HPN536 / Merck (MSD) - LARVOL DELTA

Predicting the starting dose and step-up regimen for first-in-human trial of T-cell engagers using mechanistic mathematical modeling (AACR 2025) - "The optimal step-up regimen is the one that minimizes peak trimer levels and results in the highest trough trimer level at the target dose. Considering once-weekly administration of the HPN536 target dose, the optimal regimen with two step-ups was as follows: 0.001 mg/kg given on day 1, 0.003 mg/kg given on day 4, and 0.01 mg/kg QW started on day 8 (target dose).Applying QSP modeling to predict MRSD in addition to the MABEL PK-driven approach might help reduce the number of dose escalation steps, exposing patients to sub-therapeutic doses in first-in-human trials, and optimize step-up dosing regimens."

P1 data • Oncology • Ovarian Cancer • Solid Tumor • MSLN

ZW171, a differentiated 2+1 T cell-engaging bispecific antibody with antitumor activity in a range of mesothelin-expressing cancers (AACR 2025) - P1 | "We previously showed that the unique geometry and 2+1 design of ZW171 facilitates tumor selective binding and potent preferential killing of MSLN-mid and -high target cells, while sparing MSLN-low expressing target cells, and enhanced antitumor activity compared to other 2+1 TCE formats and the clinical benchmark HPN536 in MSLN-expressing PBMC-engrafted CDX models. To address the evolving clinical landscape and assess antitumor activity in additional indications and more translationally relevant models, we assessed ZW171 activity in advanced patient-derived organoid and xenograft models and benchmarked to other MSLN-targeting TCE including AMG 305, JNJ-79032421 and CT95...Overall, ZW171 demonstrates differentiated and potent antitumor activity in a range of MSLN-expressing cancers. ZW171 is being evaluated in a Phase 1 clinical trial in MSLN-expressing solid tumors (NCT06523803)."

Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • MSLN

Mechanistic translational modeling to predict first-in-human dose for T-cell engager: HPN536 case study (SITC 2024) - "Conclusions PK/RO/PA model provided more accurate prediction of MRSD for HPN536. Application of mechanistic modeling to predict MRSD in addition to MABEL PK-driven approach might help to reduce the number of dose escalation steps exposing patients to sub-therapeutic doses in first-in-human trials."

Case study • Clinical • P1 data • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • IFNG • IL2RA • MSLN • TNFA

Study of HPN536 in Patients With Advanced Cancers Associated With Mesothelin Expression (clinicaltrials.gov) - P1 | N=95 | Completed | Sponsor: Harpoon Therapeutics | Phase classification: P1/2 ➔ P1

Metastases • Phase classification • Gastrointestinal Cancer • Oncology

Prediction of first-in-human dose for HPN536, a T-cell engager targeting mesothelin: MABEL vs mechanistic translational PK/RO/PA modeling (SITC 2023) - "4 However, doses recommended by mechanistic modeling are higher, e. g. , 50% PA is observed in the model at doses around 1000 ng/kg or greater. This prediction is validated by the fact that maximal tolerated dose in HPN536 first-in-human trial was not reached even at dose 3600 ng/kg."

P1 data • Oncology • Ovarian Cancer • Solid Tumor • IFNG • IL2RA • MSLN • TNFA

Study of HPN536 in Patients With Advanced Cancers Associated With Mesothelin Expression (clinicaltrials.gov) - P1/2 | N=95 | Completed | Sponsor: Harpoon Therapeutics | Active, not recruiting ➔ Completed | N=200 ➔ 95 | Trial completion date: May 2023 ➔ Jan 2023

Enrollment change • Trial completion • Trial completion date • Gastrointestinal Cancer • Lung Cancer • Oncology • Solid Tumor

[VIRTUAL] Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs) and checkpoint inhibitors in preclinical models (AACR 2021) - P1/2 | "TriTAC molecules are currently being investigated in multiple phase 1/2 clinical trials in solid tumors, including HPN424 targeting prostate-specific membrane antigen (PSMA) in prostate cancer (NCT03577028), HPN536 targeting mesothelin (MSLN) in multiple malignancies (NCT03872206) and HPN328 targeting Delta Like Canonical Notch Ligand 3 (DLL3) in small cell lung cancer (SCLC) (NCT04471727). In addition, in the MSLN-expressing NCI-H292 lung cancer model that co-expresses constitutive, high levels of PD-L1, both anti-PD1 and anti-PDL1 antibodies significantly enhanced the antitumor effects of the MSLN-targeting TriTAC HPN536 in vivo. Together these results demonstrate the potential utility of PD1/PDL1 blockade to enhance the potency of TriTAC-mediated tumor cell killing, supporting further investigation of these combinatorial approaches in patients."

Checkpoint inhibition • Preclinical • Genito-urinary Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • DLL3 • MSLN

Study of HPN536 in Patients With Advanced Cancers Associated With Mesothelin Expression (clinicaltrials.gov) - P1/2 | N=200 | Active, not recruiting | Sponsor: Harpoon Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Cancer • Lung Cancer • Oncology • Solid Tumor

Harpoon Therapeutics Reports First Quarter 2022 Financial Results and Provides Corporate Update (GlobeNewswire) - "HPN217 (BCMA) Phase 1/2 trial for relapsed, refractory multiple myeloma: Maximum tolerated dose (MTD) has not been reached and enrollment in escalation cohorts continues in first half of 2022. Harpoon plans to initiate a Phase 2 dose expansion trial in the second half of 2022; HPN536 (MSLN) Phase 1/2a trial for tumors expressing mesothelin: The dose escalation phase of the ongoing Phase 1/2a clinical trial for cancers expressing mesothelin is ongoing and is expected to be complete by year-end 2022."

Enrollment status • New P2 trial • Trial status • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor

A multispecific T cell engager binding to both membrane proximal and membrane distal epitopes of MSLN with low affinity CD3 for the treatment of AML and solid tumors (AACR 2022) - "Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP)... Collectively, these data demonstrate strong anti-tumor efficacy by this novel multispecific bivalent T cell engager. These data indicate the therapeutic potential of this molecule to activate T cells and improve the clinical efficacy in AML and MSLN-expressing solid tumors."

Acute Myelogenous Leukemia • Biliary Cancer • Breast Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • MSLN • MUC16

Study of HPN536 in Patients With Advanced Cancers Associated With Mesothelin Expression (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: Harpoon Therapeutics | Trial completion date: May 2022 ➔ May 2023 | Trial primary completion date: Apr 2022 ➔ Feb 2023

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Oncology • Solid Tumor

Harpoon Therapeutics Reports Fourth Quarter and Full Year 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - "HPN328: Harpoon to continue dose escalation to determine RP2D by year-end 2022; HPN217: Harpoon to select an RP2D and initiate dose expansion cohort by mid-2022; HPN536: Complete dose escalation by year-end 2022."

Trial status • Lung Cancer • Oncology • Small Cell Lung Cancer

Harpoon Therapeutics Provides Pipeline Development Milestones for 2022 (GlobeNewswire) - "Anticipated 2022 Milestones...HPN328 – Continue dose escalation to determine RP2D by year-end 2022; HPN217 – Select the RP2D and initiate dose expansion cohort during the first half of 2022; HPN536 – Complete dose escalation by year-end 2022; HPN424 – Complete dose escalation during the second half of 2022; HPN601 – IND submission by year-end 2022"

IND • Trial status • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor

Harpoon Therapeutics Reports Second Quarter 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - “Research and development expense for the second quarter ended June 30, 2021, was $18.3 million compared to $11.9 million for the quarter ended June 30, 2020. For the six months ended June 30, 2021, R&D expense was $34.5 million compared to $24.4 million for the six months ended June 30, 2020. The increase for both periods, primarily arose from higher clinical development and personnel-related expense, which included conducting preclinical studies and the continuation and preparation of the clinical trials for HPN424, HPN536, HPN217 and HPN328…HPN424 – initiate a dose expansion cohort of the Phase 1/2a trial by year end 2021.”

Commercial • Trial status • Oncology

Harpoon Therapeutics Provides Progress Update for TriTAC Clinical Programs and ProTriTAC Platform (GlobeNewswire) - "HPN536 (mesothelin TriTAC) Phase 1/2a clinical trial continues dose escalation...The Company expects to present interim data at a medical conference in 2021; Dose escalation for HPN217 (BCMA TriTAC) Phase 1/2 clinical trial making good progress...A presentation of interim data is anticipated as well as initiation of a dose expansion cohort in the second half of 2021; Dose escalation for HPN328 (DLL3 TriTAC) Phase 1/2 clinical trial initiated in late 2020 and has shown rapid progress...Presentation of initial interim data is planned for the second half of 2021."

P1/2 data • Trial status • Hematological Malignancies • Multiple Myeloma • Oncology • Small Cell Lung Cancer • Solid Tumor

Harpoon Therapeutics Reports First Quarter 2021 Financial Results and Provides Corporate Update (GlobeNewswire) - "Anticipated 2021 milestones: (i) HPN424 - present interim data from the dose escalation phase of the ongoing Phase 1/2a trial in the first half of 2021, and initiate the dose expansion cohort mid-year 2021; (ii) HPN536 - in the second half of 2021, initiate the dose expansion cohort of the ongoing Phase 1/2a trial and, by year end 2021, present interim Phase 1 data from the dose escalation phase of the trial."

P1 data • P1/2 data • Trial status • Genito-urinary Cancer • Oncology • Prostate Cancer

Study of HPN536 in Patients With Advanced Cancers Associated With Mesothelin Expression (clinicaltrials.gov) - P1/2; N=180; Recruiting; Sponsor: Harpoon Therapeutics; N=87 ➔ 180; Trial completion date: May 2021 ➔ May 2022; Trial primary completion date: May 2021 ➔ Apr 2022

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Oncology • Ovarian Cancer • CRP

Harpoon Therapeutics Announces Data from Poster Presentations at the AACR Annual Meeting 2021 (GlobeNewswire) - "Combinatorial antitumor effects of CD3-based trispecific T cell activating constructs (TriTACs®) and checkpoint inhibitors in preclinical models...Abstract #: 1573...Data presented today show that the combination of HPN536 with a PD-L1 inhibitor led to more potent antitumor activity in an MSLN expressing ovarian cancer xenograft model. Similar enhanced anti-tumor effects were shown in an MSLN expressing lung cancer model for HPN536 in combination with anti-PD1 or an anti-PD1 antibody. These data demonstrate the potential utility of PD1/PD-L1 blockade to enhance the potency of TriTAC® mediated tumor cell killing."

Clinical data • Preclinical • Oncology

Harpoon Therapeutics Announces Poster Presentations and Publication of Abstracts for AACR Annual Meeting 2021 (GlobeNewswire) - "Harpoon Therapeutics, Inc...today announced publication of abstracts for three poster presentations at the American Association for Cancer Research (AACR) Annual Meeting. The AACR Annual Meeting Week 1 will be held virtually from April 10-15, 2021. Posters will be available on Harpoon’s website following the presentations."

Preclinical • Oncology

Harpoon Therapeutics Reports Fourth Quarter and Full Year 2020 Financial Results and Provides Corporate Update (GlobeNewswire) - “Anticipated 2021 Milestones: HPN424 – in the first half of 2021, present interim data from the dose escalation phase of our Phase 1/2a trial and initiate the dose expansion cohort; HPN536 – in the second half of 2021, initiate the dose expansion cohort of our Phase 1/2a trial and, by year end 2021, present interim Phase 1 data from the dose escalation phase of the trial; HPN217 – in the second half of 2021, initiate the dose expansion cohort of our Phase 1/2 trial, and, in 2021, present interim data from the dose escalation phase of the trial; HPN328 – in the second half of 2021, present interim data from the dose escalation phase of our Phase 1/2 trial.”

Clinical data • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Multiple Myeloma • Oncology • Ovarian Cancer • Prostate Cancer

Harpoon Therapeutics Announces Pricing of Public Offering of Common Stock (GlobeNewswire) - "Harpoon Therapeutics, Inc...announced today the pricing of an underwritten public offering of 5,882,352 shares of its common stock at a price to the public of $17.00 per share...the net proceeds of the offering, together with other available funds, to fund the continued clinical development of HPN424 in metastatic castration-resistant prostate cancer, HPN536 in ovarian cancer and other solid tumors, HPN217 in multiple myeloma, and HPN328 for the treatment of small cell lung cancer and other neuroendocrine tumors expressing Delta-like canonical Notch ligand 3; to advance the development of....HPN601..."

Commercial • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor

Harpoon Therapeutics Reports Third Quarter 2020 Financial Results and Provides Corporate Update (GlobeNewswire) - "Additionally, we expect to advance our HPN424, HPN536, and HPN217 clinical programs in the fourth quarter and present preclinical data at SITC for our first ProTriTAC development program, HPN601, for the treatment of solid tumor malignancies.”"

Clinical • Preclinical • Oncology • Solid Tumor

Harpoon Therapeutics Reports Clinical Progress Across All Four TriTAC Pipeline Development Programs (GlobeNewswire) - P1/2, N=87; NCT03872206; Sponsor: Harpoon Therapeutics; "Pharmacokinetic analysis shows median half-life of more than 70 hours. Among the relapsed/refractory ovarian cancer patients with at least one post-baseline scan, 8 of 12 (67%) patients showed stability of target lesions...HPN536 appears to be well tolerated...Initiation of an expansion cohort is anticipated by the second half of 2021, with a presentation of Phase 1 data by year-end 2021."

P1 data • Trial status • Gastrointestinal Cancer • Gynecologic Cancers • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Peritoneal Cancer

HARPOON THERAPEUTICS TO HOST CLINICAL PIPELINE PROGRAMS UPDATE CALL AND WEBCAST ON DECEMBER 8, 2020 (GlobeNewswire) - “Harpoon Therapeutics, Inc…announced that it will host a conference call and webcast to review the status and provide a clinical update for its three most advanced TriTAC® programs. The discussion will be focused on HPN424 for the treatment of metastatic castration resistant prostate cancer, HPN536 initially in development for ovarian and pancreatic cancer and mesothelioma, and HPN217 for relapsed/refractory multiple myeloma.”

Clinical • Gastrointestinal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Hematological Malignancies • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer

Preclinical Characterization of HPN536, a Trispecific, T Cell-activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors. (PubMed, Clin Cancer Res) - P1/2 | "HPN536 is potent, well tolerated and exhibits extended half-life in non-human primates. It is current in phase 1 clinical testing in patients with MSLN-expressing malignancies (NCT03872206)."

Journal • Preclinical • Breast Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • MSLN