Tuesday, 4 December 2012

ECTRIMS 2012: rituximab and ocrelizumab safety

#MSBlog: Anti-CD20 or anti-B cell therapies look relatively safe in MS! Let's keep our fingers crossed.

"In response to a comment regarding the safety of rituximab and ocrelizumab in MS. This poster was presented at ECTRIMS. This is very reassuring in that the anti-CD20 look as if they will be in the upper zone of efficacy and if they prove to be safe they will steal all the limelight."

Kappos et al. Risk of infections and malignancies after treatment with anti-CD20 monoclonal antibodies: ocrelizumab and rituximab in rheumatoid arthritis and multiple sclerosis. ECTRIMS 2012.

Background: Ocrelizumab (OCR) and rituximab (RTX) are CD20 targeting B cell depleting monoclonal antibodies. Safety data from their use in MS and rheumatoid arthritis (RA) may inform about expected risks in MS studies. 


Methods: Data from all available OCR (RA n=2820; MS n=220), RTX studies (RA n=3914; MS n=569) and post-approval data (RTX RA only; exposure n>188 000) were reviewed for rates of infection and serious infection (SI), including progressive multifocal leucoencephalopathy (PML) and incidence of malignancies. 

Results

RTX RA: In the long-term safety extension of the Phase 3 studies (n=3194; <=9.5y follow-up), AE and SAE rates for RTX were comparable vs pooled placebo (PBO) arms from those double-blind Phase 3 studies. SI event (SIE) rates for RTX were comparable vs PBO (all-exposure RTX: 3.94/100 patient-treated years (PTY) [95% CI 3.60–4.31] vs 3.79/100 PTY [2.80–5.13]), and stable over time and multiple treatment courses up to 9.5y. Serious opportunistic infections (OIs) were rare (all-exposure RTX 0.06 events/100 PTY; PBO 0.09 events/100 PTY). There was no increased risk of malignancy with RTX (all-exposure RTX 0.99/100 PTY [95% CI 0.79–1.23] vs 1.05/100 PTY [1.01–1.09] for adult RA patients). Risk of PML with RTX was rare with 6 confirmed cases in >188 000 RA pts. 

OCR RA: In a pooled safety analysis of the double-blind PBO-controlled phases of all pivotal Phase 3 OCR studies, SIE rates were comparable between low-dose (200mg x2 or 400mg x1) OCR and PBO. High-dose OCR (500mg x2) was associated with higher SIE rates vs PBO, mainly due to Asia/Pacific data where both dose groups had increased SIE rates. OIs were more frequent with OCR vs PBO irrespective of dose (9 vs 1 event). SIE and OI resolved with appropriate therapy. No PML was reported. 

RTX RRMS: SIE rates were similar for RTX (2.9%) and PBO (5.7%) in the phase 2 HERMES study; no PML was reported. OCR RRMS: Incidence of infections (serious and non-serious) was similar for both doses of OCR vs PBO (SIEs 0% vs 1.9% during week 0–24, respectively) and did not increase over time with continued OCR; no PML or other OIs were reported. 

Conclusions: Incidence of SIEs and OIs with RTX and OCR treatment were generally low. No PML has been reported with OCR. These data inform the anticipated safety of OCR in ongoing phase 3 MS trials where a lower risk of SIEs and/or OIs may be expected owing to disease- (pathophysiology, co-medication, age) and trial design-inherent (dose, region) factors.

CoI: multiple

2 comments:

  1. What about the posted comments of some neurologists called 'the shameful story of rituximab'- I just googled it. Rituximab's patent is due to expire in 2015, and they suggest this is one of the reasons ocrelizumab has been developed although it is not as safe as rituximab and one patient died of a systemic inflammatory syndrome in phase 2 trials. This isn't mentioned above- is it selective reporting by the drug company?

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    Replies
    1. Possibly; there is only so much you can say in an abstract. The deaths are listed in the poster:

      http://www.posters2view.com/ectrims2012/view.php?nu=848

      and more data is presented in their other poster.

      http://www.posters2view.com/ectrims2012/view.php?nu=283

      There are also well defined scientific reasons for taking ocrelizumab forward in MS, rather than rituximab. I am sure these and business factors helped Roche decide. Who would spend over half a billion dollars developing a drug that is coming off patent? This is why we need another system in place to incentivise the repurposing of off-patent drugs for MS.

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