ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1500

Preclinical and Clinical Characterization of MK-8457, a Selective Spleen Tyrosine Kinase and Zeta-Chain-Associated Protein Kinase 70 Inhibitor, in Normotensive and Hypertensive Cardiovascular Models

Hani Houshyar1, Alan Bass2, Judith Boice3, Michael Ellis4, Patrick Fanelli5, Tomoko Freshwater6, Jane Guo7, Kimberly Hoagland5, Janet Kerr5, Alan Northrup4, Mathew Maddess8, Richard Miller9, Marcella Ruddy10, Stella Vincent11, Jayanthi Wolf5, Haoling Weng3, Gloria Zingaro5 and Gene Marcantonio3, 133 Avenue Louis Pasteur, Merck & Co., Boston, MA, 2Safety Assessment, Merck & Co., Boston, MA, 3Merck & Co., Whitehouse Station, NJ, 4Medicinal Chemistry, Merck & Co., Boston, MA, 5Merck & Co., West Point, PA, 6PPDM Early Stage, Merck & Co., Rahway, NJ, 7Immunology, Merck & Co., Boston, MA, 8Discovery Process Chemistry, Merck & Co., Boston, MA, 9Biochemistry & Biophysics, Merck & Co., Boston, MA, 10Merck & Co., Boston, MA, 11PPDM Preclinical ADME, Merck & Co., Boston, MA

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , ,

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) and Zeta-chain-associated protein kinase 70 (ZAP70) are non-receptor protein kinases that bind phosophorylated receptor tyrosine-based activation motifs, critical in immune receptor signaling in multiple hematopoietic and non-hematopoietic cells, supporting potential utility of SYK/ZAP70 inhibitors in multiple indications including rheumatoid arthritis.  While neither SYK nor ZAP70 are implicated in blood pressure (BP) regulation, the non-selective SYK/ZAP70 inhibitor, Fostamatinib, is associated with BP increases both preclinically and in patients.  Fostamatinib’s impact on BP has been attributed to off-target activity on vascular endothelial growth factor receptor 2 (VEGF-R2).  Here, we report the in vitro, in vivo, and clinical profile of MK-8457 to demonstrate that a highly selective SYK/ZAP70 inhibitor does not affect BP.

Methods:

The in vitro off-target activity of MK-8457 vs. Fostamatinib on VEGFR-2 was assessed in enzymatic as well as cellular assays.  In vivo, the BP effects of MK-8457 were compared with Fostamatinib in conscious telemetered normotensive Wistar rats and Beagle dogs.  In the clinic, MK-8457 was studied in a multi-center, randomized, double-blind, placebo controlled 2-period crossover ambulatory BP measurement (ABPM) trial in men and women with mild to moderate hypertension.  This study in 29 subjects was powered to detect a 5 mmHg increase in BP, to rule out a Fostamatinib-like BP effect.

Results:

In contrast to Fostamatinib, MK-8457 is devoid of off-target VEGFR2 activity in both enzymatic and cellular assays.  Whereas Fostmatinib produces dose-dependent increases in BP in conscious telemetry instrumented rats, MK-8457 does not.  Similarly, MK-8457 does not significantly affect BP in conscious telemetry instrumented dogs.  In the ABPM study, MK-8457 was studied at a dose of 100 mg BID for 10 days, a dose projected to result in nearly complete 24 hour inhibition of SYK and ZAP70.  At this dose, MK-8457 does not result in a statistically significant change in BP.  The mean treatment difference (MK-8457-placebo) in 24 hr mean systolic and diastolic ABPM change from baseline was 2.02 and 1.57 mmHg, respectively. 

Statistical Comparison of 24-Hour Change From Baseline in Ambulatory BP Parameters Following 10 days of Multiple dosing of MK-8457 or Matching Placebo in Hypertensive Patients 

Parameters

MK-8457

Placebo

MK-8457 – Placebo

 

N

LS Mean †

95 % CI

N

LS Mean†

95 % CI

Mean Difference

90 % CI

Systolic blood pressure  (mm Hg)     

 29

-0.47  

 (-2.60, 1.66)          

 28

-2.49  

 (-4.66, -0.31)         

    2.02

(-0.52, 4.56)           

Diastolic blood pressure (mm Hg)     

 29

0.22   

 (-1.33, 1.78)          

 28

-1.35  

 (-2.93, 0.23)          

    1.57

(0.19, 2.96)            

†    Least square Mean using linear mixed effect model where the response was average 24-hour change from baseline for Day 10 and the model contained period, treatment as fixed effect and Day -1 baseline as a fixed continuous covariate and subject as a random effect.

Conclusion:

These data illustrate that full SYK and ZAP70 inhibition with a selective inhibitor does not significantly impact BP preclinically or clinically in a sensitive population.

Disclosure:

H. Houshyar,

Merck Pharmaceuticals,

3;

A. Bass,

Merck Pharmaceuticals,

3;

J. Boice,

Merck Pharmaceuticals,

3;

M. Ellis,

Merck Pharmaceuticals,

3;

P. Fanelli,

Merck Pharmaceuticals,

3;

T. Freshwater,

Merck Pharmaceuticals,

3;

J. Guo,

Merck Pharmaceuticals,

3;

K. Hoagland,

Merck Pharmaceuticals,

3;

J. Kerr,

Merck Pharmaceuticals,

1;

A. Northrup,

Merck Pharmaceuticals,

3;

M. Maddess,

Merck Pharmaceuticals,

3;

R. Miller,

Merck Pharmaceuticals,

3;

M. Ruddy,

Merck Pharmaceuticals,

3;

S. Vincent,

Merck Pharmaceuticals,

3;

J. Wolf,

Merck Pharmaceuticals,

3;

H. Weng,

Employee of Merck Co.,

3;

G. Zingaro,

Merck Pharmaceuticals,

3;

G. Marcantonio,

Merck Pharmaceuticals,

3.

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