The MOD-Wars are coming

Olsson T, Boster A, Fernández O, Freedman MS, Pozzilli C, Bach D, Berkani O, Mueller MS, Sidorenko T, Radue EW, Melanson M. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014 Mar 21. doi: 10.1136/jnnp-2013-307282. [Epub ahead of print]

OBJECTIVE: This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS).
METHODS: 464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated.
RESULTS: The mean cumulative number of new T1 Gd+ lesions at weeks 12-24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.
CONCLUSIONS: Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RMMS is under consideration.

You already have FingoliMOD and SiphoniMOD, which are spinogosine-1-phosphate modulators, this is being developed by the same company, now you have PonesiMOD and is being developed here. So we may have another cartel member..sorry competitor and maybe you will get some price competition :-). There are plenty of other MODs in the wings. 

Likewise we have a placebo control…..Is this ethical? You have drugs that clearly work in RRMS should people be getting nothing when “Time is Brain”

If you have a sphinogosine-1-phosphate modulator it would be amazingly unusual if it is not going to work. Surely in this day and age the ethical approach should be a non-inferiority trial against an active comparator like Gilenya. 

The MRHA do not give a stuff about the cost of drugs,so maybe it time that Ethical Committees should not give a stuff about commercial sensitivities and insist on an active comparator

Is this marketing suicide if it worse? 

Is it right that companies shift their trials to places were drugs are not readily available so they can push people into volunteering from placebo-controlled trials. A 50-75% chance of something verses 100% chance of nothing if they don’t do it. 

Is this a morally corrupt stance by pharma to do this or should they be congratulated for giving some people access to a drug?

Alemtuzumab did not go against placebo and look at the problems it is having. Some people don’t think it works, but then again there are people who think the Earth is Flat. 

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  • A non-inferiority trial against an active comparator, say Gilenya. This raises the question: are all the Mod drugs similar in efficacy in that they block the same S1P1 receptor? Maybe there will be slight non-significant differences. This seems analogous to the inteferons: avonex, rebif, betaseron; different routes of administration, dosing schedule but basically the same molecule.

  • There may be subtle differences but if it is deemed non-inferior e.g. say 10% less than the licenced drug you accept that is working, so as you say the differences are non significant and so don't need to have a placebo arm whose inferiority can be calculated from published data with the active comparator. The drug may be superior in other ways like the number of times you have to administer it better side effect profile, etc. but this means no one is on placebo getting nothing

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