Clinical Trials

Date: 2017-02-09

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in Multiple Sclerosis Journal

Company: Merck KGaA (Germany)

Product: cladribine

Action mechanism:

• nucleoside analog/immunomodulating agent. Cladribine (2-chlorodeoxyadenosine) is a synthetic deoxyadenosine analog,This immunomodulatory agent produces targeted, sustained reduction of T and B lymphocytes.

Disease: relapsing remitting multiple sclerosis (RRMS)

Therapeutic area: Neurodegenerative diseases

Country:

Trial details:

• The clinical development program for Cladribine Tablets includes:
• • The CLARITY (CLAdRIbine Tablets Treating MS OrallY) study and its extension: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of Cladribine Tablets as a monotherapy in patients with relapsing remitting multiple sclerosis and its two-year extension designed to provide data on the long-term safety and efficacy of extended administration of cladribine tablets for up to four years. The CLARITY study  randomized 1,326 people with relapsing remitting multiple sclerosis. Study participants were randomised to one of three different treatment groups consisting of two different dose regimens of cladribine tablets or matching placebo tablets (1:1:1 ratio). The primary endpoint of the CLARITY study was the relapse rate over 96 weeks. Secondary endpoints included MRI endpoints, proportion of subjects relapse-free and disability progression at 96 weeks.
• • The ORACLE MS (ORAl CLadribine in Early MS) study: a two-year Phase III placebo-controlled study designed to evaluate the efficacy and safety of cladribine tablets as a monotherapy in patients at risk of developing multiple sclerosis (patients who have experienced a first clinical event suggestive of multiple sclerosis).
• • The ONWARD (Oral Cladribine Added ON To Interferon beta-1a in Patients With Active Relapsing Disease) study: a Phase II placebo-controlled study designed primarily to evaluate the safety and tolerability of adding cladribine tablets treatment to patients with relapsing forms of multiple sclerosis, who have experienced breakthrough disease while on established interferon-beta therapy.
• • PREMIERE (Prospective Observational Long-term Safety Registry of Multiple Sclerosis Patients Who Have Participated in Cladribine Clinical Studies) study: interim long-term follow-up data from the prospective registry, PREMIERE, to evaluate the safety and efficacy of cladribine tablets. The follow-up will consist of over 10,000 patient years of exposure in total, with followup in some patients exceeding eight years at completion.

Latest news:

• • On February 9, 2017, Merck KGaA announced the publication of the results of a post hoc analysis of the Phase III CLARITY study in Multiple Sclerosis Journal. The post hoc analysis showed that cladribine tablets reduced the annualised rate of brain volume loss – also known as brain atrophy – compared with placebo in patients with relapsing remitting multiple sclerosis. In addition, the analysis found that patients with lower rates of brain atrophy showed the highest probability of remaining free from disability progression at two years. This supports existing findings that increased brain volume loss over time is associated with worse clinical outcomes such as increased disability progression and cognitive changes, in patients with multiple sclerosis. The CLARITY study primary (rate of relapse at 96 weeks) and key secondary endpoints  (proportion of patients who were relapse free and the time to sustained progression of disability) were met. These outcomes and safety results were published in The New England Journal of Medicine. The brain atrophy analysis evaluated the effect of cladribine tablets on brain volume loss (BVL) over 2 years in RMS and the association of BVL with confirmed disability progression in 1,025 (77.3%) of the patients in CLARITY. The mean percentage  brain volume loss per year was significantly reduced in patients treated with cladribine tablets 3.5 mg/kg (–0.56%±0.68, p=0.010, n=336) and 5.25 mg/kg (–0.57%±0.72, p=0.019, n=351) compared with patients treated with placebo (–0.70%±0.79, n=338). The risk of disability progression was also significantly lower in patients treated with cladribine tablets 3.5 mg/kg (HR 0.63, 95% CI 0.438, 0.894; p=0.010) and 5.25 mg/kg (HR 0.58, 95% CI 0.406, 0.833; p=0.003) than in those treated with placebo. After adjusting for treatment group, percentage brain volume loss per year showed a significant correlation with the cumulative probability of disability progression in the overall study population (HR 0.67, 95% CI 0.571, 0.787; p<0.0001). Lymphopenia was the most commonly reported adverse event in patients treated with cladribine tablets. The incidence of infections was 48.3% with cladribine tablets and 42.5% with placebo, with 99.1% and 99.0% rated mild-tomoderate by investigators.
• • On September 16, 2016, Merck KGaA announced new efficacy data for cladribine tablets in two oral presentations at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The findings, from the phase III CLARITY and CLARITY EXTENSION trials and from the open-label maintenance period of the phase III ORACLE-MS study, demonstrated durable efficacy of cladribine tablets in patients with multiple sclerosis along with a well-characterized safety profile.
• CLARITY and CLARITY EXTENSION studies confirmed that 20 days of oral dosing over two years was effective in reducing the frequency of relapses and slowing disability progression for up to four years. In one oral presentation, data from the two-year phase III CLARITY trial and its two-year extension study (CLARITY EXTENSION) showed that patients with relapsing multiple sclerosis who received placebo in CLARITY and were switched to cladribine tablets in CLARITY EXTENSION had significantly reduced annualised relapse rates (ARR) (0.26 vs. 0.10, P<0.0001) and were significantly more likely to be relapse free (58.0 percent vs. 79.6 percent, P<0.0001) at the end of the extension phase. ARR were maintained for patients who received cladribine tablets for two years in CLARITY and were then switched to placebo for two years in the extension phase. The second oral presentation reported data from the open-label maintenance period of the phase III ORACLE-MS study. ORACLE-MS showed that, for patients with a first demyelinating event, treatment with cladribine tablets significantly reduced the risk of progression to clinically definite MS compared with placebo. For the open-label portion of the study, patients who converted to clinically definite multiple sclerosis during the initial treatment period were switched to Rebif® therapy. The new data presented at ECTRIMS show that patients who had received cladribine tablets in the initial treatment phase had lower ARR over the maintenance period (median time on Rebif = 56.0 weeks) compared with those who had received placebo in the initial treatment phase [0.14 for cladribine tablets 3.5 mg/kg (n=25), 0.24 for Cladribine Tablets 5.25 mg/kg (n=24) and 0.42 for placebo (n=60)]. The European Medicines Agency (EMA) has accepted for review the Marketing Authorization Application (MAA) of cladribine tablets for the treatment of relapsing-remitting multiple sclerosis.

Is general: Yes