Updated Interim Results from a Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (RRMM)

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting T cell engager (TCE) designed to redirect T cells to kill BCMA expressing multiple myeloma (MM) cells. HPN217 contains 3 binding domains: anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is under investigation in patients with heavily pretreated relapsed/refractory MM (RRMM). Updated, interim results are presented including safety, PK, PD, response assessment from new dose level cohorts and durability of response.

Methods The ongoing Phase 1 study evaluates escalating doses of HPN217 in patients with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted therapy. Prior exposure to BCMA-targeting agents is permitted. Primary objectives are characterization of safety, tolerability, PK, and determination of the Recommended Phase 2 Dose. Secondary objectives are assessment of immunogenicity and preliminary anti-myeloma activity. Dose escalation evaluates fixed-dose and step-dose regimens. HPN217 is administered intravenously, once weekly. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Clinical activity is investigator assessed per International Myeloma Working Group Response Criteria.

Results As of June 27, 2022, 49 patients were treated with HPN217. The highest fixed-dose level administered was 2860 μg/wk. The highest step-dose level assessed was 12000 μg/wk, dose escalation in step-dose regimens is ongoing. Patients received a median of 6 prior systemic regimens (84% prior transplantation, 69% penta-exposed, 22% prior BCMA-targeted therapy). Median age (range) was 70 (38-78). Median duration of treatment is 10.1 weeks (0.1 - 64 weeks; patient at 64 weeks ongoing with a continued response). The most common (≥20%) treatment-emergent adverse events (TEAEs) were anemia (49%), fatigue (37%), CRS (25%), nausea (22%), arthralgia (20%), diarrhea (20%) and transaminitis (20%). All CRS events were G1-G2 (no ≥ G3 events reported). In step-dose regimens, all CRS events were G1. No events of Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) were reported. Two dose-limiting toxicities (DLTs) of transaminitis were reported at 2860 μg/wk. No sequelae of liver failure were associated with these events. No DLTs have been reported in the step-dose regimen and the MTD has not been reached.

HPN217 continues to exhibit linear and dose proportional PK across dose levels with a median half-life of 66 h (range 26 to 197 h). Transient cytokine increases are higher with initial dosing compared to subsequent and step dosing. Patients with objectives responses (PR or better) have on treatment reduction in soluble BCMA, higher cytokine elevations and higher upregulation of the activation marker CD69 on CD8+ T cells.

Responses have been observed at all dose levels ≥ 2150 μg/wk. Dose escalation is continuing in step-dose regimens at 24000 μg/wk. Updated data including duration of response will be presented at the meeting.

Conclusions HPN217 is a novel half-life extended BCMA-targeting TCE that continues to be well tolerated in patients with RRMM resulting in durable responses. Treatment was well tolerated, TEAEs have been transient and manageable across dosing regimens. Step dosing has enabled continued dose escalation. No DLTs have been reported in the step-dose regimen and the MTD has not been reached. Changes in biomarkers associated with clinical responses were observed. NCT04184050

Cowan:Abbvie: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy; BMS: Consultancy, Research Funding; EUSA: Consultancy; GSK: Consultancy; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Research Funding; Sanofi: Research Funding; Secura Bio: Consultancy. Leleu:BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Amgen, Merck, BMS, GSK, Janssen, Oncopeptide, Takeda, Roche, Novartis, AbbVie, Sanofi, Gilead, Pfizer, Harpoon Therapeutic, Regeneron, Iteos: Consultancy, Honoraria; Amgen, BMS/Celgene, Janssen, Takeda, Novartis, Sanofi, Merck, Oncopeptide, Karyopharm, Roche, Abbvie, Carsgen, GSK, and Harpoon Therapeutics: Honoraria. Lipe:Bristol-Myers Squibb: Consultancy, Research Funding; Sanofi: Consultancy; GSK: Consultancy; Seagen Inc.: Research Funding; Amgen: Research Funding; Harpoon: Research Funding; Janssen: Consultancy, Research Funding. Costello:BMS, Takeda, Janssen, Pfizer: Honoraria, Research Funding. Hillengass:Adaptive: Honoraria; Amgen: Honoraria; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria; Beijing Life Oasis Public Service Center: Honoraria; Beijing Medical Award Foundation: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Oncopeptides: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Morillo Giles:Abbvie: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Oriol:Bristol Myers Squibb: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy. Yaron:Harpoon Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ng:Harpoon Therapeutics: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Madan:Janssen, Amgen, GSK, BMS, Karyopharm, Oncopeptide, Pfizer: Honoraria, Speakers Bureau.