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805 ELA026, a Monoclonal Antibody Targeting Signal Regulatory Protein-α/β1/γ, Rapidly Controls Inflammation and Improves 2-Month Survival in Treatment-Naïve Malignancy-Associated Hemophagocytic Lymphohistiocytosis

Program: Oral and Poster Abstracts
Type: Oral
Session: 201. Granulocytes, Monocytes, and Macrophages: From Inflammation to Hemophagocytic Lymphohistiocytosis
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Clinical Research, Study Population, Human
Monday, December 9, 2024: 2:45 PM

Abhishek Maiti, MBBS1, Naval Daver, MD2, William T. Johnson, DO3, Gaurav Goyal, MD4, Catherine M. Broome, MD5, Satyen Gohil, MD PhD6*, Jan Van Laar7*, Javier Lopez Jimenez, MD, PhD8*, David McCall, MD9, Hayley Lane10*, Benjamin Kim, MD, MPhil10, Sandip Panicker, PhD10, Gary Patou, MD10*, Stephen Moore11*, Brian Mangal12*, Kelly Covert13*, Graham Carl Parry, PhD13*, Kathy Dong, MBA, PharmD11*, Carl Allen14* and Swaminathan P Iyer, MD15*

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2MD Anderson Cancer Center, Houston, TX
3Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
4Research Collaborator (limited-tenure), Division of Hematology, Mayo Clinic, Birmingham, AL
5Division of Hematology, MedStar Georgetown University Hospital, Washington, DC, USA, Washington
6University College London Hospitals NHS Foundation Trust, London, United Kingdom
7Erasmus University Medical Center, Rotterdam, NLD
8Hosp Universitario Ramon Y Cajal, Madrid 28034, ESP
9Division of Pediatrics, MD Anderson, Bellaire, TX
10Star Therapeutics, Inc., South San Francisco, CA
11Electra Therapeutics, South San Francisco, CA
12Solara Consulting Corp, North Vancouver, Canada
13Electra Therapeutics Inc., South San Francisco, CA
14Texas Children's Cancer Center, Houston, TX
15Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: ELA026 is a first-in-class human monoclonal antibody directed against signal regulatory protein (SIRP)α1/γ and is under clinical investigation in secondary hemophagocytic lymphohistiocytosis (sHLH). sHLH is a life-threatening hyperinflammatory condition caused by failure to terminate the activation and proliferation of natural killer (NK), T cells and macrophages after an initial immune response. There are no approved therapies for sHLH. With a mortality rate of approximately 50% at 2 months (Lionel et al. 2023), malignancy-associated HLH (mHLH) is the deadliest subtype of sHLH. Cytotoxic, multi-agent chemotherapy (including etoposide) does not address the poor prognosis associated with mHLH (Xie et al. 2013). Directly targeting the pathogenic SIRP(+) myeloid cells and T lymphocytes represents a novel approach to resolving this severe hyperinflammatory condition.

Methods: This is an open-label, single-arm, Phase 1b global multicenter study (NCT05416307) evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of ELA026 in adult and pediatric patients with newly diagnosed and previously treated sHLH. The study is expanding enrollment to evaluate a fixed-dose regimen consisting of a priming phase of 0.1 mg/kg Day 1 and 0.3 mg/kg Days 2-4, followed by a maintenance phase of 0.5 mg/kg twice weekly beginning on Day 8. ELA026 is administered intravenously, with the option to transition to subcutaneous administration upon hospital discharge. The treatment period is 12 weeks with the option to extend in patients deriving ongoing clinical benefits. Enrollment in this cohort is restricted to frontline settings based on the experience that relapsed/refractory sHLH patients exhibited poor survival even with HLH disease control and died from complications related to severe baseline comorbidities. Response is evaluated using a modified HLH-2004 criteria (Locatelli et al. 2020) and survival is calculated from the time of HLH diagnosis. All patients receive dexamethasone as background therapy and premedication initially. Patients with mHLH may also receive cancer-directed therapies concurrently. Primary pharmacodynamic (PD) effects (monocyte and lymphocyte reduction) and secondary PD effects (C-reactive protein [CRP], ferritin, and sCD25 reduction) were best evaluated and attributed to ELA026 during windows of treatment without concurrent chemotherapy effects.

Results: As of July 15, 2024, 12 treatment-naïve mHLH patients have enrolled in all cohorts of the study, with a median age of 47 years (range 21-78). The following malignancies were represented: 7 T-cell lymphoma, 2 DLBCL, 1 AML, 1 Hodgkin lymphoma, and 1 T-cell ALL. In this group, response rate was 100% with 2 mCR and 9 PR by Week 4 and survival was 88% at 2 months (7/8; 4 patients are alive and have not reached 2 months on study). Median survival has not been reached; median follow-up is 2.3 months (range 0.1-15.9 months). In terms of PD effects, monocyte and lymphocyte reduction generally occurred following the first priming dose and ferritin and CRP were reduced by an average of 40% and 50% by Day 6, respectively, for patients with windows of ELA026 treatment without concurrent chemotherapy effects. Study-wide (all patients dosed), treatment-related infusion reactions (~20%) and cytopenias (~30%) were generally manageable with supportive care and dosing modifications. One serious adverse event, a grade 4 infusion reaction, was assessed as related in a relapsed/refractory mHLH patient with acute liver failure and poor hemodynamic reserve. Infection risks are expected for this patient population, which were mitigated with growth factor support and antimicrobial prophylaxis. No deaths were related to study drug. Updated study results will be provided at the 2024 ASH meeting in San Diego.

Conclusion: Data suggest ELA026 is well-tolerated to date in sHLH patients and results in a 100% response rate and improved 2-month survival in treatment-naïve mHLH patients. The study is enrolling in an expanded cohort to further assess efficacy in this patient population.

Disclosures: Maiti: CytoMed Therapeutics: Research Funding; Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; Indapta Therapeutics: Research Funding; Inspirna: Research Funding; Lin Biosciences: Research Funding. Daver: Agios: Consultancy; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Shattuck Labs: Consultancy; Celgene: Consultancy; KITE: Research Funding; Menarini Group: Consultancy; Trovagene: Research Funding; Syndax: Consultancy; Hanmi: Research Funding; Astellas: Consultancy, Research Funding; Jazz: Consultancy; Arog: Consultancy; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding. Johnson: Electra Therapeutics: Other: Advisory Board; Sobi: Other: Advisory Board; BioNTech: Consultancy. Goyal: Opna Bio, Seagen: Membership on an entity's Board of Directors or advisory committees; Recordati: Consultancy. Broome: Alpine: Consultancy, Honoraria, Research Funding; argenx: Consultancy, Honoraria, Research Funding; Electra: Research Funding; Novartis: Research Funding; Alexion: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Gohil: Gilead: Speakers Bureau; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; EUSA/Recordati: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Electra Pharma: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Takeda: Other: Travel and conference support; Novalgen​: Consultancy, Patents & Royalties; UCL Business: Patents & Royalties; Abbvie: Honoraria, Other: travel support. Van Laar: Simbercoin / Electra: Membership on an entity's Board of Directors or advisory committees. Lane: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kim: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Panicker: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Patou: Star Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Iyer: Innate: Research Funding; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Acrotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Crispr: Membership on an entity's Board of Directors or advisory committees, Research Funding; Salarius: Consultancy; Ono: Research Funding; IMPaRT.AI: Other: Stock, Founder; Trillium: Research Funding; Astra Zeneca: Research Funding; Merck: Research Funding; Yingli: Membership on an entity's Board of Directors or advisory committees, Research Funding; Legend: Research Funding; Seagen/Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; JCO-CCI: Other: Editor.

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