DOP100 RXC008, a first-in-class gastrointestinal restricted pan-ROCK inhibitor developed for treatment of intestinal fibrosis shows GI restriction and tolerability: Results from the phase 1 program in healthy participants.
Authors: Rieder F , Marshall A , Houslay K , Kilgour E , Naveed T , Huettner S , Koch A , Khan N , Timmis H 
Published: January 2025

Abstract

Background
Rho-associated coiled kinase (ROCK), comprising ROCK 1 and ROCK 2 is a nodal target for antifibrotic therapies. Systemic treatment with pan-ROCK inhibitors leads to adverse hypotensive effects1,2. RXC008, a highly potent and selective gastrointestinal (GI) tract restricted pan ROCK inhibitor was specifically designed to achieve antifibrotic effects in the GI tract without significant systemic exposure, thus avoiding unwanted systemic effects. This Phase 1 study aimed to assess the safety, tolerability, local and systemic exposure of RXC008 in healthy participants as part of a clinical development program for intestinal fibrosis.

Methods
We performed a single ascending dose (SAD) followed by a multiple ascending dose (MAD) study. In the SAD, 6 cohorts were randomised 2:1 to single oral doses of RXC008 or placebo between 10 and 1000 mg.
In the MAD, 3 cohorts were randomised 3:1 to RXC008 or placebo daily, at doses of 30, 100 and 300 mg, for 14 days.
Safety, tolerability and systemic exposure were assessed in both parts. 24 hour blood pressure monitoring and telemetry were used to evaluate hypotensive effects in the SAD and in the first cohort of the MAD.
MAD participants underwent Day 14 ileocolonoscopy to assess tissue drug concentrations in biopsies from the ileum and colon.

Results
Fifty-nine participants were randomised (36 in SAD, 23 in MAD).
RXC008 was well tolerated with no safety signals at any tested dose. There were no adverse events (AEs) reported in the SAD study. In the MAD, all AEs were mild or moderate with no trends observed. One adverse event of reduced appetite was considered to be related to study drug in a patient on 30 mg. There were no serious adverse events and no AEs leading to treatment discontinuation. No cardiovascular effects were observed in any participant. One participant receiving 30 mg withdrew from the study on day 11 due to personal reasons.
Systemic exposure was low or below the level of quantification at all doses and did not reach the pre-defined safety cut off for cardiovascular side effects predicted from preclinical studies. Tissue concentrations in the ileum and colon at all MAD doses were within the efficacious ranges predicted from preclinical fibrosis models.

Conclusion
Oral administration of RXC008 up to 1000 mg as a single dose and up to 300 mg once daily for 14 days is safe and well tolerated. We confirmed the GI restricted nature of the compound with robust tissue exposure and no clinically relevant systemic exposure. RXC008 is a promising treatment for patients with fibrostenotic Crohn’s disease and planning for a Phase 2 study is ongoing.

References
1.Noma, K. et al: Physiological role of ROCKs in the cardiovascular system. Am J Physiol Cell Physiol. 2006 Mar;290(3):C661-8.
2.Fujita H, Fukumoto Y, Saji K, Sugimura K, Demachi J, Nawata J, Shimokawa H. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels. 2010 Mar;25(2):144-9. doi: 10.1007/s00380-009-1176-8. Epub 2010 Mar 26. PMID: 20339976.