Friday, 19 February 2016

Ozanimod another S1P1

Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, Olson A, Frohna PA, Selmaj KW; RADIANCE Study Group. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.Lancet Neurol. 2016 Feb 12. pii: S1474-4422(16)00018-1.

BACKGROUND:Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients withmultiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis.
METHODS: RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18-55 years, had an Expanded Disability Status Scale (EDSS) score of 0-5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12-24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov, number NCT01628393. The 2-year phase 3 trial is ongoing.
FINDINGS: The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12-24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08-0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06-0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod.
INTERPRETATION: Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing.


So we have another S1P1 modulator that inhibits relapsing MS and phase III are on going. So another compound to compete against fingolimod. The side-effects associated with fingolimod is short term heart arthymia and this drug was not marked in this study. The drug blocked lesion formation and is now in phase III. 
So another placebo controlled study in RRMS? Surely show it is not inferior to fingolimod but 90 people on drug would cost a few million. But if we are to get new DMT surely we need to think of ways to not give trial participants nothing.

 Who will win out on the s1P1 wars that will loom. But by the time this compound gets to Market maybe fingolimod may be out of patent (planned for 2019 in USA unless they can extend this.. If the price drops the golden goose escapes.

Time will tell

CoI:None 

3 comments:

  1. It is saddening to hear that 88 people were on a placebo for a 'me too' MS drug at this time in history.

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    Replies
    1. You're right, I wonder how they were allowed to get away with this?

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    2. Spineless people on ethical committees :-)

      I suspect the argument would be made that the trial would have to be much bigger ?

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