placebo.

Lead author Gavin Giovannoni noted that “our study shows that cladribine tablets prevent relapses and slow down the progression of the disease, making patients feel better. Importantly, it does so without the need for constant injections that are associated with unpleasant side effects.” He added that “we will continue to follow the patients in the trial to see how they fare in the long-term.” Meanwhile, Lee Dunster, head of research at the MS Society, commented that the drug’s oral formulation “will be a huge step forward for people with MS.”

Merck reiterated that it plans to submit the drug for approval by US and EU regulators in mid-2009.

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