An Interim Report on a Phase 1/2 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC ®) Targeting B Cell Maturation Antigen for the Treatment of Relapsed/Refractory Multiple Myeloma
Authors: Madan Sumit , Abdallah Al-Ola , Cowan Andrew J. , Bensinger William I. , Hillengass Jens , Leleu Xavier , Medvedova Eva , Costello Caitlin , Lipe Brea , Schade Henning , Nath Rajneesh , Sun Liping Laura 
Published: November 2021

Abstract
Background
B cell maturation antigen (BCMA) is a clinically validated target for multiple myeloma (MM) based on its restricted expression profile and potential functional role in promoting MM cell survival. HPN217 is a BCMA-targeting T cell engager derived from the Harpoon Tri-specific T cell Activating Construct (TriTAC ®) platform. It is a recombinant polypeptide of approximately 50 kDa, engineered to be a small globular protein to enable efficient drug diffusion and exposure in tumor tissue and have a prolonged serum half-life at the same time. It contains three humanized antibody-derived binding domains, targeting BCMA for MM cell binding, albumin for half-life extension, and CD3ε for T cell engagement, activation, and cytolytic function differentiation.
Methods
The ongoing Phase 1 study initially evaluates escalating doses of once weekly IV administrations of HPN217 in patients with relapsed/refractory (R/R) MM 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 agent is permitted for this initial part of the trial. Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor. Primary endpoints are safety, tolerability, and determination of maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D). Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-myeloma activity.
Results
As of July 5, 2021, 22 patients have been treated with HPN217 in 8 individual cohorts ranging from 5 to 2150 µg/week. Patients treated received a median of 8 (range of 4 - 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel. No dose-limiting toxicities (DLTs) have been observed and MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) are hematological changes including anemia, neutropenia, and thrombocytopenia. No CRS was observed in dose cohorts receiving 5 - 270 µg/week (n=7). CRS (Grade 1, 2) was observed in 4 of 15 patients receiving ≥810 µg/week. In one patient treated at 810 µg/week, transient elevated liver transaminases (Grade 4 AST and Grade 3 ALT) was observed. A second patient in the 270 µg/week cohort also showed Grade 1 AST increase. All CRS events and liver enzyme increases resolved, and all patients were successfully re-treated with escalating doses. HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 - 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increases in serum cytokines and chemokines (e.g., IL-6, IL-8, IL-10, TNFα). A transient reduction in circulating T lymphocytes accompanied by upregulation of the activation markers CD25 and CD69 were also observed. Patient response to treatment will be reported.
Conclusions
HPN217 represents a novel half-life extended BCMA-targeting T cell engager that can be safely administered to patients with R/R MM at a dose of up to 2150 µg weekly. TEAEs have been transient and manageable. Transient serum cytokine/chemokine increase, T cell margination and upregulation of T cell activation markers, indicate target engagement of BCMA on plasma cells and CD3 on T cells, respectively, supporting the proposed mechanism of action for HPN217. Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050

Disclosures
Madan: Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Cowan: Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Cellectar: Consultancy; Nektar: Research Funding; GSK: Consultancy; Harpoon: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Hillengass: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau. Leleu: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; AbbVie: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Nath: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company. Sun: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.