F-652 for aGvHD of the lower GI tract

During the recent Transplantation and Cellular Therapy (TCT) Meetings of ASTCT and CIBMTR, Doris M. Ponce, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, presented abstract #68. This abstract discussed a phase II study of a novel tissue-targeted recombinant human interleukin (IL)-22 dimer for the treatment of newly diagnosed acute graft-versus-host disease (aGvHD), specifically affecting the lower gastrointestinal (GI) tract.¹

Why target IL-22?

• IL-22 is produced by T cells and is up-regulated during inflammation²
• IL-22 has a crucial role in controlling bacterial infection, homeostasis, and tissue repair²
• IL-22 exerts these effects by binding to the cell surface IL-22 receptor and forming a complex, which subsequently activates the STAT3 signaling pathways²
• The IL-22 receptor complex consists of IL-22 R1 and R2. IL-22R1 is specifically expressed on epithelial cells, such as those in the intestine, but not in hematopoietic or immune cells²
• IL-22 supports the intestinal mucosa following damage¹:
  • Promotes epithelial survival and regeneration
  • Induces innate antimicrobial molecules, like REG3
• In murine models, the induction of GvHD led to elimination of host-derived IL-22-producing cells that correlated with increased mortality and GI pathology¹
• Treatment with exogenous IL-22 in mice with GvHD reduced GI pathology and improved survival¹

What is F-652?³

• F-652 is a recombinant fusion protein of two human IL-22 molecules linked to an immunoglobulin constant region
  • The IL-22 dimer mimics the binding of IL-22 to receptor IL-22R1
  • The immunoglobulin constant region extends the serum half-life
• A phase I, first-in-human, randomized, double-blind dose escalation study in healthy male volunteers found F-652, administered intravenously, was well tolerated, with favorable pharmacokinetics
• F-652 is also under investigation as a treatment for acute pancreatitis and alcoholic hepatitis²

Hypothesis¹

• Adding IL-22 to corticosteroids may improve the healing of GI tract injury caused by aGvHD and improve response to treatment in patients with newly diagnosed aGvHD of the lower GI tract
• The study was considered positive if a GvHD response rate of 60% or more was achieved, or negative if a response of ≤ 35% was achieved

Study design¹

• Phase II, open-label, multicenter, single cohort, prospective study (NCT02406651)^1,4
• 27 adult patients with biopsy proven, new onset lower GI aGvHD following allogeneic hematopoietic stem cell transplant (allo-HSCT) were enrolled
  • Median age: 55 years
  • Predominantly received peripheral blood stem cells as part of allo-HSCT
  • Most had Grade II–IV lower GI aGvHD (63%), with 22% having Grade III and 22% having Grade IV

Dosing of F-652¹

• 45 µg/kg, once per week for four weeks
  • Rate: 100 mL/hour for one hour per week⁴
• In combination with standard corticosteroids, such as prednisone (2 mg/kg/day)⁴

Endpoints¹

• Primary: pharmacokinetics, number of adverse events, and Day 28 lower GI aGvHD treatment response^1,4
• Other: Day 56 treatment response, changes to gut microbiota by 16S sequencing, and evaluation of plasma GvHD biomarkers

Responses¹

• Detectable levels of F-652 were achieved in all patients
• Of 27 evaluable patients
  • aGvHD Day 28 overall response rate: 70% (90% CI, 56–79)
• Of 20 patients whose response could be evaluated, treatment response according to Ann Arbor risk group, was
  • High risk: 58% (7/12)
  • Intermediate risk: 75% (3/4)
  • Low risk: 100% (4/4)
• Day 56 response rate: 59% had continued responses
• Three patients had a repeat GI biopsy post treatment and GI epithelial injury was improved
• Seventeen patients had stool samples collected; microbial diversity (p = 0.082) and abundance of protective commensal Blautia (p = 0.048) appeared higher in patients with a clinical response to F-652

Safety¹

• Serious treatment-emergent adverse events (TEAEs) occurred in 40% of patients (n = 11):
  • Enterocolitis: 1
  • Pyrexia: 1
  • Infection: 5
    • Sepsis: 2
    • Device-related: 1
    • Pneumonia: 1
    • Sinusitis: 1
  • Musculoskeletal: 2
  • Respiratory: 1
  • Squamous cell carcinoma 8 months post treatment: 1

Conclusion¹

• IL-22 plus corticosteroids led to a 70% response rate in patients with lower GI aGvHD, meeting the primary efficacy endpoint of the study
• Combining standard immunosuppression with tissue-supportive strategies was well tolerated and may provide a way to improve treatment response in GvHD