On December 18, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported a potential best-in-class KRAS G12D oral inhibitor as the lead program of its discovery and development collaboration with GenFleet Therapeutics ("GenFleet") (Press release, Verastem, DEC 18, 2023, View Source [SID1234638667]).

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"We are pleased to announce this oral KRAS G12D inhibitor with a potential best-in-class profile as the lead program from our collaboration with GenFleet supporting our mission to bring needed therapies to patients with RAS pathway-driven cancers," said Dan Paterson, President and Chief Executive Officer of Verastem Oncology. "Although there has been significant progress in therapeutics targeting KRAS mutations, there are currently no available therapies approved by the U.S. Food and Drug Administration targeting KRAS G12D, the most prevalent KRAS mutation across human cancers. The GLP toxicology studies are complete and we look forward to GenFleet’s anticipated filing of the IND for this KRAS G12D inhibitor in the first half of 2024."

GFH375/VS-7375 is an orally bioavailable, potent and selective small molecule KRAS G12D (ON/OFF) inhibitor. Preclinical models demonstrate strong tumor regression as a single agent and support approaches in combination with Verastem Oncology’s RAF/MEK clamp avutometinib as well as other rational combinations across KRAS G12D-driven cancers. KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancer. KRAS G12D mutation occurs most commonly in pancreatic (37%), colorectal (12.5%), endometrial (8%) and non-small cell lung (5%) cancers.

As previously announced, the discovery and development collaboration between Verastem Oncology and GenFleet aims to advance three oncology discovery programs related to RAS pathway-driven cancers. The collaboration builds on the strengths of both companies in oncology small molecule drug development, enabling Verastem Oncology to partner its clinical development and regulatory expertise with GenFleet’s accomplished discovery capabilities. This synergistic collaboration includes Verastem Oncology’s experience and established network of collaborators, including scientific and clinical experts in RAS biology and RAS pathway-driven cancers and GenFleet’s accomplishments with its KRAS G12C inhibitor program. The IND filing and initial Phase 1 studies will be led and funded by GenFleet in China. The collaboration provides Verastem Oncology with an exclusive option to obtain a license to each of the three compounds in the collaboration after successful completion of pre-determined milestones in a Phase 1 trial. The licenses would give Verastem Oncology development and commercialization rights outside of China while GenFleet would retain development and commercialization rights inside of China.

About Avutometinib

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS pathway inhibition. Avutometinib is currently in late-stage development.

In contrast to currently available MEK inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The U.S. Food and Drug Administration granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, its FAK inhibitor, for the treatment of all patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its RAMP (Raf And Mek Program) trials. RAMP 201 is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation. Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205, a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

On December 18, 2023 Anagenex and Nimbus Therapeutics (Nimbus) reported that they have initiated a research collaboration (Press release, Nimbus Therapeutics, DEC 18, 2023, View Source [SID1234638666]). Anagenex, a pioneering drug discovery company pairing large-scale data generation with proprietary artificial intelligence (AI), will work closely with Nimbus to discover small molecule drugs for multiple challenging targets.

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Through this multi-target collaboration, the companies will apply Anagenex’s AI driven parallel biochemistry platform to generate billions of experimentally measured datapoints for each of Nimbus’ nominated targets. Anagenex will then use the resulting data to train proprietary AI models that will generatively design 100 million new target-specific molecules to experimentally probe structure activity relationships at an unprecedented scale and speed ultimately identifying highly selective and potent drug candidates. Under the terms of the agreement, Anagenex will receive an upfront payment and will be eligible for option and R&D milestone payments from Nimbus on each of the programs under the collaboration.

"We are thrilled to be partnering with Nimbus, one of the original and most successful computationally aided drug discovery and development companies," said Nicolas Tilmans, CEO of Anagenex. "We’re very excited to join forces with them in attacking new targets beyond oncology a few hundred million compounds at a time."

"Anagenex’s platform is highly synergistic with Nimbus’ computational and structure-based drug discovery expertise," said Peter Tummino, Ph.D., Nimbus’ Chief Scientific Officer. "At Nimbus, we have prioritized important but difficult-to-drug targets across multiple therapy areas. This new collaboration with Anagenex perfectly complements our broader efforts across early discovery to advance new small molecule medicines against these targets with the goal of improving patients’ lives."

On December 18, 2023 Daiichi Sankyo reported that the first patient has been dosed in two global, randomized phase 3 trials evaluating the efficacy and safety of Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) datopotamab deruxtecan (Dato-DXd) in combination with durvalumab, AstraZeneca’s anti-PD-L1 therapy, in two types of breast cancer (Press release, Daiichi Sankyo, DEC 18, 2023, View Source [SID1234638665]).

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Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca.

TROPION-Breast04 is evaluating neoadjuvant datopotamab deruxtecan plus durvalumab followed by adjuvant durvalumab with or without chemotherapy in patients with stage II-III triple negative breast cancer (TNBC) or hormone receptor (HR) low, HER2 low or negative breast cancer. TROPION-Breast05 is evaluating datopotamab deruxtecan alone and in combination with durvalumab in patients with locally recurrent inoperable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10).

Approximately 300,000 people worldwide are diagnosed annually with TNBC, accounting for approximately 15% of all breast cancer diagnoses.1,2 TNBC is characterized by its aggressive nature and high likelihood of recurrence and progression regardless of stage.3 Standard treatment for patients with early-stage disease (stage II-III) is typically chemotherapy alone or in combination with immunotherapy prior to tumor resection.5 For patients with metastatic disease, standard first-line treatment can include chemotherapy alone or in combination with immunotherapy.2,3,4

In addition to patients with TNBC, TROPION-Breast04 will enroll patients with HR low, HER2 low or negative breast cancer whose tumors express low levels of hormone receptors (estrogen and/or progesterone receptor levels 1% to < 10%). Patients with HR low, HER2 low or negative disease have historically been excluded from TNBC research as their tumors are not triple negative. However, these patients tend to have worse outcomes relative to those with hormone receptor-strongly positive tumors (estrogen and/or progesterone receptor levels ≥ 10%) on standard endocrine therapies.5

"While the addition of immune checkpoint inhibitors to chemotherapy has led to survival improvements for patients with triple negative breast cancer, the overall prognosis for these patients remains poor," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "These two phase 3 trials will evaluate whether combining datopotamab deruxtecan, a TROP2 directed antibody drug conjugate, with durvalumab may offer a more effective option for patients across different settings of breast cancer."

"In an early phase trial, the datopotamab deruxtecan and durvalumab combination has shown robust and durable tumor responses and a manageable safety profile in patients with previously untreated advanced triple negative breast cancer," said Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca. "The initiation of the TROPION-Breast04 and TROPION-Breast05 phase 3 trials underscores our confidence in this promising combination and our commitment to researching its potential across multiple settings of triple negative breast cancer and in HR low disease."

Daiichi Sankyo and AstraZeneca have two additional ongoing phase 3 trials evaluating datopotamab deruxtecan in TNBC. TROPION-Breast02 is evaluating datopotamab deruxtecan versus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-1/PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without durvalumab versus investigator’s choice of therapy in patients with stage I to III TNBC with residual disease after neoadjuvant therapy.

About TROPION-Breast04
TROPION-Breast04 is a global, randomized, open-label, double-arm, phase 3 trial evaluating the efficacy and safety of neoadjuvant datopotamab deruxtecan plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in patients with previously untreated stage II or III TNBC or HR low, HER2 low or negative breast cancer.

The primary endpoints of TROPION-Breast04 are pathological complete response and event-free survival. The key secondary endpoint is overall survival (OS) and additional secondary endpoints include distant disease-free survival, pharmacokinetics, immunogenicity, safety and tolerability.

TROPION-Breast04 will enroll approximately 1,700 patients with previously untreated TNBC or HR low, HER2 low or negative breast cancer at study sites in Asia, Europe, North America, Oceania and South America. For more information, visit ClinicalTrials.gov.

About TROPION-Breast05
TROPION-Breast05 is a global, randomized, open-label, three-arm phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan alone and in combination with durvalumab versus investigator’s choice of chemotherapy plus pembrolizumab in participants with locally recurrent inoperable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10). Patients must have completed treatment for stage I to III breast cancer, if indicated, and ≥ 6 months have elapsed between completion of treatment with curative intent and the first documented recurrence.

The primary endpoint of TROPION-Breast05 is progression-free survival (PFS) as assessed by blinded independent central review. The key secondary endpoint is OS and additional secondary endpoints include PFS as assessed by investigator, objective response rate, duration of response, pharmacokinetics, immunogenicity, safety and tolerability.

TROPION-Breast05 will enroll 625 patients with TNBC at study sites across Asia, Europe, North America and Oceania. For more information, visit ClinicalTrials.gov.

About Triple Negative Breast Cancer
Breast cancer is the most common cancer in the world and leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

While some breast cancers test positively for estrogen receptors, progesterone receptors or an overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.2 Approximately 15% of breast cancer tumors or 300,000 cases annually are considered triple negative.1,2 Standard treatment for patients with early stage disease (stage II-III) is typically chemotherapy alone or in combination with immunotherapy prior to tumor resection.6 For patients with metastatic disease, standard first-line treatment can include chemotherapy alone or in combination with immunotherapy.2,3,4 The median OS of patients living with metastatic TNBC is 12 to 18 months, with only about 12% of patients living five years following diagnosis.7,8

TNBC is characterized by its aggressive nature and high likelihood of progression and recurrence regardless of stage.4 There is a great need for innovative therapeutic options across disease stages and treatment settings.

TROP2 is a protein broadly expressed in several solid tumors, including TNBC.9 TROP2 is associated with increased tumor progression and poor survival in patients with breast cancer.10

About Hormone Receptor Low, HER2 Low or Negative Breast Cancer
HR low, HER2 low or negative breast cancers test positively for hormone receptors but at low levels (estrogen and/or progesterone receptor levels 1% to < 10%) and low or negatively for HER2 (immunohistochemistry [IHC] scores of 0 or 1+ or IHC 2+/ISH-).11,12 HR low breast cancer occurs in approximately 2 to 3% of patients with HR positive disease and continues to represent a clinical challenge as limited data are available regarding optimal treatment for these patients.12

HR expression is a key prognostic and predictive biomarker in breast cancer. While HR positive tumors (estrogen and/or progesterone receptor levels 1% to ≥ 10%) are likely to derive clinical benefit from standard endocrine therapies, HR low tumors do not.12 Patients with HR low tumors have also historically been excluded from TNBC research given their tumors are not triple negative. However, early research suggests HR low tumors may be more similar to TNBC than HR positive tumors, supporting the inclusion of these patients in TNBC clinical trials.

On December 18, 2023 Blueprint Medicines Corporation (Nasdaq: BPMC) reported that Kate Haviland, Chief Executive Officer, will present a corporate overview and 2024 outlook at the 42nd Annual J.P. Morgan Healthcare Conference on Monday, January 8, 2024, at 10:30 a.m. PT (1:30 p.m. ET) (Press release, Blueprint Medicines, DEC 18, 2023, View Source [SID1234638664]).

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A live webcast of the presentation will be available by visiting the Investors & Media section of Blueprint Medicines’ website at View Source A replay of the webcast will be archived on Blueprint Medicines’ website for 30 days following the presentation.

On December 18, 2023 Nectin Therapeutics Ltd., (Nectin), a biotechnology company developing novel targeted immunotherapies that address resistance to approved immune oncology treatments, reported that it has progressed its Phase 1 clinical trial of NTX1088 to include a combination therapy arm with the immune-oncology drug KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, and expanded the clinical trial to five global sites (Press release, Nectin Therapeutics, DEC 18, 2023, View Source [SID1234638663]).

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The clinical trial sites include City of Hope in California, Sheba Medical Center and Hadassah Medical Center in Israel, along with MD Anderson Cancer Center in Houston, Texas and Ochsner MD Anderson Cancer Center in Louisiana. Notably, the NTX1088 clinical trial is the first to enroll patients at the new Ochsner MD Anderson Cancer Center partnership that was established to ensure that Ochsner cancer patients have access to the most advanced care, including to clinical trials of innovative therapies.

"As a leader in cancer care, Ochsner MD Anderson Cancer Center is committed to providing world-class care to the southeastern Louisiana community," said Dr. Marc Matrana, Director, Precision Cancer Therapies and Research Program at Ochsner. "Part of that commitment is ensuring that our patients have access to clinical trials of innovative new cancer therapies. We are impressed by the promising preclinical data and the novel mechanism of action of PVR blockade, and we are delighted to join with Nectin Therapeutics to support the Phase 1 trial of NTX1088."

NTX1088 is Nectin’s first-in-class lead candidate – a highly potent monoclonal antibody directed against PVR (CD155), a transmembrane protein expressed on cancer cells and associated with resistance to PD1 and PDL1 immune checkpoint inhibitors. PVR blockade by NTX1088 is the first and only therapeutic approach aimed at restoring the antitumor immune activity of DNAM1 (CD226). DNAM1 is a cell surface glycoprotein, central to the function of T-cells and NK cells, which are degraded by PVR on tumor cells. Restoring the expression and activation of DNAM1 by blocking PVR results in increased antitumor activity from T-cells and NK cells. Additionally, PVR blockade by NTX1088 further stimulates an antitumor immune response by preventing the suppressing signaling of several immune checkpoint receptors, including TIGIT and CD96. NTX1088 is currently being clinically evaluated as a monotherapy and in combination with KEYTRUDA in patients with advanced solid tumors.

"We are encouraged by the rapid progress of our NTX1088 clinical program," said Dr. Keren Paz, Chief Development Officer of Nectin Therapeutics. "Our collaboration with Merck, and the rapid expansion of our clinical trial sites significantly increase cancer patients’ access to the trial. We value the commitment of our new partners to the mission of developing life-saving therapies and look forward to advancing innovative medicines to improve the lives of cancer patients."

The NTX1088 Phase 1 trial is being conducted with support from The Cancer Focus Fund, a unique investment fund established in collaboration with The University of Texas MD Anderson Cancer Center. The fund provides investment support to advance promising cancer therapies along with the clinical trial expertise and infrastructure of MD Anderson Cancer Center sites.

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

About NTX1088
NTX1088 is a first-in-class monoclonal antibody directed against a key immune checkpoint, PVR (CD155), currently in a Phase I clinical trial. NTX1088 blocks the interaction between PVR and DNAM1 (CD226), a transmembrane molecule involved in the activation of anti-cancer T-cells and NK cells. By preventing internalization and degradation of DNAM1, NTX1088 leads to restoration of DNAM1 expression on the surface of immune cells, resulting in robust antitumor activity. NTX1088 also blocks PVR interactions with its other ligands, such as TIGIT and CD96, preventing their immune inhibitory signaling. NTX1088 demonstrated superior antitumor activity compared to approved and investigational immune checkpoint inhibitors in preclinical models and had a favorable safety profile in non-human primates. NTX1088 is currently being clinically evaluated as a monotherapy and in combination with KEYTRUDA (pembrolizumab) in patients with advanced solid tumors.