POS0899 FIRST-IN-HUMAN SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS DATA WITH MK-6194, A MODIFIED FORM OF INTERLEUKIN-2, DESIGNED TO SELECTIVELY ACTIVATE REGULATORY T-CELLS – SINGLE ASCENDING DOSE AND MULTIPLE ASCENDING DOSE TRIALS

Background:

Regulatory T cells (Tregs) maintain immune homeostasis and suppress inflammation. MK-6194 is an Fc-conjugated, modified form of IL-2, designed to selectively activate Tregs and attenuate inflammatory processes associated with a variety of autoimmune disorders.

Objectives:

We describe safety, pharmacokinetics (PK), and pharmacodynamics (PD) from two phase 1, double-blind, randomized, placebo-controlled trials of MK-6194 in healthy participants.

Methods:

Participants in the first-in-human single ascending dose (SAD) trial received subcutaneous (SC) MK-6194 or placebo (3:1 ratio) in consecutive dose levels: 1, 3.5, 5, 7.5, and 10 mg. Participants in the multiple ascending dose (MAD) trial received the SC MK-6194 or placebo (3:1 ratio): 0.5, 1, 2, or 3.5 mg every 2 weeks (Q2W) (3 doses), 5 mg Q2W (2 doses), and 5 mg every 4 weeks (Q4W) (2 doses). Safety and tolerability were assessed by monitoring adverse events (AE) and clinical laboratory testing. PK parameters of interest included AUC, Cmax, Tmax, and t1/2. PD endpoints included flow cytometry-based evaluation of Treg expansion, conventional T cells, and natural killer (NK) cells in addition to an orthogonal approach to measure Treg expansion with an epigenetic qPCR assay of the FOXP3 Treg-Specific Demethylated Region (TSDR).

Results:

A total of 56 and 54 participants were randomized in the SAD (no discontinuations) and MAD trials (7 discontinuations - 5 due to AEs and 2 withdrew consent), respectively. Participants were mostly male (57% and 83% in SAD and MAD, respectively) and mean age was 36 years in both studies. MK-6194 was generally well-tolerated, with no serious AEs or dose-limiting toxicities. In both studies, the most common AE in participants receiving MK-6194 was injection site erythema: 16.7% in the SAD trial and 87.8% in the MAD trial. Of note, a total of 51.2% of participants receiving MK-6194 in the MAD trial experienced elevated eosinophil counts. No participants developed severe eosinophilia (eosinophil count >5000/μL) or clinical signs of eosinophil-mediated organ damage. PK analysis showed dose-proportional PK after both single and multiple SC administrations (Figure 1). In the MAD trial, a dose-dependent Treg expansion was observed over time, peaking at 8-11 days post dose and returning close to baseline 14-29 days post dose with no indications of attenuation after repeat dosing. Minimal impact was observed on total T lymphocyte or natural killer (NK) cell counts in both studies. FOXP3 TSDR analysis also indicated dose-dependent increases in Tregs (Figure 2).

Conclusion:

MK-6194 was generally well-tolerated up to a dose of 10 mg administered as a single SC dose and up to 5 mg administered SC Q2W or Q4W in healthy participants. The PK of MK-6194 was linear and dose-proportional, and observed Treg expansion was dose dependent without attenuation after repeat dosing. These results support further development of MK-6194 for the treatment of autoimmune disorders. REFERENCES: NIL.

Acknowledgements:

NIL.

Disclosure of Interests:

Johannes Scheid Merck & Co., Inc., Merck & Co., Inc., Amy Cunningham-Bussel Merck & Co., Inc., Merck & Co., Inc., Nancy Kim Merck & Co., Inc., Merck & Co., Inc., Shiuli Agarwal Merck & Co., Inc., Merck & Co., Inc., Garrett Nieddu Merck & Co., Inc., Merck & Co., Inc., Josee Cote Merck & Co., Inc., Merck & Co., Inc., Lieselotte Lemoine Merck & Co., Inc., Merck & Co., Inc., Tatjana Decaestekar Merck & Co., Inc., Merck & Co., Inc., Luis Mendez Merck & Co., Inc., Merck & Co., Inc., Erina Paul Merck & Co., Inc., Merck & Co., Inc., Latisha Love-Gregory Merck & Co., Inc., Merck & Co., Inc., Alejandra Virginia Contreras Merck & Co., Inc., Merck & Co., Inc., Ling Pang Merck & Co., Inc., Merck & Co., Inc., Gretchen Baltus Merck & Co., Inc., Merck & Co., Inc., Maribel Beaumont Merck & Co., Inc., Merck & Co., Inc., Ketal Shah Merck & Co., Inc. , Merck & Co., Inc. , Nathan Higginson-Scott Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc. , Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc. , Katalin Kis-Toth Former employee of Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Former employee of Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Kevin Otipoby Former employee of Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Former employee of Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Joanne L. Viney Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Rahway, NJ, USA, Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Eric Sicard: None declared, Sylvie Rottey: None declared, John S. Sundy Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pandion Therapeutics, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Kristien Vandyck Merck & Co., Inc., Merck & Co., Inc., Tine Laethem Merck & Co., Inc., Merck & Co., Inc., Patrick Larson Merck & Co., Inc., Merck & Co., Inc., Santosh Sutradhar Merck & Co., Inc., Merck & Co., Inc., Richard Wnek Merck & Co., Inc., Merck & Co., Inc., Tjerk Bueters Merck & Co., Inc., Merck & Co., Inc., Eseng Lai Merck & Co., Inc., Merck & Co., Inc., Aubrey Stoch Merck & Co., Inc., Merck & Co., Inc., Marian Iwamoto Merck & Co., Inc., Merck & Co., Inc., Jonathan Robbins Merck & Co., Inc., Merck & Co., Inc.