Fighting Rheumatoid Arthritis with small molecules (PKI)

I have been wondering as well which of the small molecules (PKI – protein kinase inhibitors) might be in the pipeline to emerge later a potent drugs fighting rheumatoid arthritis. I can’t be sure, what the pharmaceutical industry will decide, we have already seen some candidates being withdrawn after a good start. Tofacitinib and fostamatinib are doing better than other and I won’t dwell on these here. Here are a few lesser known candidates. But is there any new drug to be expected from these small molecules?

Ruxolitinib
Ruxolitinib is a JAK1/JAK2 inhibitor, which could be useful to treat rheumatoid arthritis. There has been a study being presented at the 2008 ACR meeting, here’s an article referring to this study. http://www.istockanalyst.com/article/viewiStockNews/articleid/2739159. Nothing new at the EULAR 2012 meeting in Berlin. Well, ruxolitinib has been approved as JAKAFI™ for treatment of patients with intermediate or high-risk myelofibrosis …
So it might well be the case that the producer decided not to follow the indication rheumatoid arthritis.


Baricitinib
Baricitinib (LY3009104, INCB28050) is a JAK1/JAK2 inhibitor. Here’s more: http://rheumatologe.blogspot.de/2012/06/baricitinib-ly3009104-at-eular-2012-in.html  


ARRY-371797
ARRY-371797 is a p38 inhibitor. There are a couple of studies:
• A Study of ARRY-371797 in Patients With Rheumatoid Arthritis
• A Study of ARRY-371797 in Patients With Active Ankylosing Spondylitis
• A Study of ARRY-371797 in Patients With Osteoarthritis of the Knee
All three studies have been completed by July 2012, but nothing has been published at the EULAR 2012 meeting in Berlin. I guess the results will be presented at the ACR 2012 in Washington.


BMS-582949
BMS-582949 is a dual action p38 kinase inhibitor. There is a study of G. Schieven and colleagues, which has been published at the 2010 ACR meeting (Arthritis Rheum 2010;62 Suppl 10 :1513 DOI: 10.1002/art.29279). There has been a study, http://clinicaltrials.gov/show/NCT00605735, which has been completed, but no study result have been published (updated: January 24, 2011). So I guess, this is another dead end.


Pamapimod
R. Alten and colleagues presented a study on “Efficacy and safety of pamapimod in patients with active rheumatoid arthritis receiving stable methotrexate therapy” in April 2009. Sorry to say, but “pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.” Actually, patients on pamapimod achieved poorer results than those on methotrexate. Some people already think that rheumatoid arthritis might be the wrong indication for this kind of drugs.


VX-702
About VX-702, a novel p38 MAPK inhibitor, not much better is to be said. N. Damjanov and colleagues of Belgrade University School of Medicine published two studies: “Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies” and concluded: “The modest clinical efficacy plus the transient suppression of biomarkers of inflammation observed in this study suggest that p38 MAPK inhibition may not provide meaningful, sustained suppression of the chronic inflammation seen in RA.”


Maybe we’ll see some results concerning Baricitinib and ARRY-371797 at the ACR 2012 meeting in Washington. I’ll be on the lookout!