DF-003 demonstrates efficacy in mouse model of ROSAH syndrome

Drug Farm, a clinical stage, biopharmaceutical company advancing two novel small molecule drugs for ROSAH syndrome and hepatitis B today announced a peer-reviewed publication, “Discovery of a selective alpha-kinase 1 inhibitor for the rare genetic disease ROSAH syndrome”, in the high impact journal Nature Communications. The publication can be accessed at https://rdcu.be/eFaUt.

The study describes the identification of a structurally novel ALPK1 inhibitor, DF-003 with pharmacokinetic properties suitable for daily oral dosing. DF-003 was shown to potently and selectively inhibit ALPK1 and the ROSAH disease-causing mutant ALPK1 [T237M]. In a mouse model of ROSAH, DF-003 was able to cross the blood-retina/brain barriers and reduce inflammatory cytokines and phenotypes associated with the disease. This work provides the preclinical rationale for the ongoing clinical trial (NCT06395285) of DF-003 in patients with ROSAH syndrome.

“We have designed a drug that treats the genetic root cause of ROSAH and is potentially applicable to other diseases driven by excessive ALPK1 activity which can lead to NF-κB–mediated inflammatory responses, including atherosclerotic cardiovascular disease,” said Tony Xu, Ph.D., corresponding author on this article and Chief Operations Officer at Drug Farm.

DF-003 is the first ALPK1 inhibitor to successfully complete a first-in-human Phase 1 study and has now entered a Phase 1b trial in patients with ROSAH syndrome.

“I am excited about the potential for DF-003 to save sight in patients with ROSAH syndrome, a disease without any approved drugs,” said Vinit Mahajan, M.D., Ph.D., Professor of Ophthalmology, Stanford University and co-author on the study.

About DF-003

DF-003 is a proprietary, first-in-class drug developed by Drug Farm that inhibits the activity of ALPK1 and variants of ALPK1 which cause ROSAH syndrome. DF-003 has therapeutic potential for ROSAH syndrome, as well as heart and kidney diseases, as the drug has shown efficacy in preclinical models of these indications. DF-003 has completed a Phase 1 clinical trial (NCT05997641) in normal healthy volunteers and is now accruing patients with ROSAH syndrome in a Phase 1b trial (NCT06395285).

About ROSAH Syndrome

ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and headache) syndrome is a rare, autosomal dominant autoinflammatory genetic disease named according to the characteristic symptoms exhibited by affected patients (1, 2). Disease-causing mutations in ALPK1 lead to ROSAH syndrome. The most common presenting symptom is a progressive decline in visual acuity that typically begins before 20 years of age, with ophthalmologic examination often revealing optic disc elevation, uveitis, and retinal nerve degeneration (2, 3). Most ROSAH patients also exhibit inflammatory features such as non-infectious low-grade fevers, arthralgia, headaches, and persistently elevated levels of inflammatory cytokines including tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), and IL-1β (3).

1. Tantravahi SK, et al. An inherited disorder with splenomegaly, cytopenias, and vision loss. Am J Med Genet A. 2012;158(3):475-81.

2. Williams LB, et al. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet Med. 2019;21(9):2103-15.

3. Kozycki CT, et al. Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Ann Rheum Dis. 2022;81(10):1453-64.

About Drug Farm

Drug Farm is a private biotechnology Company developing innovative treatments targeting innate immunity for hepatitis B, heart and kidney diseases, and ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis and headache) syndrome. Drug Farm's unique IDInVivo platform combines breakthrough technologies in genetics and AI to discover new treatments. IDInVivo technology allows the direct assessment of gene targets in living animals with intact immune systems. Using the IDInVivo platform, Drug Farm has identified novel innate immunity pathways and targets and is now rapidly advancing multiple first-in-class drug candidates into clinical development. For more information please visit: https://www.drug-farm.com.

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