No slowing of MS therapeutic pipeline

Available treatments for multiple sclerosis have increased markedly over the last decade and there is unlikely to be a slowing of this therapeutic progress over the next 10 years, according to Benjamin M. Greenberg, MD, MHS, who presented an overview of emerging therapies at the CMSC 2020 virtual meeting.

Greenberg, who is director of the neuroimmunology program at the University of Texas Southwestern in Dallas, noted, however, that there is a spectrum of both efficacy and safety as one considers drugs that are considered immune modulating, and that “there seems to be a trend that the more immune remodeling we do, the greater the success we get from them.”

Considering relapsing-remitting MS (RRMS), Greenberg focused on three categories:

  • Anti-CD20 agents: ofatumumab and ublituximab.
  • S1P receptor modulating agents: ozanimod and penesimod.
  • Brutons tyrosine kinase inhibitors: evobutinib and SAR442168.

Ofatumumab is a fully humanized monoclonal antibody to CD20 administered by subcutaneous injection and it is FDA approved for treatment of chronic lymphocytic leukemia. In the phase II MIRROR study, it reduced new Gd+ lesions by 55% compared to placebo, Greenberg said. And, in a phase III trial that compared it to teriflunomide, it reduced the annualized relative relapse rate by 50.5%.

Ublituximab, a novel glycoengineered anti-CD20 monoclonal antibody, demonstrated safety in a phase II study, and at two time points (week 24 and week 48), “no T1 gadolinium-enhancing lesions (P = 0.003) and a 10.6% decrease in T2 lesion volume (P = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA),” according to findings published in the Multiple Sclerosis Journal, Greenberg said.

Turning to S1P receptor modulators, Greenberg noted that the recently approved ozanimod joins two other agents — fingolimod and siponimod — in this group. “But they target different S1P receptors,” he noted; Ozanimod targets S1p1 and S1P5.

Ozanimod received FDA approval based on findings from the pivotal SUNBEAM trial, which compared ozanimod to interferon beta-1a for treatment of patients with RRMS. The trial enrolled 1,346 participants and randomized 447 to ozanimod 1.0 mg, 451 to ozanimod 0.5 mg, and 448 to interferon beta 11a 30 μg. The annualized relapse rates (ARR) “were 0.35 (0.28-0.44) for interferon beta-1a, 0.18 (95% CI 0.14-0.24) for ozanimod 1.0 mg (rate ratio [RR] of 0.52 [0.41-0.66] vs interferon beta-1a; P<0.0001), and 0.24 (0.19-0.31) for ozanimod 0.5 mg (RR 0.69 [0.55-0.86] versus interferon beta-1a; P=0.0013),” Comi, G et al, reported in The Lancet.

In a CMSC 2020 poster, John DeLuca, PhD, of the Kessler Foundation and Rutgers University Medical School, looked at the effects of ozanimod on information processing speed using data from the Phase 3 SUNBEAM and its extension trial (DAYBREAK).

He noted that in the initial SUNBEAM study, ozanimod at the 1 mg dose “improved information processing speed (IPS), measured with the Symbol Digit Modalities Test (SDMT, a component of a secondary endpoint), compared with interferon β-1a (IFN).”

DAYBREAK, an open-label extension trial, enrolled 397 of the 447 SUNBEAM patients who were treated at the 1 mg dose, as well as 395 of the original 448 interferon β-1a patients. All participants receive ozanimod 1 mg.

Among the findings:

  • At baseline, the mean SDMT scores in the ozanimod group were 47.7 and 47.1 in the interferon β-1a group.
  • After 12 months, 35.6% of the original ozanimod group and 27.9% of the interferon β-1a had improved processing scores.
  • But after 12 months, SDMT scores in 22.0% of the original ozanimod group and 28.2% of controls were worse.

“At month 24, 41.2% (113/274) of those who received continuous ozanimod HCl 1 mg and 34.5% (91/264) of those originally assigned to IFN in SUNBEAM had SDMT improvement; 21.9% (60/274) and 25.4% (67/264), respectively, worsened relative to SUNBEAM baseline,” DeLuca and colleagues reported.

They concluded that their exploratory analysis demonstrated that “the percentage of participants with SDMT improvement increased over 24 months of continuous treatment with ozanimod HCl 1 mg. The percentage of participants with SDMT improvement was higher at month 24 than month 12 among those who transitioned from IFN to ozanimod HCl 1 mg during the latter 12 months as part of the DAYBREAK study.”

It is, however, unclear why a number of patients worsened over the course of the study, but it does illustrate a theme that Greenberg emphasized in his presentation: one size is unlikely to fit all MS patients.

Looking then at another emerging class of therapeutics — Brutons tyrosine kinase inhibitors — evobutinib and SAR442168 were also covered at the virtual CMSC 2020 meeting.

Results of phase II trial of evobutinib in The New England Journal of Medicine seemed likely to herald its early demise: In a study of 267 patients, those who “received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose.” But the is now being studied in a phase 3 trial, Greenberg said.

Another drug in this class, the investigational agent SAR442168, was reported to have met its endpoints in a phase IIb trial. Those findings, though unpublished, were presented at the American Academy of Neurology’s virtual meeting in April and it, too, is advancing to phase III studies.

Finally, Greenberg noted one barrier to continued progress in developing treatments for MS. The problem, he said, is a good one, in that MS patients continue to do well — a testament to the progress of recent decades. But that progress means patients are at a good place in their treatment, which makes it more difficult to recruit patients for trials since fewer patients are seeking better treatments.

  1. Be aware that this report describes off-label use or use of novel therapies that are not yet FDA approved.

  2. Note that findings from an open-label extension study of ozanimod in patients with RRMS indicates that long term treatment may provide continued improvement in processing speed.

Peggy Peck, Editor-in-Chief, BreakingMED™

Deluca disclosed grant funding from Biogen IDEC, EMD Serono, Canadian MS Society, National MS Society, and the Consortium of MS Centers, as well as consulting fees from Celgene Corporation, Biogen IDEC, Consortium of MS Centers, Novartis, Sanofi-Genzyme, and Canadian MS Society, and EXCEMED.

Greenberg received consulting fees from Alexion, Genentech, EMD Serono, and Novartis. He received grant support from GLENE Nanomedicine, NIH, NMSS, Guthy Jackson Charitable Foundation, the Siegel Rare Neuroimmune Association, and PCORI. He also serves as an unpaid member of the board for Siegel Rare Neuroimmune Association.

Cat ID: 130

Topic ID: 82,130,730,130,36,764,192,925,763