On December 10, 2024 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported that it has dosed the first patient in the IDEAYA-sponsored Phase 1 trial evaluating the combination of IDE161, the company’s investigational, potential first-in-class, small molecule poly (ADP-ribose) glycohydrolase, or PARG, inhibitor, in combination with Merck’s (known as MSD outside of the US and Canada) anti-PD-1 therapy, KEYTRUDA (pembrolizumab), in endometrial cancer patients with high microsatellite instability (MSI-high) and microsatellite stable(MSS) (Press release, Ideaya Biosciences, DEC 10, 2024, View Source [SID1234649005]).

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"We continue to progress our IDE161 program and are excited to have the first patient dosed evaluating IDE161 in combination with KEYTRUDA in MSI-high and MSS endometrial cancer patients. This trial is part of our overall IDE161 clinical combination strategy that is focused on high conviction rational combinations," commented Dr. Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences.

"We are continually looking for ways to improve outcomes for patients with MSI-high and MSS endometrial cancer, and PARG has shown promising potential as a precision oncology target in these settings. IDE161 has shown robust anti-tumor activity in preclinical models, and I look forward to evaluating IDE161’s impact on endometrial cancer patients in combination with KEYTRUDA," added Dr. Panos Konstantinopoulos, M.D., Ph.D., Director of Translational Research and attending oncologist in the Division of Gynecologic Oncology at Dana-Farber Cancer Institute, and an Associate Professor of Medicine at Harvard Medical School.

IDE161 is a potential first-in-class inhibitor of poly(ADP-ribose) glycohydrolase (PARG), a novel, mechanistically distinct target in the same clinically validated biological pathway as poly(ADP-ribose) polymerase (PARP). IDE161 has been granted two FDA Fast Track designations in platinum-resistant advanced or metastatic ovarian cancer patients having tumors with BRCA1/2 mutations, and in pretreated advanced or metastatic HR+, Her2-, BRACA1/2 mutant breast cancer.

Under the clinical trial collaboration and supply agreement, Merck will provide KEYTRUDA to IDEAYA, the sponsor of the Phase 1 clinical combination trial. IDEAYA and Merck each retain all commercial rights to their respective compounds, including as monotherapy or as combination therapies.

The safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of IDE161 in combination with KEYTRUDA is being evaluated as an arm in IDE161-001 (NCT05787587), an IDEAYA-sponsored Phase 1 trial of IDE161 in solid tumors. The selection of an initial Phase 1/2 monotherapy expansion dose has been made in a priority tumor type based on adverse event (AE) profile and preliminary clinical efficacy observed.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

On December 10, 2024 Tasca Therapeutics Corp. ("Tasca"), a biotechnology company leveraging a unique drug discovery platform that identifies and maps novel lipid-binding pockets on proteins to develop new medicines to treat human diseases, reported a $52 million Series A financing, co-led by Regeneron Ventures and Cure Ventures, with participation by Invus Group (Press release, Tasca Therapeutics, DEC 10, 2024, View Source [SID1234649022]). This funding will be used to advance Tasca’s novel drug discovery platform, progress its lead program, CP-383, into Phase 1/2 clinical proof-of-concept studies, and to expand its drug candidate pipeline.

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"We are excited to enter this next phase of company growth with financial support from such leading life science investors and the continued backing of our pioneering scientific co-founders – Xu Wu, Ph.D., David Fisher, M.D., Ph.D., and Duojia Pan, Ph.D.," said Milenko Cicmil, co-founder and chief executive officer of Tasca. "Our first development candidate, CP-383, is a unique first-in-class molecule demonstrating excellent efficacy across multiple cancer types and we are looking forward to progressing it into the clinic."

Named after the Italian word for "pocket," Tasca is harnessing the power of mass spectrometry-based proteomics, coupled with the use of proprietary reagents, to identify proteins that undergo a specific post-translational modification called auto-palmitoylation. The specific sites of auto-palmitoylation, once mapped and characterized, serve as unique binding sites for novel therapeutics that can be developed to modify the function of the target protein. The auto-palmitoylated proteins Tasca identified represent a rich source of druggable targets across a range of therapeutic indications.

Tasca’s most advanced drug candidate, CP-383, is a first-in-class molecule that has demonstrated robust anti-cancer activity in both in vitro and in vivo studies across a broad range of human cancers, and will initially be evaluated in small cell lung cancer, colorectal cancer, head and neck cancer, and brain cancer patients.

Expert Executive Leadership Team

Tasca’s executive leadership team brings decades of experience in drug discovery and development, as well as a successful history of launching and leading new biotechnology programs and start-ups. Tasca’s executives have held major roles at several big pharma companies, including Merck, AstraZeneca, Bristol Myers Squibb, and Novartis. Their deep understanding of oncology matched with drug development and business expertise will enable them to find creative solutions for challenges faced by early-stage biotechnology companies.

"I was immediately impressed by Tasca’s in vivo data, that combined with the amazing leadership that Milenko provides and backing of strong firms like Regeneron Ventures and Cure Ventures," said Praveen Tipirneni, M.D., and chairman of the board. "I look forward to bringing my Morphic Therapeutic experience to the Tasca team."

Added Dave Fallace, co-founder and managing partner at Cure Ventures: "We founded Cure Ventures to help develop curative technologies and Tasca is expanding the boundaries of science with the potential of their platform. The prospect of being able to drug previously undruggable targets in oncology and potentially other indications differentiates Tasca from the competition. We’re confident in their programs and look forward to supporting them as they advance their platform and pipeline."

On December 10, 2024 Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) reported preliminary data from the ongoing Phase 1b portion of the TACTIVE-U sub-study of vepdegestrant in combination with abemaciclib among patients with locally advanced or metastatic estrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (Press release, Arvinas, DEC 10, 2024, View Source [SID1234648974]). These data will be presented in a poster at the 2024 San Antonio Breast Cancer Symposium (SABCS) in San Antonio, Texas.

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Preliminary results from 16 patients in the Phase 1b sub-study demonstrated a tolerable safety profile for the combination of abemaciclib 150 mg twice daily (BID) with the recommended Phase 3 monotherapy dose of vepdegestrant (200mg once daily; QD). An encouraging clinical benefit rate of 62.5% was observed among patients with both mutant ESR1 and wild-type ESR1 disease who had all been previously treated with a CDK4/6 inhibitor.

Pharmacokinetic data demonstrated no significant drug-drug interaction between vepdegestrant and abemaciclib and no clinically meaningful effect on abemaciclib exposure was observed. In addition to tolerability, the results demonstrated a safety profile consistent with both the known properties of abemaciclib and observed data in other clinical trials for vepdegestrant. These findings support the ongoing Phase 2 portion of the study, which is evaluating full dose abemaciclib (150mg BID) in combination with vepdegestrant (200 mg QD) in post-CDK4/6 advanced breast cancer.

"The preliminary results from this Phase 1b sub-study in patients whose cancer had previously progressed after receiving a CDK4/6 inhibitor are encouraging," said Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at Arvinas. "These data further reinforce our belief that vepdegestrant can be used in multiple combination regimens across the metastatic breast cancer setting and has the potential to become a best-in-class backbone ER therapy. We are pleased to continue in the Phase 2 portion of the study evaluating the standard starting dose of abemaciclib in combination with vepdegestrant."

"With vepdegestrant, we aim to develop a novel agent that has the potential to become a new backbone endocrine therapy in ER+ metastatic breast cancer," said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer​. "We are pleased to see these initial results, which complement previously reported data demonstrating the potential of combination therapy with vepdegestrant to address unmet needs for patients."

Additional detail on the TACTIVE-U poster presentation at SABCS follows below:

Title: Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Preliminary Phase 1b Results
Date: Thursday, December 12, 2024
Time: 5:30 – 7:00 p.m. CDT
Poster: P4-12-03

Key findings included in the poster (data cut-off: August 30, 2024):

100% of patients had prior treatment with a CDK4/6 inhibitor.
Tolerability is generally consistent with the profile of abemaciclib and with results previously observed in other clinical trials of vepdegestrant. The most common any grade treatment-emergent adverse events (TEAE) were diarrhea, nausea and fatigue. There were no dose-limiting toxicities and no grade 4 or 5 TEAEs.
There was no significant drug-drug interaction, and data reflected vepdegestrant has no clinically meaningful effect on abemaciclib exposure.
Encouraging preliminary antitumor activity is observed with a clinical benefit rate (CBR, defined as the rate of confirmed complete response, partial response, or stable disease ≥ 24 weeks) of 62.5% in all CBR-eligible patients (10/16), 62.5% in patients with mutant ESR1 (5/8), and 62.5% in patients with wild-type ESR1 (5/8).
The objective response rate (ORR) in evaluable patients was 26.7% overall (4/15), 37.5% in patients with mutant ESR1 (3/8), and 14% in patients with wild-type ESR1 (1/7).
Five patients remained on study treatment as of the August 30, 2024 data cut-off.
Arvinas and Pfizer are continuing to evaluate data from the ongoing TACTIVE-U clinical trial, which includes combinations of vepdegestrant plus abemaciclib, ribociclib or samuraciclib (ClinicalTrials.gov Identifiers: NCT05548127, NCT05573555, and NCT06125522).

About Vepdegestrant
Vepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy and as part of combination therapy across multiple treatment settings for ER+/HER2- metastatic breast cancer.

In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits.

The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.

On December 10, 2024 NextCure, Inc. (Nasdaq: NXTC), a clinical-stage biopharmaceutical company committed to discovering and developing novel, first-in-class, and best-in-class therapies to treat cancer, reported that the U.S. Food and Drug Administration (FDA) accepted an Investigational New Drug (IND) application for initiation of a Phase 1 clinical trial to evaluate LNCB74, a B7-H4-targeting antibody-drug conjugate (ADC) as a therapeutic for treating multiple cancers (Press release, NextCure, DEC 10, 2024, View Source [SID1234648990]).

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"Acceptance of the IND application for LNCB74 represents an important milestone for NextCure as we focus our resources on advancing our ADC program," said Michael Richman, NextCure’s president and CEO. "The IND application leverages LNCB74 preclinical data that highlights the differentiation of our B7-H4 ADC from other ADCs targeting B7-H4. We believe LNCB74 has the potential to transform treatment for patients and we look forward to advancing LNCB74 into clinical development."

An IND is a request submitted to the regulatory authorities seeking permission to test a new drug or therapeutic substance in humans. The IND includes detailed information about the drug, its composition, pharmacology, toxicology, data from preclinical studies, proposed clinical trial protocols, and information on manufacturing and quality control. With the IND application acceptance now complete, NextCure can proceed with the Phase I trial.

LNCB74 is being developed in partnership with LigaChem Biosciences, Inc. as part of a collaboration and co-development agreement.

On December 10, 2024 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in discovering, developing, and commercializing therapies to address global unmet medical needs primarily for malignancies, reported that it has released the follow-up safety and efficacy data of the company’s investigational Bcl-2 selective inhibitor, lisaftoclax (APG-2575), in combination with azacitidine (AZA) for the treatment of patients with myelodysplastic syndrome (MDS), in a Poster Presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place in San Diego, CA, the United States (Press release, Ascentage Pharma, DEC 10, 2024, View Source;ascentage-pharma-releases-updated-data-of-bcl-2-inhibitor-lisaftoclax-in-mds-that-demonstrates-potential-clinical-benefits-and-favorable-safety-302327621.html [SID1234649006]).

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the most cutting-edge scientific research and latest data of investigational therapies that represent leading scientific and clinical advances in the global hematology field. Garnering growing interest from the global research community, results from multiple clinical and preclinical studies on four of Ascentage Pharma’s drug candidates (olverembatinib, lisaftoclax, APG-2449, and APG-5918) have been selected for presentations, including two Oral Reports, at this year’s ASH (Free ASH Whitepaper) Annual Meeting.

Thes data underscored the potential clinical benefit and manageable safety of lisaftoclax in combination with AZA in MDS. In the results, the combination regimen demonstrated an overall response rate (ORR) of 75% in patients with treatment-naïve (TN) or relapsed/refractory (R/R) MDS, and no patient withdrew from the study due to intolerable toxicities.

Prof. Jie Jin, the principal investigator of the study from the First Affiliated Hospital, Zhejiang University School of Medicine, noted, "For a long time, there has not been much progress in the treatment of higher-risk MDS and the outcome of the current standard treatment with hypomethylating agents has been disappointing. In patients with MDS, the investigational novel Bcl-2 inhibitor lisaftoclax in combination with AZA has demonstrated clinical benefit and manageable safety that support continued treatment. These observations suggest that the regimen can potentially offer a new standard treatment in MDS."

Prof. Huafeng Wang, the presenter of this study from the First Affiliated Hospital, Zhejiang University School of Medicine, commented, "Patients with higher-risk MDS often have inadequate marrow function and low tolerance for therapeutic agents. The investigational novel Bcl-2 inhibitor lisaftoclax in combination with AZA has shown encouraging clinical benefit, manageable safety, and low suppression on bone marrow function. More importantly, the regimen showed a low rate of treatment-related infections that were mostly mild, and a low rate of mortalities in early treatment, thus overcoming some of the biggest clinical challenges in this patient population."

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said, "These updated efficacy and safety data of lisaftoclax in combination with AZA are very encouraging as they reaffirmed the therapeutic potential of this novel drug candidate. A global registrational Phase III study of lisaftoclax in combination with AZA for the first-line treatment of MDS is currently ongoing and an NDA for lisaftoclax in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma has already been accepted and granted the Priority Review designation in China. Fulfilling our founding mission of addressing unmet clinical needs in China and around the world, we will expedite the global clinical development of our key drug candidates to bring more safe and effective therapies to patients as soon as possible."

Highlights of the data this study reported at ASH (Free ASH Whitepaper) 2024 are as below:

Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor, in Combination with Azacitidine in Treatment of Patients with Myelodysplastic Syndrome (MDS)
Format: Poster Presentation
Abstract#: 3202
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster II

Highlights:

Background: Hypomethylating agents (HMAs) remain the standard of care in higher-risk MDS. However, its clinical efficacy is limited, and patients who have failed or are resistant to HMAs have a poor prognosis, leaving them in need of new therapeutic options.

Introduction: Preclinical data have shown that novel investigational Bcl-2 inhibitor lisaftoclax combined with an HMA can synergistically induce apoptosis in cancer cells in AML and MDS. Reported here are the follow-up safety and efficacy data from a Phase Ib/II clinical trial evaluating lisaftoclax combined with azacitidine in adults (≥18 years) with MDS.

Enrolled Patients and Study Methods:

This study enrolled patients with higher-risk MDS (IPSS-R score > 3.5; blasts > 5%), including those with TN or R/R disease. Lisaftoclax at an assigned dose (400, 600, or 800 mg) was administered orally once daily from Days 1 to 14 and combined with azacitidine (75 mg/m2/day) on Days 1 to 7 in repeated 28-day cycles. A daily ramp-up was used before the first cycle to prevent TLS. The primary objectives of the study were to assess the efficacy and safety of the combination regimen in patients with MDS and establish the recommended Phase III dose for lisaftoclax. Complete response (CR) and marrow CR (mCR) rates were evaluated in accordance with 2006 International Working Group (IWG) criteria.
As of July 1, 2024, 49 patients were enrolled: 8 had R/R MDS (lisaftoclax 600 mg [n=5] and 800 mg [n=3]) and 41 had TN MDS (lisaftoclax 400 mg [n=16], 600 mg [n=23], and 800 mg [n=2]). The median (range) age was 66 (22-83) years, and 55.1% of patients were male. IPSS-R risk categories were intermediate (12/49 [24.5%]), high (24/49 [49.0%]), and very high (13/49 [26.5%]). Among the 39 patients with genetic mutational profile data, 9 (23.1%) had TP53 mutations; 11 (28.2%) had TET2 mutations; 10 (25.6%) had ASXL1 mutations; and 10 (25.6%) had RUNX1 mutations. At baseline, 70.8% of patients reported grade ≥ 3 anemia; 54.2% had grade ≥ 3 neutropenia; and 45.8% had grade ≥ 3 thrombocytopenia.
Efficacy Results: In 8 patients with R/R MDS, the median (range) duration of treatment (DOT) was 3.2 (1.2-9.4) months. The ORR (CR[12.5%]+marrow CR[62.5%]) was 75.0% (95% CI, 34.9-96.8). In 40 efficacy-evaluable patients with TN MDS, the median DOT (range) was 4.5 (0.5-12.1) months; the ORR was 77.5% (95% CI, 61.5-89.2); and the CR rate was 25.0% per IWG 2006 criteria. Furthermore, the ORR and CR rate in 23 patients with TN MDS treated with lisaftoclax 600 mg combined with azacitidine were 73.9% and 30.4%, respectively; because these patients had a relatively longer median DOT (6.01 months), we conducted further analyses per IWG 2023 criteria. The composite CR rate (CR2023 = CR [52.2%] + CRL [17.4%]) was 69.6%, and the median time to CR (range) was 2.84 (1.1-8.7) months. Both the median progression-free survival and overall survival rates were not reached.

Safety Results:

Grade ≥ 3 infections were reported in 46.9% of patients, of which 26.5% were treatment related. Treatment delays between cycles due to AEs occurred in 11 (22.4%) patients, with a median delay time (range) of 12 (1-63) days.
A total of 95.9% of patients reported TRAEs, of which 87.8% were grade ≥ 3 AEs and 28.6% were serious AEs. Common grade ≥ 3 hematologic TRAEs included leukocyte count decreased (71.4%), neutropenia (65.3%), thrombocytopenia (65.3%), anemia (20.4%), and febrile neutropenia (12.2%).
Neither 60-day mortality nor TLS was reported.
Conclusions: The clinical data support an emerging role for lisaftoclax in combination with azacitidine for treatment of patients with higher-risk TN or R/R MDS. The combination therapy was efficacious and well tolerated, resulting in no 60-day mortality, few dose modifications, and low infection rates, supporting further clinical development of this combination in patients with higher-risk MDS.