Tuesday, June 17, 2014

Protein kinase inhibitors at the EULAR 2014 Meeting in Paris

Again Id like to look how much hype or hope lies in protein kinase inhibitors. Xeljanz (tofacitinib) is on the market in the US for rheumatoid arthritis, but still lacks approval in Europe. Otezla has been approved in the US for psoriatic arthritis, but also waits for approval in Europe.

There is light, but there are also some deep black shadows.

Apremilast (Otezla)
A. Kavanaugh and colleagues presented: "APREMILAST, AN ORAL PHOSPHODIESTERASE 4 INHIBITOR, IS ASSOCIATED WITH LONG-TERM (52-WEEK) IMPROVEMENT IN MEASURES OF DISEASE ACTIVITY IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS FROM 3 PHASE 3 [The PALACE 1, 2, and 3], RANDOMIZED, CONTROLLED TRIALS". Conclusions: "APR demonstrated clinically meaningful improvements in measures of PsA disease activity throughWeek 52. APR demonstrated an acceptable safety profile and was generally well tolerated through 52 weeks."
A. Adebajo and colleagues presendted the PALACE 4 study: "LONG-TERM SAFETY AND TOLERABILITY OF APREMILAST, AN ORAL PHOSPHODIESTERASE 4 INHIBITOR, IN PATIENTS WITH PSORIATIC ARTHRITIS: A PHASE 3, RANDOMIZED, CONTROLLED TRIAL" . Conclusions: "APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks; the nature, incidence, and severity of AEs were comparable over the 24-wk and 52-wk periods. Similar to data from other phase 3 trials assessing pts previously treated with DMARDs, these data do not indicate a need for laboratory monitoring."
C. Edwards and colleagues presented: "APREMILAST, AN ORAL PHOSPHODIESTERASE 4 INHIBITOR, IS ASSOCIATED WITH LONG-TERM (52-WEEK) IMPROVEMENTS IN ENTHESITIS AND DACTYLITIS IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS FROM THE PALACE 4 PHASE 3, RANDOMIZED, CONTROLLED TRIAL". Conclusions: "Among pts continuously treated with APR through 52 wks, sustained improvements in both enthesitis and dactylitis were observed in pts with active PsA, who had enthesitis and dactylitis at BL. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks." I think an important issue with patients suffering from psoriatic arthritis.
Three more studies, but I miss data on radiographic progression and as this has been an issue with tofacitinib in Europe, I doubt that Otezla will get an approval without such data.

Y. Tanaka and colleagues presented: "EFFICACY AND SAFETY OF BARICITINIB IN JAPANESE RHEUMATOID ARTHRITIS PATIENTS AT 12 WEEKS". Conclusions: "Clinical efficacy was demonstrated in this Phase 2b study of baricitinib in combination with background MTX in Japanese RA pts through 12 weeks. Safety signals observed through 12 weeks were consistent with a previous study of baricitinib in non-Japanese pts with RA."
And that's all there is. I've talked to the Lilly people and they told me that phase 3 studies haven't completed recruiting. So we still have to wait for these important studies.

Filgotinib (GLPG0634)
F. Namour  and colleagues presented: "DOSE SELECTION OF GLPG0634, A SELECTIVE JAK1 INHIBITOR, FOR RHEUMATOID ARTHRITIS PHASE 2B STUDIES: PK/PD AND EXPOSURE-DAS28 MODELING APPROACH". Conclusions: "Current modeling and simulation on the basis of early clinical data suggests that the pharmacokinetics of GLPG0634 is dose proportional at doses up to 200 mg QD, in agreement with observed data, and shows that both GLPG0634 and its main metabolite contribute to biomarker response. Simulations of the pSTAT1 and DAS28 dose-response relation suggest that the efficacy is favorable up to a daily dose of 200 mg GLPG0634, with clinical response in the range of that observed with registered compounds. A daily dose range from 50 to 200 mg is currently being tested in the DARWIN Phase 2B program."
And a CIA rat study ...
And drug drug interaction study ...
Will take a couple of years until we see phase 3 studies.

Tofacitinib (Xeljanz)
There has been a multitude of studies. For me the most interesting one is the following study.
K. Katayama  and colleagues presented: "LONG TERM RESULTS OF INHIBITION OF RADIOGRAPHIC JOINT DAMAGE PROGRESSION IN SMALL AND MEDIUM AND LARGE JOINTS IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TOFACITINIB MONOTHERAPY". Conclusions: "Progression of small and M-L sized joints were effectively inhibited by tofacitinive mono-therapy." Reads good, doesn't is? The only problem is: N=8. For this small number it's a big conclusion!
Also some interesting data on psoriatic arthritis, but still lacking the data from well powered phase 3 studies on radiographic progression. So we still have to waitfor tofacitinib, in Europe that is.

VX-509 (Decernotinib)
R. van Vollenhoven and colleagues presented: "A PHASE 2B, 24-WEEK STUDY OF VX-509 (DECERNOTINIB), AN ORAL SELECTIVE JANUS KINASE 3 INHIBITOR, IN COMBINATION WITH BACKGROUND METHOTREXATE IN RHEUMATOID ARTHRITIS". Conclusions: "All tested doses of VX-509 significantly improved signs and symptoms of RA versus placebo when administered in combination with stable background MTX therapy for 24 weeks. VX-509 was associated with small increases in AE rates, serious infections, and mostly minor laboratory abnormalities. These results support and provide guidance for the further development of VX-509." N=358!
OK, just one big phase 2b study, but it looks promising.

I think it will take a while until we see protein kinase inhibitors at bedside in Europe.


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