On January 9, 2025 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered therapies targeting cytokine pathways designed to address areas of unmet need for patients with a variety of cancers, reported it has reached the 75% of overall survival (OS) events necessary for the planned interim analysis of ARTISTRY-7, its potentially registrational trial of nemvaleukin in combination with pembrolizumab in platinum resistant ovarian cancer (PROC), and that it has extended its cash runway projection into Q1 2026 beyond key upcoming catalysts (Press release, Mural Oncology, JAN 9, 2025, View Source [SID1234649543]).

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The company expanded its pipeline in Q4 2024, by nominating two development candidates, one for its interleukin-18 (IL-18) program and one for its IL-12 program. MURA-8518 is designed to be a half-life extended, binding protein-resistant IL-18 in order to overcome the native cytokine’s limitations as a therapeutic. Mural expects to submit an Investigational New Drug (IND) Application or Clinical Trial Application (CTA) for a phase 1 trial of MURA-8518 in Q4 2025. MURA-7012 is comprised of targeted split IL-12 sub-units that preferentially self-assemble at the tumor site and are designed to limit systemic exposure.

"In just over a year since becoming an independent company, we have transformed Mural from a biotech with a binary readout expected in 2025 into a robust organization with multiple expected data catalysts. Not only have we stayed on track with our milestones as planned, we have also extended our cash runway into the first quarter of 2026 through operational efficiency," said Caroline Loew, Ph.D., CEO of Mural Oncology. "With two readouts in our late-stage trials on the horizon, nemvaleukin has the potential to become a new treatment option for patients with high unmet need in platinum-resistant ovarian cancer and mucosal melanoma. 2025 will be a pivotal year for Mural, and we look forward to advancing our clinical programs to bring value to patients and shareholders alike."

Upcoming catalysts:

Late Q1/early Q2 2025: Interim data readout of ARTISTRY-7, Mural’s potentially registrational phase 3 trial in PROC. The trial is evaluating nemvaleukin in combination with pembrolizumab versus investigator’s choice single agent chemotherapy. Consistent with Mural’s prior timing projections, the trial has now reached the 75% of OS events necessary for the planned interim analysis. The data will remain blinded to the company until after the independent data monitoring committee (IDMC) has reviewed the interim analysis, which is expected to be in late Q1/early Q2 2025. Consistent with interim analyses, there is a higher statistical bar for success at the interim analysis compared to the final analysis. If the hazard ratio meets this pre-specified higher bar for success at the interim analysis (0.727, or a 27.3% reduction in the risk of death assuming exactly 215 OS events), the company plans to submit a Biologics License Application (BLA) for nemvaleukin in combination with pembrolizumab for the treatment of PROC in 2025. If the hazard ratio does not meet the statistical threshold for success at the interim analysis and the company deems the study to have a high probability of success for the final analysis, Mural expects to continue the trial to the protocol-specified final OS analysis, where the maximum hazard ratio for success is 0.788, or a 21.2% reduction in the risk of death, assuming exactly 286 OS events. The company expects to report these final OS results in the second quarter of 2026, subject to event accrual.
Q2 2025: Top-line data readout of Cohort 2 of ARTISTRY-6, Mural’s potentially registrational phase 2 trial of nemvaleukin monotherapy in patients with unresectable or metastatic mucosal melanoma previously treated with immune checkpoint blockade. Nemvaleukin has been granted Orphan Drug Designation by the FDA for the treatment of mucosal melanoma. The target response rate in the ARTISTRY-6 trial is 25%. Mural believes that in this rare and highly aggressive tumor, which has historically had poor outcomes even in the first line setting, demonstrating durable responses with a response rate of 20-25% would be meaningful for patients, and would support a discussion with the FDA regarding a BLA submission and potential accelerated approval.
1H 2025: Preliminary data readout of Cohort 3 of ARTISTRY-6, an evaluation of a less-frequent intravenous (LFIV) dose of nemvaleukin monotherapy in patients with cutaneous melanoma. Patient enrollment in this cohort is now complete. If the data are promising, following subsequent clinical evaluation, LFIV dosing could offer a more convenient dosing regimen for patients and providers alike.
2H 2025: Preliminary data readout of Cohort 4 of ARTISTRY-6, an evaluation of a LFIV dose of nemvaleukin in combination with pembrolizumab in patients with cutaneous melanoma.
Q4 2025: Mural expects to submit an IND or CTA for a phase 1 trial of MURA-8518, its IL-18 development candidate.

On January 9, 2025 Lyell Immunopharma, Inc. (Nasdaq: LYEL), a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with cancer, reported pipeline updates, including its plans to advance IMPT-314, a potentially best-in-class therapy for aggressive large B-cell lymphoma, into pivotal trials (Press release, Lyell Immunopharma, JAN 9, 2025, View Source [SID1234649542]). IMPT-314 is an autologous dual-targeting CD19/CD20 chimeric antigen receptor (CAR) T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma.

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"Based on the positive initial clinical data reported at ASH (Free ASH Whitepaper) and the promising emerging clinical profile, we are accelerating the development of IMPT-314 as a potentially transformative product with differentiated benefit in overall and complete response rates as well as duration of response over first-generation CD19 CAR therapies in patients with aggressive large B-cell lymphoma," said Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. "Having presented an initial dataset that demonstrated an overall response rate of 94% and a complete response rate of 71% in patients treated in the 3rd-line+ setting, we are focusing our resources on advancing IMPT-314 for patients with large B-cell lymphoma in both the 2nd and 3rd line+ settings. To ensure a sustainable cost structure that delivers multiple clinical readouts with our current balance sheet, we have streamlined and focused our pipeline and organization to prioritize investment in IMPT-314 and early-stage research programs for solid tumors."

Pipeline Focus

Lyell is focused on advancing next-generation CAR T cell therapies with the potential to deliver higher response rates and longer duration of responses for patients with hematologic malignancies and solid tumors. Lyell is developing products enhanced with its novel technologies and manufacturing protocols.

In hematologic malignancies, Lyell is focused on advancing products designed to deliver improved outcomes over first-generation CD19 CAR T cell therapies. Lyell’s lead program, IMPT-314, is a dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the currently approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma. IMPT-314 is designed with a true ‘OR’ logic gate to target B-cells that express either CD19, CD20 or both and is manufactured through a process that enriches for CD62L-expressing cells to generate more naïve central memory CAR T cells with enhanced stemlike features and antitumor activity.

To realize the potential of cell therapy for solid tumors, Lyell is also developing next-generation CAR T-cell product candidates enhanced with anti-exhaustion and additional arming technologies, and manufactured with proprietary protocols. These approaches are designed to endow CAR T cells with attributes needed to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical responses – the ability to resist exhaustion, maintain qualities of durable stemness and function in the hostile tumor microenvironment.

Upcoming Milestones and Financial Outlook

For IMPT-314, a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate for the treatment of large B-cell lymphoma:

Present data from the ongoing Phase 1-2 trial in mid-2025, including more mature data from the 3rd line+ cohort and initial data from the 2nd line cohort
Present more mature clinical data from the 2nd line cohort in late 2025
Initiate a pivotal trial in the 3rd line+ setting in mid-2025
Initiate a pivotal trial in the 2nd line setting by early 2026
For early-stage solid tumor programs:

Submit first IND application for a new solid tumor CAR T-cell product candidate in 2026
To accelerate the pivotal trials of IMPT-314 and focus resources on next-generation solid tumor CAR T-cell programs in preclinical development, Lyell has streamlined its operations and is discontinuing development of LYL119, its ROR1-targeting CAR T cell product candidate, and IMPT-514, an autoimmune disease program previously initiated by ImmPACT Bio that was acquired by Lyell in connection with its acquisition of ImmPACT Bio.

Lyell expects net cash use in 2025 to be $175 million – $185 million, which extends its cash runway further into 2027 through multiple clinical milestones.

J.P. Morgan Healthcare Conference

Members of Lyell’s senior management team will present and participate in the 43rd Annual J.P. Morgan Healthcare Conference on Wednesday, January 15th at 9:00 am PT.

A live webcast of the presentation can be accessed through the Investors section of the Company’s website at www.lyell.com. Following the live presentation, a replay of the webcast will be available on the Company’s website.

About IMPT-314

IMPT-314 is a next-generation dual-targeting CD19/CD20 CAR T-cell product candidate designed to increase complete response rates and prolong the duration of the responses as compared to the approved CD19‑targeted CAR therapies for the treatment of large B-cell lymphoma.

IMPT-314 is designed with a true ‘OR’ logic gate to target, with high potency, B cells that express either CD19, CD20 or both. IMPT-314 is manufactured to produce a CAR T-cell product with higher proportions of naïve and central memory T cells through a process that enriches for CD62L-expressing cells. This manufacturing process is designed to generate more naïve central memory CAR T cells with enhanced stemlike features and antitumor activity.

IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of relapsed/refractory aggressive B-cell lymphoma.

Initial data from 23 patients with relapsed or refractory, CAR T-naive large B-cell lymphoma who received IMPT-314 were reported at the 2024 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. The efficacy evaluable population consisted of 17 patients. The overall response rate was 94% (16/17 patients), with 71% (12/17 patients) achieving a complete response by three months. The median follow up was 6.3 months (range 1.2 – 12.5 months) and 71% of patients were in response at last follow-up. In the safety evaluable population of 23 patients, no Grade 3+ CRS was reported. Grade 3 ICANS was reported in 13% (3/23) of patients with a median time to complete ICANS resolution of 5 days, and rapid improvement to Grade 2 or lower with standard therapy.

On January 9, 2025 FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, reported its recent pipeline achievements and provided its key strategic objectives for 2025 (Press release, Fore Biotherapeutics, JAN 9, 2025, View Source [SID1234649541]).

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William Hinshaw, Chief Executive Officer of Fore Biotherapeutics, will detail progress and discuss anticipated milestones in a presentation at the 43rd Annual J.P. Morgan Healthcare Conference. The presentation will take place on Tuesday, January 14, 2025, at 5:30 p.m. PT in San Francisco, CA.

"2025 will be an exciting year at Fore, with multiple value-creating catalysts anticipated in the near-term across our trials. Our focus in 2025 will be continued execution of our differentiated monotherapy development of plixorafenib, which represents a multi-billion dollar opportunity, and the potential for expansion into developing plixorafenib as a combination agent. Plixorafenib’s unique mechanism of action supports the potential to reset the standard for patients with BRAF driven tumors, which have been underserved and underpenetrated due to the limitations of current agents. Plixorafenib is designed to inhibit not only the constitutively active BRAFV600 monomers targeted by first-generation RAF inhibitors, but also disrupt constitutively active dimeric BRAF class II mutants, fusions, splice variants and others, which differentiates it from current approved therapies. We are encouraged by the compelling safety and efficacy profile we have seen and the progress in our registrational trials," said William Hinshaw, Chief Executive Officer of Fore.

2024 Achievements

Strengthened Leadership Team: In 2024, Fore strengthened its leadership team with the appointment of William Hinshaw as Chief Executive Officer, Michael Byrnes as Chief Financial Officer and Payman Darouian, as Senior Vice President, Corporate Development, Strategy and Commercial. The new management team brings extensive experience from large pharmaceutical companies and multiple high-growth, publicly traded biotechnology companies adding to the strong existing capabilities of the team.
Continued Execution of FORTE Master Protocol: The FORTE Master Protocol is a global clinical trial which includes baskets evaluating plixorafenib in distinct patient populations. The three monotherapy indications currently under evaluation are BRAF V600 Recurrent Primary Central Nervous System (CNS) Tumors, Rare BRAF V600 Mutated Solid Tumors and Solid Tumors with BRAF Fusions.
Advanced Plixorafenib in BRAF V600 Recurrent Primary Central Nervous System Tumors: Continued enrollment in registration-intended basket in up to 50 patients with BRAF V600-mutated recurrent primary CNS tumors. This BOP2 design trial enrolls patients who are naïve to MAPK pathway inhibitor (MAPKi) treatment. Major efficacy endpoints include overall response rate (ORR) and duration of response (DOR). The study builds upon a previous clinical trial of plixorafenib in which six out of nine, or 67%, of MAPKi naïve adults with recurrent BRAF V600-mutated primary CNS tumors demonstrated a partial response (PR) with a median DOR (mDOR) of 13.9 months.
Advanced Plixorafenib in Rare BRAF V600 Mutated Solid Tumors: Initiated enrollment in registration-intended basket in up to 75 patients with rare BRAF V600-mutated solid tumors. This BOP2 design trial enrolls patients who are naïve to MAPKi treatment. Major efficacy endpoints include ORR and DOR. The study builds upon a previous clinical trial of plixorafenib in which 42% of MAPKi naïve adults with BRAF V600-mutated solid tumors demonstrated a PR with a mDOR of 17.8 months.
Advanced Plixorafenib in Solid Tumors with BRAF Fusions: Continued enrollment in registration-intended basket in up to 75 patients with BRAF fusion advanced solid tumors. This BOP2 design trial enrolls patients with tumors harboring BRAF fusions, excluding those with prior treatment with MAPK inhibitors as well as patients with colorectal or pancreatic ductal adenocarcinoma. The primary endpoint is ORR, as determined by RANO criteria or RECIST v1.1 for primary CNS tumors or other solid tumors, respectively. The study builds upon a previous clinical trial of plixorafenib that demonstrated promising single agent activity including one complete response with a DOR of 66.7+ months, one PR with a DOR of 9.2+ months, and seven stable disease, out of 14 adults evaluable for efficacy.
Reported Supportive Nonclinical Data at AACR (Free AACR Whitepaper) 2024: Fore reported nonclinical data at AACR (Free AACR Whitepaper) 2024 demonstrating that plixorafenib in combination with binimetinib, a MEK inhibitor, is more potent than other BRAF and pan-RAF inhibitors combined with binimetinib, as well as the synergistic activity of plixorafenib with MEK inhibition across all BRAF alterations tested.
Reported Supportive Safety and Efficacy Data at International Symposium on Pediatric Neuro-Oncology (ISPNO 2024): Fore reported safety and efficacy data at ISPNO 2024 building on the existing evidence of plixorafenib in children and adults with BRAF-altered recurrent primary CNS tumors.
Reported Supportive Safety and Efficacy Data in Ovarian Cancer at 15th Biennial Ovarian Cancer Research Symposium (OCRS): Fore reported safety and efficacy data at OCRS 2024, including durable partial responses in three out of three patients with BRAF V600-mutated ovarian cancer, who were all heavily pre-treated.
2025 Strategic Objectives and Anticipated Milestones

Continued Execution of the FORTE Master Protocol with Interim Analyses in Three Monotherapy Indications Anticipated in 2025
BRAF V600 Primary Recurrent Central Nervous System Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the third quarter of 2025. Pending a positive recommendation from the data monitoring committee, topline data from this trial would be anticipated in the second half of 2026. The company anticipates that this trial, with sufficient demonstration of safety and efficacy, would enable the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) under the Accelerated Approval pathway.
Rare BRAF V600 Mutated Solid Tumors: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025.
Advanced Solid Tumors with BRAF Fusions: An interim efficacy analysis from the first 25 evaluable patients is anticipated to be conducted in the fourth quarter of 2025.

On January 9, 2025 Exelixis, Inc. (Nasdaq: EXEL) reported it has been notified by the U.S. Food and Drug Administration (FDA) that the supplemental New Drug Application (sNDA) for cabozantinib (CABOMETYX) for the treatment of adults with previously treated advanced pancreatic neuroendocrine tumors (pNET) and advanced extra-pancreatic (epNET) will no longer be the subject of discussion at an Oncologic Drugs Advisory Committee meeting (Press release, Exelixis, JAN 9, 2025, View Source [SID1234649539]). The sNDA remains under consideration by FDA with a Prescription Drug User Fee Act action date of April 3, 2025.

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On January 9, 2025 CatalYm reported the appointment of Scott Clarke as Chief Executive Officer. Mr. Clarke brings over two decades of executive leadership experience in driving company growth, developing products, and shaping and executing transactions in the biopharmaceutical industry (Press release, Catalym, JAN 9, 2025, View Source [SID1234649538]). He takes the helm as CatalYm enters a new stage of corporate and clinical development, including the initiation of a broad Phase 2b program for its lead candidate, visugromab, in non-squamous non-small-cell lung cancer and additional tumor indications. Based in the US, he will oversee both EU and US operations.

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"Scott Clarke is a fantastic addition to CatalYm’s leadership team. The company is in a strong position following its oversubscribed $150 million Series D financing and its recent publication in Nature of positive visugromab data. These events provide significant momentum for Scott’s start as CEO," said Jon Edwards, Interim Chair of CatalYm’s Board of Directors. "We are confident that his experience in oncology and partnering will be a substantial asset as we initiate CatalYm’s broad Phase 2b program with visugromab in hard-to-treat, metastatic solid tumor indications."

"I am impressed by CatalYm’s compelling clinical data demonstrating that visugromab is uniquely positioned as a novel cancer treatment capable of reversing key resistance mechanisms and reinstating an efficient anti-tumor response," said Scott Clarke, Chief Executive Officer at CatalYm. "I am very excited to join the CatalYm team at such a pivotal stage. I am committed to realizing visugromab’s potential to deliver unprecedented cancer remission depth and durability for patients with very limited therapeutic options."

Scott Clarke joins CatalYm from Ambagon Therapeutics, where he oversaw the company’s $85 million Series A financing and the evolution of its discovery pipeline of molecular glues. Previously, he served as CEO at Tizona Therapeutics, overseeing significant transactions and the development of its first-in-class anti-CD39 antibody for advanced cancers. Earlier in his career, he led oncology partnering at Roche, and was responsible for product development at BioMarin, contributing to multiple approved medicines. Mr. Clarke earned a Bachelor of Science in Chemical Engineering at the University of California, Berkeley, a Master of Science in Biotechnology at Northwestern University, and an MBA at London Business School.