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4709 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)

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, Antibody Therapy, Therapies, Monoclonal Antibody Therapy
Monday, December 12, 2022, 6:00 PM-8:00 PM

Sameem Abedin, MD1, Mehdi Hamadani, MD1, Shernan G Holtan, MD2, Gary J. Schiller, MD3, Molly Gallogly, MD, PhD4, Edmund K. Waller, MD, PhD5, Satyajit Kosuri, MD6*, Sunil H Abhyankar, MD7, Sarah M. Anand, MD8*, Mahasweta Gooptu, MD9, Iming Cho, PhD10*, Simona Reed, PhD10*, Shih-Yao Lin, MD, PhD10*, Jesse W Hall, MD10* and Paul J Martin, MD11

1The BMT & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI
2University of Minnesota, Minneapolis, MN
3David Geffen School of Medicine at UCLA, Los Angeles, CA
4University Hospitals Seidman Cancer Center, Cleveland, OH
5Winship Cancer Institute, Emory University, Atlanta, GA
6University of Chicago Medical Center, Chicago, IL
7University of Kansas Cancer Center, Westwood, KS
8University of Michigan, Ann Arbor, MI
9Dana-Farber Cancer Institute, Boston, MA
10AltruBio Inc, San Francisco, CA
11Fred Hutchinson Cancer Research Center, Seattle, WA

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 26th 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.

Disclosures: Abedin: Actinium Pharmaceuticals: Research Funding; Pfizer: Research Funding; Helsinn Healthcare: Research Funding; AltruBio Inc.: Research Funding; Stemline: Honoraria; Amgen: Honoraria; Incyte: Research Funding; AbbVie: Honoraria; Daichi Sankyo: Honoraria; Servier: Honoraria. Hamadani: Novartis: Consultancy; ADC Therapeutics: Consultancy, Research Funding, Speakers Bureau; BioGene: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Legend Biotech: Consultancy; AstraZeneca: Speakers Bureau; Kadmon: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; Takeda: Research Funding; Spectrum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Kite: Consultancy; Genmab: Consultancy; SeaGen: Consultancy; Gamida Cell: Consultancy; Incyte Corporation: Consultancy; MorphoSys: Consultancy; Medical University of Wisconsin: Current Employment. Holtan: CSL Behring: Other: Clinical trial adjudication; Vitrac Therapeutics: Research Funding; Incyte: Research Funding. Schiller: Cyclacel: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Pfizer: Research Funding; PreCOG LLC: Research Funding; AltruBio: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Stemline: Research Funding; AVM Biopharma: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Samus: Research Funding; Cellectis: Research Funding; Forma: Research Funding; Sellas: Research Funding; CTI: Research Funding; Cellerant: Research Funding; Ono Pharma: Honoraria; Novartis: Honoraria, Other: Speaker fees, Research Funding; Glycomimetics: Research Funding; Deltafly: Research Funding; Kite, a Gilead Company: Research Funding, Speakers Bureau; Regimmune: Research Funding; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; FujiFilm: Research Funding; Constellation: Research Funding; Millennium: Research Funding; AstraZeneca: Honoraria; Trovagen: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Sangamo: Research Funding; Onconova: Research Funding; Stemline: Speakers Bureau; Janssen: Research Funding; Mateon: Research Funding; Geron: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Medimmune: Research Funding; Gilead: Research Funding; Actuate: Research Funding; Deciphera: Research Funding; Jazz: Consultancy; Arog: Research Funding; Takeda: Research Funding; Tolero: Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Agios: Consultancy, Honoraria; Actinium: Research Funding; AbbVie: Research Funding, Speakers Bureau. Waller: Orca Bio: Research Funding; Verastem Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kosuri: Seres Therapeutics: Research Funding. Abhyankar: Incyte: Consultancy, Research Funding, Speakers Bureau; Therakos: Consultancy, Research Funding, Speakers Bureau; Talaris: Membership on an entity's Board of Directors or advisory committees. Hall: AltruBio: Current Employment, Current holder of stock options in a privately-held company.

*signifies non-member of ASH