Progressive multiple sclerosis patients — with primary or secondary progressive disease — treated with high doses of oral ibudilast in a Phase 2 clinical trial showed a 48 percent slowing in the progression of brain atrophy, or shrinkage, relative to those given a placebo, study data show.
What this decline might mean in terms of daily disability or other clinical benefits for patients is still difficult to say, because a Phase 2 trial is a proof-of-concept study. As such, it’s relatively small — 255 progressive MS patients enrolled at 28 academic sites in the U.S., with 244 completing the study — and not powered to determine such outcomes, said Robert Fox, MD, the trial’s principal investigator in an interview with Multiple Sclerosis News Today. Fox is vice-chair for research at the Cleveland Clinic’s Neurological Institute.
Still, with treatment options for progressive MS patients “very limited” and primarily targeting “younger patients with more active inflammation,” Fox said, a 48% improvement in a measure that might translate to lesser disability and greater quality of life “compares quite favorably with what we see with … therapies” approved or being tested for progressive patients.
Ocrevus, in pivotal trials that led to its approval for both relapsing-remitting and progressive MS, showed a 17.5% slowing in brain atrophy, and siponimod — a potential oral progressive MS treatment — 15% in its clinical trials. Those results were reported in the study “Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis,” published in the New England Journal of Medicine, with Fox as its lead author.
Those numbers, however, should not be taken as comparisons of likely benefit, Fox emphasized, because of the vast differences in the number of patients involved in “concept” Phase 2 trials and pivotal Phase 3 ones — the latter essential to estimating treatment outcomes in patients-at-large — and the fact that these medicines were not compared head-to-head.
But “the magnitude of this [Phase 2 result] was quite remarkable,” Fox said, adding “I think the data set provided here is robust enough to justify going to a Phase 3 trial.”
Whether such a trial will take place is not guaranteed, because the costs of Phase 3 testing — which Fox placed at between $100 million and $125 million — far outstrip the capacities of the 28 U.S. academic centers involved in the trial, the National Institutes of Health, and nonprofit patient advocacy groups like the National Multiple Sclerosis Society, all of which largely supported the 96-week Phase 2 SPRINT-MS study (NCT01982942).
MediciNova, the pharmaceutical company that is developing ibudilast and helped fund the Phase 2 work, would need to sponsor a Phase 3 trial alone or in collaboration with others. To date, it expressed an intention to do just that.
“With a convenient oral administration, a very favorable safety and tolerability profile, and the potential for better efficacy than other drugs for progressive MS, we believe ibudilast could become the best-in-disease drug,” Yuichi Iwaki, MD, MediciNova’s president and CEO, said in an August press release.
Fox remains hopeful a pivotal Phase 3 study of this somewhat repurposed tablet — ibudilast, which MediciNova licensed from Kyorin Pharmaceutical, has been approved to treat asthma and stroke since 1989 in Japan — will be underway soon.
“I’m an MS neurologist and my patients need therapies available out in regular clinical use for their disease,” Fox said. “So, I’m eager for this drug to move forward.”
Ibudilast, a small molecule which acts on numerous sites in the brain, is among other things known to prevent immune cells called macrophages from migrating. As such, it works to suppress the formation of pro-inflammatory molecules called cytokines, and to promote the production of brain growth factors.
Its anti-inflammatory potential first brought it to MS attention, leading to a Phase 2 trial in 297 relapsing-remitting MS patients.
But ibudilast (given daily at 30 or 60 mg) failed to prevent or slow new and active brain lesions from appearing in treated patients compared to placebo, the study’s primary goal. Yet, at the higher dose, a lessening in the proportion of active lesions that progressed to “persistent black holes” — representing severe injury — was seen, according to data published in the journal Neurology in 2010. Fewer treated patients showed confirmed disease progression at two years in Expanded Disability Status Scale (EDSS) scores, a measure of disability accumulation over time.
“Other MRI measures suggested benefit: a decrease in active lesions, gadolinium-enhancing lesions converting to black holes,” said Fox, who was invited at the time by the journal’s editors to write an accompanying editorial on what he saw as an impressive “second line of evidence, relatively independent from brain atrophy, to suggest a neuroprotective action of the drug.”
He concluded by noting “it would be an ideal therapy to carry forward into progressive MS.”
That 2010 editorial caught MediciNova’s attention, and planning began for what would become the SPRINT-MS trial. The company supplied the treatment and is listed as the study’s sponsor, but its work at 28 trial sites and two coordinating centers was largely funded by a $12.5 million grant from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH), and a more than $500,000 grant from the National MS Society, Fox said.
Opening in 2013, the 96-week randomized and double-blind safety, tolerability and activity trial involved 255 progressive MS patients, ages 21-65. Of these, 129 (with an average age of 55) took 10 mg capsules of ibudilast (taken up to 10 times a day, for a maximum 100 mg dose) and 127 (average age, 57) were given placebo. A majority in both study arms had primary progressive MS or PPMS (53% in the treatment arm, and 52% in the placebo group); the remainder were secondary progressive (SPMS) patients.
All had EDSS scores showing moderate-to-severe disability (between 3.0 and 6.5 on a rising scale) with evidence of progression in the two years that preceded the study, as seen in increasing EDSS scores and poorer walking and upper limb dexterity, data show. Eleven patients withdrew before a first comparison of effect could be made, including eight in the ibudilast group, citing adverse events.
Patients underwent magnetic resonance imaging (MRI) brain scans every six months, and researchers were allowed to lower treatment doses during the study’s first two months to 60 or 80 mg daily as they thought best, Fox said. A majority kept to the 100 mg daily target dose, a dose whose safety was established in preclinical testing and checked throughout the trial via blood tests and cardiac monitoring. No cumulative toxicity was found, Fox noted.
Rather, two years out, treated patients showed a better brain volume retention than those on placebo, a 48 percent difference that translates to about 2.5 milliliters less brain tissue loss, data show. Fewer active lesions were seen on MRIs as well, representing a relatively independent line of evidence that suggests a neuroprotective role for ibudilast, Fox added.
There also were signs of “a potential neuromodulation of pain … [the] possibility of ibudilast having a second benefit in progressive MS patients,” Fox said. But data supporting this and other measures of the investigative treatment’s potential — how its activity might have been influenced by other therapies used by participants, or whether differences exist between treated patients with PPMS and those with SPMS — are still being studied, he added.
The neurologist said he doubts a notable difference between these two groups will be found, noting “a growing sense in the field that primary and secondary progressive MS are much more similar than they are different.”
Safety was established at the study’s high doses, with the most common side effects being gastrointestinal (diarrhea, nausea), headaches, and depression, but no evidence of suicidal thoughts or opportunistic infections. Side effects were felt more by treated patients than those receiving placebo, and rates of treatment discontinuation were 5% to 6% higher in the ibudilast group. A total of 71 people discontinued the trial regimen, 38 citing adverse events (18% ibudilast group, 12% placebo).
Like most Phase 2 trials, SPRINT-MS “was not powered to see a clinical benefit; if it were then we’d call it a Phase 3 trial,” Fox said. Still there were glimpses “of the clinical relevance of the [lowering in] brain atrophy itself.”
Paving Way for Trials Yet to Come
As an academic-led trial, SPRINT-MS also touched on larger topics, like whether measures more specific and profound than brain atrophy might better capture treatment effects in progressive MS patients.
For relapsing-remitting MS patients, there are “very robust” biomarkers of response to therapy: T1 lesions that convert to “black holes,” new or enlarging gadolinium-enhancing or T2 lesions seen on MRI scans.
No such “granular measures of tissue integrity” exist for PPMS or SPMS, said Fox, who has a strong interest in advanced imaging metrics for neuroprotection. Whole brain atrophy is valid and well-established, he added, but its lacks equivalent specificity. It’s “just a single measure of a brain, sort of like measuring someone’s health by putting them on a scale,” he added.
Accordingly, secondary trial goals were “to explore other potential biomarkers for treatment response,” Fox said. Among these were cortical atrophy, diffusion sensor imaging, retinal nerve fiber layer in the back of the eye, and magnetization transfer ratio.
For the purposes of the ibudilast trial, however, only cortical atrophy — or thickness — gave robust enough results to justify extensive data collection, Fox said. If future trials agree, it “might allow us to study fewer patients over a shorter period of time — thereby levering the same amount of money to do more trials.”
Data on all these secondary explorations, still being evaluated, might show their value in another Phase 2 trial in another therapy, he said.
For now, though, focus remains on ibudilast and MediciNova’s possible next steps.
Asked if he would recommend his patients enroll in a Phase 3 trial of this oral small molecule, Fox hesitated. That recommendation, he said, couldn’t be made without knowing the trial’s design and structure, and whether he might be an investigator, because “I would caution anyone who runs the trial needs to keep arm’s length distance from enrolling patients.”
“That said,” he added, “I’m excited about this drug and bringing into treatment. … I would be excited to encourage patients to consider enrolling into a trial with ibudilast, because it does look to be like such a promising therapy.”