Rheumatoid Arthritis and future treatments by MABs

I’ve read an abstract recently on “Monoclonal antibody treatments for rheumatoid arthritis” by L. Bossaller and A. Rothe (Link: http://www.ncbi.nlm.nih.gov/pubmed/23789825).
As we already have quite a number of agents and more will be added, let’s have a look at targets already being uses successfully and possible targets.

TNF-alpha: TNF stands for tumor necrosis factor. We already have five TNF-alpha-Inhibitors.

IL-6: IL stands for interleukin. Interleukins for a large group of cytokines, which have the task to communicate between white blood cells (leukocytes), hence the word interleukins. IL-6 is a multitask cytokine, which induces acute phase proteins, plays a role in B cell differentiation and hepatocytes as well as others. We already use one IL-6 inhibitor – tocilizumab. Another IL-6 inhibitor is near to be launched: Sarilimumab (Link: http://rheumatologe.blogspot.de/2013/07/sarilumab-at-eular-2013-meeting.html). An we have an anti-IL-6 receptor nanobody® (ALX-0061), which would be different to the the MABs, but also interfering with the IL-6 signal.

IL-1: we already have anakinra, an interleukin-1 receptor antagonist, which isn’t as successful as TNF alpha inhibitors, when it comes to rheumatoid arthritis. Anakinsa is successful in some familial periodic fever syndromes. Maybe to treat RA it’s the wrong approach.

IL-17: some IL-17 inhibitors are studied in rheumatoid arthritis: secukinumab, ixekizumab and brodalumab (Link: http://rheumatologe.blogspot.de/2013/06/targeting-interleukin-17-in-patients.html). I’m not too optimistic we’ll hear much more about IL-17 inhibition as a treatment of rheumatoid arthritis.

VEGF: Vascular endothelial growth factor is a signal protein that stimulates vasculo-/angiogenesis. TNF alpha stimulates the release of VEGF in rheumatoid arthritis, so that more capillaries are formed and permeability of vessels is increased, which would result in more swelling. “VEGF – appears to be a promising avenue for the future treatment of RA.” Were the concluding remarks of Ewa M Paleolog in 2002 (Link: http://www.biomedcentral.com/content/pdf/ar575.pdf). As we haven’t heard more by now, it doesn’t seem to be the broad road to a successful therapy.

RANKL: it’s the receptor activator of nuclear factor kappa-B ligand, which is important for otheoclast formation and differentiation. Osteoclasts break down bone tissue. As this is what happens in erosions, RANKL is interesting in the treatment of rheumatoid arthritis. We already have denosumab, a RANKL inhibitor (MAB), which has been developed against osteoporosis, and is effective against erosions, but it isn’t effective against articular signs and symptoms of rheumatoid arthritis (Link: http://www.hopkinsarthritis.org/arthritis-news/denosumab-suppresses-erosions-but-has-no-effect-on-articular-signs-and-symptoms-in-rheumatoid-arthritis/).


B-cell function (CD20 [rituximab], CD38 [only of use in leukaemia?], B-cell activating factor [doubtful in RA], transmembrane activator and calcium-modulating and cyclophilin interactor) T-cell function (CD3 [CIA study in 2010], CD4 [no big breakthrough during the past 3 years], CD28 [?]) will be added later.

CD 20: We have rituximab. Other MABs are being studied: ocaratuzumab, which failed to show new data at the EULAR 2013 (Link to more information: http://rheumatologe.blogspot.de/2012/12/ocaratuzumab-at-acr-2012-in-washington.html), or ocrelizumab, which also failed to show new data at the EULAR 2013 (Link: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html). But there’s also ofatumumab, on which there had been news prior to the EULAR meeting (Link: http://rheumatologe.blogspot.de/2013/06/ofatumumab-just-before-eular-2013.html). All in all there is activity to get a new anti-CD 20 MAB, but it isn’t a new principle. So it’s only someone else reaching for the pie.

CD 38: There’s bortezomib being tested in multiple myeloma. A. Chillemi and colleagues don’t mention rheumatoid arthritis in a recent overview article (Link: http://molmed.org/files/1047).

BAFF: Tabalumab is an anti-BAFF Monoclonal Antibody, which has been disappointing at the EULAR 2013 (Link: http://rheumatologe.blogspot.de/2013/06/tabalumab-at-eular-2013-meeting.html), but there are two articles on tabalumab in the fresh from the press issue of the Annals of the Rheumatic Diseases (September 2013), so that I might have to revise my former statement on tabalumab. I’ll deal with this new information in a blog post of its’ own.

TACI: TACI is short for transmembrane activator and calcium modulator and cyclophilin ligand interactor, which also interacts with BAFF. There’s atacicept, but it isn’t working in RA (Link: http://rheumatologe.blogspot.de/2012/06/atacicept.html).

CD 3: There has been a CIA study in 2010, but I haven’t found anything new since then.

CD 4: The lack 0f CD 4 cell depletion in rituximab patients is associated with no response (Link: http://www.ncbi.nlm.nih.gov/pubmed/23918413). There had been a study in mice, which Rawarrior commented on 3 years ago (Link: http://rawarrior.com/will-cd4-lead-to-a-rheumatoid-arthritis-cure/). Since then nothing new.

CD 28: Do you remember TGN1412? Here’s the Wikipedia link: http://en.wikipedia.org/wiki/TGN1412. Maybe we do better not trying the luck of people again.   

To treat rheumatoid arthritis, we might get another IL-6 inhibitor (sarilimumab), another anti-CD 20 agent, and maybe tabalumab will prove to be effective (I’m still sceptical, but I’ll tell you more about the recent studies on tabalumab in another blog post).

Atacicept

At the ACR 2011 in Chicago there had 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 looked at patients with rheumatoid arthritis and an inadequate response to methotrexate. The authors had to conclude: “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.”
Has atacicept shown new efficacy? Well let´s look at the data first. R.F. van Vollenhoven and colleagues presented a new study on atacicept, this time in combination with rituximab. It somehow shows the desperation to get the drug working. But the results have been sobering, as “addition of atacicept to rituximab was associated with an increased risk of events”.


[THU0090] SAFETY AND EFFICACY OF ATACICEPT IN COMBINATION WITH RITUXIMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM THE ATACICEPT FOR REDUCTION OF SIGNS AND SYMPTOMS IN RHEUMATOID ARTHRITIS TRIAL (III)
R.F. van Vollenhoven1, S. Wax2, S. Copt3, P.P. Tak4. 1Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden; 2Rheumatology, EMD Serono Inc, Rockland, MA, United States; 3Biostatistics, Merck Serono SA, Geneva, Switzerland; 4Division of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, Netherlands
Conclusions: In this exploratory trial, addition of atacicept to rituximab was associated with an increased risk of events that could be hypersensitivity-related. There was no increase in the clinical response rate.


I think we should abandon the idea that atacicept is a new drug to treat rheumatoid arthritis.

Some Emerging or Submerging New Therapeutic Agents in Rheumatoid Arthritis

Though I had had a look at the new kids on the block, here’s some more information on emerging or submerging new therapeutic agents in rheumatoid arthritis. The list is incomplete, which also depends on the definition of new.

Atacicept
Atacicept, a recombinant fusion protein designed to inhibit B cells has been studied in patients with rheumatoid arthritis and an inadequate response to methotrexate, but failed to meet primary endpoint (ACR20-CRP response) in a phase 2 study and will not be further studied in rheumatoid arthritis.

BMS-945429
Atacicept BMS-945429, an aglycosylated, humanized MAB to IL-6, is still studied in a phase 2B in rheumatoid arthritis, no study published yet.

BT-061
BT-061, a humanized Treg activating agonistic MAB, is studied, no study published yet.

Pamapimod
S.B. Cohen and colleagues looked at pamapimod, a p38 MAP kinase inhibitor, but the study showed that pamapimod was not as effective as MTX in the treatment of active rheumatoid arthritis.

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.

I’ll have a look into B-cell-depletion and new candidates to do so later.