Safety, Pharmacokinetic and Pharmacodynamic Evaluation of ... · • CTP-543 was evaluated in...
Transcript of Safety, Pharmacokinetic and Pharmacodynamic Evaluation of ... · • CTP-543 was evaluated in...
Safety, Pharmacokinetic and Pharmacodynamic Evaluation of CTP-543 (Deuterated Ruxolitinib) in a Phase I Healthy Volunteer Study
www.concertpharma.comLexington, MA 02421
Copyright © 2014 Concert Pharmaceuticals, Inc. All rights reserved.
Jana von Hehn, PhD; Colleen Hamilton; Vinita Uttamsingh, PhD; Kristine Hogan; Ara M Aslanian, PhD; Brett Grotbeck; Gary W Bridson; Christopher L Brummel, PhD; Virginia Braman; James Cassella, PhD
DCEPlatform®
8 mg CTP-543
or placebo
Cohort 1 6 active
2 placebo
16 mg CTP-543
or placebo
32 mg CTP-543
or placebo
48 mg CTP-543
or placebo
Cohort 26 active
2 placebo
Cohort 3 6 active
2 placebo
Cohort 46 active
2 placebo
8 mg QDCTP-543
or placebo
Cohort 18 active
2 placebo
Cohort 28 active
2 placebo
Cohort 38 active
2 placebo
8 mg BIDCTP-543
or placebo
24 mg QDCTP-543
or placeboCohort 48 active
2 placebo
Cohort 58 active
2 placebo
16 mg BIDCTP-543
or placebo
32 mg QDCTP-543
or placebo
Part A: Single Ascending Dose Study DesignCTP-543
Dose Cmax (nM) Tmaxa
(hr)T1/2(hr)
AUC0-inf(nM*hr)
CL/F (L/hr)
8 mg 376 (28%) 1.25 (0.5-1.5) 3.1 (29%) 1875 (32%) 14.9 (35%)
16 mg 687 (24%) 1.75 (0.5-3.0) 3.3 (26%) 3959 (30%) 14.5 (47%)
32 mg 1702 (29%) 1.25 (0.5-2.0) 3.5 (16%) 7831 (26%) 13.9 (30%)
48 mg 2714 (26%) 1.50 (0.5-2.0) 3.6 (21%) 13237 (35%) 12.7 (34%)
Data presented are preliminary results; a Median values (range)
Part B: Multiple Ascending Dose Study Design
CTP-543 Dose
Cmax(nM)
Tmaxa
(hr)T1/2(hr)
AUC0-24(nM*hr)
CLss/F (L/hr)
8 mg QD 480 (34%) 1.0 (0.25-1.5) 3.5 (21%) 2131 (28%) 12.7 (25%)
24 mg QD 986 (23%) 1.0 (0.5-2.0) 3.5 (25%) 4868 (25%) 16.5 (22%)
32 mg QD 1564 (18%) 0.75 (0.5-2.0) 3.5 (37%) 6684 (28%) 16.5 (33%)
Figure 1
Figure 2
CTP-543 Dose
Cmax(nM)
Tmaxa
(hr)T1/2(hr)
AUC0-12(nM*hr)
CLss/F (L/hr)
8 mg BID 564 (24%) 1.5 (0.25-2.0) 3.9 (34%) 2615 (36%) 10.7 (34%)
16 mg BID 917 (36%) 0.75 (0.5-2.0) 3.5 (19%) 3577 (26%) 15.0 (24%)
Results and Conclusions• 77 subjects were dosed (60 received CTP-543; 17 received placebo)• CTP-543 was rapidly absorbed and did not accumulate with repeat dosing • No serious adverse events were reported • The most common adverse event reported was headache • No withdrawal or dose modification related to CTP-543 occurred• Cases of mild neutropenia resolved or trended toward recovery after dosing completion. Severe
neutropenia (Grade 3 or 4) was not observed. • In the Phase 1 study, CTP-543 was generally well tolerated with a favorable PK profile to support
selection of doses for Phase 2 clinical trials in patients with alopecia areata
Methods• CTP-543 was evaluated in healthy volunteers in a randomized, double-blind, placebo controlled,
sequential, two-part Phase 1 study • Part A evaluated the safety and pharmacokinetics of single oral doses of 8, 16, 32 and 48 mg
CTP-543 (Figure 1)• Part B assessed escalating once or twice daily doses of CTP-543 administered for 7 consecutive
days (Figure 2)• The plasma concentrations of CTP-543 after single and multi-dose administration were measured
Introduction• CTP-543 is Janus Kinase (JAK) inhibitor being developed as an oral treatment for adults with
alopecia areata (AA)• CTP-543 is a deuterium-modified analog of ruxolitinib• Inhibitors of JAK signaling have shown efficacy in autoimmune disorders including a published study
with non-deuterated ruxolitinib resulting in hair regrowth in AA (Mackay-Wiggan, et al, JCI Insight.2016 Sep:1(15):e89790.)
• The safety and PK parameters observed support the further clinical evaluation of CTP-543 in AA• Pharmacodynamic markers of JAK inhibition by CTP-543 are being analyzed and will be discussed in
a subsequent presentation
Mean (CV%) Multiple Ascending Dose Steady-State PK Parameters
Mean (CV%) Single Ascending Dose PK Parameters
7 days of dosing
Data presented are preliminary results; a Median values (range)