Rates of overall infections in patients taking the newly approved multiple sclerosis (MS) treatment ozanimod (Zeposia), an oral sphingosine-1-phosphate (S1P) receptor modulator, did not increase with longer exposure, but opportunistic infections were an exception.
Relapsing MS patients with mean ozanimod exposure of 32 months experienced overall infections at the same rate as those in phase III trials, whose mean exposure was about 18 months, reported Hans-Peter Hartung, MD, of Heinrich-Heine University in Dusseldorf, Germany, and co-authors.
But herpes zoster infection rates, while low, increased over time, as did overall opportunistic infection rates.
The as part of the American Academy of Neurology a platform for research from the AAN annual meeting, which was cancelled due the COVID-19 pandemic.
In the and phase III studies of 882 relapsing MS patients, incidence of any infection was 35.1% and the incidence rate was 300.5/1,000 person-years. In the overall population of 2,361 relapsing MS patients who had been exposed to ozanimod (which included the extension study and incorporated participants from phase I and II trials), infection incidence was 48.6% and the incidence rate was 270.1/1,000 person-years.
Herpes zoster infections, including varicella-zoster virus, had an incidence rate of 3.7/1,000 person-years in the phase III trials and 5.3/1,000 person-years in the overall cohort. All opportunistic infections had an incidence rate of 12.0/1,000 person-years in the phase III trials and 16.4/1,000 person-years in the overall cohort.
No serious opportunistic infections and no cases of -- severe brain inflammation caused by latent JC virus reactivation, which has been linked to several MS drugs including another S1P receptor modulator, -- have been seen with ozanimod.
But that may not continue forever, one MS specialist told 鶹ý.
"As soon as you have the potential of one opportunist, the party's on, and anybody else can come along," said Mark Freedman, MD, of the University of Ottawa in Canada, who wasn't involved with the study. "PML might be inevitable, especially if the drug has to be maintained, which it does."
Phase III trials typically don't enroll patients with comorbidities or other risk factors for adverse effects, Freedman noted.
"If we stuck to the inclusion and exclusion criteria of the original fingolimod studies, there'd probably be no cases of PML today," he pointed out. "But there are about 20 or some cases of PML now, and these have arisen in patients who were slightly older and had some comorbidities."
Like fingolimod, ozanimod causes lymphocyte retention in lymphoid tissues, which may increase susceptibility to infections. Fingolimod has been linked to increased varicella-zoster virus infection, including rare fatal cases.
, a study of at least 12 months of treatment, and , a 24-month study, were phase III trials comparing oral ozanimod HCl 1 mg/day and 0.5 mg/day with intramuscular interferon beta-1a (Avonex) 30 µg/week in adults with relapsing MS. Participants who completed any ozanimod relapsing MS clinical trial were eligible to enroll in DAYBREAK, an ongoing open-label extension trial of ozanimod HCl 1 mg/day.
In the ozanimod analysis, the phase III population and overall relapsing MS population had similar ages (35 and 36, respectively) and similar proportions of women (65% and 67%, respectively). In both groups, about 29% of patients had prior exposure to any MS disease-modifying therapy.
Absolute lymphocyte count (ALC) was measured at baseline, at month 1 during phase I and II studies only, month 3, and every 3 months after that. In the phase III population, 3.3% of participants had ALC less than 0.2 × 109/L on at least one laboratory measurement during the study; in the overall population, that figure was 6.9%.
Analysis showed ALC less than 0.2 × 109/L was not related to serious or opportunistic infections. Among DAYBREAK participants, one serious infection (pyelonephritis) and one non-serious opportunistic infection (oral herpes) were connected to ALC less than 0.2 × 109/L.
Disclosures
The study was sponsored by Celgene (Bristol-Myers Squibb).
Hartung reported relationships with Bayer Healthcare, Biogen Idec, CSL Behring, GeNeuro, Genzyme, MedImmune, Merck Serono, Novartis, Opexa, Receptos, Roche, Sanofi, Teva, and Viela Bio.
Freedman reported relationships with Sanofi-Genzyme, Hoffman-La Roche, EMD Actelion, Alexion, Biogen Idec, Celgene, Merck Serono, Novartis, Teva Canada Innovation, Atara Biotherapeutics, Bayer Healthcare, Clene Nanomedicine, GRI Bio, Magenta Therapeutics, and MedDay.
Primary Source
American Academy of Neurology
Hartung H-P, et al "Low Rate of Infections With Long-term Use of Ozanimod in Relapsing Multiple Sclerosis Trials" AAN Science Highlights; Abstract P7.005.