On October 9, 2024 Boehringer Ingelheim and Circle Pharma (Circle) reported a new research collaboration and license agreement with the shared goal to develop a first-in-class cyclin inhibitor that can halt the growth of cancer cells potentially offering hope to those living with hard-to-treat cancers (Press release, Circle Pharma, OCT 9, 2024, View Source;utm_medium=rss&utm_campaign=boehringer-ingelheim-and-circle-pharma-announce-new-research-collaboration-to-develop-a-novel-precision-cancer-treatment [SID1234647107]).

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Uncontrolled cell growth is a common feature in most tumor types and is a driving force in the formation of tumors. Genetic alterations like mutations or amplifications in the genes encoding the regulatory machinery of cell division contribute to malignant growth in a significant fraction of all solid tumors. That is why Boehringer Ingelheim is targeting the proteins involved in this process, a promising strategy for new cancer treatments.

Current methods targeting cyclin-dependent kinases can be limited by low selectivity and toxicity. Circle has developed a possible solution to these challenges by creating macrocycle therapies that directly inhibit cyclins, the proteins that regulate cell division.

"We’re delighted to be joining forces with Circle’s scientists to develop an innovative cancer treatment based on their proprietary macrocycle platform molecules to achieve our goal of transforming the lives of people living with cancer," said Clive R. Wood, Ph.D., Senior Vice President and Global Head of Discovery Research at Boehringer Ingelheim. "This new collaboration complements our oncology research portfolio, and further reinforces our commitment to tackling intractable targets."

David Earp, Ph.D., JD, chief executive officer, Circle Pharma said, "With our lead program, CID-078, a Cyclin A/B RxL inhibitor, we have demonstrated the capability of our MXMOTM platform to deliver oral macrocycles against a target that was previously considered to be undruggable. We’re excited to partner with Boehringer Ingelheim to leverage the platform against another challenging cyclin target that offers the potential to address high unmet need cancer indications."

This partnership is a significant step toward Boehringer Ingelheim’s goal of transforming cancer care. It bolsters the already robust oncology pipeline of cancer cell-directed and immuno-oncology investigational therapies for smart combinations that may offer the greatest benefit for people living with cancer.

As part of the agreement, Circle Pharma will receive an upfront payment and potential development, regulatory, and sales milestone payments of up to USD $607 million.

On October 9, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported further details for its late-breaking presentation of mature data from the ongoing Phase 2 RAMP 201 (ENGOT-ov60/GOG-3052) clinical trial to be presented as an oral presentation at a plenary session at the International Gynecologic Cancer Society (IGCS) Annual Global Meeting taking place October 16-18, 2024 in Dublin, Ireland (Press release, Verastem, OCT 9, 2024, View Source [SID1234647125]).

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The late-breaking abstract is embargoed until the morning of the presentation at IGCS. The oral presentation will include updated safety and efficacy data from the RAMP 201 trial evaluating the combination of avutometinib, an oral RAF/MEK clamp, and defactinib, an oral, selective FAK inhibitor, in patients with recurrent low-grade serous ovarian cancer (LGSOC), including overall response rate, progression free survival, and duration of response.

IGCS Oral Presentation Details

Title: Efficacy and Safety of Avutometinib + Defactinib in Recurrent Low Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-ov60/GOG-3052/RAMP 201
Session: Plenary 03: Oral Abstract Presentations
Date/Time: October 17, 2024, at 11:42 AM ET/4:42 PM Irish time [GMT +1].
Presenter: Professor Susana N. Banerjee, MBBS, MA PhD, FRCP, global lead investigator of the study, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Team Leader in Women’s Cancers at The Institute of Cancer Research, London
Conference Call and Webcast Information

Verastem will hold an investor conference call and webcast on October 17, 2024 at 4:30 p.m. EDT, to review the mature data from the RAMP 201 trial. To access the conference call, please dial (844) 763-8274 (local) or (412) 717-9224 (international) at least 10 minutes prior to the start time and ask to be joined into the Verastem Oncology conference call. A live audio webcast of the call, along with accompanying slides, will be accessible under "Events & Presentations" in the Investors & Media section of the company’s website at www.verastem.com.

About the Avutometinib and Defactinib Combination

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/MAPK pathway inhibition. In contrast to currently available MEK-only 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 MEK-only inhibitors.

Verastem Oncology is currently conducting clinical trials with avutometinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. Verastem is currently enrolling patients and activating sites for RAMP 301 (NCT06072781), an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib, a selective FAK inhibitor, versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC). RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and enrollment has been completed for the entire RAMP 201 trial, including regimen selection and expansion of the go forward regimen.

Verastem initiated a rolling New Drug Application (NDA) submission in May 2024 to the U.S. Food and Drug Administration (FDA) for the investigational combination of avutometinib and defactinib in adults with recurrent KRAS mutant LGSOC who received at least one prior systemic therapy and expects to complete its NDA submission in the second half of 2024 with a potential FDA decision in the first half of 2025. The FDA granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib for the treatment of all patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.

Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. The RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. FDA granted Orphan Drug Designation to avutometinib and defactinib combination for the treatment of pancreatic cancer.

On October 9, 2024 Castle Biosciences, Inc. (Nasdaq: CSTL), a company improving health through innovative tests that guide patient care, reported that it will present new data related to its DecisionDx-Melanoma and DecisionDx-UM tests for patients with cutaneous melanoma (CM) and uveal melanoma (UM), respectively, at the 21st International Congress of the Society for Melanoma Research (SMR), taking place Oct. 10-13, 2024, in New Orleans (Press release, Castle Biosciences, OCT 9, 2024, View Source [SID1234647126]).

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"In large prospective and retrospective studies, our DecisionDx-Melanoma test has been shown to provide clinical value above and beyond current staging paradigms and other tests currently available for patients with cutaneous melanoma," said Derek Maetzold, president and chief executive officer of Castle Biosciences. "Clinical use studies have shown that clinicians act upon these results to improve risk-aligned treatment pathway decisions which are associated with improved outcomes."

Details regarding Castle’s posters at SMR are included below. Posters will be available for viewing starting the evening of Thursday, Oct. 10, through the evening of Saturday, Oct. 12.

DecisionDx-Melanoma

Poster title: In a prospective, multicenter study, the 31-GEP identified patients at increased risk of tumor recurrence and added significant prognostic value to AJCC staging
Poster #: 40
Summary: This study included 876 patients with Stage I-III CM from multiple centers who received DecisionDx-Melanoma testing as part of their clinical care. The data show DecisionDx-Melanoma stratified patients by their risk of recurrence and was a significant predictor of recurrence; patients with Class 1A (lowest risk) test results had significantly higher three-year recurrence-free survival than those with a Class 1B/2A (increased risk) or Class 2B (highest risk) test result (p<0.001). Importantly, the test added significant predictive value to American Joint Committee on Cancer (AJCC) staging, considered the standard of care in melanoma management. These findings provide evidence that use of the test with melanoma patients enables better risk-aligned care decisions, which have been shown to lead to improved patient outcomes.1,2
DecisionDx-UM

Poster title: Confirmation of PRAME status as a risk modifier of 15-gene expression profile class in a large real-world population-based cohort of uveal melanoma patients
Poster #: 134
About DecisionDx-Melanoma

DecisionDx-Melanoma is a gene expression profile risk stratification test. It is designed to inform two clinical questions in the management of cutaneous melanoma: a patient’s individual risk of sentinel lymph node positivity and a patient’s personal risk of melanoma recurrence and/or metastasis. By integrating tumor biology with clinical and pathologic factors using a validated proprietary algorithm, DecisionDx-Melanoma is designed to provide a comprehensive and clinically actionable result to guide risk-aligned patient care. DecisionDx-Melanoma has been shown to be associated with improved patient survival and has been studied in more than 10,000 patient samples. DecisionDx-Melanoma’s clinical value is supported by more than 50 peer-reviewed and published studies, providing confidence in disease management plans that incorporate the test’s results. Through June 30, 2024, DecisionDx-Melanoma has been ordered more than 173,000 times for patients diagnosed with cutaneous melanoma. Learn more at www.CastleBiosciences.com.

About DecisionDx-UM

DecisionDx-UM is Castle Biosciences’ 15-gene expression profile (GEP) test that uses an individual patient’s tumor biology to predict individual risk of metastasis in patients with uveal melanoma (UM). DecisionDx-UM is the standard of care in the management of newly diagnosed UM in the majority of ocular oncology practices in the United States. Since 2009, the American Joint Committee on Cancer (AJCC; v7 and v8) Staging Manual for UM has specifically identified the GEP test as a prognostic factor that is recommended for collection as a part of clinical care. Further, the National Comprehensive Cancer Network (NCCN) guidelines for UM include the DecisionDx-UM test result as a prognostic method for determining risk of metastasis and recommended differential surveillance regimens based on a Class 1A, 1B and 2 result. DecisionDx-UM is currently the only prognostic test for UM that has been validated in prospective, multi-center studies, and it has been shown to be a superior predictor of metastasis compared to other prognostic factors, such as chromosome 3 status, mutational status, AJCC stage and cell type. It is estimated that nearly 8 in 10 patients diagnosed with UM in the United States receive the DecisionDx-UM test as part of their diagnostic workup. Learn more at www.CastleBiosciences.com.

On October 9, 2024 Nimbus Therapeutics, LLC ("Nimbus Therapeutics" or "Nimbus"), a biotechnology company that designs and develops breakthrough medicines for patients through its powerful computational drug discovery engine, reported that it will present the first preclinical data on its novel Werner syndrome helicase (WRN) inhibitor in a poster presentation at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024 in Barcelona, Spain (Press release, Nimbus Therapeutics, OCT 9, 2024, View Source [SID1234647109]).

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WRN is a helicase required for DNA replication and DNA repair and is a validated target for tumors with microsatellite instability (MSI). Nimbus will present preclinical data on NTX-452, a novel WRN inhibitor developed using the company’s computational drug discovery platform.

Details of the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium presentation are as follows:

Abstract Title: Preclinical Characterization of NTX-452, a Potent, Selective and Highly Efficacious WRN Inhibitor for the Treatment of MSI-H Tumors

Date: Friday, October 25, 2024

Time: 9:00 a.m. – 3:00 p.m. CEST

Session Title: DNA Repair Modulation (e.g. PARP, CHK, ATR, ATM)

Abstract Number: 356

On October 9, 2024 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that the company will present a poster at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics to be held October 23-25, 2024, in Barcelona, Spain (Press release, ORIC Pharmaceuticals, OCT 9, 2024, View Source [SID1234647110]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Poster presentation details:

Title: ORIC-114, a highly selective, brain penetrant EGFR and HER2 inhibitor, demonstrates best-in-class properties against exon 20 insertions and other atypical EGFR mutations
Poster #: PB050
Poster Session: Molecular Targeted Agents
Date & Time: Wednesday, October 23, 2024, 9:00 – 11:00 a.m. CEST
Location: Exhibition Hall

Abstract highlights:
ORIC-114 is a highly selective, brain penetrant, orally bioavailable, irreversible inhibitor that selectively targets EGFR and HER2 with high potency against exon 20 insertion mutations and other atypical EGFR mutations. It has previously demonstrated systemic and intracranial clinical responses in patients with EGFR and HER2 exon 20 insertion mutations. In an expanded preclinical comparative analysis, ORIC-114 demonstrated best-in-class properties including brain penetrance, superior kinome selectivity, potent activity across EGFR PACC mutations and exon 20 insertion mutations, relative to firmonertinib, zipalertinib, and BDTX-1535. Additionally, evidence of molecular response in ctDNA from patients whose tumors harbored PACC mutations and exon 20 insertion mutations was observed with ORIC-114 treatment. ORIC-114 is a promising potential therapy for patients with non-small cell lung cancer harboring atypical mutations in EGFR, including those presenting with active CNS metastases, and is being evaluated in a global clinical trial (NCT05315700).

Full abstracts are available for viewing on the symposium website here.