The MODs are replicating, ozanimod is on the way

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Fingolimod was the first Sphingosine-1-phophate receptor to be approved, then there was Siponimod and we have a load more to arrive. Here is the data for ozanimod. The efficacy looads in the small ball part of that seen with cladribine and alemtuzumab. If is an S1P1 and S1P5 modulator and so like Siponimod. It does not seem to have the heart issues which are inpart caused by S1P3 which fingolimod also hits. We now have to wait to see when the regulators approve this and what the cost will be. More mods on the way. Will we forget about fingolimod before its patent runs out, clearing the way for a first line agent.

Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L; RADIANCE Trial Investigators. Lancet Neurol. 2019 Sep 3. pii: S1474-4422(19)30238-8.

BACKGROUND: Ozanimod is a sphingosine 1-phosphate receptor modulator, which selectively binds to sphingosine 1-phosphate receptor subtypes 1 and 5 with high affinity. In the RADIANCE phase 2 study in participants with relapsing multiple sclerosis, ozanimod was associated with better efficacy than placebo on MRI measures and was well tolerated. The RADIANCE phase 3 study aimed to confirm the safety and efficacy of ozanimod versus interferon beta-1a in individuals with relapsing multiple sclerosis

METHODS: We did a 24-month, multicentre, double-blind, double-dummy phase 3 trial in participants with relapsing multiple sclerosis at 147 medical centres and clinical practices in 21 countries. Participants were aged 18-55 years, had multiple sclerosis according to 2010 McDonald criteria, a relapsing clinical course, brain MRI lesions consistent with multiple sclerosis, an expanded disability status scale score of 0·0-5·0, and either at least one relapse within 12 months before screening or at least one relapse within 24 months before screening plus at least one gadolinium-enhancing lesion within the 12 months before randomisation. Participants were randomly assigned (1:1:1) via an interactive voice response system to daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment allocation. The primary endpoint was annualised relapse rate (ARR) over 24 months. The primary analysis was done in the intention-to-treat population of all participants who received study drug and safety was assessed in all randomly assigned participants who received study drug, grouped by highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, NCT02047734, and EudraCT, 2012-002714-40.

FINDINGS: Between Dec 27, 2013, and March 31, 2015, we screened 1695 participants, of which 375 did not meet inclusion criteria. 1320 participants were enrolled and randomly assigned to a group, of whom 1313 received study drug (433 assigned to ozanimod 1·0 mg, 439 assigned to ozanimod 0·5 mg, and 441 assigned to interferon beta-1a) and 1138 (86·7%) completed 24 months of treatment. Adjusted ARRs were 0·17 (95% CI 0·14-0·21) with ozanimod 1·0 mg, 0·22 (0·18-0·26) with ozanimod 0·5 mg, and 0·28 (0·23-0·32) with interferon beta-1a, with rate ratios versus interferon beta-1a of 0·62 (95% CI 0·51-0·77; p<0·0001) for ozanimod 1·0 mg and 0·79 (0·65 to 0·96; p=0·0167) for ozanimod 0·5 mg. The incidence of treatment-emergent adverse events was higher in the interferon beta-1a group (365 [83·0%] of 440 participants) than in the ozanimod 1·0 mg group (324 [74·7%] of 434) or the ozanimod 0·5 mg group (326 [74·3%] of 439). More participants in the interferon beta-1a group had treatment-emergent adverse events leading to treatment discontinuation than in the ozanimod groups. Incidences of infections and serious treatment-emergent adverse events were similar across treatment groups. No cases of ozanimod-related symptomatic reduction in heart rate and no second-degree or third-degree cases of atrioventricular block were reported.

INTERPRETATION: In this 24-month phase 3 study in participants with relapsing multiple sclerosis, ozanimod was well tolerated and associated with a significantly lower rate of clinical relapses than intramuscular interferon beta-1a. These findings show the potential of ozanimod as an effective oral therapy for individuals with relapsing multiple sclerosis.

Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Ding N, Cohen JA; SUNBEAM Study Investigators. Lancet Neurol. 2019 Sep 3. pii: S1474-4422(19)30239-X

BACKGROUND: Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis.

METHODS:SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18-55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0-5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014-002320-27.

FINDINGS: Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or interferon beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0·35 (0·28-0·44) for interferon beta-1a, 0·18 (95% CI 0·14-0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41-0·66] vs interferon beta-1a; p<0·0001), and 0·24 (0·19-0·31) for ozanimod 0·5 mg (RR 0·69 [0·55-0·86] vs interferon beta-1a; p=0·0013). Few ozanimod-treated participants discontinued treatment because of adverse events (13 [2·9%] who received ozanimod 1·0 mg; seven [1·5%] who received ozanimod 0·5 mg; and 16 [3·6%] who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported. The incidence of serious adverse events was low and similar across treatment groups (13 [2·9%] participants who received ozanimod 1·0 mg; 16 [3·5%] who received ozanimod 0·5 mg; and 11 [2·5%] who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.

INTERPRETATION:In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.

No doubt ProfG will have something to say

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  • I’m probably being dim and missing something but people would know if they were using an injection (interferon) or taking tablets (ozanimod). This isn’t blinded! Why wasn’t it run against fingolimod?? To prove safer and at least as effective.
    Yep, sounds like fingolimod days are numbered….

  • Wow! All the biggest hitters in the MS industry comparing ozanimod to CRAB drugs and using relapses as an endpoint. MS patients are in fact doomed.

    This is not furthering research or treatment of MS in the least. I sure hope they got paid a lot of money to live with themselves.

    How is their long term endpoints on disease progression, which is the only endpoint that matters?

    Why do approving bodies allow comparison of a new drug to a CRAB drug instead of the best drug out there? This is complete and utter insanity. I highly doubt this drug even outperforms fingolimod. A very sad state of affairs indeed in the innovation in treatment of MS.

    • Agree completely but this is what happens when drug development is squarely in the hands of big pharma. This drug isn’t about offering new and innovative treatments. It’s about developing a drug that will meet its primary endpoint(s) and be patentable ($$$$).

      How many S1P modulators do we need? Similarly, how many anti- CD20 treatments do we need? This is not moving MS research forward.

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