The investigative therapy reported a relative difference of 48% in brain atrophy reduction versus placebo, but investigators are still uncertain of its benefits.
Robert J. Fox, MD
While there are currently more than a dozen therapies approved in the US for multiple sclerosis (MS), the more aggressive form of the disease—progressive MS—has only the monoclonal antibody ocrelizumab (Ocrevus) and the chemotherapy agent mitoxantrone. With such few treatment options, investigative therapies like ibudilast are under clinical scrutiny.
Unfortunately, new phase 2 trial results indicate that ibudilast may need more analysis before reaching the sparse progressive MS market.
In the phase 2, 96-week trial, 255 patients with primary or secondary progressive MS were randomized to receive either 60 mg ibudilast (n = 129) or placebo (126) for an initial 2-week period. Following that period, patients received an increased dose of 100 mg of either ibudilast or matching placebo.
Of those patients in the ibudilast group, 53% had been diagnosed with primary progressive MS.
The primary endpoint included the rate of brain atrophy, as measured by the brain parenchymal fraction via magnetic resonance imaging (MRI). Safety was determined by the adverse events (AEs) and serious adverse events (SAEs) reported and assessed by site investigators.
Investigators reported an annual absolute difference of .0009 (95% CI; .00004-.0017; P = .04) of brain parenchymal fraction change between patients treated with ibudilast (-.0010) and patients treated with placebo (-.0019). This absolute difference translated into approximately 2.5 ml less brain tissue loss with ibudilast treatment compared to placebo, amounting to a relative difference of 48%.
As for safety measures, 92% of patients administered ibudilast reported AEs compared to 88% in placebo. The most common AEs were gastrointestinal symptoms, headaches, and depression. Another 16% of patients treated with ibudilast reported SAEs compared to 19% of those treated with placebo. No deaths nor opportunistic infection were reported.
In an interview with MD Magazine®, Robert J. Fox, MD, principal investigator from the Cleveland Clinic, noted that ibudilast was found to cut brain atrophy rates by nearly half.
“Side-effects of ibudilast included gastrointestinal symptoms, headache, and depression, with no increased rate of serious adverse events or infections,” Fox said. “This combination of benefit on atrophy progression and safety profile points to a potential new therapy for progressive multiple sclerosis.”
Investigators noted clinical limitations included the unknown relevance of their own findings—most notably, how the clinical effect of slowing brain atrophy is beneficial for progressive MS patients.
Fox added that since this was only a phase 2 trial, it was not powered to measure an impact on clinical disability. In the future, he hopes that the robust slowing in progression of brain atrophy will translate to a clinical benefit in terms of disability progression; however, an additional, larger trial will need to be conducted in order to know if that is indeed the case.
His team called for additional trials in order to assess whether the effect on brain atrophy found in the trial can be reproduced, and whether it is involved with slowed progression of neurological disability.
That said, Fox reiterated the significance of finding ibudilast slowed the progression of brain atrophy by 48%.
In a previous placebo-controlled trial, ocrelizumab—which is currently the only US Food and Drug Administration-approved therapy for progressive MS—had slowed brain atrophy progression by 17.5%. Considering ibudilast’s significant improvement on that rate, investigators believe it is worth further assessing.
The study, "Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis," was published online in the New England Journal of Medicine on Wednesday.