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)
[OP0078]
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."
[SAT0377]
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."
[SAT0389]
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.
Baricitinib
[THU0149]
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)
[THU0123]
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.
[THU0131]
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)
[OP0151]
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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