The Challenges of Treating Primary Progressive MS

For most patients with multiple sclerosis (MS), the disease begins with a stage called relapsing remitting (RRMS), characterized by flare-ups and periods of recovery. For the majority, about two-thirds, the disease converts into secondary progressive MS (SPMS) within a 20-year period.

But for a minority of patients, about 10%, the disease starts as primary progressive disease (PPMS). These patients, who tend to be older at the onset of MS, have few treatment options.

The challenges of finding treatments for PPMS was the topic of a session during MSVirtual2020, the 8th joint meeting of ACTRIMS-ECTRIMS, which began Friday and concludes today.

When PPMS does strike, it affects men and women in equal numbers and impairs mobility due to its involvement of the spinal cord, said Xavier Montalban, MD, PhD, chair of Neurology-Neuroimmunology at the Hospital Universitari de la Vall d'Hebron in Barcelona, Spain.

Right now, Ocrevus (ocrelizumab, Genentech) is the only disease-modifying therapy (DMT) approved to treat PPMS. The therapy is also approved for RRMS, along with Zeposia (ozanimod) and Mayzent (siponimod), a selective S1P modulator that is approved for RMS and active SPMS. Most other trials for treatment of PPMS have failed to show the therapy could stop the decline toward disability.

Mechanisms that define in primary MS (PMS), which is neither active nor progressing, help explain why it has been so challenging to create a drug for this indication, Montalban said. PMS involves disease processes and mechanisms that are likely present in other forms of MS, but he said, it’s a matter of degree. Some of these characteristics include inflammation, axonal degeneration, microglial activation, mitochondrial injury, oxidation byproducts, and glutamate excitotoxicity.

Montalban identified three reasons why drug trials fail in progressive MS:

• the pathogenic mechanisms in the progressive phase are different from those in the relapsing phase of MS
• the trials do not recruit appropriate patient populations
• there are methodological issues with the trials, and the designs may not be sensitive enough to detect disease worsening over a short time period.

The search for different treatments for PMS includes interferon beta-1a and interferon beta-1b, glatiramer acetate, and rituximab. In the phase 3 ASCEND study, Biogen’s natalizumab did not meet statistical significance for PMS, he noted.

Another presenter, Mattia Fonderico, a PhD candidate at the University of Florence, Italy, discussed data that show how DMT may offer a patient with PPMS more time without a wheelchair.

A real-life cohort study examined the effectiveness of DMTs in whether patients reached Expanded Disability Status Scale (EDSS) 6 and 7, which is the point where a patient starts to help moving. The study of 1,214 patients over nearly 12 years linked use of DMTs with a slower rate of progression in SPMS, Fonderico said. Those who had the longest periods of treatment and who started receiving DMTs closest to their date of diagnosis took longer to reach EDSS 7, which is defined by the patient being unable to walk. There was less difference in the time it took reach EDSS 6, which is defined by the need for occasional help from a cane or other assistance.