Monday, June 17, 2013

Mavrilimumab at the EULAR 2013 Meeting

There have been two studies on mavrilimumab (a human IgG4 MAB that targets GM-CSFRα) at the EULAR 2013 Meeting in Madrid.

M. Bombardieri and colleagues published a study on ... rodents, better "human RA synovial tissue engrafted onto SCID / Beige mice" [OP0303]: "Mavrilimumab reduces pro-inflammatory cytokines and cd68 positive macrophages in synovial explants from rheumatoid arthritis subjects engrafted into scid/beige mice". Results showe also: "Mavrilimumab significantly inhibited IL-6, IL-1 and CCL2 in the explant tissue. The level of cytokine suppression was equivalent to that observed with infliximab." The conclusion is of course that mavirililumab inhibits human proinflammatory cytokine signals. The study would have been more appropriate prior to the ongoing studies as "mavrilimumab does not cross-react with rodent GM-CSFRα we are unable to evaluate it in classical animal models of arthritis". But the study might be also important for MedImmune to keep the component going.

G. Burmester, T. Takeuchi and colleagues looked at [FRI0232]: "Consistent efficacy and safety outcomes between European and Japanese subjects with rheumatoid arthritis following treatment with mavrilimumab in the phase 2 - EARTH study." In "results" the authors state that "response to mavrilimumab was generally similar in EU and JA subjects." The primary endpoint had been defined as a DAS28-CRP reduction of ≥1.2. And this endpoint was met "by 54.2% of mavrilimumab subjects (EU 55.1% and JA 50.0%) vs 32.6% PBO subjects (p=<.001; EU 34.7; p=.005 and JA 23.5; p=.081)". I see a clear difference at the primary endpoint between European and Japanese subjects. Most people will think of different genetic predispositions due to the racial differences. I think more of differences in applying the inclusion criteria to patients to get into the study between the teams in Japan and Europe. Maybe I'm speculating too much, but this would have consequences, IF the drug comes out and will be used under real life conditions. The authors concluded: "Mavrilimumab showed rapid (after 1 dose and within 2 wks) and significant clinical effect vs PBO, especially in the 100 mg dose cohort. DAS28 and HAQ-DI responses were maintained for 12 wks after cessation of mavrilimumab 100 mg." And of course they think that the results support further clinical development of mavrilimumab.

The "Phase 2b Study to Evaluate the Efficacy and Safety of Mavrilimumab in Subjects With Moderate-to-Severe Rheumatoid Arthritis" has an estimated end of study in April 2014. So preliminaries could be expected at the EULAR 2014 as earliest date, probably at the ACR 2014.

Would I stop the further development of mavrilimumab? No. Am I confident, that we'll get a mavrilimumab on the market? No. I think mavrilimumab needs more time. I would be happy to be wrong with my scepticism.

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