Continued use of ozanimod for RMS brings no new safety concerns

Longer duration of treatment with ozanimod, a sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator, did not trigger new safety signals, according to findings reported in Multiple Sclerosis and Related Disorders. Those findings are described in an article published June 14, 2021 and republished as part of BreakingMED’s year-end review of clinical news. Click here to view the original article and obtain CME/CE credit.

In a large population of patients with relapsing multiple sclerosis (RMS) who had longer and greater exposure to treatment with ozanimod, safety results were consistent with those seen in previous phase III trials, with no new safety concerns, according to a recent integrated safety analysis published in Multiple Sclerosis and Related Disorders.

“Ozanimod is a sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator approved in multiple countries for the treatment of relapsing multiple sclerosis (RMS). Ozanimod blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. While the exact mechanism of ozanimod in RMS is unknown, it may involve reduced migration of lymphocytes into the central nervous system,” wrote Professor Krzysztof W. Selmaj, of the University of Warmia and Mazury, Olsztyn, Poland, and fellow researchers.

In an email correspondence with BreakingMED, James Bowen, MD, Medical Director of the Multiple Sclerosis Center at the Swedish Neuroscience Institute, Seattle, explained this mechanism of action in more detail.

“The proposed mechanism of action for S1P modulators relates to lymphocyte trafficking through lymph nodes. Some have proposed an additional mechanism of action with direct effects of the S1P modulators on brain tissue, including neuroprotective effects on neurons and myelin. These drugs remove the S1P receptor from the surface of lymphocytes. This receptor is necessary to guide lymphocytes through the lymph node and back into the circulation,” he noted.

“The simplistic view of the immune mechanism is that this reduces the circulating lymphocytes leading to less immune attack on the nervous system. However, the S1P modulators actually trap primarily naïve and central memory lymphocytes in the lymph node while not affecting effector and effector memory lymphocytes very much. Even the lymphocytes trapped in the lymph node may eventually make it back to the circulation after a prolonged stay in the lymph node,” Bowen added.

“So, what benefit results from sequestering naïve cells that do not participate in the immune attack, while not sequestering effector cells that are responsible for the immune attack? It remains speculative, but one of the primary mechanisms of eliminating autoreactive lymphocytes is in the lymph nodes, where naïve lymphocytes that strongly bind to antigens, particularly self-antigens, are eliminated. Ultimately, this decreases the number of self-reactive lymphocytes available to participate in an immune attack on the nervous system,” he concluded.

To assess the safety of extended exposure to ozanimod in patients with RMS from all clinical trials and compare it with data from phase III trials, Selmaj and colleagues pooled incidence and study-duration-adjusted incidence rates (IR) of treatment-emergent adverse events (TEAEs) from clinical trials conducted through Jan. 31, 2019, of RMS patient treated with ozanimod.

Data from 2,631 RMS patients were available. They had been exposed to treatment with ozanimod (0.92 mg) for a mean of 32.0 months, and 2,787 had exposure to either ozanimod 0.46 or 0.92 mg (mean 37.1 months). The IRs per 1,000 person-years for any TEAE and serious TEAEs was similar to those seen in phase III trials (896.1 and 31.2, respectively). In all, 772.2 TEAEs occurred and 33.2 serious TEAEs.

No second-degree or higher atrioventricular blocks occurred, and only 0.4% of patients treated with 0.92-mg ozanimod in any trials experienced ischemic heart conditions. No serious opportunistic infections occurred, and over time, elevations in hepatic enzymes—which were “generally asymptomatic, transient, and did not lead to severe drug-induced liver injury”—declined, Selmaj and colleagues stressed.

With longer exposure, malignancy rates were also low. The overall IR of malignancy was similar to that seen in patients with 24 months or longer exposure to ozanimod in phase III trials (289.3/100,000 person-years vs 298.2/100,000 person-years, respectively). Among patients with any ozanimod exposure in any RMS study, there were 11 nonmelanoma skin cancers, one melanoma, and 13 noncutaneous malignancies that were classified as treatment emergent.

Confirmed macular edema (ME) was seen in seven patients, including three in the ongoing open-label extension trial. “ME rates with ozanimod were 0.3% to 0.4%, and all confirmed cases had predisposing comorbid conditions,” wrote researchers.

Eight deaths occurred: three due to malignancies, one from pneumonia, two accidental, and two from causes that were most likely unrelated to treatment (pulmonary embolism and chronic kidney failure).

Treatment or RMS with ozanimod, as a S1P modulator, offers several advantages, and some disadvantages as well, Bowen told BreakingMED.

“The sphingosine-1-phosphate receptor (S1P) modulators have advantages of oral administration, once a day dosing, good efficacy data and few side effects that patients would notice. Some disadvantages include rare cases of certain infections including PML, cryptococcus and viruses in the herpes family. Macular edema may be seen with any of the S1P modulators. These drugs also can lead to a rebound of MS attacks if they are abruptly discontinued,” he noted. “Within the S1P modulators, ozanimod has advantages of not requiring heart rate monitoring during the first dose (fingolimod requires this). It does not require liver CYP2C9 enzyme genotyping prior to prescribing (siponimod requires this).”

Important considerations for clinicians include the potential of ozanimod to interact with other medications, he added.

“One disadvantage of the S1P modulators is theoretical interactions with other medications. These are warnings rather than contraindications. Strong CYP3A4 inducers might interact with siponimod or ponesimod. UGT1A1 inducers might interact with ponesimod. Strong CYP2C8 inhibitors or inducers, BCRP inhibitors, MAO inhibitors, adrenergic medications and serotonergic medications might interact with ozanimod. The article by Selmaj helps address some of these potential drug interactions with ozanimod,” noted Bowen.

“Serotonergic drugs were taken by 20.6% (n=573) of patients in the study and there were no episodes of serotonin syndrome. Likewise, 3 patients were treated with MAO inhibitors without complications. This gives us more confidence in prescribing ozanimod in the setting of these concomitant medications,” he told BreakingMED.

“Ozanimod is a good choice for patients preferring oral therapy, administered once a day, with few side effects that the patient would experience. For example, there is no flushing or gastrointestinal side effects. It is less optimal for patients with cardiac conduction diseases. Those with prior histories of uveitis or diabetes have an increased risk of macular edema, though this is not an absolute contraindication,” Bowen added.

Researchers noted that further long-term safety data will be available after analysis of results from DAYBREAK, their ongoing open-label extension study.

Limitations of the study include the lack of a control group and that patients were primarily White and of Eastern European descent.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The ozanimod RMS trials were sponsored by Celgene International II, and additional support was provided by Peloton Advantage LLC and Bristol Myers Squibb.

Selmaj reports consulting for Biogen, Celgene, Genzyme, Merck, Novartis, Ono Pharma, Roche, Synthon, and Teva.

Bowen has received support from and/or consulted or served on advisory committees for Abbie, Alkermes, Biogen IDEC, Bristol Meyers Squibb, EMD Serono, Genentech, Genzyme, Novartis, Roche, and Sanofi; and reported stock ownership with Amgen.

Cat ID: 130

Topic ID: 82,130,282,730,130,36,192,925