ARTICLE IN BRIEF
In a double-blind, placebo-controlled trial, fewer Gd-enhancing lesions were observed in relapsing-remitting MS patients taking an experimental drug, ONO-441.
NEW ORLEANS—ONO-4641, an investigational oral drug, reduced the number of lesions detected by MRI in people with relapsing remitting multiple sclerosis (RRMS) — the primary outcome for the phase 2b Drug Research EvaluAtion for MS (DreaMS) trial. And while the investigators hope the drug will be safer and more effective than other drugs with similar mechanisms, they noted that the current trial did not measure clinical efficacy. Ono Pharmaceuticals funded the trial.
ONO-4641 is a potent selective sphingosine-1-phosphate (S1P) receptor agonist, stimulating primarily the S1P1 and S1P5 receptors, thus inhibiting the infiltration of lymphocytes into MS lesions. Fingolimod is an approved oral drug for MS that also exerts its effect on the S1P receptor. Another S1P inhibitor potentially useful in MS called BAF is being developed by Novartis.
“In that this new compound is somewhat more selective in its S1P activation pattern than fingolimod, it is our hope that it will have good efficacy with improved safety. We will see if this is borne out in future research,” Timothy Vollmer, MD, professor of neurology at the University of Colorado Health Sciences Center, and medical director of the Rocky Mountain MS Center at Anschutz Medical Center, said. He reported the findings of the double-blind, placebo-controlled trial here at the AAN annual meeting in April.
The dose-ranging trial enrolled 407 RRMS patients between the ages of 18 and 55 years from 11 different countries, including the US. They were randomized to three daily doses of ONO-4641 —.05 mg, .10 mg, or .15 mg — or placebo, and treated for 26 weeks. To be eligible to participate, they had to have had two or more relapses in the previous two years; one or more relapses within the previous year; or one or more new T1 gadolinium (Gd)-enhancing lesions on MRI within the previous three months. Patients were evaluated with MRI scans every four weeks from week 10 to week 26.
The primary endpoint was the cumulative number of T1 Gd-enhancing lesions, not clinical efficacy. At week 26, fewer Gd-enhancing lesions were observed in 82 percent of the .05 mg group; 92 percent of the .10 mg group; and 77 percent in the .15 mg group versus placebo. All three doses of ONO-4641 were significantly superior to placebo for the secondary endpoint of cumulative number of new or enlarged T2 lesions (p<.0001).
Most adverse events in the group of patients treated with ONO-4641 were dose-related, including cardiovascular events. Asymptomatic, transient first- and second-degree atrioventricular block and bradycardia were associated with initiation of dosing; no cases required discontinuation and all resolved with no need for treatment. Maximum mean reduction in heart rate was 8.4 bpm, with the highest dose of ONO-4641. Liver enzyme elevations of varying degrees were seen in slightly less than half of all treated patients compared with 27 percent of placebo patients. Gastrointestinal disorders were slightly less common. Grade 4 lymphopenia was reported in 4 percent of the group receiving the highest dose (0.15 mg) and 1 percent of those on the 0.10 mg dose. Most serious adverse events were related to MS itself.
“ONO-4641 was well tolerated by the study population with no unexpected adverse events,” Dr. Vollmer commented.
IS IT SAFER?
“Both ONO-4641 and BAF have undergone dose-ranging studies with the goal of finding the effective dose with the fewest side effects. These drugs differ from fingolimod in that fingolimod is a prodrug, while these two drugs are active once ingested. The hope is that these drugs can avoid the first-dose effect seen with fingolimod, including cardiovascular and lymphopenia, but it appears that this won't happen. The phase 2b study [of ONO-441] shows that lower doses will be safer,” said Mark S. Freedman, MD, professor of medicine (Neurology) at the University of Ottawa and director of the Multiple Sclerosis Research Unit at the Ottawa Hospital, Ontario, Canada.
Watch here as Neurology Today Editor-in-chief Steven P. Ringel, MD, and Associate Editor Robert Holloway, MD, discuss the growing interest in these oral and increasingly expensive MS drugs. http://bit.ly/Jiz1JM