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Abstract Number: 1495

Preclinical and Clinical Phase I Profile of MK-8457, a Selective Spleen Tyrosine Kinase and Zeta-Chain-Associated Protein Kinase 70 Inhibitor, Developed for the Treatment of Rheumatoid Arthritis

Gene Marcantonio1, Alan Bass2, Gretchen Baltus3, Judith Boice1, Hongmin Chen4, Michael Crackower5, Jeroen Elassaiss-Schaap6, Michael Ellis7, Tomoko Freshwater8, Francois Gervais9, Jane Guo10, Sammy Kim9, Lily Moy5, Alan Northrup7, Jie Zhang-Hoover4, Mathew Maddess11, Richard Miller12, Marcella Ruddy5, Stella Vincent13, Haoling Weng1 and Hani Houshyar14, 1Merck & Co., Whitehouse Station, NJ, 2Safety Assessment, Merck & Co., Boston, MA, 3Immunomodulatory Regulators, Merck & Co., Boston, MA, 4Pharmacology, Merck & Co., Boston, MA, 5Merck & Co., Boston, MA, 6Clinical PK-PD, Merck & Co., Oss, Netherlands, 7Medicinal Chemistry, Merck & Co., Boston, MA, 8PPDM Early Stage, Merck & Co., Rahway, NJ, 9Cell Pathways and Proteins, Merck & Co., Boston, MA, 10Immunology, Merck & Co., Boston, MA, 11Discovery Process Chemistry, Merck & Co., Boston, MA, 12Biochemistry & Biophysics, Merck & Co., Boston, MA, 13PPDM Preclinical ADME, Merck & Co., Boston, MA, 1433 Avenue Louis Pasteur, Merck & Co., Boston, MA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Animal models, B cell targeting, kinase and rheumatoid arthritis (RA), T cells

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Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Novel therapies, Biosimilars, Strategies and Mechanisms in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Spleen tyrosine kinase (SYK) is a potential target for treatment of several diseases including rheumatoid arthritis.  SYK is a member of the Zeta-chain-associated protein kinase 70 (ZAP70) family of non-receptor protein kinases, critical in signaling downstream of Fc epsilon receptor I (FceRI) in mast cells and basophils, B-cell receptor (BCR) in B cells, and the collagen receptor in platelets.  ZAP70, plays a predominant role in T-cell receptor (TCR) signaling in mature T cells.  Here, we report the in vitro, in vivo, and early clinical characterization of a highly selective and potent dual SYK/ZAP70 inhibitor, MK-8457. 

Methods: The in vitro characteristics of MK-8457 were evaluated in a series of biochemical and cellular assays.  The in vivo characteristics of MK-8457 were evaluated in the rat adjuvant- and collagen-induced arthritis models.  MK-8457 preclinical PK-PD-Efficacy relationship was established to select clinical doses required for efficacy in RA.  Healthy volunteer clinical studies assessed the PK, PD, and safety of MK-8457 in single- and multiple-rising dose studies. 

Results: MK-8457 is a potent, reversible ATP competitive inhibitor of SYK and ZAP70, displaying comparable cellular activity for these two kinases despite 40x enzymatic selectivity for SYK vs. ZAP70.  Beyond ZAP70, out of 191 off-target kinases tested, MK-8457 inhibits only 3 kinases (TRKC, SRC, BLK) with IC50 values less than 100-fold above the SYK IC50.  In vitro, MK-8457 is a potent inhibitor of (1) FceRI-mediated anti-IgE induced degranulation in primary human mast cells (38 ± 20 nM) and human whole blood basophils (797 ± 365 nM), (2) BCR-mediated anti-IgM induced pBLNK activation in human RAMOS cells (35 ± 27 nM) and anti-CD79b induced CD69 upregulation in human whole blood B cells (1398 ± 505 nM), and (3) TCR-mediated anti-CD3 induced IL-2 production in Jurkat cells (84 ± 26 nM) and human whole blood phytohemagglutinin induced IL-2 production (1175 ± 362 nM).  MK-8457 also inhibits collagen-induced platelet aggregation in human platelet rich plasma, with 20x reduced potency (19 ± 3 uM) as compared with the human whole blood basophil, B-cell, and T-cell assays.  MK-8457 produces dose-dependent inhibition of adjuvant- and collagen-induced arthritis, as assessed by changes in paw thickness.  Preclinical PK-PD-Efficacy modeling and simulations suggest that high level of SYK/ZAP70 inhibition (69%) is required to attain nearly full suppression of the CIA response.  In healthy volunteers, MK-8457 is rapidly absorbed, shows increased exposure with dose, with a terminal half-life estimated to be 10-20 hours.  MK-8457 was generally safe and well-tolerated in single dose up to 800 mg and multiple doses of 200 mg twice daily for up to 10 days.  There was evidence of increased bleeding times at the Tmax in single dose studies; however, there were no bleeding adverse events.  The Cmaxfor this effect in healthy volunteers is ~2x higher than observed at steady state for the highest dose (100 mg BID) tested in Phase II RA studies. 

Conclusion: These data suggest that MK-8457 has the appropriate characteristics for assessment of the hypothesis that a selective SYK/ZAP70 inhibitor is efficacious in RA patients.


Disclosure:

G. Marcantonio,

Merck Pharmaceuticals,

3;

A. Bass,

Merck Pharmaceuticals,

3;

G. Baltus,

Merck Pharmaceuticals,

3;

J. Boice,

Merck Pharmaceuticals,

3;

H. Chen,

Merck Pharmaceuticals,

3;

M. Crackower,

Merck Pharmaceuticals,

3;

J. Elassaiss-Schaap,

Merck Pharmaceuticals,

3;

M. Ellis,

Merck Pharmaceuticals,

3;

T. Freshwater,

Merck Pharmaceuticals,

3;

F. Gervais,

Merck Pharmaceuticals,

3;

J. Guo,

Merck Pharmaceuticals,

3;

S. Kim,

Merck Pharmaceuticals,

3;

L. Moy,

Merck Pharmaceuticals,

3;

A. Northrup,

Merck Pharmaceuticals,

3;

J. Zhang-Hoover,

Merck Pharmaceuticals,

3;

M. Maddess,

Merck Pharmaceuticals,

3;

R. Miller,

Merck Pharmaceuticals,

3;

M. Ruddy,

Merck Pharmaceuticals,

3;

S. Vincent,

Merck Pharmaceuticals,

3;

H. Weng,

Employee of Merck Co.,

3;

H. Houshyar,

Merck Pharmaceuticals,

3.

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