| Reference | 1. J Dermatolog Treat. 2016 Aug;27(4):332-8. doi: 10.3109/09546634.2015.1115819.
Epub 2016 Jan 14. <br />
<br />
A randomized, double-blind, placebo-controlled, dose-escalation study of the
safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients
with stable, chronic plaque psoriasis. <br />
<br />
Bissonnette R(1), Luchi M(2), Fidelus-Gort R(2), Jackson S(2), Zhang H(2), Flores
R(2), Newton R(2), Scherle P(2), Yeleswaram S(2), Chen X(2), Menter A(3). <br />
Author information: <br />
(1)a Innovaderm Research Inc , Montreal , Quebec , Canada .
(2)b Incyte Corporation , Wilmington , DE , USA , and.
(3)c Division of Dermatology , Baylor University Medical Center , Dallas , TX ,
USA. <br />
BACKGROUND: Chronic plaque psoriasis is partially mediated by elevation of
proinflammatory cytokines, including several within the Janus kinase/signal
transducer and activator of transcription (JAK/STAT) pathway.<br />
OBJECTIVE: To evaluate the safety and efficacy of the oral selective JAK1
inhibitor INCB039110 in stable, chronic plaque psoriasis.<br />
METHODS: This was a phase 2, randomized, double-blind, placebo-controlled,
dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg
twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean
percent change from baseline in the static Physician Global Assessment (sPGA) at
day 28. The protocol was institutional review board approved.<br />
RESULTS: Of 50 patients, 48 completed the study. At day 28, mean percent
reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p
 =  0.270 vs. placebo), 29.4% for 200 mg once daily (p  =  0.118), 35.2% for
200 mg twice daily (p  =  0.053), 42.4% for 600 mg once daily (p  =  0.003) and
12.5% for placebo. Across groups, 11.1% to 45.5% achieved an sPGA score of 1
versus 0% for placebo. INCB039110 was generally well tolerated; the most common
treatment-emergent adverse event was nasopharyngitis (18.4%).
CONCLUSION: INCB039110 produced significant improvements in sPGA, demonstrating
proof of concept in chronic plaque psoriasis. <br />
<br />
2. Drug Metab Dispos. 2015 Apr;43(4):485-9. doi: 10.1124/dmd.114.060673. Epub 2015
Jan 20. <br />
<br />
Impact on creatinine renal clearance by the interplay of multiple renal
transporters: a case study with INCB039110. <br />
<br />
Zhang Y(1), Warren MS(2), Zhang X(2), Diamond S(2), Williams B(2), Punwani N(2),
Huang J(2), Huang Y(2), Yeleswaram S(2). <br />
Author information: <br />
(1)Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and
Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.)
[email protected].
(2)Incyte Corporation, Wilmington, Delaware (Y.Z., S.D., B.W., N.P., S.Y.), and
Optivia Biotechnology, Menlo Park, California (M.W., X.Z., J.H., Y.H.). <br />
Serum creatinine is commonly used as a marker of renal function, but increases in
serum creatinine might not represent changes in glomerular filtration rate (GFR).
INCB039110
(2-(3-(4-(7H-pyrrolo[2,3-day]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(t
rifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile) is an
inhibitor of the Janus kinases (JAKs) with selectivity for JAK1. In a phase 1
study, a modest and reversible increase in serum creatinine was observed after
treatment with INCB039110. However, a dedicated renal function study with
INCB039110, assessed by iohexol plasma clearance, conducted in healthy volunteers
indicated no change in GFR. In vitro studies were therefore conducted to
investigate the interaction of INCB039110 with five transporters that are likely
involved in the renal clearance of creatinine. Cell systems expressing individual
or multiple transporters were used, including a novel quintuple-transporter model
OAT2/OCT2/OCT3/MATE1/MATE2-K. INCB039110 potently inhibited OCT2-mediated uptake
of creatinine as well as MATE1-/MATE2-K-mediated efflux of creatinine. Given the
interactions of INCB039110 with multiple transporters affecting creatinine uptake
and efflux, an integrated system expressing all five transporters was sought; in
that system, INCB039110 caused a dose-dependent decrease in transcellular
transport of creatinine with weaker net inhibition compared with the effects on
individual transporters. In summary, a molecular mechanism for the increase in
serum creatinine by INCB039110 has been established. These studies also underline
the limitations of using serum creatinine as a marker of renal function. <br />
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