Thursday, December 8, 2016

New Monoclonal Antibodies in Rheumatoid Arthritis



I’ve selected a few MABs, which are possible candidates for the treatment of rheumatoid arthritis with a few additions, which could be more useful in psoriatic arthritis. Even if research has been stopped for some, it might not be that the case is closed permanently. Pharmaceutical firm look at the MABs from an investor’s point of view that means research will be directed at the most promising MAB first.

Afasevikumab
Afasevikumab is a human monoclonal IgG1κ antibody targeting IL-17A and IL-17F. There had been a phase 1 trial in “autoimmune disorder”, but this research has been stopped. Nothing on PubMed.
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Bimekizumab (UCB4940)
Bimekizumab (UCB4940) is a monoclonal antibody targeting IL-17A and IL-17F. S. Glatt and colleagues presented a study at the EULAR 2016 meeting in London. In this proof-of-concept-study bimekizumab demonstrated rapid onset and sustained efficacy on disease activity both in skin and joints. AdisInsight reports phase II studies in ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and rheumatoid arthritis as well as ulcerative colitis.
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Briakinumab
Briakinumab (ABT-874) is a human monoclonal antibody that targets IL-12 and IL-23. Last entry on the drug on this blog had been after the 2012 ACR Annual Meeting, where nothing new had emerged. Further drug development for psoriasis had been stopped in 2011.  There is one phase 2b study however on the possible use of briakinumab in Crohn’s disease.
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Brodalumab
Brodalumab is a human monoclonal antibody targeting the IL-17 receptor and inhibits the binding of several types of IL-17 to the receptor. The Dermatologic and Ophthalmic Drugs Advisory Committee to the FDA has voted for the approval of brodalumab for adult patients with moderate-to-severe plaque psoriasis (July 2016) despite safety concerns (suicides). I have already mentioned the problem in a blogpost on Apremilast. Nothing on arthritis studies at both the 2016 EULAR and ACR Annual Meetings.
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Clazakizumab (ALD518)
Clazakizumab (formerly ALD518) is a humanized monoclonal antibody against IL-6. I had written about Clazakizumab after the EULAR 2014 Annual Meeting in Paris. I haven’t seen any new study at both the 2016 EULAR and ACR Annual Meetings.  
There had been a study in 2015 by M.E. Weinblatt and colleagues that showed treatment with clazakizumab in combination with methotrexate or clazakizumab monotherapy in patients with rheumatoid arthritis was well tolerated, and patients achieved significant improvements in disease activity with higher rates of remission.
P.J. Mease and colleagues published a study on clazakizumab in patients with psoriatic arthritis. They concluded: “This is the first clinical trial of an IL-6-targeted therapy in PsA. Clazakizumab may be an effective treatment option for musculoskeletal aspects of PsA, but because of the lack of a dose response in this study, further studies are required to confirm the appropriate dose.” The study doesn’t make me as enthusiastic as the authors. Maybe TNF-alpha is a much better target in psoriatc arthritis that IL-6.
In May 2016 “Alder BioPharmaceuticals has licensed exclusive worldwide rights to its Phase II inflammation candidate clazakizumab”.
Summing it up, clazakizumab might be a candidate, but approval as a drug is still a far goal.
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Clenoliximab
Clenoliximab is a monoclonal antibody against CD4, which has been investigated for the treatment of rheumatoid arthritis. There had been a study by T.W. Hepburn in 2003 with the conclusion: “Decrease in the density of CD4 on the T-lymphocyte surface is caused by antibody-mediated stripping.” As no other study has been published afterwards, we may well assume, that clenoliximab is history in the treatment of rheumatoid arthritis.
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Fezakinumab
Fezakinumab is a human monoclonal antibody targeting IL-22.  Adinsight reports discontinuation of studies in psoriasis in 2011. I haven’t seen any new study at both the 2016 EULAR and ACR Annual Meetings. So I guess, we won’t see more of fezakinumab in rheumatology.
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Fletikumab
Fletikumab is a monoclonal antibody targetting IL-20 for the treatment of rheumatoid arthritis. Careful, it’s IL-20 and not CD20. As IL-20 plays a role in keratinocytes during inflammation, one should think more of a possible usefulness in treating psoriatic arthritis, or even more in placque psoriasis, than rheumatoid arthritis. Nevertheless there had been phase 2 studies in rheumatoid arthritis patients, which had been discontinued in September 2014. There haven’t been any new studies at both the 2016 EULAR and ACR Annual Meetings. Dead end?
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Ixekizumab
Ixekizumab is a humanized monoclonal antibody, which targets IL-17A and is also known as LY2439821. I’ve written already about ixekizumab several times, especially after 2013 EULAR Annual Meeting in Paris. P.J. Mease and colleagues presented a study at the 2016 EULAR Annual Meeting (SPIRIT-P1). They looked at 304 patients with psoriatic arthritis. The authors concluded: “IXE [Ixekizumab] demonstrated clinically significant improvement in signs and symptoms of PsA including arthritis, dactylitis and enthesitis as well as skin manifestations across treatment groups in the EP [Extension Period].” More studies were presented, like effect on work productivity, quality of life and so on. There have been even more studies at the 2016 ACR Annual Meeting. FDA and EMA approved Taltz (ixekizumab) to treat adults with moderate-to-severe plaque psoriasis. This and the commitment to studies on psoriatic arthritis will most probably lead to the approval of Taltz for rheumatologic indications in the future.
Links:
DOI: 10.1136/annrheumdis-2016-eular.1172

Lulizumab pegol (BMS-931699)
Lulizumab pegol is a monoclonal antibody, which targets CD28. Maybe you remember another MAB targeting CD28 -: TGN1412, which caused multiple organ failure. “CD28 has also been found to stimulate eosinophil granulocytes where its ligation with anti-CD28 leads to the release of IL-2, IL-4, IL-13 and IFN-γ.” But it seems that lulizumab is past this point of concern. At the moment phase 2 studies in patients with Sjogren’s syndrome are under way. A study in systemic lupus erythematodes is still recruiting patients. There haven’t been any studies presented at both the 2016 EULAR and ACR Annual Meetings.
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Mavrilimumab
Mavrilimumab is a human monoclonal antibody for treatment of rheumatoid arthritis, which targets human granulocyte macrophage colony-stimulating factor receptor (GM-CSF-R). I’ve followed the development of mavrilimumab closely since 2012 (please look at my blog).
G.R. Burmester and colleagues presented a study at the 2016 ACR Annual Meeting [Abstract 1616]: “Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor-α Monoclonal Antibody: Long-Term Safety and Efficacy for up to 158 Weeks of Treatment in Patients with Rheumatoid Arthritis”. Data comes from an open label extention study. The authors conclude: “[…] Mavrilimumab 100 mg eow is suboptimal compared with 150 mg eow in DMARD-IR pts; however, efficacy results remain comparable with previous studies, validating the use of mavrilimumab to target GM–CSFR-α.” So I guess it doesn’t come as a great surprise that there still isn’t any move towards approval by FDA or EMA. And let me add – where is data on radiographic progression?
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Ocrelizumab  
Ocrelizumab is a humanized anti-CD20 monoclonal antibody that targets mature B lymphocytes. But ocrelizumab has been abandoned in rheumatology (RA and SLE) in 2010 because of excess deaths due to opportunistic infections. But now FDA granted a breakthrough status for ocrelizumab in multiple sclerosis. The FDA would be well advised not to accelerate the process for approval. In rheumatology only 200 mg were supposed to be safe. And now they test 2000 mg. The FDA will come to a decision by the end of 2016.
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Ofatumumab
Ofatumumab is a human monoclonal antibody which targets the CD20. I had written about ofatumumab just before the 2013 EULAR Annual Meeting.
I had hoped that the EULAR 2013 meeting would bring more information than a phase 1/2 study, but it didn’t. There haven’t been any new studies at both the 2016 EULAR and ACR Annual Meetings. Ofatuzumab is available as Arzerra (sounds like a Basque word to me) in the indication chronic lymphatic leukemia.
Links:

Olokizumab
Olokizumab is a humanized monoclonal antibody that targets IL-6. I had written on olokizumab earlier this year. MC Genovese and colleagues published at both the 2016 EULAR and ACR annual meetings. No earth-shattering break through data, though.
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Pateclizumab
Pateclizumab is a humanized monoclonal antibody that binds to lymphotoxin alpha, which is also known as Tumor necrosis factor-beta (TNF-β). I’ve written about pateclizumab right after the 2013 EULAR Annual Meeting: “I don't think that pateclizumab will make it to the market as the demand for modest improvement isn't too big with better alternative options already in use. I'm a bit disappointed as two years ago [2011] I thought targeting lymphotoxin-αlpha could be an interesting approach. I guess we'll have to wait if pateclizumab is abandoned silently.” There haven’t been any studies presented at both the 2016 EULAR and ACR Annual Meetings. I’ve lately written on Google+: “The story of pateclizumab ends here. A dead end.
Links:

Perakizumab
Perakizumab is a humanized monoclonal antibody targets IL-17A. Adisinsight tells us, that a phase 1 study for psoriatic arthritis has been discontinued in July 2012. A search in Pubmed didn’t yield any study paper on perakizumab. My guess -: it’s a dead end.
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Placulumab (CEP-37247)
Placulumab is a human monoclonal antibody that targets TNF alpha. Further development of placulumab has been discontinued in 2012. There had been an abstryact at the 2013 ACR Annual Meeting by Matthew M. Seavey and colleagues [# 2316]: “Anti-Human TNF-Alpha Domain Antibody Construct, CEP-37247/Placulumab, is as Efficacious as Other Leading TNF-Alpha-Blockade Therapies in a Humanized Mouse Model of Rheumatoid Arthritis”.
So why stop it? There are already five TNF alpha inhibitors on the market. But as for the advent of more and more biosimilars, new originator drugs could find a niche in the market. Too bad, but that’s the way it is.
Links:

Risankizumab (BI-655066)
Risankizumab is a humanized monoclonal antibody that targets IL-23A. Only two weeks ago an extension phase 2 study for psoriatic arthritis has been initiated. I had written on risankizumab after the 2015 ACR Annual Meeting. I had ended then: “So, we have to wait for Boehringer to sponsor a proper study on psoriatic arthritis.” But now Abbvie is in charge (AdisInsight). Nothing on arthritis studies at both the 2016 EULAR and ACR Annual Meetings. My guess is, that Abbvie / Boehringer will first try to get an approval for psoriasis.
Links:

Ruplizumab (BG9588)
I had a first glimpse of ruplizumab recently. Ruplizumab is a humanized monoclonal antibody that targets CD40 ligand. AdisInsight lists as most recent event: “A study has been added to the adverse events and Transplant Rejection therapeutic trials sections” for August 2001. There had been a safety signal for thromboembolism, so all studies of had been stopped. Another dead end.
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Sapelizumab
Sapelizumab is a humanized monoclonal antibody that targets IL-6 receptor. ImMunoGeneTics (IMGT) lists a phase 3 study for Neuromyelitis optica. There haven’t been any studies presented at both the 2016 EULAR and ACR Annual Meetings. If sapelizumab would be a follow-up drug to tocilizumab for Chugai, they should have started already phase 2 studies by now. So my guess is, we won’t see sapelizumab in rheumatology.
Links:

Sarilumab
Sarilumab is a human monoclonal antibody that targets IL-6 receptor. My first blogpost is from 2011. I’ve looked at sarilumab in 22 blogposts. In the blogpost of 2015 I asked for data on radiographic progression. There had been at the 2016 EULAR Annual Meeting by D. van der Heijde and  colleagues [SAT0058] to address this topic: “Consistency of Radiographic Responses with Sarilumab plus Methotrexate across Subpopulations of Patients with Rheumatoid ArthritisiIn a Phase 3 Study“. Conclusions:” Sarilumab generally inhibited radiographic progression to a similar extent across a wide spectrum of subgroups. Nonetheless, the treatment effect appeared to be greater in subgroups with poor prognostic markers such as high levels of CRP and more structural damage at baseline, as well as in nonsmokers and patients with low BMI.” Another study [SAT0160] looked at clinical and radiographic outcomes after 2 years. At the 2016 ACR Annual Meeting D. van der Heijde and colleagues presented the following study [#1633]: “Clinical and Radiographic Outcomes after 3 Years of Sarilumab in Patients with Rheumatoid Arthritis“.Conclusions: “Active treatment with sarilumab 200 mg q2w resulted in durable clinical response and stabilization of radiographic progression at 3 years irrespective of prior treatment, though the initial sarilumab 200 mg group showed the most favorable outcomes. Adverse events were consistent with the anticipated effects of IL-6 inhibition and the known safety profile of sarilumab”.
However, Sanofi received a formal letter by the end of October tthis year from the FDA saying it would not be approving the drug because of “certain deficiencies identified during a routine good manufacturing practice inspection of the Sanofi Le Trait facility where sarilumab is filled and finished.” Approval process by EMA has started in August 2016, when Sanofi submitted the necessary documents.
Links:
DOI: 10.1136/annrheumdis-2016-eular.4363
DOI: 10.1136/annrheumdis-2016-eular.4389
http://acrabstracts.org/abstract/clinical-and-radiographic-outcomesafter-
3-years-of-sarilumab-in-patients-with-rheumatoid-arthritis  

Sirukumab (CNTO-136)
Sirukumab (CNTO-136) is a human monoclonal antibody that targets IL-6. I’ve been following the development of sirukumab since the 2012 EULAR Annual Meeting in Berlin. In 2015 after the ACR Annual Meeting I asked myself, why we’d need another anti-IL-6-MAB and why Janssen isn’t pushing to get to the market. GlaxoSmithKline announced the regulatory submission to EMA seeking approval of sirukumab for the treatment of adult patients with rheumatoid arthritis in early September 2016. Janssen Biotech announced seeking approval of sirukumab for the treatment of adult patients with moderately to severely active rheumatoid arthritis to the FDA in September 2016. There have been 11 abstracts on sirukuman at the 2016 ACR Annual Meeting. G. Karpouzas and colleagues presented [#2650]: “Prediction of Inhibition of Radiographic Progression By Sirukumab, an Anti–IL-6 Cytokine Monoclonal Antibody, in Patients with Active Rheumatoid Arthritis Despite Disease-Modifying Anti-Rheumatic Drug Treatment: Results of a Global, Phase 3 Trial”. This phase 3 study showed a significant higher rate of radiographic non-progression with sirukumab compared to placebo.
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Tildrakizumab
Tildrakizumab is a humanized monoclonal antibody that targets IL-23. Tildrakizumab demonstrated positive results in phase 3 clinical trials for the treatment of moderate-to-severe plaque psoriasis. There haven’t been any studies presented at both the 2016 EULAR and ACR Annual Meetings. But that doesn’t mean that there won’t be any in the future.
Links:

Toralizumab (IDEC 131)
Toralizumab is a humanized monoclonal antibody that targets CD40 ligand. Possible indications include rheumatoid arthritis. As with ruplizumab I had already looked for information on this MAB. As there had been a safety signal for thromboembolism, all studies of toralizumab had been stopped. AdisInsight lists a move by IDEC Pharmaceutical towards the FDA to remove the clinical hold status on toralizumab in April 2003. Last entry is in August 2004 for a phase 1 study in Japan. We most probably won’t hear anything on this MAB in the future.
Links:

Tregalizumab (BT-061)
Tregalizumab is a humanised monoclonal antibody that targets CD4. In a phase 2b study (TREAT 2b) in patients with moderate to severe rheumatoid arthritis tregalizumab did not meet its primary endpoint. I had become interested in Tregalizumab at the 2013 ACR Annual Meeting in San Diego; “the abstract [#1412 – 2015 ACR] informs us of very early data, so I think we have to wait for more, stressable data”. At the 2015 ACR Annual Meeting Ronald F. van Vollenhoven and colleagues presented a phase 2b study [#972], which concluded: “No tested doses of tregalizumab demonstrated significant efficacy improving signs and symptoms of active RA based on ACR20 responses at wk 12 and 24 despite dose dependent down-modulation of CD4 expression.” Hence, there haven’t been any new studies at both the 2016 EULAR and ACR Annual Meetings.
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Vobarilizumab
Vobarilizumab is a humanized monoclonal antibody that targets IL-6 receptor. Only a month ago I’ve written about Vobarilizumab as one of my readers brought the MAB to my knowledge. Please refer for the discussion on studies to my blogpost “The Mystery of Vobarilizumab”. Fierce BioTech reports: “While the ACR data suggest vobarilizumab works, they fall short of showing how it can take market share from Roche’s rival IL-6 drug.” And: “When paired to DAS28 data that may favor the use of vobarilizumab over Actemra, Ablynx thinks these factors amount to a compelling case. The $75 million question is, does AbbVie agree?” So there’s some kind of suspense about vobarilizumab.
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Zanolimumab
If you look for zanolimumab, you’ll find a study on mycosis fungoides and Sézary syndrome a study from 2008!). Zanolimumab is a human monoclonal antibody that targets CD4. Fierce BioTech noted: “Zanolimumab is currently in a Phase III pivotal study to treat cutaneous T-cell lymphoma (CTCL)”. But I’m more interested in result concerning rheumatic diseases. There haven’t been any studies presented at both the 2016 EULAR and ACR Annual Meetings. My guess is that we won’t see any study in the rheumatologic section.
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And don’t miss Wikipedia’s „List of therapeutic monoclonal antibodies”, which lists about a zillion MABs - https://en.wikipedia.org/wiki/List_of_therapeutic_monoclonal_antibodies.

Started: 08.12.2016
New entries: 09.12.2016 / 12.12.2016 / 13.12.2016 / 14.12.2016

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