ORACLE-MS: Cladribine Effective in MS Subgroups

Nancy Melville

June 14, 2019

Cladribine (Mavenclad, EMD Serono), among the latest in the growing field of disease-modifying therapies for multiple sclerosis (MS), shows efficacy in reducing lesions on MRI across different patient subgroups, new research shows.

"Our post-hoc analysis showed that cladribine tablet treatment 3.5 mg/kg reduced mean cumulative numbers of T1 gadolinium-enhancing lesions, new or enlarging T2 lesions, and combined unique or active lesions over the double-blind period, with nominal significance vs placebo,” said lead author Thomas Leist, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania, in discussing the findings here at the 2019 annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). "The treatment effect was consistent across subgroups."

Cladribine received approval from the US Food and Drug Administration (FDA) in March for relapsing MS after being denied approval nearly a decade ago because of safety concerns. The new approval comes with the caveat of a Boxed Warning for malignancies and fetal risks.

The drug, a tablet formulation which had gained widespread use in Europe and other countries outside the US prior to the FDA approval, is administered in two short courses of 2-week treatments spread over 2 years, with the 2 treatment weeks each year occurring 1 month apart.

The new post-hoc analysis is from the phase 3 ORACLE-MS study of 616 patients with a first demyelinating event and at high risk of converting to MS.

Consistent with other studies, that trial showed significant reductions in the risk of the number of new or persisting lesions among 3.5 mg/kg and 5.25 mg/kg-treated groups for T1-weighted gadolinium-enhancing brain lesions; for active T2 lesions; and for combined unique active lesions on MRI scan (all P < .0001 compared with placebo).

The patients were treated with the standard regimen of cladribine 10 mg, administered in the 2-week treatments (3.5 mg/kg or 5.25 mg/kg cumulative dose) over 2 years.

The aim of the new post-hoc analysis was to determine if the effects remained consistent among subgroups.

Leist and colleagues evaluated data on the outcomes of patients treated in the 3.5 mg/kg group (n = 206), 5.25 mg/kg group (n = 204) and placebo (n = 206) according to age (under 30 or 30 and older), sex, the first classification of the demyelinating event (monofocal or multifocal), presence of T1 gadolinium-enhancing (Gd+) lesions and number of active T2 lesions (under 9 vs greater than 9 lesions).

They found no significant differences in treatment effect among any of the subgroups treated with 3.5 mg/kg cladribine in terms of the mean number of T1 Gd+, active T2, and combined unique active lesions per patient, per scan.

The analysis, meanwhile, showed reductions in lesion counts in the 3.5 mg/kg-treated patients ranging from 60% to 89% for T1 lesions, 49% to 80% for active T2 lesions, and 61% to 83% for combined unique active lesions.

"There was a significant favoring of cladribine tablet treatment with respect to gadolinium enhancement in the cladribine 3.5 mg/kg group irrespective of whether we looked at age, sex, multifocal or monofocal demyelinating events, gadolinium-enhancing lesions, and T2 active lesions," Leist said.

However, he noted that the results were less uniform in the 5.25 mg/kg group and there were higher safety and lymphopenia events.

"There was no efficacy outcome benefit [with the 5.25 mg/kg group] and this dose was not pursued for development," Leist added.

In addition to the ORACLE trial, data supporting the cladribine FDA approval included the phase 3 CLARITY trial of 1326 patients showing the 3.5 mg/kg or 5.25 mg/kg doses reduced patient relapse rates by more than 50%.

The FDA approval for cladribine is specifically for relapsing MS and active secondary progressive disease, and stipulates its use should be for patients who have had an insufficient response to other MS agents.

Age a Notable Factor

Dr Michael Racke

Commenting on the research, CMSC president Michael K. Racke, MD, of The Ohio State University Wexner Medical Center in Columbus, noted that similar subgroup analyses in other MS drugs, including rituximab and ocrelizumab, have shown age, in particular, to be an important factor; therefore the cut-off of age 30 in the cladribine trials may need further study.

"In the cladribine studies, some groups did not show differences, for example age. However, the split was above and below age 30, and if an older subgroup was examined, it may not have shown the same efficacy," he told Medscape Medical News.

He noted that the drug has an unusual history of research in the treatment of MS that extends back 30 years, with some initial promise seen in progressive multiple sclerosis, particularly in reducing inflammatory events on MRI (gadolinium-enhancing lesions).

However, with those patients continuing to show disability progression, studies shifted to relapsing remitting MS, Racke explained.

"These studies showed clinical results that in general were more impressive than interferons, glatiramer acetate, and teriflunomide," he said.

Cladribine's FDA approval ultimately came after subsequent analyses eventually showed the drug's toxicities were not significantly worse than other approved MS agents, and like the others, are weighed against their benefits, Racke said.

"Cladribine probably is most similar to alemtuzumab [Lemtrada, Sanofi/Genzyme] in that it causes long term lymphopenia and immunosuppression, which results in positive effects regarding anti-inflammatory effects," but also increases risk for infection and potential risks as a result of malignancy, he said.

Additional safety recommendations for cladribine include the following: The drug should not be used in MS patients with clinically isolated syndrome or those with current malignancies, and clinicians are recommended to evaluate patients with a prior malignancy or increased risk of malignancy on an individual basis. White blood cell counts should be monitored before, during, and after treatment.

Because of safety issues, it is recommended that women and men using cladribine use birth control before and at least 6 months after the last dose of the drug, and women who are pregnant or breast-feeding are advised not to take the drug.

Consistent with the recommendations, Racke says cladribine should find a niche for the treatment of patients who are not responding to front-line agents.

"I think it will find use in patients who have failed other agents and do not have contraindications to its use, such as prior malignancy or female patients who may be interested in getting pregnant," he said.

ORACLE-MS was supported by Merck Serono SA Geneva, a subsidiary of Merck KGaA, Darmstadt, Germany. Leist reported relationships with Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, Ono, Pfizer, and Teva Neuroscience. Racke has disclosed no relevant financial relationships relating to cladribine.

Consortium of Multiple Sclerosis Centers (CMSC) 2019 Annual Meeting: Abstract DXM05. Presented May 30, 2019.

For more from Medscape Neurology, join us on Twitter and Facebook


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: