LONDON — Merck Serono has decided to try for a second time to gain approval for an oral formulation of cladribine as a treatment for multiple sclerosis (MS), with longer-term follow-up of clinical trials showing durable efficacy, without the safety signal that led to its initial rejection, leading investigators say.

Some of the latest data from the cladribine trials were presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016 meeting recently held here.

The drug was rejected by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2011. The agencies cited concerns about a signal of cancer risk in the initial results of the phase 3 CLARITY trial.

Lead investigator of the study, Gavin Giovannoni, MD, Barts and The London School of Medicine and Dentistry, United Kingdom, told Medscape Medical News that at the time, Merck was undergoing restructuring and decided not to pursue development of cladribine for MS.

"But some of us involved in the clinical trials thought this was rather premature — another clinical trial of cladribine in clinically isolated syndrome was already underway, and other data from registry studies had not been analyzed," he said.

Professor Giovannoni says that Merck has now had a change of heart. "A few years later and the regulatory climate around MS seems to have changed, possibly due to the approval of alemtuzumab," he explained. "Alemtuzumab is similar to cladribine in that it is given as a few short courses up front with no maintenance therapy — a sort of induction therapy — and alemtuzumab received a liberal indication in some countries even though it has quite a severe side-effect profile."

He added: "Merck has had a rethink and has spent a year reanalyzing all the data. Our group looked at the data from CLARITY again with longer follow-up, and this suggested that the cancer signal was probably false, as there were no cancers in the placebo group and rates in the treatment group were in line with what would be expected. In addition, there was a lot more data from registries, and this does not support any safety risk."

The company has now filed a new approval application for the product with EMA and is in discussions on how to proceed with the FDA. The drug is already approved for treatment of hairy cell leukemia and B-cell chronic lymphocytic leukemia.

CLARITY Extension

At the recent ECTRIMS conference, Professor Giovannoni presented the latest data from the extension phase of CLARITY, showing that two to four short oral courses (one dose per day for 4 to 5 days) of cladribine in year 1 and another two short courses in year 2 were associated with durable efficacy, he said, "with around 60% of patients still in remission several years later. And there was even more benefit in the subset of patients with highly active disease."

Other data from the ORACLE study in patients with clinically isolated syndrome (CIS) show "the best responses seen with any drug over time in terms of treating very early MS," he added.

Specific figures on cancers were not reported, but Professor Giovannoni said, "The confidence intervals have come right down. The numbers are well within what would be expected."

He believes cladribine could change the MS field. "It offers induction therapy with an agent that it is easy to give as oral tablets and without the need for intensive monitoring," he said. "Yes, lymphocyte counts need to be measured before redosing — it does cause some lymphopenia, and it is obviously advisable to wait for the lymphocyte count to recover before giving the second dose, but this is not a serious problem. It is a much gentler agent than alemtuzumab."

In his presentation at ECTRIMS, Professor Giovannoni reported data from the 2-year CLARITY trial and its 2-year extension study showing that patients with relapsing-remitting MS who received placebo in CLARITY and were switched to cladribine for the extension study had significantly reduced annualized relapse rates (0.26 vs 0.10; P < .0001) and were significantly more likely to be relapse free (79.6% vs 58.0%; P < .0001) at the end of the extension phase.

Annualized relapse rates were maintained for patients who received cladribine in the original trial and the extension.

Coinvestigator Giancarlo Comi, MD, Vita-Salute San Raffaele University, Milan, Italy, said these latest results suggest that "the clinical benefits of cladribine can be maintained in most patients for an additional 2 years without the need for redosing." He added: "Although multiple therapies are available for patients with MS, there is still a large unmet need within this patient community, including for therapies that offer lasting benefits."

Professor Comi also presented latest results from the extension phase of the ORACLE study in patients with a first demyelinating event (CIS). Results from the main trial reported previously showed a significant reduction in the risk for progression to clinically definite MS in patients treated with cladribine compared with placebo.

Patients who converted to clinically definite MS during the initial study (n = 109) were switched to interferon-β therapy and entered into the extension phase of the study. Results showed a lower relapse in this part of study for patients who had taken cladribine in the original trial.

After a median time on interferon-β of 56 weeks, estimated annualized relapse rates were 0.14 for the 25 patients originally treated with cladribine 3.5 mg/kg, 0.24 for the 24 patients originally treated with 5.25 mg/kg, and 0.42 for the 60 patients originally receiving placebo.

No Evidence of Disease Activity

Another presentation at ECTRIMS reported a pooled analysis of the CLARITY and ONWARD studies, showing higher rates of "no evidence of disease activity" (NEDA) with cladribine vs placebo.

Both studies evaluated cladribine vs placebo given in short courses annually for 2 years to patients with relapsing multiple sclerosis. In CLARITY, patients did not receive any other treatment, while in ONWARD, cladribine was an add-on to patients who had experienced at least one relapse while receiving interferon-β.

The pooled analysis involved a total of 1540 patients (494 receiving placebo; 573, cladribine 3.5 mg/kg; and 473, cladribine 5.25 mg/kg).

NEDA was defined as no qualifying relapses, no 3-month confirmed Expanded Disability Status Scale progression, no new T1 gadolinium-enhancing lesions, and no activeT2 lesions during the course of the two studies.

Results showed that 15.1% of placebo patients achieved NEDA compared with 41.7% of patients who received cladribine 3.5 mg/kg and 43.6% of those who received cladribine 5.25 mg/kg (P < .0001 vs placebo for both doses).

Professor Giovannoni serves on advisory boards for Merck, Biogen Idec, and Vertex Pharmaceuticals; has received speaker honoraria and consulting fees from Bayer Schering Pharma, FivePrime, GlaxoSmithKline, GW Pharma, Merck, Biogen Idec, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, UCB, Vertex Pharmaceuticals, Genzyme Corp, Ironwood, and Novartis; serves on the Merck speakers bureau; and received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood. Professor Comi has received consulting fees from Novartis, Teva Pharmaceutical Industries Ltd, Sanofi-Aventis, Merck, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation; and trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd, Sanofi-Aventis, Merck, Biogen Dompè, and Bayer Schering.

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2016. Abstracts 70, 164, 601. Presented September 14–16, 2016.

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