On January 9, 2025 TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics ("BBOT" or the "Company"), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to BBO-8520, an investigational oral therapy for the treatment of adult patients with previously treated, KRASG12C-mutated metastatic non-small cell lung cancer (NSCLC) (Press release, BridgeBio, JAN 9, 2025, View Source [SID1234649558]).

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BBO-8520 is designed to inhibit the "ON and OFF" state to provide optimal target coverage and to address KRASG12C amplification and receptor tyrosine kinase activation – the two key mechanisms of adaptive resistance to current "OFF" state inhibitors. It drives substantial tumor growth inhibition in multiple preclinical models, even after emergence of resistance to sotorasib, an FDA approved "OFF" state inhibitor of KRASG12C.i The discovery of BBO-8520 was the result of a collaboration between the National Cancer Institute RAS Initiative at Frederick National Laboratory for Cancer Research, Lawrence Livermore National Laboratory, and BBOT.

"Receiving Fast Track designation for BBO-8520 is a significant milestone in our efforts to overcome the limitations of existing therapies for KRASG12C-mutant cancers," said Yong Ben, MD, Chief Medical and Development Officer of BBOT. "BBO-8520 represents a first-in-class approach with potential to address high unmet medical needs and shift the paradigm for cancer treatment. We will continue to work closely with the FDA to expedite the development of BBO-8520, which is currently being evaluated in a Phase 1 study (NCT06343402) of KRASG12C NSCLC patients pre-treated with first generation KRASG12C "OFF" inhibitors or with no prior KRASG12C targeted therapy experience."

Fast Track designation is intended to help rapidly advance the development and review process for promising therapeutic candidates for serious conditions that may fill an unmet medical need.

On January 9, 2025 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported a re-alignment of resources and a re-prioritization of its clinical portfolio to focus on the continued advancement of its Phase 1 clinical programs, RP-1664 (PLK4 inhibitor) and RP-3467 (Polθ ATPase inhibitor) (Press release, Repare Therapeutics, JAN 9, 2025, View Source [SID1234649557]). Repare also announced its intention to seek partnering opportunities across its portfolio, including for lunresertib and camonsertib ("Lunre+Camo") prior to any start of pivotal development. The consequent savings of late-stage clinical funding combined with planned cost and headcount reductions are expected to extend Repare’s cash runway into mid-2027.

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"While Lunre+Camo demonstrated positive results from our Phase 1 clinical trial, after careful consideration we have decided to progress this program into pivotal trials contingent on securing a strategic partner to fund further development. We are focused on achieving near-term inflection points for our Phase 1 clinical assets, RP-1664 and RP-3467, both of which have the potential to address significant unmet patient needs and deliver important catalysts in 2025," said Lloyd M. Segal, President and Chief Executive Officer of Repare. "Combined with other initiatives, these changes, which we will implement later this quarter, provide the foundation for meaningful value creation."

Recent Pipeline Progress & Upcoming Milestones of Prioritized Clinical Programs:

RP-1664: First-in-class, highly selective, oral inhibitor of PLK4

Repare is evaluating RP-1664 as a monotherapy in the Phase 1 LIONS clinical trial in adult and adolescent patients with TRIM37-high solid tumors.

Upcoming Expected Milestones:

Q3 2025: Initiation of a Phase 1/2 expansion trial in pediatric neuroblastoma
Q4 2025: Initial topline safety, tolerability and early efficacy data from the LIONS trial
Mid-2026: Trial completion, final trial readout for proof-of-concept from the LIONS trial
RP-3467: Potential best-in-class Polθ ATPase inhibitor

Repare is dosing patients in the Phase 1 POLAR clinical trial evaluating RP-3467 alone and in combination with the poly-ADP ribose polymerase (PARP) inhibitor, olaparib. This trial is enrolling patients with locally advanced or metastatic epithelial ovarian cancer, metastatic breast cancer, metastatic castration-resistant prostate cancer, or pancreatic adenocarcinoma.

Upcoming Expected Milestones:

Q3 2025: Topline safety, tolerability and early efficacy data from the POLAR trial in monotherapy and in combination with olaparib.
Lunresertib and Camonsertib

Repare recently reported positive efficacy and safety data from the Phase 1 MYTHIC gynecologic expansion clinical trial evaluating the combination of lunresertib and camonsertib (Lunre+Camo) at the recommended Phase 2 dose (RP2D) in patients with endometrial cancer (EC) and platinum-resistant ovarian cancer (PROC). Nearly half of patients with gynecologic cancers maintained progression-free survival (PFS) at 24 weeks, comparing favorably to PFS for current standard of care. Repare intends to seek partnering opportunities for this program as a condition to advancing the program into planned and regulatory-supported pivotal development.

Repare is currently evaluating lunresertib in combination with Debio 0123, a highly selective, brain-penetrant, clinical WEE1 inhibitor, in patients with advanced solid tumors harboring CCNE1 amplification or FBXW7 or PPP2R1A deleterious alterations as part of an ongoing 50/50 cost sharing collaboration with Debiopharm.

The Company will not continue to develop lunresertib or camonsertib in other studies, including the ongoing camonsertib non-small cell lung cancer expansion study, absent securing a partnership with a development partner.

Upcoming Expected Milestone:

Q2 2025: Enrollment completion of MYTHIC trial evaluating lunresertib in combination with Debio 0123 (WEE1 inhibitor)
Cash Position and Financial Guidance:

Repare ended 2024 with approximately $153 million in cash, cash equivalents and marketable securities, which is anticipated with the implementation of the cost-saving measures announced above to fund the Company’s streamlined operations into mid-2027.

On January 9, 2025 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) reported a new strategic collaboration and worldwide license agreement with MediLink Therapeutics (Suzhou) Co., Ltd. ("MediLink") to use MediLink’s TMALIN antibody-drug conjugate (ADC) platform for the development of a novel LRRC15 ADC, ZL-6201, consisting of an antibody discovered by Zai Lab (Press release, Zai Laboratory, JAN 9, 2025, View Source [SID1234649556]).

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Through this collaboration, Zai Lab further expands its global oncology pipeline with another potential first-in-class ADC targeting multiple solid tumors and addressing significant unmet medical needs. ZL-6201 has demonstrated encouraging preclinical data with an IND expected to be filed in 2025.

"MediLink has built a differentiated proprietary ADC technology platform, and we are excited to broaden our global partnership," said Rafael G. Amado, M.D., President, Head of Global Research and Development at Zai Lab. "Building on the promising findings from our ongoing clinical trials for ZL-1310, this new collaboration demonstrates our continued focus on developing cancer therapies with ADC drugs and enriches our global oncology pipeline to address unmet medical needs. We look forward to working with MediLink to advance this compound into the clinic soon."

"Zai Lab’s strong commitment to innovation and proven track record of global development impressed us through our existing collaboration," said Tony Xue, PhD, CEO at MediLink. "This new partnership further validates our technology and enhances our strategic partnership. We believe our collaboration with Zai Lab will bring this innovative therapy to patients worldwide."

About LRRC15

Leucine-rich repeat-containing protein 15 (LRRC15) is a type I transmembrane protein involved in cell-cell and cell-extracellular matrix (ECM) interactions. It is overexpressed in various mesenchymal tumors such as sarcoma, glioblastoma and melanoma, where it promotes tumor metastasis. Additionally, LRRC15 is upregulated in cancer-associated fibroblasts (CAFs) across various cancer types, contributing to immune-excluded and immune-suppressive tumor microenvironment (TME). This makes LRRC15 an appealing target for cancer therapy.

On January 9, 2025 Mabwell (688062.SH), an innovative biopharmaceutical company with entire industry chain, reported a significant milestone for its proprietary Nectin-4 targeted ADC (9MW2821). On January 8, 2025, 9MW2821 was granted Breakthrough Therapy Designation (BTD) by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China (Press release, Mabwell Biotech, JAN 9, 2025, View Source [SID1234649555]). 9MW2821 is given in combination with toripalimab, an anti-PD-1 monoclonal antibody, for treatment-naïve, unresectable, locally advanced or metastatic urothelial carcinoma(la/mUC). Up to now, 40 treatment-naïve patients with la/mUC were enrolled and received the combination therapy. ORR was 87.5% (comfirmed ORR was 80%) and DCR was 92.5%. Median PFS and DoR were not reached.

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A pivotal Phase III study of 9MW2821 in combination with PD-1 is ongoing. Compared with similar ADC and PD-1 combos, 9MW2821 has shown significant increase in ORR. Previously, 9MW2821 had been granted BTD by the CDE as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma that has failed to platinum-based chemotherapy and PD-(L)1 inhibitor therapy.

The BTD is a recognition aimed at expediting the development of new medicines for serious diseases. It is awarded to therapies that have shown significant efficacy or safety advantages over existing treatments in early-stage clinical trials. For drugs included in the BTD list, the CDE prioritizes resource allocation to facilitate communication and provide guidance, thereby accelerating both clinical development progress and speeding up market review and approval processes.

On January 9, 2025 Servier reported updates to two of its Phase 3 programs evaluating TIBSOVO (ivosidenib tablets) in isocitrate dehydrogenase 1 (IDH1)-mutated cancers (Press release, Servier, JAN 9, 2025, View Source [SID1234649554]). The first patient has been enrolled in the CHONQUER study, a pivotal Phase 3 clinical trial evaluating the efficacy and safety of TIBSOVO versus placebo in patients with IDH1-mutated conventional chondrosarcoma. In addition, the Phase 3 PyramIDH clinical trial has been initiated, and sites are actively recruiting across the globe. The PyramIDH study is evaluating TIBSOVO (ivosidenib tablets) monotherapy and azacitidine monotherapy in the treatment of patients with IDH1-mutated myelodysplastic syndromes (MDS) who have not previously been treated with a hypomethylating agent.

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"As the leader in IDH-mutated cancers, Servier aspires to provide new treatment options for those impacted by newly diagnosed IDH1-mutated conventional chondrosarcoma and IDH-1 mutated MDS. The advancement of two of our Phase 3 registration enabling studies is an incredibly important milestone for our TIBSOVO clinical development program and underscores our commitment to understanding the application of IDH1m inhibition in a broad range of malignancies to meet the needs of patients," said Susan Pandya, MD, Vice President, Clinical Development and Global Head of Oncology LS/LCM, Servier Pharmaceuticals. "We are deeply grateful to the patients, families and healthcare providers who are participating in this important research."

The use of TIBSOVO in patients with IDH1-mutated conventional chondrosarcoma, as well as, patients with IDH1-mutated myelodysplastic syndromes who have not previously been treated with a hypomethylating agent are investigational, and its safety and efficacy in these cases have not been evaluated by any regulatory authority.

About the PyramIDH Trial (NCT06465953)
PyramIDH is a pivotal Phase 3, multicenter, open label, randomized clinical trial of TIBSOVO (ivosidenib tablets) monotherapy and azacitidine monotherapy in adult patients with myelodysplastic syndromes (MDS) with an isocitrate dehydrogenase protein, 1 (IDH1) mutation, who have not received treatment with a hypomethylating agent previously. The primary endpoint of PyramIDH is complete remission (CR) or partial remission (PR) as per International Working Group (IWG) 2006 criteria at 4 months. Secondary outcome measures include overall response (OR) rate, event-free survival (EFS) and overall survival (OS).

About the CHONQUER Trial (NCT06127407)
CHONQUER is a pivotal Phase 3, multicenter, double-blind, randomized, placebo-controlled crossover clinical trial of TIBSOVO (ivosidenib tablets) in adult patients with locally advanced or metastatic conventional chondrosarcoma with an isocitrate dehydrogenase protein, 1 (IDH1) mutation who are untreated or were previously treated with one systemic treatment regimen in the advanced/metastatic setting for conventional chondrosarcoma. The primary endpoint of CHONQUER is progression-free survival (PFS) in Grades 1 and 2 participants. Key secondary outcome measures include endpoints such as PFS in all randomized participants, overall survival (OS) in Grades 1 and 2 participants, and OS in all randomized participants. The study also will evaluate the impact of TIBSOVO on health-related quality of life (HRQoL) and health economic outcomes.

About TIBSOVO (ivosidenib tablets)
TIBSOVO is a precision medicine that targets a specific type of mutation known as isocitrate dehydrogenase 1 (IDH1). TIBSOVO is approved in five indications globally, including approvals in the U.S., European Union, Australia and China.

In the U.S., TIBSOVO is approved for the treatment of adults with IDH1-mutant relapsed or refractory AML and in monotherapy or in combination with azacitidine for adults with newly diagnosed IDH1-mutant AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy, as monotherapy for the treatment of adult patients with IDH1-mutant relapsed or refractory MDS, and for patients with previously treated IDH1-mutated cholangiocarcinoma.

For more information about TIBSOVO in the U.S., please visit www.tibsovo.com.

About Myelodysplastic Syndromes
Myelodysplastic Syndromes (MDS) are disorders in which progenitor (stem) cells do not mature into healthy blood cells.1 In the U.S., approximately 16,000 new cases of MDS are reported each year.2 Approximately 3.6% of MDS patients have an IDH1 mutation,3 which is considered an early "driver" mutation.4 For MDS patients with an IDH1 mutation, the prognosis has often been associated with worse overall outcomes and in an increased risk of transformation to AML.3 Prior to the approval of TIBSOVO, there were no approved targeted therapies for this molecularly defined subset.

About Chondrosarcoma
Chondrosarcoma is a group of bone tumors that are made up of cells that make too much cartilage.1 Chondrosarcoma, the second most common sarcoma of the bones following osteosarcoma,5 accounts for 20-30% of all skeletal sarcomas and has an estimated incidence of 1 in 200,000 per year in the U.S.6 Conventional primary chondrosarcoma is the most common variant and makes up 85% of all cases.2 IDH mutations are found in 50-70% of chondrosarcomas.7 Surgery currently remains the mainstay of treatment for conventional chondrosarcoma as both radiation and chemotherapy have been shown to be ineffective.