Tabalumab at the EULAR 2014 Meeting in Paris

I've already said bye bye to tabalumab a year ago as I had been very disappointed with the data shown during the past two years, but here we still are. Tabalumab (LY2127399) is a human IgG4 monoclonal antibody against B-cell activating factor (BAFF). And there have been two abstracts/posters.

J.S. Smolen and colleagues presented [FRI0326]: "EFFICACY AND SAFETY OF TABALUMAB, AN ANTI-B CELL ACTIVATING FACTOR MONOCLONAL ANTIBODY, IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAD AN INADEQUATE RESPONSE TO METHOTREXATE THERAPY: RESULTS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY". Conclusions: "In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity. There were no differences in reports of AEs of interest and no new or unexpected safety findings for RA pts receiving tabalumab."

M. Schiff and colleagues presented [AB0438]: "EFFICACY AND SAFETY OF TABALUMAB, AN ANTI-B CELL ACTIVATING FACTOR MONOCLONAL ANTIBODY, IN PATIENTS WITH RHEUMATOID ARTHRITIS WHO HAD AN INADEQUATE RESPONSE TO TNF-ALPHA INHIBITORS: RESULTS FROM A PHASE 3 MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY". Conclusions: "In this phase 3 study, tabalumab demonstrated no clinical efficacy despite evidence of biologic activity, suggesting that targeting BAFF may not be a viable therapeutic approach to treating pts with RA. There were no differences in reports of infection or allergic/hypersensitivity events and no new or unexpected safety findings for RA pts receiving tabalumab."

In the case of tabalumab I hate to be proven right: it's bye bye tabalumab!

Link:

http://rheumatologe.blogspot.de/2013/06/tabalumab-at-eular-2013-meeting.html 

Tabalumab in Rheumatoid Arthritis – new developments?

Today I received the September issue of the Annals of the Rheumatic Diseases. I was quite surprised looking at two articles on tabalumab in rheumatoid arthritis.

Mark C Genovese and colleagues: “Extended report: A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate” (Ann Rheum Dis 2013;72:9 1453-1460 Published Online First: 18 April 2013 doi:10.1136/annrheumdis-2012-202864).

Mark C Genovese and colleagues: “Extended report: Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors” (Ann Rheum Dis 2013;72:9 1461-1468 Published Online First: 25 December 2012 doi:10.1136/annrheumdis-2012-202775).

The first study showed “significantly higher ACR50 and ACR20 response rates versus placebo (p smaller than 0.05)” in the 120 mg dose group. After the completion of this study phase 3 were undertaken, but recently discontinued, because the expected efficacy wasn’t met. Link: http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=738769.

In the second study we look at the following conclusion: “At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points.” As this study already had been accepted in December 2012, Lilly’s discontinuation of the Phase 3 rheumatoid arthritis (RA) program for tabalumab could not be included.

So, all in all the published data rounds up the picture I already had (Link: http://rheumatologe.blogspot.de/2013/06/tabalumab-at-eular-2013-meeting.html - maybe I should have consulted Lilly’s announcement earlier!). Tabalumab isn’t a drug, which could be used for the benefit of patient with rheumatoid arthritis. Let’s wish tabalumab all the best concerning Lupus.

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).

Tabalumab at the EULAR 2013 Meeting

I had been disappointed about tabalumab at the ACR 2012 Meeting. Even as there had been four studies in Washington. The reasons for my disappointment are here: http://rheumatologe.blogspot.de/2012/12/tabalumab-at-acr-2012-in-washington.html How about Madrid?

E. R. Dow and colleagues presented [SAT0005]: “Human C-type lectin domain family 4, member C gene expression level helps predict future clinical response to tabalumab blockade of BAFF in rheumatoid arthritis”. In German we have the idiom “BAFF erstaunt sein”, which means to be flabbergasted. That’s describes my feelings. Only one study at the EULAR and … it’s an abstract, which had already been presented at the ACR 2012 Meeting.

Bye bye tabalumab.

Tabalumab at the ACR 2012 in Washington

Tabalumab is an anti-BAFF Monoclonal Antibody. http://rheumatologe.blogspot.de/2012/06/tabalumab-ly2127399-anti-baff.html. I’ve been very sceptical about benefits of tabalumab in RA.

Maria W. Greenwald et al. presented: "Long-Term Safety and Efficacy of Tabalumab, an Anti-B-Cell Activating Factor Monoclonal Antibody, in Patients with Rheumatoid Arthritis: A 52-Week, Open-Label Extension Study" (Abstract No. 447). The study doesn’t give a conclusion. In my eyes it’s a weird study, it’s unclear if all patients from the RCTs are included in this extension study or only responders.

There’s another study by the same authors: Abstract No. 1276. W. J. Komocsar and colleagues presented: "Gene Expression Profiling and Pathway Changes Associated with Clinical Response to Tabalumab Blockade of Membrane Bound and Soluble B Cell Activating Factor in Rheumatoid Arthritis" Conclusion: “Tabalumab treatment reduced total B cells, mature naive B cells and serum Igs, while memory B cells were increased. Total B cells were only partially depleted and recovered in all pts during the post treatment follow -up period. There was no indication that reductions in B cells or in serum Igs below the LLN were associated with an increased frequency of infections. […]”

Wendy J. Komocsar and colleagues presented further results in abstract No. 1315: “Gene Expression Profiling and Pathway Changes Associated with Clinical Response to Tabalumab Blockade of Membrane Bound and Soluble B Cell Activating Factor in Rheumatoid Arthritis.” The authors observed “changes in genes related to B cell development and maturation”. I observe a study, which seems to have only the purpose to link tabalumab to rheumatoid arthritis.

The same applies to the next study, abstract No. 1321 by Ernst R. Dow and colleagues: “C-Type Lectin Domain Family 4, Member C Gene Expression Level Helps Predict Future Clinical Response to Tabalumab Blockade of B Cell Activating Factor in Rheumatoid Arthritis.” In conclusions the authors hint at a “large phase 3 clinical trial of tabalumab”.

I am very disappointed. I can’t help but think that these studies only try to keep the interest in the drug alive. Maybe I am mistaken.

Tabalumab (LY2127399) - Anti-BAFF Monoclonal Antibody

Has LY2127399 (an anti-BAFF monoclonal antibody) been studied further?
Maybe…
Here is the study by Genovese et al., which had been presented at the 2011 EULAR meeting in London:


eular 2011 / OP0017] A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITISM.
Genovese et al.
Conclusions: The LY safety profile in this study was similar to available RA therapies and no unexpected safety signals were seen. The 120mg dose group demonstrated significant reductions in the signs and symptoms of RA, and this was not contingent on complete B cell depletion. These results support further exploration of LY to treat RA


At least I’ve found out the real name behind LY2127399: it’s tabalumab (source: http://www.cancer.gov/drugdictionary?cdrid=600180). It is a human IgG4 monoclonal antibody against B-cell activating factor (BAFF). Lilly tests this drug in rheumatoid arthritis, multiple myeloma, multiple sclerosis, lupus, and maybe more. A study on relapsing-remitting multiple sclerosis by N. Putzki, M. Yildiz & A. Mueller (Multiple Subcutaneous Doses of LY2127399, an Anti-BAFF Human Antibody, in Subjects With Relapsing-Remitting Multiple Sclerosis) has been stopped. “A Study of LY2127399 in Rheumatoid Arthritis”, a phase 2 study will investigate tabalumab (LY2127399) in patients with rheumatoid arthritis, who are not adequately responding to methotrexate. This study is currently recruiting participants. (Last Updated on May 24, 2012 / http://clinicaltrials.gov/ct2/show/NCT01576549)
Nothing new at the 2012 EULAR meeting in Berlin!
The drug is tested in a broad spectrum of diseases, one study has been stopped. Does it mean, Lilly is desperate to find a use for tabalumab? Let's find out at the next ACR meeting in Washington.