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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I participated on a workshop concerning B-cell depletion and rheumatoid factor about 2 years ago. I had found out about problems with ocrelizumab prior to the meeting, in fact Roche stopped research on ocrelizumab (but only for the indication rheumatoid arthritis). I was quite surprised that none of the other specialists knew about this breaking news in rheumatology.
Afterwards I had been looking carefully into the publication of results in research of ocrelizumab.
This is what I’ve written post ACR meeting 2011: http://rheumatologe.blogspot.de/2011/12/b-cell-depletion-and-other-b-cell.html?spref=tw.
And this is what I’ve written after this year’s EULAR meeting in Berlin: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html.
So, summing up I thought that ocrelizumab had been buried.
And now I see the following article on ocrelizumab:
Stohl, W. and colleagues: 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.
http://www.ncbi.nlm.nih.gov/pubmed/22307942
This article means that ocrelizumab is trying to be rituximab’s successor. But is it a resurrection? Or will we see the coming of a zombie? It’s hard to decide right away. We have to look, if ocrelizumab at 200 mg is equal to rituximab, both in efficacy and adverse events.
I think we're going to have another interesting topic to discuss at the ACR 2012 meeting in Washington.
SBI-087 has been evaluated in a phase 2 study. IT’s called a SMIP and SMIP has been trade marked as SMIP™ and means mono-specific protein therapeutic. Wyeth also has another SMIP™ in the pipeline, TRU-015, of which I haven’t seen anything, yet. SBI-087 is a humanized SMIP™, which is directed at B cell and leads to a dose dependant B cell depletion. The drug is administered subcutaneously twice per day, evaluation has been done with groups having received one day of treatment, two days at different times and three days. The subcutaneous injections have been done “in combination with 40 mg oral prednisone or equivalent, acetaminophen, and an antihistamine prior to dosing and 20 mg oral prednisone or equivalent 4 hours post dose.” So; we’re already in the study presented by N. Damjanov and colleagues. ACR20 reached 70% in the three days treatment group. “The DAS28 mean changes from baseline at week 16 were -2.12 in the Day 1, 15, and Week 12 arm versus -1.52 in the placebo arm (p<0.05).” In adverse events there were leukopenia and others like headache, diarrhea, nausea, and increased ALT, but also pyrexia despite the premedication. The authors concluded for positive results.
[OP0024] SAFETY AND EFFICACY OF SBI-087 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
N. Damjanov1, M. Tlustochowicz2, J. Aelion3, A. Dimic4, M. Greenwald5, A. Diehl6, I. Bhattacharya7, S. Menon7, I. Gourley6. 1Belgrade University School of Medicine, Belgrade, Serbia; 2Wojskowy Instytut Medyczny, Warsaw, Poland; 3Arthritis Center, Jackson, United States; 4Institute for Treatment and Rehabilitation, Niska Banja, Serbia; 5Desert Medical Advances, Palm Desert; 6Pfizer Inc., Collegeville; 7Pfizer Inc., Cambridge, United States
Conclusions: SBI-087 administered subcutaneously was generally well tolerated. The 200 mg SBI-087 Day 1, 15, and Week 12 treatment arm achieved significant improvement in RA disease activity by week 16 compared to placebo.
It seems that B cell depletion will become easier in the future. On the other hand, if patients might suffer from immediate adverse events, you don’t want them to do so alone, so the advantage of a SC injections melts away.
30.11.2016:
Interestingly Adinsight informs that all phase 1 and 2 studies have been discontinued. B cell depletion hasn't become easier. We had seen ofatumumab, ocrelizumab, and veltuzumab being taken off the study in regard of rheumatoid arthritis earlier.
Links:
http://adisinsight.springer.com/drugs/800027994
http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html
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I have done some talks on B cell depletion and especially on rituximab, but I’ve never found an illustrative model to explain how B cell depletion works, so far.
Rituximab or an other monoclonal anti CD20 antibody binds to CD20, which is widely expressed on the surface of B cells. Already early pre-B cells carry CD20. All B cells do with the exception of plasma cells. And also stem cells and pro B cells don’t express CD20. Plasma cells produce antibodies. The exact mode of action of rituximab still is unclear.
Stem cell / pro B cell / pre B cell / immature B cell / mature B cell / activated B cell / memory cell / plasma cell
The marked cells carry CD20.
Imagine there’s a big company, stem cell and pro B cell represent the CEO, pre B to memory cells represent the research and development (R&D) department, plasma cells stand for production. Plasma cells still produce known antibodies. But there’s no development of new antibodies. That’s the reason why you have to get vaccinated [pneumococcal conjugate vaccine (PCV 7) (e.g.Prevena)] before receiving rituximab.
Rituximab
William Rigby and colleagues looked at patients with inadequate response to a biologic / rituximab, who then received a combination of Rituximab and another biologic DMARD. The study is open-label and combinations were heterogenuous, so results need to be treated with caution. Patients received 500 mg rituximab plus their current biologic (etanercept, adalimumab, infliximab, or abatacept) and non-biologic DMARD treatment at a stable dose. Proportion of development of serious adverse event within 24 weeks of receiving first course of rituximab has been selected as primary endpoint of the study. The safety profile was consistant with previously reported results for rituximab with methotrexate and rituximab with other nonbiologic DMARDs.
Will these results be stable over a longer period of time?
[TUE] 2196
Safety of Rituximab in Combination with Other Biologic Disease- Modifying Antirheumatic Drugs in Rheumatoid Arthritis: 48-Week Data From SUNDIAL.
William Rigby1, Philip J. Mease2, Ewa Olech3, Mark Ashby4 and Swati Tole4.
1Dartmouth Medical School, Lebanon, NH, 2Swedish Medical Center, Seattle, WA, 3Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Genentech, Inc., South San Francisco, CA
Conclusion: The overall safety profile of RTX used in combination with a biologic DMARD at 48 wks was consistent with that previously reported for RTX methotrexate and RTX nonbiologic DMARDs. Despite patterns consistent with clinical benefit, conclusions regarding efficacy results cannot be drawn due to the lack of a control group and differences in baseline characteristics compared with previous studies.
Ocrelizumab
Ocrelizumab didn’t show aclear advantage over rituximab and concerns about serious and opportunistic infection rates has led to the cessation of the programme for RA and SLE, though the patients were still followed (?).
[SUN] 873
The poster on Ocrelizumab had been withdrawn.
Ofatumumab
Ofatumumab is an anti-CD20 MAB, but nothing on ofatumumab at the ACR 2011. This seems strange as M. Østergaard and colleagues published a study in 2010: Arthritis Rheum 2010 Aug;62(8):2227-38. They looked at “Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study.” Conclusion: “Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.”
Epratuzumab
Epratuzumab is a humanized anti-CD22 drug, which has a more immunomodulatory effect and a combination of mild B-cell depletion. Target disease might be Sjoegren's syndrome.
No posters on epratuzumab in rheumatoid arthritis at the ACR 2011.
Veltuzumab
There’s another another B-cell depleting agent under development, called veltuzumab, a human anti-CD20 MAB, but nothing has been published at the ACR 2011 meeting.
Atacicept
Besides B-cell depletion alternative components of the B-cell pathway may be targeted: BLyS (B-lymphocyte stimulator) and APRIL (A PRoliferation Inducing Ligand) are such candidates. Atacicept inhibits BLyS and APRIL to bind to B-cells. Atacicept is a human recombinant fusion protein. There has been a study by R.F. van Vollenhoven and colleagues: Arthritis Rheum 2011 Jul;63(7):1782-92. The phase II, randomized, placebo-controlled trial of Atacicept has ben done in patients with rheumatoid arthritis and an inadequate response to methotrexate. Conclusion: “The primary end point (ACR20-CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.”
For B-cell depletion and other B-cell directed therapies in rheumatoid arthritis it seems we have to stick to rituximab, a well established therapy.
Though there might be no other CD-20 therapy on the horizon for rheumatoid arthritis, it may be that in about two years there’ll be a similar. Rituximab is cheaper than other biologic agents in Germany. Longer intervals are possible, but I haven’t found any data on how to predict prolonging intervals between twin infusions of rituximab without loosing efficacy. Interesting will also be combinations with other bisologics. How about combining rituximab with denosumab in our osteoporotic patients?
