Researchers Detail Treatment Challenges in Primary Progressive MS

The challenges of developing treatments for primary progressive multiple sclerosis (PPMS), which affects a minority of patients but shares many of the same features as other types of MS, was discussed at a session on the first day of the MSVirtual2020: 8th Joint ACTRIMS-ECTRIMS Meeting.

In most patients, MS starts with a relapsing remitting course (RRMS), which may later transform into secondary progressive MS (SPMS). About 65% of patients with RRMS will convert to SPMS within 20 years.

But about 10% of patients with MS may skip that phase and go straight to PPMS. In PPMS, there is typically an older age at onset with mobility impairment due to spinal cord involvement and it affects men and women equally, said Xavier Montalban, MD, PhD, chair of Neurology-Neuroimmunology at the Hospital Universitari de la Vall d'Hebron in Barcelona, Spain.

Currently, ocrelizumab is the only approved disease-modifying therapy (DMT) for the treatment of PPMS, said Montalban. It is also approved for relapsing MS (RMS), as is ozanimod and siponimod, a selective S1P modulator that is approved for RMS and active SPMS.

Most other randomized clinical trials for PPMS have failed to demonstrate efficacy at halting the slide into disability. Some of the mechanisms in primary MS (PMS), which is not active or progressing, may factor into why it is challenging to create a drug for this indication, said Montalban. While the disease processes and mechanisms likely all exist in most forms of MS, the degrees to which they do vary, he said, citing inflammation, axonal degeneration, microglial activation, mitochondrial injury, oxidation byproducts, and glutamate excitotoxicity.

There are 3 reasons why drugs fail in progressive MS, he said: the pathogenic mechanisms in the progressive phase are different from those in the relapsing phase of MS; patient populations in clinical trials are not appropriate; and issues with clinical trials themselves, where outcomes may not be sensitive enough or trials not set up to detect disease worsening over a short time period.

History's efforts in searching for different treatments for PMS include interferon beta-1a and interferon beta-1b, glatiramer acetate, and rituximab. More recently, Biogen’s natalizumab did not meet statistical significance in the phase 3 ASCEND study for PMS, he noted.

Another presentation during the session discussed data about how DMT may delay the time to when a patient with PPMS needs 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 need assistance to move about.

A recently published study reported that DMTs are linked with a slower rate of progression in SPMS, noted the presenter, Mattia Fonderico, a PhD candidate at the University of Florence, Italy.

Using the Italian MS Registry, researchers selected patients with PPMS with at least 3 EDSS evaluations and 3 years of follow-up. The study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients.

The researchers classified the DMTs into 2 categories, moderately effective and highly effective. The moderately effective therapies included interferons, glatiramer, dimethyl fumurate, teriflunomide, methotrexate and azathioprine. The highly effective therapies included biologics, mitoxantrone, cladribine, and fingolimid.

The study included 1214 patients. Those treated for the longest amount of time, and who had started DMTs closer to when they were diagnosed, had a lower risk of disability, Fonderico said.

In the entire cohort, after a mean follow-up of 11.6[6.3] years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not affect the risk of reaching EDSS 6 (adjusted hazard ratio [aHR] = 1.1; 95% CI, 0.95-1.28, P= .181) and EDSS 7 (aHR = 0.93; 95% CI, 0.77-1.12; P = .454).

But it did affect the risk of reaching EDSS 7 (aHR = 0.73; 95% CI, 0.56-0.95; P = .021). Patients who received DMT for the longest amount of time were younger at baseline (mean age 44.1 [10.6]; P < .001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years [6.1]; P = .002).

The findings could have future implications for treatment, he said.