麻豆传媒

LONDON -- Data from a pair of extension trials have bolstered the long-term safety and efficacy of oral cladribine for relapsing multiple sclerosis, researchers reported here.

In an extension phase of the CLARITY trial, reductions in annualized relapse rates (ARR) were maintained, while patients who switched from placebo had reduced relapse rates (0.26 to 0.10, P<0.0001), , of Queen Mary University of London, reported at the ECTRIMS meeting here.

And in an extension phase of the ORACLE-MS trial of patients with a first demyelinating event, those who ultimately went on to develop MS and started taking interferon had lower relapse rates if they'd been given cladribine in the initial trial instead of placebo (0.14 for 3.5 mg/kg and 0.24 for 5.25 mg/kg versus 0.42), , of Università Vita-Salute San Raffaele in Milan, reported here.

The findings are part of a large package that Merck KGaA, the company's German manufacturing unit, will use to try to have the drug approved in Europe for relapsing-remitting MS, following a rejection by EU regulators in 2010. It submitted a with the EMA on July 18.

The FDA denied approval of cladribine for MS in March 2011, and the company halted its development program in June 2011. Merck KGaA did not respond to a 麻豆传媒 inquiry as to whether it also planned to file an NDA with the FDA.

While regulators were initially concerned about an increase in malignancies with the drug, several other agents with comparable adverse event profiles have been approved since that time -- and the company is reassured that additional analyses show few safety concerns and an appropriate risk-benefit ratio.

"In our field over the last 5 or 6 years, there's been approval of other, more powerful medications, so this is now in the context where we have, for instance, alemtuzumab with its risks that patients are willing to take on," said , MD, of Mount Sinai, who was not involved in the study. "We have a more nuanced understanding of Tysabri and PML and that risk that people are willing to take on."

"It's a somewhat different climate in terms of what risk-benefit ratio is acceptable for a medication thought to have high efficacy," Krieger said.

Cladribine is a chemotherapeutic agent that targets white blood cells and is used to treat certain blood cancers. Merck developed a pill formula for treating MS.

At ECTRIMS, there were two oral presentations and more than a half a dozen posters on the drug, which included data from CLARITY and ORACLE-MS and their respective extensions, as well as from the phase II ONWARD study which looked at the drug as an add-on to interferon.

Giovannoni reported data from the 2-year extension phase of the CLARITY trial, in which patients initially on placebo were switched to 3.5 mg/kg cladribine, while those on the drug were re-randomized to either 3.5 mg/kg or to placebo.

He reported no significant differences in ARR during the extension phase compared with the initial phase, except for a reduction among those who switched from placebo (from 0.26 to 0.10, P<0.0001).

The proportion of patients who were relapse-free was similar in both groups at greater than 70%, but it improved for those who switched from placebo to 3.5 mg/kg of the drug (58% versus 79.6%, P<0.0001).

Giovannoni said the findings demonstrate the durable efficacy of cladribine, adding that there were no benefits of additional cladribine treatment.

In the ORACLE-MS study, cladribine reduced conversion to MS compared with placebo (38% versus 14% for 3.5 mg and 16% for 5.25 mg), and the extension phase enabled the 109 patients who converted to MS to be treated with interferon (25 on cladribine 3.5 mg/kg; 24 on 5.25 mg/kg; 60 on placebo).

In an exploratory analysis for the open-label period, they found that annualized relapse rates were lower among those originally treated with cladribine compared with those who got placebo at enrollment:

• 3.5 mg/kg: 0.14 (95% CI 0.00-0.27)
• 5.25 mg/kg: 0.24 (95% CI 0.07-0.40)
• Placebo: 0.42 (95% CI 0.28-0.56)

However, Comi cautioned that few patients completed the full 2 years of the extension phase: 7 in the placebo group, 2 in the 3.5-mg group, and 6 in the 5.25 mg group.

In a separate poster that focused on assessing safety data from CLARITY and ORACLE-MS and their respective extensions, as well as the PREMIERE registry, researchers found that rates of lymphopenia were higher for those on the 3.5 mg dose of the drug than placebo (8.8 versus 1.16 per 100 person-years).

The analysis also showed that herpes zoster was reported more frequently in patients who had Grade 3 or 4 lymphopenia.

And the rate of neoplasms, both malignant and benign, was similar but numerically slightly higher for the 3.5-mg drug group than the placebo group (1.14 and 1.01), the researchers said, adding that there was "no clustering of malignancies with a common etiology, and no hematological malignancies commonly associated with immunosuppression."

Should the drug be approved, the question remains as to where it fits into the current treatment landscape.

Krieger noted that it may also be more likely to be adopted in Europe, which has historically been more tolerant of induction therapy -- compared to the U.S., in which escalation therapy is typically preferred.

"Europeans have always historically used more potent immune-suppressing medications for MS: alemtuzumab for 20 years, mitoxantrone, cyclophosphamide, rituximab off-label," he said. "They are more comfortable with that approach to MS than doctors in the U.S."