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S1P receptor modulators a ‘go-to’ for MS treatment
The management of multiple sclerosis has improved considerably over the past decade with broadening of the therapeutic armamentarium including the introduction of oral disease modifying therapies.
Fingolimod (Gilenya, Novartis) was the first FDA approved oral therapy for relapsing forms of MS in 2010. This paved the way for other oral drugs to be approved for MS, including siponimod (Mayzent, Novartis). Fingolimod and siponimod are sphingosine 1-phosphate (S1P) receptor modulators and are thought to block trafficking of lymphocytes by retaining them in the lymph nodes thereby reducing entry of self-reactive lymphocytes into the central nervous system.
“Currently, S1P receptor modulators are one of the oral go-to’s for MS treatment,” Thomas Leist, MD, PhD, director of the Comprehensive MS Center at Jefferson, told Healio. “Trials with these agents have shown that an oral medication can have an effect that is superior to that of the prior first line medications such as interferons-beta and glatiramer acetate.” Second generation S1P modulators including siponimod, ozanimod and ponesimod have greater receptor subtype specificity and have been studied with titration schemes at therapy start that may make first dose observation necessary only in select patients, according to Leist.
Safety, efficacy
The approval of fingolimod was based on three randomized, double-blind phase 3 trials, FREEDOMS I and II and TRANSFORMS. These trials indicated that fingolimod improved the relapse rate, the risk for disability progression and outcomes on MRI among patients with MS, compared with placebo.
“While fingolimod demonstrated positive outcomes for efficacy, it carries a number of warnings and precautions,” Kathleen Costello, MS, CRNP, MSCN, associate vice president of health care access at the National MS Society, told Healio.
For instance, fingolimod may increase the risk for bradyarrythmias, atrioventricular block, prolonged QTc interval, infections, macular edema, liver injury, posterior reversible encephalopathy syndrome, respiratory symptoms, hypertension and malignancies, particularly of the skin, according to Costello. Additionally, common side effects include headache, liver transaminase elevation, diarrhea, couch, influenza, sinusitis, back pain, abdominal pain and extremity pain, she said.
During the first dose of fingolimod, patients must be monitored for bradycardia for at least 6 hours, Costello advised.
If patients discontinue fingolimod, there is an increased risk for disability and tumefactive MS, so they should be monitored closely, she said.
Siponimod received approval for the treatment of patients with clinically isolated syndromes, relapsing remitting MS and active secondary progressive MS based on the EXPAND phase 3 trial that demonstrated a reduction in the risk for disability progression among patients with secondary progressive MS. Siponimod has a similar safety profile to fingolimod, according to Costello. Headache, increased blood pressure and increased liver transaminase levels are common adverse effects, she said.
“Concomitant use of siponimod and certain types of drugs, including CYP2C9 inhibitors and inducers and CYP3A4 inhibitors and inducers, is not recommended,” Costello said.
It is necessary to test for genetic markers before the first dose because siponimod should not be used with the CYP2C9*3/*3 genotype and dosing should be altered with other specific genotypes, she noted. Additionally, patients with a heart rate less than 55 beats per minute, first- or second-degree heart block or a history of a heart attack or heart failure should be monitored during the first dose, she said. Siponimod has a half-life of about 30 hours making retitration necessary if a patient misses greater than four consecutive days of treatment, Leist said.
S1P modulators in the pipeline
The next S1P modulator that will probably be approved is ozanimod, Leist said. The approval will most likely occur around the end of March 2020, he noted.
“This agent has been studied in phase 3 trials against the interferon beta 1-a (Avonex, Biogen) and showed efficacy in terms of relapse rate reductions,” he said.
There are also intriguing data regarding the potential effects of ozanimod on gray matter atrophy and neurofilament levels, he said.
“The data on gray matter and the neurofilament light go beyond the primary efficacy claims of the agent. It remains to be seen whether the FDA will allow such data into the prescribing information,” Leist said.
In the trials an initial dose titration was used. It is not yet known for which patients a first dose observation will be recommended, according to Leist.
Ponesimod is the third S1P receptor agonist for which phase 3 data are available In the Optimum study, ponesimod was compared to dimethyl fumarate and demonstrated significant decreases in relapse rate, he said.
The secondary efficacy outcome in the Optimum study was fatigue. Fatigue was reduced in the ponesimod arm compared to controls on tecfidera according to Leist.
“This is the first time in a registration/efficacy phase study that we see a patient-reported outcome as a key secondary efficacy outcome,” he said. “It will be very interesting to see how the FDA will handle a patient-reported outcome as a key secondary efficacy measure when determining clinical indication of the product.”
Unanswered questions
Although the S1P receptor modulators have demonstrated efficacy for the treatment of relapsing forms of MS, there are risks associated with the treatment, Costello said.
“One question is: in practice, will increased selectivity of the S1P receptor modulators significantly reduce treatment emergent risks associated with these medications?” she noted.
It also needs to be determined whether there is actually a meaningful difference in terms of the biological effect between fingolimod and these newer, more selective S1P inhibitors, according to Leist.
“This last question is important to the extent that generic versions of fingolimod will become available whether lack of a first dose observation suffices to choose over one of the newer, more selective S1Ps in view of likely easier availability of the generic version,” he said.
More research in this space is warranted because the mechanism of action of the S1P receptor modulators has not been fully elucidated, Costello said.
Treatment for secondary progressive MS is an area that remains underserved, Leist said.
Costello agreed, stating that, “additional research in progressive forms of MS is needed as this is an unmet need for those who do not have ‘active’ secondary progressive MS and those with primary progressive MS.”
References
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- Kappos L, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0909494.
- Novartis. Novartis receives FDA approval for Mayzent (siponimod), the first oral drug to treat secondary progressive MS with active disease. Available at: https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-mayzent-siponimod-first-oral-drug-treat-secondary-progressive-ms-active-disease. Accessed on February 5, 2020.
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