On December 17, 2024 IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported the Independent Data Monitoring Committee (IDMC) recommendation of a move-forward dose and the completion of the Part 2a dose optimization consistent with the U.S. Food and Drug Administration’s (FDA) Project Optimus guidelines for the potential registration-enabling Phase 2/3 trial evaluating the combination of darovasertib and crizotinib in the first-line (1L) setting in patients with HLA-A2-negative (HLA-A2(-)) metastatic uveal melanoma (MUM) (Press release, Ideaya Biosciences, DEC 17, 2024, View Source [SID1234649173]).

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"We are pleased with the recommendation of the IDMC and the selection of the move-forward dose for our potential registration-enabling trial evaluating the darovasertib and crizotinib combination in first-line HLA-A2(-) MUM patients. This allows us to complete the Part 2a portion of the study and seamlessly continue to enroll in Part 2b towards a potential accelerated approval based on the primary endpoint of median progression free survival," said Darrin M. Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences.

"The combination of darovasertib and crizotinib as first-line treatment has shown compelling preliminary clinical results in patients with HLA-A2(-) MUM. The IDMC recommendation of the move-forward dose supports the advancement of this potentially registration-enabling Phase 2/3 trial and is an important step in bringing a new treatment option to patients with MUM. Additionally, the continued rapid enrollment further validates the strong interest from physicians and patients, and highlights the significant unmet need in these patients, who historically have faced a poor prognosis," added Meredith McKean, M.D., MPH, Director, Melanoma and Skin Cancer Research at Sarah Cannon Research Institute, and clinical investigator on the potential registration-enabling clinical trial.

The darovasertib and crizotinib combination in MUM has FDA Fast Track designation and is currently being evaluated in two clinical trials: a potentially registration-enabling Phase 2/3 trial of darovasertib and crizotinib combination in first-line HLA-A2(-) MUM (NCT05987332) and a Phase 2 trial (NCT03947385). Additionally, darovasertib as neoadjuvant monotherapy is currently being evaluated in a Phase 2 trial in primary uveal melanoma (NCT05907954). IDEAYA is also finalizing a clinical trial protocol and is targeting to initiate a potential Phase 3 registration-enabling study for neoadjuvant uveal melanoma patients in the first half of 2025.

On December 17, 2024 Expert Systems, a leader in AI-powered drug discovery, reported the promising clinical results of oral once-daily lonitoclax, a next-generation BCL-2 inhibitor developed in collaboration with Lomond Therapeutics (Press release, Lomond Therapeutics, DEC 17, 2024, View Source [SID1234649172]). The results of the single ascending dose Phase 1 studies demonstrate important advantages of lonitoclax over venetoclax and venetoclax-like molecules for chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and potentially other oncology indications.

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Lonitoclax demonstrated no significant safety signals at exposures sufficient to achieve robust inhibition of BCL-2, as measured via ex vivo activation of caspase in primary CLL cells. Importantly, the co-administration of itraconazole—a potent CYP 3A4 inhibitor—did not significantly alter lonitoclax exposures. These results highlight a key differentiation from venetoclax and similar molecules, which require complex dose titration and ritonavir co-administration, and emphasize important advantages in safety, tolerability, and feasibility of outpatient treatment.

"Lonitoclax’s promising Phase 1 results highlight the strength of our AI-enabled platform in driving the development of next-generation therapies," said Bill Farley, Chief Business Officer at Expert Systems. "Our platform de-risks early-stage drug development by reducing time and costs while delivering data-driven insights to optimize safety and efficacy. We are proud to support Lomond Therapeutics in advancing this innovative BCL-2 inhibitor, which has the potential to transform the treatment landscape for CLL and AML patients."

About Lonitoclax

Lonitoclax is a next generation BCL-2 inhibitor that has demonstrated best-in-class molecular pharmacology with the highest selectivity against BCL2, a key pro-survival protein that is overexpressed in many cancers. To mitigate the hematologic and immune toxicities observed with venetoclax, lonitoclax was designed with a unique binding mode to improve selectivity for BCL-2 over BCL-XL. In addition, a shorter half-life and reduced P4503A4 inhibition properties were built into the molecule to mitigate tumor lysis syndrome and drug accumulation risk, respectively. Lonitoclax has demonstrated monotherapy activity in pre-clinical models, as well as synergistic activity when combined with azacitidine, FLT3 inhibitors, and menin inhibitors in AML xenograft models. Unlike venetoclax, lonitoclax had minimal immunosuppressive activity on B cells, CD8 T cells, and NK cells in preclinical models.

On December 17, 2024 A2A Pharmaceuticals, Inc. ("A2A" or "the company"), a clinical-stage pioneering biopharmaceutical company focused on developing innovative cancer therapies, reported progress in its clinical studies exploring TACC3 (Transforming Acidic Coiled-Coil 3) PPI inhibition in patients with ovarian cancer, triple-negative breast cancer (TNBC), and endometrial cancer (Press release, A2A Pharmaceuticals, DEC 17, 2024, View Source [SID1234649167]).

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A2A has progressed into cohort 4, an important inflection point in its Phase 1 clinical trial to assess the safety and efficacy of its lead TACC3 inhibitor, AO-252. Early results have shown strong safety profiles with the potential for a wide therapeutic index in these patient populations.

"We are excited about the advancements in our TACC3 program and its potential for patients with challenging cancer diagnoses. The company is continually exploring collaborations and partnerships to accelerate development timelines and enhance patient access to cutting-edge treatments," said Sotirios Stergiopoulos, M.D., CEO of A2A.

"While our current focus with AO-252 is on addressing the unmet needs in ovarian, TNBC, and endometrial cancers, we are equally excited about its potential to benefit patients in additional indications in the near future," added Robbin Frnka, Vice President of Clinical Operations."

The selected cancers are characterized by limited treatment options and high rates of recurrence in patients. A2A’s TACC3 PPI inhibitor is designed to disrupt critical cellular mechanisms involved in cancer cell proliferation, providing a much-needed new avenue of treatment for patients battling these aggressive malignancies.

"This trial represents a promising step forward in delivering therapies that could impact the standard of care for patients," said Alex Spira, M.D., principal investigator of Next Oncology Virginia. "A2A Pharmaceuticals shows dedication to supporting the cancer community by advancing novel therapies that target the underlying biology of tumors."

Beyond these indications, pre-clinical studies suggest A2A’s TACC3 PPI inhibitor may also show efficacy in other solid tumors, including gastric, prostate cancers, and sarcomas, etc. Ongoing research efforts are focused on expanding the indication spectrum and optimizing treatment regimens for diverse cancer types.

On December 17, 2024 Gilead Sciences, Inc. (Nasdaq: GILD) and Terray Therapeutics, Inc. reported that the companies have entered into a strategic collaboration to discover and develop novel, small molecule therapies across multiple targets (Press release, Gilead Sciences, DEC 17, 2024, View Source [SID1234649163]).

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Terray’s tNova platform combines high-throughput chemical experimentation and computational analysis with a generative AI-driven drug discovery engine. The company’s iterative approach applies AI-empowered methods to an extensive library of quantitative, purpose-built, structure activity data to find the right molecules to solve complex problems in drug discovery.

"Next-generation, AI-driven platforms using custom-generated large, relevant data sets will serve as important tools in our efforts to shape the future of drug discovery in our ongoing pursuit of innovative treatments across our therapeutic areas of focus," said Flavius Martin, M.D., Executive Vice President, Research, Gilead Sciences. "We are excited to collaborate with Terray and explore how their integrated discovery platform will complement our own internal research capabilities and expertise."

"We’re proud to strategically partner with Gilead," said Jacob Berlin, Ph.D., Chief Executive Officer, Terray Therapeutics. "We’re very excited to put tNova’s unique blend of experimentation and computation to work alongside the deep expertise of our collaborators at Gilead to find transformational small molecule therapeutics that bring relief to patients in need."

Terms of the Agreement

Under the terms of the agreement, Terray will utilize the Terray tNova platform to discover and develop small molecule compounds against a set of targets selected by Gilead. If Gilead exercises its option to exclusively license the compounds directed to a target, Gilead will be responsible for further development and commercialization activities for products resulting from the collaboration. Terray will receive an upfront payment and is eligible to receive milestone payments associated with the achievement of preclinical, clinical, and sales milestones as well as tiered royalties on net sales of products commercialized by Gilead in connection with the collaboration.

Gilead does not exclude acquired IPR&D expenses from its non-GAAP financial measures. This transaction with Terray is expected to reduce Gilead’s GAAP and non-GAAP 2024 EPS by approximately $0.01.

On December 17, 2024 Plus Therapeutics, Inc. (Nasdaq: PSTV) ("Plus" or the "Company"), a clinical-stage pharmaceutical company developing targeted radiotherapeutics with advanced platform technologies for central nervous system cancers, reported data updating the progress of its ReSPECT-LM Phase 1 clinical trial of Rhenium (186Re) Obisbemeda (Rhenium Nanoliposome, 186RNL) in leptomeningeal disease (LM) with a specific focus on breast cancer patients (Press release, Plus Therapeutics, DEC 17, 2024, View Source [SID1234649162]). The data were presented at the 2024 San Antonio Breast Cancer Symposium on December 10-13.

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The data were presented in a session titled "Rhenium (186Re) Obisbemeda (Rhenium Nanoliposome, 186RNL) for the Treatment of Leptomeningeal Metastases (LM): Update on Phase 1 Dose Escalation Study," by Andrew Brenner, M.D., Ph.D., Professor and Kolitz/Zachry Endowed Chair Neuro-Oncology Research; Co-Leader, Experimental and Developmental Therapeutics Program, University of Texas Health, San Antonio.

Key Highlights from the Presentation:

Nine of 20 patients with LM primary breast cancer were treated and evaluable through five dose escalation cohorts, with the maximum tolerated dose yet to be reached
Primary breast cancer biomarker status across the 9 patients were:
ER positive/HER2 negative: n=3
HER2 positive: n=2
Triple negative: n=4
Patients received a single intrathecal dose of Rhenium (186Re) Obisbemeda, ranging from 6.6 to 66.14 mCi of radiation
Only one dose-limiting toxicity (thrombocytopenia) was reported (Cohort 5)
A linear increase in absorbed dose was observed from Cohorts 1 through 5, with an average absorbed dose of 253 Gy to the cranial subarachnoid space in Cohort 5
Circulating tumor cell (CTC) and radiographic (MRI) response data were available for 8 of the 9 breast cancer patients with LM, and clinical response data were available for 7 of the 9 patients
Best response rates (response only) were:
CTC: 88% (7/8)
MRI imaging: 25% (2/8)
Clinical: 29% (2/7)
Clinical benefit rates (response and stable disease) were:
CTC: 100% (8/8)
MRI imaging: 75% (6/8)
Clinical: 71 % (5/7)
Median overall survival for 9 breast cancer patients was 9 months, with 2 patients surviving beyond 600 days post-treatment
Next steps:

Initiate ReSPECT-LM Phase 1b single-dose breast expansion cohort in Q1 2025 to further evaluate single-dose safety and efficacy of Rhenium (186Re) Obisbemeda
"Breast cancer is the most common primary cancer associated with leptomeningeal metastases," said Marc H. Hedrick, M.D., Plus Therapeutics’ President and Chief Executive Officer. "Based on the promising data observed thus far, we intend to move forward rapidly into a breast cancer focused expansion cohort along with our planned multiple dose expansion trial."

About Leptomeningeal Metastases (LM)
LM is a rare complication of cancer in which the primary cancer spreads to the cerebrospinal fluid (CSF) and leptomeninges surrounding the brain and spinal cord. All malignancies originating from solid tumors, primary brain tumors, or hematological malignancies have this LM complication potential with breast cancer as the most common cancer linked to LM, with 3-5% of breast cancer patients developing LM. Additionally, lung cancer, GI cancers and melanoma can also spread to the CSF and result in LM. LM occurs in approximately 5% of people with cancer and is usually terminal with 1-year and 2-year survival of just 7% and 3%, respectively. The incidence of LM is on the rise, partly because cancer patients are living longer and partly because many standard chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells; yet, there are no FDA-approved therapies specifically for LM patients, who often succumb to this complication within weeks to several months, if untreated.

About Rhenium (186Re) obisbemeda
Rhenium (186Re) obisbemeda is a novel injectable radiotherapy specifically formulated to deliver direct targeted high dose radiation in CNS tumors in a safe, effective, and convenient manner to optimize patient outcomes. Rhenium (186Re) obisbemeda has the potential to reduce off target risks and improve outcomes for CNS cancer patients, versus currently approved therapies, with a more targeted and potent radiation dose. Rhenium-186 is an ideal radioisotope for CNS therapeutic applications due to its short half-life, beta energy for destroying cancerous tissue, and gamma energy for real-time imaging. Rhenium (186Re) obisbemeda is being evaluated for the treatment of recurrent glioblastoma and leptomeningeal metastases in the ReSPECT-GBM and ReSPECT-LM clinical trials. ReSPECT-GBM is supported by an award from the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH), and ReSPECT-LM is funded by a three-year $17.6M grant by the Cancer Prevention & Research Institute of Texas (CPRIT).