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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)