On December 18, 2023, Kronos Bio, Inc. (the "Company") reported an update on its pipeline (Press release, Kronos Bio, DEC 18, 2023, View Source [SID1234638681]). After a review of data from the phase 1b portion of its phase 1b/2 trial of lanraplenib, a SYK inhibitor, in combination with gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia, the Company has decided not to proceed to phase 2. This decision was based on a review of the data from 24 patients across the four dose cohorts (20 – 90 mg lanraplenib in combination with 120 mg gilteritinib). While there were blast reductions in some patients, no complete response (CR) or CR with partial hematologic recovery (CRh) was observed, with a number of patients discontinuing early in treatment. Patients in the study were older, more heavily pre-treated and frailer than the relapsed/refractory patients in earlier studies. Many patients experienced non-drug related infectious disease complications leading to discontinuation during the first two months of treatment without achieving the count recovery needed to achieve a CR or CRh. The Company believes there could be utility for lanraplenib in other indications and is open to further development of lanraplenib with a partner.

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The Company also announced the designation a new development candidate, KB-9558, which targets the lysine acetyltransferase (KAT) domain of p300, a critical node of the IRF4 transcription regulatory network (TRN). IRF4 is a key driver in multiple myeloma. KB-9558 is the second molecule to emerge from the Company’s proprietary product engine, and is currently in IND-enabling studies, which are expected to be completed in the fourth quarter of 2024.

The Company’s first internally discovered molecule, KB-0742, an inhibitor of CDK9, has demonstrated on-mechanism, single agent anti-tumor activity and a manageable safety profile in pre-treated patients with transcriptionally addicted solid tumors. KB-0742 recently cleared the 80 mg dose in the dose escalation portion of the ongoing phase 1/2 trial. Patients currently in the two expansion cohorts will now be able to receive the 80 mg dose. The Company expects to provide data from the expansion phase of the trial in mid-2024.

On December 18, 2023 HighField Biopharmaceuticals, a clinical stage immuno-oncology company using lipid-based therapeutics to treat cancer, reported the dosing of its first patient in its Phase 1 clinical trial of HFK1, a drug encapsulated immunoliposome containing doxorubicin for treatment of solid tumors (Press release, HighField Biopharmaceuticals, DEC 18, 2023, View Source [SID1234638669]).

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The multi-regional, open-label, clinical trial is enrolling patients who have advanced refractory solid tumors with HER2 low and HER2+ expression. HER2 expressing solid tumors include breast, bladder, pancreatic, ovarian, stomach, colon, prostate, lung, uterus and cervix cancers.

This trial is being conducted in the U.S., China and other countries. The first patient was dosed at Mary Crowley Cancer Research in Dallas, TX. A Phase 1a dose escalation portion of the study will enroll 24 patients followed by Phase 1b dose expansion trial with up to 60 patients. Both the Phase 1a and 1b studies will assess the safety and preliminary efficacy of HFK1. Preliminary results are expected in the fourth quarter.

"Our immunoliposomes may offer effective alternatives to most current HER2 drugs that cannot target low HER2 tumors," said HighField CEO Yuhong Xu. "HFK1 is designed to bind and deliver the chemotherapeutic doxorubicin to tumor cells at even very low HER2 expression levels."

Minal Barve, MD, is the Chief Medical Officer/Executive Medical Director and the principal investigator at Mary Crowley Cancer Research, a specialized clinical research center that offers access to new investigational therapies. "It is important to treat the full range of HER2 cancer expression levels. It opens the possibility of reaching more cancer cells within the patient, not just those with high HER2 expression levels. I hope that HFK1 will provide a treatment option for a broad range of tumor types that have HER2 expression, not just the strongly HER2 positive tumors," Dr. Barve said.

"At Mary Crowley Cancer Research, we are focused on rapidly advancing the discovery of potential new therapies that can positively impact the care of cancer patients in their lifetime," Dr. Barve added. "We are grateful for our partnership with HighField to provide even more patients with hope."

HighField’s immunoliposomes represent a new generation of targeted chemotherapy drugs following the success of antibody drug conjugates (ADCs). Due to their unique features, HighField’s immunoliposomes may offer better safety with greater efficacy in treatment of a broad range of solid tumor types.

"A key differentiating factor of our immunoliposomes," observed HighField CBO Donald Wyatt, "is they not only are suitable for less toxic payloads than ADCs, but also are designed to have larger drug to antibody ratios that result in wider therapeutic windows, targeting more cancer cells with lower toxicity."

In the Phase 1a dose escalation portion of the clinical trial, patients will be enrolled into one of six dose groups to determine the highest tolerated dose. The Phase 1b study will assess HF158K1 in two types of solid tumors, and patients will be enrolled in one of two dose groups based on the Phase 1a findings. For more information visit NCT05861895 on clinicaltrials.gov.

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.