M9466 / Jiangsu Hengrui Pharma, EMD Serono - LARVOL DELTA

Itareparib: A potent, selective and non-trapper PARP1 inhibitor for combination therapy with DNA damaging agents in solid tumors (AACR 2026) - "Multiple first generation non-selective, trapping PARP1/2 inhibitors have been successful as single agent cancer treatments in homologous recombination (HR)-deficient malignancies; on the other hand, first-generation PARPi such as olaparib (a strong PARP1 trapper), or veliparib (a PARP1 trapper with medium potency), have not been successful in combination with chemotherapy due to a poor therapeutic window. Recently, second generation trapper PARP1-selective inhibitors (e.g. saruparib, M9466, SNV1521 and palacaparib) have entered clinical development, based on preclinical evidence that PARP2 inhibition is associated with anemia and dispensable for anti-tumor efficacy...Indeed, all these inhibitors trap PARP1 on DNA lesions, causing hematological adverse effects that are overlapping with those caused by chemotherapy agents such as temozolomide (TMZ) and topoisomerase I inhibitors (TOP1i), thus limiting their combination potential. We used biochemical and cellular assays to..."

Combination therapy • Brain Cancer • Glioma • High Grade Glioma • Lung Cancer • Oncology • Ovarian Cancer • Small Cell Lung Cancer • Solid Tumor • PARP2 • SLFN11

Merck KGaA drops pipeline assets from SpringWorks buyout, Hengrui licensing deal (FierceBiotech) - "Merck KGaA has opted not to continue development of SW-682, a Hippo pathway inhibitor that was included in Merck KGaA’s third-quarter financial presentation but was absent from its end-of-year presentation. The company picked up the drug as part of its SpringWorks purchase last year.... A Merck KGaA spokesperson confirmed to Fierce that the asset is no longer being pursued. Another asset, a PARP1 inhibitor called M9466, was listed in Merck KGaA’s third-quarter financial statement. The candidate was licensed from Hengrui for $169 million in 2023. The colorectal cancer therapy was no longer listed in the company’s year-end presentation, and its phase 1b trial is listed as terminated. A Merck KGaA spokesperson confirmed that the candidate is being completely culled."

Pipeline update • Colorectal Cancer

M9466 in Combination With Topoisomerase 1 Inhibitors-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511) (clinicaltrials.gov) - P1 | N=3 | Terminated | Sponsor: EMD Serono Research & Development Institute, Inc. | N=54 ➔ 3 | Trial completion date: Apr 2026 ➔ Dec 2025 | Suspended ➔ Terminated | Trial primary completion date: Apr 2026 ➔ Dec 2025; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Colorectal Cancer • Oncology • Solid Tumor

M9466 Alone or in Combination in Advanced Solid Tumors (DDriver 501) (clinicaltrials.gov) - P1 | N=141 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Solid Tumor

A Study of HRS-5041 Tablets Combined With Antitumor Therapy in Subjects With Advanced Prostate Cancer (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd. | Trial completion date: Dec 2026 ➔ Jun 2027 | Trial primary completion date: Sep 2025 ➔ Jun 2026

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

M9466 Alone or in Combination in Advanced Solid Tumors (DDriver 501) (clinicaltrials.gov) - P1 | N=141 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | N=96 ➔ 141 | Trial completion date: Mar 2026 ➔ Feb 2027 | Trial primary completion date: Mar 2026 ➔ Feb 2027

Enrollment change • Trial completion date • Trial primary completion date • Solid Tumor

Phase 1 Study of M9466 Combined With Carboplatin and Platinum-based Anticancer Therapy (DDRiver 521) (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: EMD Serono Research & Development Institute, Inc. | N=54 ➔ 0 | Trial completion date: Oct 2027 ➔ May 2025 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Oct 2027 ➔ May 2025

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Oncology • Solid Tumor

M9466 (HRS-1167): A highly potent and selective PARP1 inhibitor with DNA trapping activity, monotherapy antitumor activity and synergistic potential with DDR inhibitors and chemotherapies (AACR 2025) - P1 | "Currently approved PARP inhibitors (PARPis) such as olaparib, niraparib and talazoparib show synthetic lethality in homologous recombination deficient (HRD) cancers including those with BRCA1/2 mutations...The screen highlighted synergistic activity of M9466 with certain DDR inhibitors (ATR and ATM kinase inhibitors) and with topoisomerase I (Topo I) inhibitors and temozolomide...Here, M9466 enhanced the antitumor efficacy of the ATR inhibitor tuvusertib and the chemotherapy carboplatin. Thus, M9466 has strong single agent synthetic lethal activity in HRD models and combinability with selected DDRis and chemotherapies. Based on these data, Phase I clinical trials are evaluating M9466-based combinations in patients with advanced solid tumors, and colorectal cancer (NCT06421935, NCT06509906)."

Monotherapy • Breast Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • HRD • PARP2

Study of HRS-1167 as Monotherapy in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=153 | Recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd. | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Ovarian Cancer • Prostate Cancer • Solid Tumor • HRD

M9466 in Combination With Topoisomerase 1 Inhibitors-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511) (clinicaltrials.gov) - P1 | N=54 | Suspended | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Suspended

Trial suspension • Colorectal Cancer • Oncology • Solid Tumor

Phase 1 Study of M9466 Combined With Carboplatin and Platinum-based Anticancer Therapy (DDRiver 521) (clinicaltrials.gov) - P1 | N=54 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Initiation date: Jan 2025 ➔ Jul 2025

Trial initiation date • Oncology • Solid Tumor

A Study for the Treatment of Metastatic Prostate Cancer With HRS-1167 Tablets Combined With Abiraterone Acetate Tablets and Prednisone (clinicaltrials.gov) - P1/2 | N=66 | Recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase 1 Study of M9466 Combined With Carboplatin and Platinum-based Anticancer Therapy (DDRiver 521) (clinicaltrials.gov) - P1 | N=54 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

Combination therapy • New P1 trial • Oncology • Solid Tumor

Neoadjuvant Treatment of gBRCA-Mutated HER2-Negative Breast Cancer With HRS-1167 and Famitinib ± Camrelizumab (clinicaltrials.gov) - P2 | N=130 | Recruiting | Sponsor: Fudan University | Not yet recruiting ➔ Recruiting | Initiation date: Jul 2024 ➔ Sep 2024

Enrollment open • IO biomarker • Trial initiation date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • BRCA

A Study for the Treatment of Metastatic Prostate Cancer With HRS-1167 Tablets Combined With Abiraterone Acetate Tablets and Prednisone (clinicaltrials.gov) - P1/2 | N=66 | Not yet recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd.

New P1/2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

M9466 in Combination With Topoisomerase 1 Inhibitors-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511) (clinicaltrials.gov) - P1 | N=54 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study of HRS-5041 Tablets Combined With Antitumor Therapy in Subjects With Advanced Prostate Cancer (clinicaltrials.gov) - P1/2 | N=100 | Recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Hengrui Medicine: HRS-1167 tablets, HRS-5041 tablets and SHR2554 tablets received drug clinical trial approval notice [Google translation] (Wallstreet.org) - "Hengrui Medicine announced that the company and its subsidiary Chengdu Shengdi Pharmaceutical Co., Ltd. recently received the 'Drug Clinical Trial Approval Notice' for HRS-1167 tablets, HRS-5041 tablets and SHR2554 tablets approved and issued by the National Medical Products Administration, and will conduct clinical trials in the near future. HRS-5041 tablets will be combined with HRS-1167 tablets, SHR2554 tablets, abiraterone acetate tablets (II) and docetaxel for clinical trials of advanced prostate cancer."

New trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Study of HRS-5041 Tablets Combined With Antitumor Therapy in Subjects With Advanced Prostate Cancer (clinicaltrials.gov) - P1/2 | N=100 | Not yet recruiting | Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Metastases • New P1/2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

M9466 as Single Agent or in Combination With Tuvusertib in Advanced Solid Tumors (DDRiver 501) (clinicaltrials.gov) - P1 | N=70 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Oncology • Solid Tumor

Neoadjuvant Treatment of gBRCA-Mutated HER2-Negative Breast Cancer With HRS-1167 and Famitinib ± Camrelizumab (clinicaltrials.gov) - P2 | N=130 | Not yet recruiting | Sponsor: Fudan University

IO biomarker • New P2 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • BRCA

M9466 in Combination With Topoisomerase 1 Inhibitors-based Regimens in Advanced Solid Tumors and Colorectal Cancer (DDRiver 511) (clinicaltrials.gov) - P1 | N=54 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

Combination therapy • Metastases • New P1 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Merck’s Innovative Oncology Pipeline of DNA Damage Response Inhibitors and Antibody-Drug Conjugates Poised to Advance Cancer Treatment (Businesswire) - "Merck...shared updates on the company’s oncology pipeline and focused approach to the research and development of potential new medicines designed to improve the futures of people with cancer...This year, the company plans to open multiple new Phase Ib and II clinical studies for tuvusertib and M9466...updates were shared at the company’s Oncology R&D Update Call...A basket trial planned to launch in early 2025 will further explore M9140 monotherapy in tumors with high CEACAM5 expression, with the potential for further exploration in various combinations...M3554 is the next ADC based on the company’s platform, linking an exatecan payload with an anti-GD2 antibody. This potentially first-in-class ADC will enter its first-in-human study later in 2024."

New P1 trial • New P2 trial • Genito-urinary Cancer • Gynecologic Cancers • Oncology • Osteosarcoma • Ovarian Cancer • Prostate Cancer • Sarcoma • Solid Tumor

A phase 1 study of HRS-1167 (M9466), a highly selective PARP1 inhibitor, in patients (pts) with advanced solid tumors. (ASCO 2024) - P1 | "HRS-1167 was well-tolerated and exhibited favorable safety and PK profiles in pts with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated pts with HRR mutations."

Clinical • Metastases • P1 data • Anemia • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD • PALB2 • PARP2 • RAD51C • RAD51D

M9466 as Single Agent or in Combination With Tuvusertib in Advanced Solid Tumors (DDRiver 501) (clinicaltrials.gov) - P1 | N=70 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

Combination therapy • Metastases • New P1 trial • Oncology • Solid Tumor