A Phase 2 Study of F-652, a Novel Tissue-Targeted Recombinant Human Interleukin-22 (IL-22) Dimer, for Treatment of Newly Diagnosed Acute Gvhd of the Lower GI Tract

Abstract

Background IL-22 has been shown to support intestinal mucosa after damage through multiple mechanisms, including promotion of epithelial survival and regeneration as well as induction of innate antimicrobial molecules such as REG3. In experimental murine models, aGVHD resulted in elimination of host-derived IL-22-producing cells, IL-22 deficiency increased GVHD mortality and GI pathology, and early initiation of treatment with exogenous IL-22 reduced GI pathology and improved survival. We thus tested if the addition of IL-22 to corticosteroids could promote healing of GI tract injury and improve treatment response in patients with lower GI aGVHD. Methods We conducted a 27-patient open-label, single-cohort, multicenter prospective phase 2 study between 05/16 and 05/19. Eligible pts were ≥ 18 yrs old and had new onset biopsy-proven grade II-IV lower GI aGVHD following an allo-HCT. Pts received F-652 once weekly at a dose of 45 μg/kg x 4 weeks in combination with standard corticosteroid treatment. Primary endpoints included PK, safety, and day 28 lower GI aGVHD response. Additional endpoints included day 56 treatment response, evaluation of changes in gut microbiota by 16S sequencing, and plasma GVHD biomarkers. The study was powered to distinguish between an unpromising response rate of 35% and a promising response rate of 60%. Results The 27 pts (median age 55 yrs, mostly PBSC recipients) had predominantly stage 2-4 lower GI GVHD (17/27, 63%), with 6/27 (22%) pts having stage 3 and 6/27 (22%) pts having stage 4 disease. All pts had detectable F-652 levels. Overall, 19/27 achieved a day 28 response (70%, 90%CI: 56-79, Fig 1A). Response to treatment based on Ann Arbor Risk, evaluable in 20 pts, was 7/12 (58%) with high, 3/4 (75%) with intermediate, and 4/4 (100%) with low risk biomarkers (Fig 1B). At day 56, 16 pts (59%) remained treatment responders. 3 pts had repeat GI biopsy after treatment and demonstrated improvement in GI epithelial injury (Fig 2). Additionally, in a subset of 17 pts with stool samples collected, microbial diversity and relative abundance of protective commensal Blautia appeared increased in pts with a clinical response to F-652 (p = 0.082 and 0.048, respectively, Fig 3A-B). Serious TEAEs were observed in 11 pts (40%) including enterocolitis (n = 1), pyrexia (n = 1), infection (2 sepsis, 1 device-related, 1 pneumonia, 1 sinusitis), musculoskeletal (n = 2), and respiratory (n = 1). One patient was diagnosed with squamous cell carcinoma 8 months after F-652 treatment. Conclusion IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response.