Higher Doses of Opicinumab as Add-on Therapy Fail to Lessen MS Disability, Phase 2 Trial Shows

Treating people with relapsing forms of multiple sclerosis (MS) with opicinumab and Avonex (interferon beta-1a) for 72 weeks did not lead to a dose-dependent reduction in disability,  results of a Phase 2 trial show. However, an ongoing study is evaluating opicinumab in a subgroup with better clinical responses.

The research, “Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial,” was published in the journal The Lancet Neurology.

Opicinumab, an antibody developed by Biogen, is intended to induce the repair of myelin (the protective layer of nerve fibers, whose degeneration is a MS hallmark) by blocking the effects of the LINGO-1 protein. This protein, found in the brain and spinal cord, suppresses the formation of cells (called oligodendrocytes) that form myelin.

Work in animal models of MS showed that opicinumab promotes myelin repair. Results of an earlier Phase 2 study called RENEW (NCT01721161) in patients who had experienced their first episode of optic neuritis, a condition that often precedes MS, showed possible clinical benefits associated with improved nerve conduction.

The Phase 2 and multi-center SYNERGY trial (NCT01864148) enrolled 418 adults (up to age 58) with relapsing forms of MS — relapsing-remitting (RRMS) or secondary progressive disease with relapses — who were treated once every four weeks with Biogen’s Avonex in combination with either intravenous opicinumab (3, 10, 30, or 100 mg/kg) or a placebo over 72 weeks.

Participants were evaluated via the Expanded Disability Status Scale (EDSS), the Timed 25-Foot Walk (T25FW) — walking 25 feet as quickly and safely as possible — the Nine-Hole Peg Test (9HPT) of finger and hand skills, and the three-second Paced Auditory Serial Addition Test (PASAT-3) of cognitive function. Brain magnetic resonance imaging (MRI) scans were conducted throughout the trial.

Confirmed benefit was defined as showing at least a one-point decrease in EDSS scores, or a 15% or better improvement in either the T25FW, 9HPT, or PASAT-3 over at least 12 weeks.

Results showed disability lessening in 21 (47%) patients on 3 mg/kg opicinumab, 59 (63%) of those on 10 mg/kg, 59 (65%) receiving 30 mg/kg, and 36 (40%) on 100 mg/kg. Similar benefits were seen in 45 (49%) of patients given placebo.

As such, higher doses of the opicinumab did not lead to greater benefits over placebo, and intermediate doses of the therapy were seen to be more effective, as reported previously.

Adverse events (AEs) were reported in 275 (85%) of the patients on opicinumab and 79 (85%) of those in the placebo group, most commonly influenza-like illness (43% in the opicinumab group vs. 40% in the placebo group), MS relapses (36% vs. 32%), and headache (16% vs. 25%).

Serious AEs deemed related to treatment included a urinary tract infection in one placebo patient, suicidal ideation and an intentional overdose in a person treated with opicinumab at 30 mg/kg, bipolar disorder in one on 100 mg/kg opicinumab, and hypersensitivity in four (4%) patients on that same high dose of the experimental treatment.

Treatment discontinuation was more frequent among those given opicinumab at the higher doses (30 mg/kg and 100 mg/kg) than the lower doses (3 mg/kg and 10 mg/kg). One patient on 30 mg/kg died during the study due to a traffic accident, considered unrelated to treatment.

“In conclusion, the SYNERGY primary analysis did not support a linear dose-response on confirmed disability improvement for opicinumab treatment versus placebo,” the researchers wrote.

A subsequent analysis showed better treatment responses in people whose first MS symptom came within the past 20 years, and who showed specific MRI findings — namely on lower magnetic transfer ratio and diffusion tensor imaging in pre-existing brain lesions. These findings might indicate myelin damage with more intact nerve fibers.

A lower proportion of patients in this group showed confirmed disability worsening with the 10 mg/kg dose of opicinumab, as well as positive effects on exploratory biomarkers of central nervous system repair. According to the research team, this may indicate a greater preservation of nerve fibers and shorter duration of myelin loss.

To further test opicinumab’s potential benefits in this group, a Phase 2b trial called AFFINITY (NCT03222973) has finished recruiting 263 patients, according to a press release. Participants will receive 750 mg opicinumab (or a placebo) as an add-on to Avonex, Bayer’s Betaferon/Betaseron (interferon beta 1b), EMD Serono’s Rebif (interferon beta-1a), or Biogen’s Plegridy (peginterferon beta-1a), Tecfidera (dimethyl fumarate) or Tysabri (natalizumab).

AFFINITY is expected to finish in 2022.