Neihulizumab (ALTB-168) in Patients with Steroid-Refractory Acute Graft-Versus-Host-Disease (SR-aGVHD) or Treatment-Refractory Acute Graft-Versus-Host-Disease (TR-aGVHD)

Background: Neihulizumab represents a novel immune checkpoint agonistic antibody that binds to human CD162 (PSGL‑1), leading to downregulation of activated T-cells. Results of early-phase trials of neihulizumab have suggested a benefit in patients with auto-immune conditions, including psoriasis, psoriatic arthritis and ulcerative colitis. Here, we report preliminary results of a Phase I study investigating the use of neihulizumab for SR‑aGVHD or TR-aGVHD (ClinicalTrials.gov Identifier: NCT03327857).

Aims: The aims of this study were to establish the pharmacokinetics, receptor occupancy (RO), safety and efficacy of neihulizumab in patients with SR-aGVHD or TR-aGVHD.

Methods: SR-aGVHD was defined as aGVHD that (1) progressed after 3 days of treatment with methylprednisolone (MP) 2 mg/kg/day equivalent, or (2) persisted after 7 days of treatment with MP 2 mg/kg/day equivalent, or (3) progressed to involve a new organ after treatment with MP 1 mg/kg/day equivalent for skin and upper gastrointestinal aGVHD, or (4) recurred during or after steroid taper. TR-aGVHD was defined as having received one prior systemic treatment for aGVHD in addition to corticosteroid. Participants with demonstrable skin SR-aGVHD were enrolled and received a single dose of neihulizumab in Cohort 1 at either 3 mg/kg (Dose Level 1 [DL 1]) or 6 mg/kg (Dose Level 2 [DL 2]). With the completion of Cohort 1 and without observation of dose limiting toxicities, participants with any grade SR-aGVHD were enrolled for multiple dose treatment of neihulizumab (Cohort 2) with first dose at 6 mg/kg followed by weekly doses of 4 mg/kg for 3 weeks (6-4-4-4 regimen).

Results: A total of 37 participants were enrolled with 13 participants in Cohort 1 and 24 participants in Cohort 2.

In Cohort 1, all 13 participants had SR-aGVHD with erythematous manifestation of cutaneous aGVHD. In Cohort 2, 12 participants had SR-aGVHD and 12 had TR-aGVHD. Notably, 11 TR-aGVHD participants received ruxolitinib prior to neihulizumab treatment. A summary of study demographics and baseline disease characteristics is shown in Table 1.

In Cohort 1, at 4 hours after the end of the neihulizumab infusion, the median RO was 91% for both DL 1 and DL 2. At Day 8, median RO decreased to 69% (range 23-80%) in DL 1 but was maintained at 91% (range 90-102%) in DL 2. In Cohort 1, most frequently observed Grade 3-4 adverse events (AE, at least 5%) were lymphocyte count decreased, platelet count decreased, hyponatremia, hyperglycemia and white blood cell decreased. Day 28 overall response rate (ORR) was 86% in DL 1 and 50% in DL 2, including 1 complete response (CR). Details are described in Table 2.

In Cohort 2, 13 participants (54%) received all four doses of neihulizumab and reached the Day 28 aGVHD evaluation, 3 (13%) received three doses, and 8 received one or two doses. In this 6-4-4-4 dosing regimen, at 1 hour after the end of the first dose of neihulizumab infusion (6 mg/kg), the median RO was 93%. For subsequent weekly infusions (4 mg/kg) for three weeks, the median RO was maintained above 80% (range 84-93%) until Day 35. Day 28 ORR was 33% among SR-aGVHD participants, including 17% CR, and 67% among TR-aGVHD participants, including 25% CR (Table 2). The most frequently observed Grade 3-4 AEs (at least 5%) were anemia, platelet count decreased, hypocalcemia, lymphocyte count decreased, hypokalemia, hypoxia, ileus, sepsis and white blood cell decreased. Among the 24 participants in Cohort 2, 5 (42%) SR‑aGVHD and 4 (33%) TR-aGVHD participants died during the study period (Day 180). The median survival was 122.5 and 124 days (by 26^th July 2022) for SR-aGVHD and TR-aGVHD, respectively.

Summary/Conclusion: Neihulizumab appeared to be well-tolerated in participants with SR‑aGVHD or TR‑aGVHD. With the current 6-4-4-4 dosing regimen (6 mg/kg followed by 4 mg/kg weekly doses for 3 weeks), RO was maintained at least 80% throughout most of the treatment period. The Day 28 ORR was 69% in Cohort 1 and 50% in Cohort 2. The higher ORR in Cohort 1 is likely due to the participants with predominantly steroid refractory skin aGVHD. Of note, the ORR in participants with TR-aGVHD, of which 11 of 12 were receiving combination ruxolitinib therapy, appeared to be higher than in those with SR-aGVHD (67% vs 33%). These promising results support further investigation of neihulizumab as an agent in ruxolitinib-refractory SR-GVHD.