Side effects

I’ll tell you more about the possible side effects of a new drug.

This new drug has a well known profile of side effects:

- it may lead to tooth decay

- nausea

- constipation

- abdominal pain

- headaches.

- obesity

- high blood pressure

- diabetes

- loss of consciousness

- stroke

- myocardial infarction

- neuropathy

- renal failure

- blindness,

- loss of limbs because of artery disease and/or gangrene

- death

Would you take this drug?

Oh – you want to know, which drug I’m talking of. Please look here:

http://rheumatologe.blogspot.de/2009/04/rrz-termine-2009.html

Olokizumab – any new developments?

I’m a bit surprised that lots of people look at my article on olokizumab today (30.09.2013).  Link: http://rheumatologe.blogspot.de/2012/12/olokizumab-at-acr-2012-in-washington.html. The results presented at the ACR 2012 in Washington were in line with UCB’s announcement on Sept. 26th, 2012. Link: http://www.ucb.presscentre.com/News/UCB-announces-top-line-phase-2-results-for-olokizumab-in-rheumatoid-arthritis-31e.aspx.

As nothing on olokizumab appeared at the EULAR meeting in Madrid in June 2013, I wondered: “Nothing! / Very strange as olokizumab targets interleukin-6 (IL-6). … Postponed or abandoned?” Link: http://rheumatologe.blogspot.de/2013/06/drugs-that-didnt-show-up-at-eular-2013.html

In July 2013 there had been another announcement by UCB: “UCB out-licenses RA drug olokizumab to Russia's R-Pharm”. Link: http://www.pharmatimes.com/article/13-07-08/UCB_out-licenses_RA_drug_olokizumab_to_Russia_s_R-Pharm.aspx.

I’m a bit surprised. Does this sudden interest in my article suggest that olokizumab is going to be tested further and eventually we’ll have another drug addressing IL-6? I’ve put olokizumab on my agenda for San Diego (ACR 2013).

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).

Pateclizumab at the EULAR 2013

Pateclizumab is an anti-lymphotoxin-alpha monoclonal antibody (the artist formely known as MLTA3698A). I hadn’t seen anything at the EULAR 2012 in Berlin. As I hadn't seen anything at the ACR 2012 in Washington, I thought to wait until the EULAR 2013 before I'd erase pateclizumab from my list of interests.
Now there have been two studies on Pateclizumab at the EULAR 2013 in Madrid.

A. E. Herman and colleagues presented a study [FRI0170]: "Pharmacodynamic biomarkers demonstrate overlapping and distinct biological pathways for lymphotoxin-αlpha and tumor necrosis factor-alpha in patients with rheumatoid arthritis". Within their conclusion you find this sentence: "LTα blockade demonstrated significant reduction in levels of CCL19, as well as CXCL13, suggesting an impact on T and B cell migration and/or lymphogenesis. However, the decrease in chemokines observed with LTα blockade was associated with only modest reduction in clinical activity (5)."
Not too overwhelming, I'd say.

But there has been a second study by W. Kennedy and colleagues [SAT0110]: "Efficacy and safety of pateclizumab (antilymphotoxin-alpha) in dmard-ir patients: results of a randomized, double-blind, placebo-controlled head-to-head phase 2 study with adalimumab". In their conclusion the authors state: "Pateclizumab treatment of DMARD-IR RA patients was associated with modest improvement in the signs and symptoms of RA, and was inferior to adalimumab after 12 weeks of treatment."

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 I thought targeting lymphotoxin-αlpha could be an interesting approach. I guess we'll have to wait if pateclizumab is abandoned silently.

More on new drug candidates against rheumatoi arthritis

There has been a comment to my blog at:

http://rheumatologe.blogspot.de/2012/07/fighting-rheumatoid-arthritis.html


Ville7 has written on 31st August 2012 12:58

Hallo Rheumatologe,
es ist Wahnsinn, wieviel Antikörper Medikamente derzeit gegen RA untersucht werden, man könnte die Liste fortführen mit

ACZ885 (Canakinumab), Target IL-1 beta
MDX-1100, Target CXCL10
MOR103, Target GM-CSF
KB-003, Target GM-CSF
Sirukumab, Target IL-6
BT061, Target CD4
Belimumab, Target BAFF
Veltuzumab, Target CD20
Golimumab, Target TNF-alpha
Mavrilimumab, Target GM-CSF

und wäre damit noch lange nicht vollständig.

Auf Clinicaltrials findet man unter dem Stichwort "rheumatoid arthritis" allein 231 Studien der Phasen 1 bis 3.


ACZ885 (Canakinumab), Target IL-1 beta, has been developed for the treatment of rheumatoid arthritis, but this indication has been abandoned. IL-1 beta isn’t a successful target in rheumatoid arthritis. Novartis tries desperately to find indications for its’ drug like gout as cryopyrin-associated periodic syndromes (CAPS) are orphan diseases.


MDX-1100, Target CXCL10, but doesn’t seem to be very effective: “The ACR50 and ACR70 response rates on day 85 did not differ between the groups.” http://www.ncbi.nlm.nih.gov/pubmed/22147649  The ACR20 response rate, however, was significantly higher among MDX-1100-treated patients. Lets wait for further results!


MOR103, Target GM-CSF, there is some interesting data, but only published by MorphoSys: http://www.morphosys.com/pressrelease/morphosyss-mor103-antibody-demonstrates-excellent-safety-and-efficacy-rheumatoid-arthritis-patients . Lets wait for the discussions at the ACR2012 next month!


KB-003, Target GM-CSF, “The study was terminated upon completion of safety run-in due to program refocus.” http://clinicaltrials.gov/ct2/show/results/NCT00995449  


Sirukumab, Target IL-6, please look at: http://rheumatologe.blogspot.de/2012/07/sirukumab-at-eular-2012.html (it’s a me too drug).


BT061, Target CD4, “Dose-finding of Multiple Dose of BT061 in Patients With Active Rheumatoid Arthritis Incompletely Controlled on Stable Methotrexate (MTX)”, Estimated Study Completion Date: December 2013. http://clinicaltrials.gov/ct2/show/NCT01481493


Belimumab, Target BAFF, “Belimumab has also undergone phase II clinical trials for rheumatoid arthritis.[6] Preliminary results in November 2005 were encouraging,[7] but no clinical trials are ongoing as of April 2012” - http://en.wikipedia.org/wiki/Belimumab.


Veltuzumab, Target CD20, VELVET, a Dose Range Finding Trial of Veltuzumab in Subjects With Moderate to Severe Rheumatoid Arthritis – the study is ongoing. Let’s wait for results! And please check: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html  

Golimumab, Target TNF-alpha, is already on the market!

Mavrilimumab, Target GM-CSF – please check: http://rheumatologe.blogspot.de/2012/07/mavrilimumab-at-eular-2012.html  


All in all I like the efforts for new drugs, but we have to wait for stable results!


Please check also: http://rheumatologe.blogspot.de/2012/05/some-small-molecules-in-pipeline.html