Is Ozanimod a Safer S1P Receptor Modulator?

Is Ozanimod a Safer S1P Receptor Modulator?

SAN DIEGO — For the treatment of relapsing multiple sclerosis (MS), ozanimod may not convey the same health risks as fingolimod, its older counterpart in the sphingosine 1-phosphate (S1P) receptor modulating class of agents, a safety analysis of two phase 3 trials suggests.

Ozanimod is an oral, once-daily immunomodulatory that was recently found to be safe and effective in the phase 3 SUNBEAM and RADIANCE trials, which compared the drug to interferon β-1a.

Primary results of those trials were presented at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017.

Investigators from these studies detailed their safety findings here at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2018.

Bruce Cree, MD, PhD, clinical research director at the University of California MS Research Center, San Francisco, told Medscape Medical News that a goal in the development of ozanimod was to improve the safety profile of the S1P receptor–targeting agents. Its selective targeting of S1P-1 and S1P-5 and its short half-life could offer advantages in this regard.

“What sets ozanimod apart from fingolimod is its safety profile. It was found to have very few off-target effects,” Dr Cree said. “Some of the other therapies that are perhaps even more potent than ozanimod have longer-lasting pharmacodynamics and may therefore have additional off-target effects that we don’t want.”

For example, fingolimod causes a slowing of the heart rate so that the first dose requires observation, he noted. “Ozanimod has essentially no effect on heart rate with first dose,” he said. “We don’t know if the Food and Drug Administration  will require first-dose observation, but the hope is that they would not, and this would make the drug easier to use in the clinic.” 

Fingolimod can also cause liver function abnormalities that require monitoring, can cause macular edema, and increases the risk for infection, he added.

“Liver function toxicity was seen, but it was transient and there was no need for patients to discontinue treatment. It’s less likely you’ll have to take the patient off the drug, while this is not infrequent with fingolimod,” he said. “Ozanimod represents a safe and effective option as initial treatment.” 

SUNBEAM and RADIANCE

This studies compared the safety of ozanimod 1 mg or 0.5 mg daily (initiated with a 7-day dose escalation) vs once-weekly intramuscular interferon β-1a 30 µg. Altogether, the trials included 2666 patients who were treated for 1 year in SUNBEAM and 2 years in RADIANCE. The studies met their primary endpoint of reduction in annualized relapse rate.

Adverse events did not notably differ between the ozanimod and the interferon β-1a treatment groups.  

Table. Summary of Investigator-Reported Adverse Events Related to Treatment

Event	Interferon β-1a		Ozanimod 0.5 mg		Ozanimod 1.0 mg
	SB	RAD	SB	RAD	SB	RAD
Any AE (%)	75.5	83.0	57.2	74.3	59.8	74.7
Serious AE (%)	2.5	6.4	3.5	7.1	2.9	6.5
AE leading to drug discontinuation (%)	3.6	4.1	1.5	3.2	2.9	3.0
AE = adverse event; RAD = RADIANCE; SB = SUNBEAM.

 

The key points of the safety analysis were these:

• Most adverse events in ozanimod-treated patients were mild.

• The most common toxicity was nasopharyngitis.

• Incidence of adverse events was low and similar to that in patients treated with interferon β-1a.

• Cardiac safety was shown; first-dose monitoring demonstrated no second-degree or higher atrioventricular blocks.

• Elevations in liver enzymes were transient and generally resolved without treatment discontinuation.

• Infection rates were similar to those seen with interferon β-1a; serious infection rates were low, and no disseminated or serious opportunistic infections were observed.

In both studies, more interferon-treated than ozanimod-treated patients experienced treatment-emergent adverse events, and more patients in the interferon group discontinued study drug because of treatment-related adverse events, the researchers emphasized. There were no deaths related to treatment.

Cardiac Safety

In RADIANCE, the largest mean change in supine heart rate on day 1 (hours 1 to 6) for patients receiving ozanimod was –0.6 beats/min at hour 5. Four patients had heart rate less than 45 beats/min; these patients were asymptomatic, and the low heart rate resolved spontaneously by hour 7 or 8.

Bradycardia and dizziness were reported in one patient with a history of vegetative-vascular dystonia of hypotensive type. The patient continued treatment uninterrupted. No second-degree or higher atrioventricular blocks were reported.

In SUNBEAM, the largest mean change in supine heart rate on day 1 (hours 1 to 6) was –1.8 beats/min at hour 5. There were no second-degree or higher atrioventricular blocks.

Altogether, a minimum supine heart rate of 45 to 54 beats/min was observed in approximately 9% to 12% of ozanimod-treated patients and in about 5% of patients receiving interferon β-1a.

No serious opportunistic infections were reported in RADIANCE. In the ozanimod groups, 8 (4.2%) patients receiving ozanimod 1 mg and 4 patients receiving 0.5 mg (0.9%), compared with none in the interferon β-1a group, had a minimum absolute lymphocyte count less than 200 cells/µL; none of these patients developed serious infections.

In SUNBEAM, infection rates were similar to those with interferon β-1a (27% to 28%). Serious infections occurred in 1.1% of the ozanimod 1.0-mg group, 0.2% in the ozanimod 0.5-mg group, and 0.7% in the interferon β-1a group. No serious opportunistic infections occurred with ozanimod, and herpetic infections were more common with interferon β-1a.

Eleven (2.5%) patients, all treated with ozanimod 1 mg, had a minimum absolute lymphocyte count less than 200 cells/µL, but none was associated with serious infections.

In RADIANCE, alanine aminotransferase (ALT) elevations at least three times the upper limit of normal were reported in 6.7% of patients receiving ozanimod 1.0 mg and in 5.9% of those receiving 0.5 mg, compared with 3.9% of those receiving interferon β-1a. 

In SUNBEAM, this was seen in 4.3%, 1.8%, and 2.2% of patients, respectively. In both studies, ALT elevations were transient and generally resolved without discontinuation of treatment.

The most common adverse event in patients receiving ozanimod was nasopharyngitis, which was seen in approximately 7% to 10% of ozanimod-treated patients in SUNBEAM and in 13% to 16% in RADIANCE. These rates were similar to those seen in the interferon β-1a group: 8% and 11%, respectively.

No “Malignancy Signal”

Dr Cree pointed out that to date there has been “no malignancy signal” with ozanimod, another concern that emerged with fingolimod. However, he cautioned this could change in the postmarketing period. With fingolimod, malignancies became a concern before marketing and are noted in the prescribing information. While these were primarily cutaneous malignancies, they do include melanoma.

“We can say that several of the safety issues that have been troubling with fingolimod, at least in this stage of drug development, don’t seem to apply to ozanimod,” he said in an interview.  

The underlying mechanism for purported differences in safety may pertain to differences in the drugs’ selectivity for the S1P receptor subtypes; in particular, ozanimod does not target S1P3, but only S1P1 and S1P5.

“But the chemicals themselves are very different,” he added. “If you compare the structure of the drugs, you don’t see common similarities, even though they are considered to be in the same class because of their effects.

“We have assumed off-target effects of fingolimod were mediated by issues pertaining to subreceptor phenotypes, but it may be there are actually off-target effects because of its chemical structure.”

What Remains to Be Seen

Mark Freeman, MD, professor of neurology at the University of Ottawa and director of the MS Research Unit at Ottawa Hospital, Ontario, Canada, commented on the findings for Medscape Medical News, saying, “Nothing about ozanimod has jumped out as a negative [safety] signal.”

“Ozanimod and all new-generation drugs have less effects on the heart,” he noted. “For one thing, they are titrating upwards, and so you don’t see as much bradycardia as with fingolimod.”

Another difference is the shorter half-life as compared with fingolimod, which might affect infection risk, he said. Fingolimod must be phosphorylated to become activated, but this varies and some of the drug remains nonphosphorylated. “There’s some thought that the nonphosphorylated fingolimod that hangs around may be triggering some of the infection risk.”

It remains to be seen whether a shorter half-life could also have negative effects, he acknowledged. “With fingolimod, we wait 6 weeks for lymphocyte counts to go up and go down. With this drug, it’s almost immediate. Is that a good thing, or not?” he asked.

“They also need to look at what happens when you stop ozanimod,” he continued. “With fingolimod, there’s a big rebound risk, where you get an incredible resurgence of disease activity. It occurs within 2 to 3 months because of the long half-life. But with ozanimod, if there’s a rebound, is it going to be immediate? With fingolimod, we have time to transition people to another drug and we don’t have to deal with it. But if this happens within 5 days, it will be hard to get another drug in.”

“So, if it’s true that the nonphosphorylated portion of fingolimod is contributing to the infectious risk, we’re not going to see this with ozanimod. But the short half-life could be a mixed blessing,” Dr Freeman suggested.

The study was sponsored by Receptos. Dr Cree and Dr Freeman have disclosed no relevant financial relationships.

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2018. Abstract  P030. Presented February 1, 2018.

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