GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the results from phase I study of GFH312 (RIPK1 inhibitor) monotherapy will be presented as a poster at the 2023 ASCPT Meeting in Atlanta on March 22nd. GFH312 is safe and well tolerated in healthy subjects in single or multiple doses with favorable PK /PD profile to support further clinical development.
As of July 2022, no grade 3 or above adverse effects were reported among all subjects. A rapid inhibition of RIPK1 phosphorylation in PBMCs was observed as soon as 2 hours post dosing in all dose groups and a sustained inhibition was achieved post multiple dosages. The data of cerebrospinal fluid (CSF) analysis from subjects receiving 120 mg daily administration suggest that GFH312 has exposure in the CNS and may potentially be useful for treating neurological indications. The phase I study of GFH312 was completed in Australia and GenFleet has been granted with the FDA approval for phase II study of GFH312.
“GFH312 is GenFleet’s first clinical-stage product granted with FDA’s IND approval for phase II study in non-oncology indication. The phase I study of GFH312 exhibited excellent safety/tolerability and fast inhibition of RIPK1 phosphorylation at the cellular level in subjects. RIPK1 is an important regulator of multiple signaling pathways in inflammation and necropoptosis. We hope to further explore multiple indications including neurological and inflammatory diseases.” said by Yu Wang, M.D.,Ph.D., Chief Medical Officer of GenFleet.
A FIRST-IN-HUMAN PHASE I STUDY OF THE GFH312 A RIPK1 INHIBITOR, EVALUATING SAFETY/TOLERABILITY AND PHARMACOKINETICS IN HEALTHY SUBJECTS
This is a randomized (3:1), double-blinded, placebo-controlled first-in-human (FIH) study to assess safety/tolerability, pharmacokinetics and pharmacodynamics of GFH312 in healthy subjects, including seven single ascending dose (SAD) and three multiple ascending dose (MAD) cohorts. As of June 8, 2022, a total of 76 subjects have been enrolled into above dose levels. No grade 3 or above AEs were reported.
GFH312 was rapidly absorbed post a single oral dose with a median Tmax of 2 h ~ 8 h and eliminated with half-life of 6.3 ~ 23.3 h. Linear pharmacokinetic (PK) behavior was observed over the dose range from 45 mg to 360 mg. Limited accumulation was observed after multiple doses with accumulation ratio (RACmax and RAAUC) <2-fold across all dose cohorts GFH312 is safe and well tolerated in healthy subjects at either single or multiple doses, the PK characteristics support further clinical development of GFH312.
About RPIK1 and GFH312
As a subtype of receptor interacting protein kinase family, RIPK1 is a central regulator of multiple immune signaling pathways. Widely expressed in human cells, the serine/threonine kinase of RIPK1 is most abundant in adipocytes, endothelial and perivascular cell clusters and also discovered in immune cell clusters (dendritic cells, macrophages and T cells). Small-molecule RIPK1 inhibitors are expected to show efficacy for treating neurological, inflammatory and autoimmune diseases (including psoriasis, rheumatoid arthritis, ulcerative colitis, etc.).
In vitro experiments demonstrate that GFH312 blocks the process of TNF-α-induced necroptosis. It’s observed in a variety of animal models that GFH312 can reduce inflammation and resist necroptosis; besides, low dosage of GFH312 can significantly improve the action capability of experimental animals and decrease the death risk caused by acute systemic inflammation. The phase I clinical trial data confirm the safety and tolerability of GFH312.