BY JAMIE TALAN
Ibudilast significantly reduced the progression of brain atrophy in primary and secondary progressive multiple sclerosis (MS), according to the findings of a phase 2 multicenter study published in the August 30 issue of the New England Journal of Medicine.
The drug has been approved for use in Japan as a treatment for asthma and post-stroke dizziness. But the study in MS was too small — 129 people received the drug and 126 people received a placebo — to answer the question of whether the pathological finding led to a functional slowing in progression of disability, the study authors said.
"Our findings showed that cortical atrophy is a robust measure of a treatment effect," said the lead investigator of the study, Robert J. Fox, MD, FAAN, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. "The study was not powered to show a clinical benefit, and we have a lot more data to analyze. We hope that the drug moves forward into phase 3 testing.
"We have very limited treatment options for progressive forms of MS," he added, so there is a big unmet need."
Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier. Other studies have shown that levels of macrophage migration inhibitory factor and toll-like receptor 4 are increased in the cerebrospinal fluid (CSF) of patients with progressive multiple sclerosis.
First approved for asthma two decades ago in Japan, the drug's anti-inflammatory properties led scientists to test it in relapsing-remitting MS. It did not reduce new lesions in a phase 2 study, so it was not going to move forward for relapsing-remitting MS. But scientists noted that the drug appeared to slow down brain atrophy in that study.
The relapsing-remitting MS study results were published in 2010 in Neurology. In an accompanying editorial, Dr. Fox suggested that although the results for the most common form of MS were disappointing, ibudilast could be an attractive therapy for progressive MS. Dr. Fox and his colleagues submitted a grant proposal to the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), a federal program funded by the National Institutes of Neurological Disorders and Stroke that brings academics, private foundations and industry together to carry out phase 2 clinical trials. This collaboration was also funded by the National Multiple Sclerosis Society and MediciNova, which contributed less than 10 percent of the cost of the clinical trial.
STUDY METHODS, FINDINGS
There were several firsts for this phase 2 study: The scientists decided to test the drug in patients with primary or secondary progressive MS. (The symptoms and the pathology are thought by many to be the same, but studies have usually separated the two patient groups.) While the primary outcome was magnetic resonance imaging (MRI) findings of brain atrophy, they also included secondary outcome measures of four other imaging modalities: diffusion tensor imaging; magnetization transfer ratio imaging; retinal nerve fiber layer imaging with an optical coherence tomography scan; and cortical atrophy measured by a cortical longitudinal atrophy detection algorithm, CLADA. This was no easy feat over 28 centers across the country, especially since imaging machines varied across the sites.
The investigators enrolled and randomized 255 men and women to receive up to 100 mg daily dose of ibudilast or an equal number of placebo pills. Patients, ranging in age between 21 and 65, could stay on their immune modulating treatments during the 96-week study. (That accounted for a third of study patients.)
In addition to the inflammatory disease activity (T1 and T2 lesion volumes and relapse rate), they also collected measures of disability and quality of life. Finally, they used the Brief Pain Inventory to collect information on neuropathic pain. Clinical disability was assessed every 24 weeks, when MRI and optical coherence tomography scanning took place.
An independent monitor, Stephen Krieger, MD, an MS neurologist at the Icahn School of Medicine at Mount Sinai, collected and reviewed safety data throughout the study period. The data was also reviewed by an NINDS-appointed data and safety monitoring board and the NeuroNEXT central institutional review board.
The primary outcome MRI measure showed a 48 percent difference in the progression of brain atrophy between those who received the drug and those who took the placebo. The rate of change in the brain parenchymal fraction — brain size relative to the volume of the outer surface contour of the brain — was −0.0010 per year with ibudilast and −0.0019 per year with placebo (p=0.04).
Dr. Fox said that this represents approximately 2.5 mL less brain-tissue loss with ibudilast over the study period. The secondary measures were also heading in the same positive direction, although Dr. Fox said that they are still analyzing the data.
The patients on the active drug reported more gastrointestinal symptoms, headache, and depression than those on placebo. (During the study, neurologists were also allowed to lower the active dose to 60 mg or 80 mg per day if they felt that the patient's side effects were compromising their quality of life.) Sixteen percent of patients on the active drug and 11 percent of the patients on placebo stopped taking the pills or withdrew from the study. Many continued with the follow-up assessments. Eight patients (6 percent) receiving ibudilast and three (2 percent) receiving placebo who withdrew from the trial were not included in the final analysis.
The scientists are still analyzing the secondary outcome data. Dr. Fox said that the number of patients may have been too small to assess whether a change in brain volume was associated with a slowed progression of neurologic disability assessed during the study. The study authors reported that there was not a statistically significant difference in the decline in disability progression between study patients on active medication and those on a placebo dose.
Study investigator, Patricia K. Coyle, MD, FAAN, professor of neurology and director of the MS Comprehensive Care Center at Stony Brook University in New York, said that the study "was a proof of principle that we can use standard and non-conventional imaging techniques across dozens of centers for MS trials. It also proved that we can include primary and secondary progressive MS when designing these studies."
Mount Sinai's Dr. Krieger, the independent medical monitor, agreed. "One of the drivers of disability is the acceleration of loss of brain volume. The hope is that reducing this is an indication of the slowing down of the degenerative process in MS. It remains to be seen whether this reduction translates into a benefit in the reduction of disability."
"This is an important study. I was skeptical that the study would be successful because the odds of hitting the primary endpoint were low. But it clearly showed an effect on overall brain volume, and a trend in slowing disability," said Bruce A. Cree, MD, PhD, FAAN, the George A. Zimmermann endowed professor in multiple sclerosis and professor of clinical neurology and clinical research director at the University of California, San Francisco Weill Institute for Neurosciences.
"Now, they need to increase the sample size," Dr. Cree said. "Also, we need to know the target in the brain. Once we know the target it could usher in the development of new treatments for progressive forms of multiple sclerosis."
"We don't think of progressive MS as an inflammatory problem as much as a neurodegenerative one," said Lauren B. Krupp, MD, FAAN, director of the MS Center at NYU Langone Health. "I think it is important that the drug had a favorable impact on brain volume. It was concerning that there was not even a trend on the clinical measures, but this was a small study with a big signal on the neuroimaging primary outcome of change in brain volume. Will it spill over into clinical measures? It will be interesting to figure out how the drug is working in these patients."
The study raises many questions, she added. "To what extent were the secondary MRI measures correlated with the primary [neuroimaging] measures? We are not even sure what all the short-term changes in these neuroimaging outcomes mean to the disease and to progression. But the fact that investigators can do them reliably over 28 centers with different scanners is very exciting and encouraging for future clinical trials."
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Fox RJ, Coffey CS, Conwit R, et al. for the NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2018; 379(9): 846-855.