On April 25, 2025 Nimbus Therapeutics, LLC ("Nimbus Therapeutics" or "Nimbus"), a biotechnology company that designs and develops breakthrough medicines through its powerful computational drug discovery engine, reported that its Phase 1/2 clinical trial of NDI-219216, the company’s investigational non-covalent Werner syndrome helicase (WRN) inhibitor, is actively enrolling and dosing patients with advanced solid tumors (Press release, Nimbus Therapeutics, APR 25, 2025, View Source [SID1234652146]).

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"The initiation of this clinical trial marks an important milestone in advancing our novel WRN inhibitor program," said Anita Scheuber, M.D., Ph.D., Senior Vice President, Therapeutic Head, Oncology at Nimbus. "We are excited to be evaluating NDI-219216 in patients with advanced disease, who currently have limited treatment options when they experience disease progression on standard of care therapies. The trial is actively enrolling across multiple clinical sites, and we look forward to generating important additional safety and efficacy data as we advance this promising candidate through clinical development."

The Phase 1/2 clinical trial (NCT06898450) is an open-label, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of NDI-219216 in patients with advanced cancer. The study will be conducted in three parts: Part A (dose escalation), Part B (dose optimization), and Part C (dose expansion).

Nimbus presented promising preclinical data on NDI-219216 (previously NTX-452) at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on Molecular Targets and Cancer Therapeutics in October 2024. The data demonstrate that NDI-219216 is a potent and selective WRN inhibitor with significant tumor regression and sustained complete responses observed at low doses in MSI-H tumor models refractory to immunotherapy and chemotherapy.

The company will present new findings comparing covalent versus non-covalent WRN inhibition mechanisms and demonstrating NDI-219216’s superior efficacy across multiple preclinical MSI-H tumor models compared with other clinical-stage WRN inhibitors in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 25-30, 2025 in Chicago. The poster entitled "NDI-219216: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors" highlights key preclinical findings related to NDI-219216, including:

Demonstration of activity against a potential resistance mutation at Cysteine 727 that could significantly reduce the efficacy of covalent WRN inhibitors
Robust tumor regression across multiple MSI-H tumor models, including those that are refractory to existing standard of care agents
Superior efficacy at lower doses and in less responsive MSI-H tumor models compared to other clinical-stage WRN inhibitors
"The data we are presenting at AACR (Free AACR Whitepaper) 2025 highlight several important features of our non-covalent WRN inhibitor," said Peter J. Tummino, Ph.D., President of Research and Development at Nimbus. "NDI-219216 has the potential for more durable target engagement than covalent inhibitors and maintains potency against potential resistance mutations. Its superior efficacy across multiple MSI-H tumor models, including those less sensitive to other WRN inhibitors and those refractory to current therapies, reinforces our belief that NDI-219216 represents a best-in-class opportunity with broad potential across multiple MSI-H tumor types with significant unmet need."

About NDI-219216

NDI-219216 is a highly potent and selective non-covalent investigational inhibitor of Werner syndrome helicase (WRN) activity being developed for the treatment of MSI-H tumors. WRN is a DNA helicase required for DNA replication and DNA repair and is a validated synthetic lethal target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of deficient mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric, and endometrial cancers. In preclinical studies, treatment with NDI-219216 exhibited robust antitumor activity across multiple cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) MSI-H tumor models, including models for colorectal, gastric, and endometrial cancers.

On April 25, 2025 NETRIS Pharma, a clinical-stage private biopharmaceutical company developing a new class of therapeutics targeting Netrin-1, reported positive interim results from the ongoing ImmunoNET Phase II trial of its lead candidate NP137 (Press release, Netris Pharma, APR 25, 2025, View Source [SID1234652145]). The multicenter, open-label, proof of concept study is designed to evaluate the clinical and biological activity of NP137 as an add-on therapy in patients with advanced or metastatic Head & Neck Cancer and Non-Small Cell Lung Cancer (NSCLC) who have progressed under standard immunotherapies.

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The interim analysis met both the primary and key secondary endpoints in secondary refractory patients. Such analysis confirms NP137 excellent safety profile and its potential to overcome secondary resistance to leading immunotherapies. Clinical benefits were observed in half of the patients with Head & Neck and NSCLC cancers who had previously progressed under approved immunotherapy.

« These interim results mark a major milestone in our mission to develop drugs that overcome therapy resistance » said Patrick Mehlen, CEO of NETRIS Pharma. « We are excited by the potential of NP137 to restore patients sensitivity to immunotherapy-based treatments and to deliver a new treatment solution for patients with limited options ».

Upcoming Data Presentations

Comprehensive study design and interim results will be presented at two of the world’s leading oncology congresses: the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in 2025, underscoring the global significance of these findings.

« We look foward to sharing these important data with the oncology community at ASCO (Free ASCO Whitepaper) and ESMO (Free ESMO Whitepaper), and to advancing NP137 into the next phase of development » added Dr. Jérome Fayette, Medical Oncologist at Centre Léon Bérard and Principal Investigator of the ImmunoNet study.

About NP137

NP137 is a humanized monoclonal antibody (IgG1) targeting netrin-1, a protein overexpressed in a large proportion of human cancers and associated with disease severity and resistance to therapy. By blocking netrin-1, NP137 is designed to restore apoptosis and reverse epithelial-to-mesenchymal transition (EMT), addressing critical mechanisms of resistance that limit the effectiveness of immune checkpoint inhibitors. Preclinical and early clinical studies have shown that NP137 has anti-cancer effects both as a monotherapy and in combination with chemotherapy or immunotherapy, with a favorable safety profile.

On April 25, 2025 FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, reported new plixorafenib results from the Phase 1/2a clinical trial that demonstrate that circulating tumor DNA (ctDNA) accurately detects BRAF mutations in tumor biopsies and change in variant allele frequency (VAF) of BRAF mutation in ctDNA may be a surrogate marker for monitoring disease (Press release, Fore Biotherapeutics, APR 25, 2025, View Source [SID1234652143]). The data is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, taking place April 25-30 in Chicago.

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"Plixorafenib was designed to inhibit mutated oncogenic BRAF V600, without causing paradoxical MAPK pathway activation, and also confers dimer–breaking properties and activity against non-V600 BRAF alterations," said Rona Yaeger, M.D., Gastrointestinal Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. "The data from this clinical study, demonstrating molecular response and durable clinical responses (including when given without a MEK inhibitor) and the absence of emergent MAPK pathway alterations on treatment, further support the unique mechanism of action and the potential to benefit patients with BRAF-altered malignancies."

"These results are important because they show additional evidence of the strong clinical activity of plixorafenib, in both BRAF V600 mutations and BRAF fusions," said Stacie Peacock Shepherd, M.D., Ph.D., Chief Medical Officer of Fore. "In addition, this analysis also demonstrated high concordance of ctDNA BRAF mutations with biopsy tissue and changes in ctDNA corresponded closely to tumor size across tumor types; thus, liquid biopsies with widely used next-generation sequencing methodologies may provide a straightforward approach to identify appropriate patients for plixorafenib treatment, monitor disease status, and response. We are excited to share this data, along with the study design for our ongoing registrational FORTE study in BRAF altered advanced solid tumors, as we develop plixorafenib to help patients with BRAF driven tumors and generate further data to inform treatment."

The ctDNA results are from over 70 plixorafenib-treated patients and were an exploratory endpoint from a previously completed Phase 1/2a study. Utilizing next-generation sequencing (NGS), the plasma ctDNA results demonstrated high concordance with tissue biopsy at baseline across tumor types and mutations. Declines of V600 VAF% were observed in 85% of study participants after one cycle of plixorafenib treatment. Declines of class 2 and class 3 BRAF alterations in ctDNA were also observed. In participants with available paired tumor biopsies, decreases in pERK validated ctDNA results and demonstrated the suppression of the MAPK pathway at clinically relevant exposures. In addition, participants with V600E-mutated advanced solid tumors, early changes in V600E VAF% may predict response to plixorafenib, as responders had larger decreases in VAF% from baseline to cycle 2. In longitudinal samples, changes in ctDNA corresponded to tumor size across tumor types, suggesting that ctDNA may be a surrogate marker for monitoring disease. Compared to acquired mutations driving resistance to early generation BRAF inhibitors, no new mutations in MAPK pathway genes were found following plixorafenib treatment, supporting the dimer–breaker property and novel mechanism of action of plixorafenib from the early generation BRAF inhibitors. In participants without response, co-occurrent drivers at baseline included RAS, MAPK-associated or NF1 mutation, including melanoma patients who all received prior MAPKi therapies.

Also being presented at AACR (Free AACR Whitepaper) 2025 is a trial in progress poster showcasing the global FORTE master protocol with a basket design, including three monotherapy sub-protocols in patients with BRAF fusions, rare BRAF V600-mutated tumors, and BRAF V600 primary recurrent central nervous system tumors. An interim analysis is planned for each of the monotherapy baskets during 2025. A fourth, exploratory sub-protocol will assess preliminary activity of plixorafenib in BRAF V600-mutated select solid tumors. Alongside primary and key secondary endpoints of overall response rate, duration of response, safety, progression-free survival, overall survival, and pharmacokinetics, key exploratory endpoint of each of the four sub-protocols is a longitudinal ctDNA assessment.

Poster Presentation Details:

Title: Circulating tumor DNA analysis of patients with BRAF-mutated advanced unresectable solid tumors treated with plixorafenib (FORE8394/PLX8394) in Phase 1/2a study
Poster Session: Liquid Biopsy Circulating Nucleic Acids 1
Date and Time: Monday, April 28, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: 3248
Presenter: Jessica C. Jang, Fore Biotherapeutics

Title: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers
Poster Session: Late Breaking and Clinical Trials – Phase II and Phase III Clinical Trials in Progress
Date and Time: Tuesday, April 29, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: CT247
Presenter: Macarena I. de la Fuente, M.D., Sylvester Comprehensive Cancer Center

On April 25, 2025 Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, reported new preclinical proof-of-concept data for its novel HER3 antibody-drug conjugate (ADC), EO-1022 (Press release, Elevation Oncology, APR 25, 2025, View Source;utm_medium=rss&utm_campaign=elevation-oncology-presents-preclinical-proof-of-concept-data-for-eo-1022-at-the-american-association-for-cancer-research-aacr-annual-meeting-2025 [SID1234652142]). The data will be presented in a late-breaking poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, being held April 25-30 in Chicago, Illinois.

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"We designed EO-1022 with several notable features, including glycan site-specific conjugation and MMAE payloads, in order to address the significant need for a novel HER3 ADC that can potentially deliver improved efficacy and safety to patients with a range of solid tumors," said Joseph Ferra, President and Chief Executive Officer of Elevation Oncology. "Today, we are excited to share preclinical proof-of-concept data for EO-1022, which indicate enhanced stability and anti-tumor activity than benchmark HER3 ADCs in the models tested in vitro and in vivo. We believe these findings support the potential of EO-1022 in treating multiple HER3-expressing cancers and look forward to progressing this program toward the clinic."

EO-1022 is an ADC containing seribantumab, a fully human IgG2 anti-HER3 monoclonal antibody, which is site-specifically conjugated at glycan to the monomethyl auristatin E (MMAE) payload with a drug-to-antibody ratio (DAR) of 4. Elevation Oncology designed EO-1022 leveraging the site-specific ADC technology platform licensed from Synaffix B.V. Elevation Oncology is developing EO-1022 for the treatment of solid tumors that express HER3, including breast cancer and non-small cell lung cancer. Elevation Oncology expects to file an Investigational New Drug (IND) application for EO-1022 in 2026.

In a poster titled, "Preclinical discovery and characterization of EO-1022, a site-specific glycan-conjugated anti-HER3 vc-MMAE ADC for treating solid tumors," Elevation Oncology scientists will present in vitro and in vivo data that show:

EO-1022 is highly stable in human serum, with a homogenous DAR of 4 and minimal free payload compared to seribantumab-vcMMAE and patritumab-DXd, two benchmark HER3 ADCs, both of which use stochastic conjugation. These findings illustrate that a key feature of EO-1022 is minimal systemic exposure to free payload, potentially resulting in reduced payload-associated toxicity in patients and an improved safety profile.
EO-1022 exhibits potent in vitro cytotoxicity that is dependent on HER3 expression levels.
EO-1022 elicits anti-tumor activity in in vivo models of low, medium and high HER3 expression levels, including in a patient derived xenograft (PDX) model of low HER3-expressing EGFR-mutant lung cancer.
The poster presentation is now available in the "Publications" section of Elevation Oncology’s website: View Source

About EO-1022

Elevation Oncology is developing EO-1022, a potentially differentiated HER3 ADC for the treatment of HER3-expressing solid tumors, including breast cancer and non-small cell lung cancer. EO-1022 consists of seribantumab, a fully human IgG2 anti-HER3 antibody, site-specifically conjugated at glycan to the MMAE payload with a DAR of 4. It leverages seribantumab’s desirable internalization properties and advanced site-specific ADC technology which makes possible the use of the potent cytotoxic MMAE payload. Elevation Oncology expects to file an IND application in 2026.

On April 25, 2025 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported preclinical data from four pipeline programs during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2025 Annual Meeting taking place in Chicago (Press release, Cogent Biosciences, APR 25, 2025, View Source [SID1234652141]).

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"We welcome the opportunity to present updated results from these programs that represent our exciting pipeline of potential best-in-class targeted therapies," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "These data demonstrate Cogent’s ability to discover and advance novel therapies for rare disease populations with high unmet medical need, and we look forward to continuing to advance these candidates."

Poster Details

Title: Identification of a potent KRAS (ON) inhibitor with selectivity for mutant KRAS over HRAS and NRAS
Session Category: Chemistry
Session Title: Lead Identification and Optimization
Session Date and Time: April 30, 2025 – 9:00 AM – 12:00 PM CT (10:00 AM – 1:00 PM ET)
Location: Poster Section 25
Poster Board Number: 3
Published Abstract Number: 6974

Mutations in KRAS are among the most prevalent mutations found in cancer, occurring most often in colorectal cancer, non-small cell lung cancer and pancreatic cancer. The poster presented today describes Cogent’s internally-developed pan KRAS(ON) inhibitor program with selectivity over HRAS and NRAS and picomolar (pM) activity across KRAS mutations. In response to our 30mg/kg oral dose we observed robust PD including 90% tumor growth inhibition in a mouse TGI model. Lead optimization of this series is ongoing.

Title: Preclinical characterization of CGT6297, a novel PI3Kα H1047R mutant-selective inhibitor
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 2
Session Date and Time: April 28, 2025 – 2:00 PM – 5:00 PM CT (3:00 PM – 6:00 PM ET)
Location: Poster Section 20
Poster Board Number: 5
Published Abstract Number: 3004

Cogent is developing a potential best-in-class, wild-type-sparing, PI3Kα inhibitor that provides coverage for the both the H1047R mutation as well as E542K and E545K helical mutants. The phosphoinositide 3-kinase (PI3K) pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kα.

In the poster being presented today, Cogent’s preclinical candidate CGT6297 demonstrates broad cellular panel profiling across multiple resistant and mutated cell lines, including, for the first time, efficacy against PI3K helical mutations. The poster also showcases the activity of CGT6297 in both ST1056 (H1047R mutant) and MCF-7 (E545K mutant) breast cancer TGI models.

Title: The Reversible and Selective FGFR2/3 inhibitor CGT4859 has superior target coverage of resistance mutations missed by leading FGFR inhibitors
Session Category: Clinical Research
Session Title: Targeted Therapies and Combinations 2
Session Date and Time: April 29, 2025 – 9:00 AM – 12:00 PM CT (10:00 AM – 1:00 PM ET)
Location: Poster Section 34
Poster Board Number: 27
Published Abstract Number: 4729

FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today describes Cogent’s internally-developed FGFR2/3 inhibitor which maintains potency on FGFR2 mutations and is selective against the entire kinome and a broad panel of channels and receptors. Exploratory pharmacokinetics (PK) studies conducted across species showed CGT4859 to be a low-clearance compound with high oral bioavailability. Further, in an AN3 CA model, CGT4859 demonstrated dose-responsive tumor growth inhibition with complete regressions at >2.5 mg/kg QD or BID and was well-tolerated.

Cogent is currently enrolling patients in an ongoing Phase 1 trial with CGT4859 in patients with confirmed FGFR2 or FGFR3 mutations, including patients with advanced cholangiocarcinoma. The trial is designed to explore the safety, tolerability and clinical activity of escalating doses with the goal of selecting an active and well tolerated dose for further clinical investigation.

Title: Identification of CGT4255 an EGFR-sparing, pan-mutant HER2 clinical development candidate with potential best-in-class brain penetration
Session Category: Experimental and Molecular Therapeutics
Session Title: Novel Antitumor Agents 3
Session Date and Time: April 29, 2025 – 2:00 PM – 5:00 PM CT (3:00 PM – 6:00 PM ET)
Location: Poster Section 21
Poster Board Number: 1
Published Abstract Number: 5623

Cogent’s potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor includes potent coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification. New data presented on this compound describes CGT4255’s exceptional stability in human whole blood and liver cytosol fractions and high oral bioavailability and low clearance across preclinical species. In addition, CGT4255 is expected to have equivalent brain to plasma exposure suggesting potential best-in class properties.

All posters will be available on the ‘Posters and Publications’ page of Cogent’s website.

New Leadership Appointments
Cogent also announced today that Ray Frost has joined Cogent as Senior Vice President, Market Access and Adam Boyd, Ph.D. has joined Cogent as Senior Vice President, Corporate Strategy.

Mr. Frost joins Cogent with over 20 years of industry experience. Previously he served as Vice President Market Access at Ono Pharma USA and Zealand Pharma (Zealand). While at Zealand he played an integral part in building the commercial infrastructure to support the launch of their first product. Prior to Zealand he held roles of increasing responsibility in Market Access and Health Policy at Melinta Therapeutics, The Medicines Company, Bayer Healthcare, Eisai and MGI PHARMA. Mr. Frost is a graduate of Hofstra University.

Dr. Boyd joins Cogent with nearly 25 years of industry experience building and leading global teams across Development functions including Biostatistics, Clinical Pharmacology, Clinical Operations, and Data Management. In these roles, he was instrumental in bringing several products to market, including Mektovi (binimetinib), Braftovi (encorafenib), Jakafi (ruxolitinib), and Folotyn (pralatrexate). Prior to joining Cogent, Dr. Boyd was Vice President, Biometrics at Intellia Therapeutics, and prior to that, held various roles of increasing responsibility at Pfizer, Array BioPharma, Novartis, and Allos Therapeutics. Dr. Boyd earned his Ph.D. in Biostatistics from the University of Colorado, where he is currently a member of the Colorado School of Public Health’s Dean’s Advisory Board.

Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)
Cogent also announced today that, on April 14, 2025, the Compensation Committee of Cogent’s Board of Directors, made up entirely of independent directors, approved the grants of "inducement" equity awards to five new employees, including Mr. Frost and Dr. Boyd, under the company’s 2020 Inducement Plan with a grant date of April 21, 2025. The awards were approved in accordance with Listing Rule 5635(c)(4) of the corporate governance rules of the Nasdaq Stock Market. The employees received, in the aggregate, nonqualified options to purchase 446,000 shares of Cogent common stock. Each option has a 10-year term, an exercise price equal to the closing price of Cogent’s common stock on the grant date, and a 4-year vesting schedule with 25% vesting on the 1-year anniversary of the grant date and the remainder vesting in equal monthly installments over the subsequent 36 months, provided such employee remains employed through each such vesting date.