Recently I stumbled upon an article on ocrelizumab in a the German pharmacist's news (Deutsche Apotheker Zeitung). A couple of years ago I had been interested in this drug, as it had been tested in rheumatoid arthritis patients (Ocrelizumab – Zombie or Resurrected Drug?). Ocrelizumab is a second-generation humanized anti-CD20 antibody.
Stohl, W. and colleagues tested ocrelizub in this study: "Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial." Conclusions: "OCR 200 mg and 500 mg with MTX in MTX-naive patients with RA were effective in inhibiting joint damage progression and improving RA signs and symptoms. OCR 500 mg with MTX was associated with an increased rate of serious infections."
According to the German pharmacist's news the FDA granted ocrelizumab a breakthrough status after the studies OPERA I and II had been published. The OPERA studies looked at patients suffering from relapsing remitting multiple sclerosis. The rate of relapses could be reduced by 47%. The ORATORIO study looked at patients with primary progressive multiple sclerosis. In this study the risk for progression could be reduced by 25%. Breakthrough status means accelerating the process of getting to an approval. Pharmaceutical firms still have to present more details and studies after approval, but the Government Accountability Office sees infractions to this obligation. The FDA doesn't punish such offences.
I am concerned about the safety of ocrelizumab. In 2014 P. Emery and collegeagues published a paper on this issue: "Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program". They concluded: "In placebo-controlled clinical trials of RA [rheumatoid arthritis], OCR500+MTX [ocrelizumab 500mg + methotrexate] was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX."
If we look at the 2010 study by P. Emery and collegues we find additional information: "Serious Infections with Ocrelizumab in Rheumatoid Arthritis: Pooled Results from Double-Blind periods of the Ocrelizumab phase III RA program." In conclusion we find this sentence: "The same infection-related safety signal seen in the OCR high-dose has not been observed with rituximab."
Ocrelizumab has been abandoned in rheumatology. So it looks as if one looks for a new playgrund for the drug.
Sorensen, P.S. and M. Blinkenberg published: "The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects."They inform us about the dosages in a phase 2 trial: " Compared with placebo, two doses of ocrelizumab (600 and 2000 mg on days 1 and 15) ...". "Serious infections occurred at similar rates in ocrelizumab and placebo-treated patients, and no opportunistic infections were reported." Somehow this can't be the whole truth. Why should the rates of serious infections / oppotunistic infections differ gravely in the quoted study, when compared to results in rheumatology? Remember, only 200 mg were supposed to be safe. And now they test 2000 mg.
The FDA would be well advised not accelerate the process for approval.
While researching on ocrelizumab in multiple sclerosis I've found an article by B. Weinstock-Guttman: "An update on new and emerging therapies for relapsing-remitting multiple sclerosis." The paper has been published in 2013. And it mentioned alemtuzumab: "... a lower frequency of infusions (eg, annually, 3-5 daily infusions over a year for alemtuzumab) that may improve patient adherence and clinical outcomes."
Cooles, F.A.H. and colleagues presented a poster at the 2016 EULAR Annual Meeting in London: "Immune Reconstitution 20 years after Treatment with Alemtuzumab in a Rheumatoid Arthritis Cohort: Implications for Lymphocyte Depleting Therapies". Alemtuzumab is a humanized monoclonal IgG1Kappa antibody, which binds to CD52 on B- and T-lymphocytes. Alemtuzumab has been studied in patients with severe rheumatoid arthritis between 1991–94. "In this unique patient cohort, after 20 years the effects of alemtuzumab treatment persist." "As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long term drug safety and stages of immune recovery."
Alemtuzumab had been traded by Genzyme as MabCampath until August 2012. Then Genzyme took it of the market and reintroduced the drug as Lemtrada for the new indication multiple sclerosis; at the same time the price increased by more than 4000%. These proceedings have been criticed by the Drug Commission of the German Physicians (Arzneimittelkommission der deutschen Ärzteschaft (AkdÄ)) as indication hopping.
If we look at ocrelizumab and alemtuzumab in treating multiple sclerosis, I must say let's stay cautious in terms of "nil nocere", we shouldn't take unnecessary risks. But maybe I hear the grass grow.
Links:
German Pharmacist's News on ocrelizumab in multiple sclerosis - https://www.deutsche-apotheker-zeitung.de/news/artikel/2016/07/01/MS-ocrevus-neues-arzneimittel-bei-multipler-sklerose
Ocrelizumab – Zombie or Resurrected Drug? http://rheumatologe.blogspot.de/2012/08/ocrelizumab-zombie-or-resurrected-drug.html
http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html
http://rheumatologe.blogspot.de/2011/12/b-cell-depletion-and-other-b-cell.html?spref=tw
Study by W. Stohl, W. and colleagues - http://www.ncbi.nlm.nih.gov/pubmed/22307942
Emery, P, Rigby, W, Tak, PP, Dorner, T, Genovese, MC, Ferracioli, G, et al; Serious Infections with Ocrelizumab in Rheumatoid Arthritis: Pooled Results from Double-Blind periods of the Ocrelizumab phase III RA program. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :414 DOI: 10.1002/art.28183 http://www.blackwellpublishing.com/acrmeeting/abstract.asp?MeetingID=774&id=89066
Paper by P. Emery and colleagues publishe in 2014 - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911947/
Sorensen, P.S. and M. Blinkenberg - http://www.ncbi.nlm.nih.gov/pubmed/26788130
B. Weinstock-Guttman - http://www.ncbi.nlm.nih.gov/pubmed/24494635
Cooles, F.A.H. et al.: Alemtuzumab - DOI: 10.1136/annrheumdis-2016-eular.4019
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