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P306 MORF-057, an oral selective α4β7 integrin inhibitor for Inflammatory Bowel Disease, leads to specific target engagement in a single and multiple ascending dose study in healthy subjects

Ray, A.(1);Cui, D.(2);Lee, D.(2);Mangada, M.M.(1);Jones, J.(2);Bain, G.(1);Traber, P.G.(3);Vrishabhendra, L.H.(4);Krzeski, P.W.(5);Vande Casteele, N.(6,7);Reardon, M.M.(8);Stern, T.P.(9);Soo, C.L.(10);Nguyen, H.(11);Rogers, B.N.(12);Linde, P.G.(13);

(1)Morphic Therapeutic, Biology and Translation, Waltham, United States;(2)Morphic Therapeutic, Dmpk, Waltham, United States;(3)University of Pennsylvania, Medicine, Philadelphia, United States;(4)Medpace CPU, Principal Investigator, Cincinnati, United States;(5)Medpace, Medical Department, Warsaw, Poland;(6)Alimentiv, Precision Medicine, San Diego, United States;(7)University of California San Diego, Department of Medicine, La Jolla, United States;(8)Morphic Therapeutic, Pharmacovigilance, Waltham, United States;(9)Morphic Therapeutic, Biostatistics, Waltham, United States;(10)Morphic Therapeutic, Clinical Operations, Waltham, United States;(11)Morphic Therapeutic, Cmc, Waltham, United States;(12)Morphic Therapeutic, Research, Waltham, United States;(13)Morphic Therapeutic, Clinical, Waltham, United States

Background

MORF-057 is an orally administered small molecule designed to inhibit the α4β7 receptor, addressing an unmet medical need in inflammatory bowel disease (IBD) patients, and avoiding the need for periodic therapeutic infusions and the risk for infusion-related reactions. This study evaluated single (SAD) and multiple ascending doses (MAD) of MORF-057 in healthy volunteers.

Methods

This was a randomized, double-blind, placebo-controlled, single and multiple doses, phase 1 study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MORF-057 conducted in a Phase I Unit in the USA. Subjects were randomized 3:1 to MORF-057 or placebo capsules once daily in the SAD cohorts: 25, 50, 100, 150, and 400 mg; or twice daily (BID) in the MAD cohorts: 100 and 200 mg total daily doses (dosed as 50 and 100 mg BID, respectively). In the MAD cohorts, trough PK samples were obtained pre‑morning or pre-evening dose following administration of 50 or 100 mg BID, respectively. Blood samples to assess receptor occupancy (RO) of α4β7 and α4β1 integrins were obtained prior to the first dose and 12 hours after treatment.

Results

To date, 51 healthy subjects were dosed; 1 subject withdrew consent on Day 2 for personal reasons. Eleven non-serious adverse events (AEs) were reported; AEs were mild and did not result in discontinuation. Two reversible mild AEs in the 200 mg MAD cohort were possibly related to MORF-057 (macular / maculopapular rash). No safety signals were identified to date. Following dosing, MORF-057 was rapidly absorbed and systemic exposure increased approximately dose-proportionally (Fig.1). Mean α4β7 RO was found to be greater than 95% after each of the three highest single doses (Fig.2). In multiple dosing, mean α4β7 RO was greater than 90% at the lower dose, while the highest dose tested resulted in α4β7 RO saturation at steady state. α4β1 RO was below the limit of quantitation with mean trough values estimated to be <10% at any of the dose levels.


Conclusion

Current results demonstrated that single and multiple ascending doses of MORF-057 were well tolerated, with only mild, non-serious AEs reported that did not result in study drug discontinuation. MORF-057 demonstrated a favorable PK profile where target engagement was confirmed and resulted in α4β7 receptor saturation in many subjects receiving higher doses. These results support further investigation of MORF-057 and provide a basis for dose selection phase 2 studies in patients with IBD. (NCT04580745)

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