On January 14, 2025 Pasithea Therapeutics Corp. (NASDAQ: KTTA) ("Pasithea" or the "Company"), a clinical-stage biotechnology company developing PAS-004, a next-generation macrocyclic MEK inhibitor, for the treatment of neurofibromatosis type 1 (NF1) and other cancer indications, reported it has opened three clinical trial sites in Eastern Europe (Press release, Pasithea Therapeutics, JAN 14, 2025, View Source [SID1234649712]). These sites in Romania and Bulgaria are actively recruiting patients along with the four open sites in the United States, for Pasithea’s PAS-004 Phase 1 trial.

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In Eastern Europe, Pasithea is working with Arensia Exploratory Medicine, Institute of Oncology Bucharest, Arensia Exploratory Medicine, Institute of Oncology Cluj-Napoca, and Arensia Exploratory Medicine, Multiprofile Hospital for Active Treatment Sveta Sofia- EOOD.

In addition, Pasithea has completed initial dosing of three patients in Cohort 4A (15mg capsule). Patient recruitment for Cohort 4B is ongoing (4mg tablet). The Company plans to present interim safety and pharmacokinetic (PK) data from Cohorts 4A and 4B in Q1 2025.

Dr. Tiago Reis Marques, Chief Executive Officer of Pasithea stated, "We are pleased to be working with Arensia in Eastern Europe, allowing PAS-004 to be tested in patients with tumor types more sensitive to single agent MEK treatment or patients who have previously failed first-generation MEK inhibitors."

The ongoing Phase 1 clinical trial is a multi-center, open-label, dose-escalation 3+3 study design to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of PAS-004 in patients with MAPK pathway-driven advanced solid tumors with a documented RAS, NF1 or RAF mutation or patients who have failed BRAF/MEK inhibition (NCT06299839).

On January 13, 2025 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported pipeline progress and outlined key anticipated milestones towards its first potential U.S. Food and Drug Administration (FDA) approval under its "OnTarget 2026" operating plan (Filing, 8-K, Nuvalent, JAN 14, 2025, View Source [SID1234649711]).

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As part of this plan, Nuvalent anticipates the following 2025 milestones:

• Report pivotal data for tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) from its ARROS-1 Phase 1/2 trial of zidesamtinib in the first half of 2025;

• Submit a New Drug Application (NDA) for zidesamtinib with initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC by mid-year 2025;

• Report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC from its ALKOVE-1 Phase 1/2 trial of neladalkib (NVL-655) by year-end 2025;

• Initiate the ALKAZAR Phase 3 randomized, controlled trial of neladalkib for TKI-naïve patients with ALK-positive NSCLC in the first half of 2025; and

• Progress the HEROEX-1 Phase 1a/1b trial of NVL-330 for patients with advanced HER2-altered NSCLC.

With the achievement of these milestones, the company anticipates that the first potential approval from its pipeline of novel kinase inhibitors will be for zidesamtinib for the treatment of TKI pre-treated ROS1-positive NSCLC in 2026.

"2025 marks our opportunity to transition to becoming a fully integrated commercial-stage biopharmaceutical company. Throughout this period of growth and evolution, our strategy remains rooted in our commitment to our core value of Patient Impact, and our responsibility to the patients and treating physicians who continue to support our clinical trials," said James Porter, Ph.D., Chief Executive Officer at Nuvalent. "Enrollment momentum in the Phase 2 portions of our ARROS-1 and ALKOVE-1 clinical trials has further accelerated following our presentation of updated Phase 1 data at ESMO (Free ESMO Whitepaper) 2024, reinforcing our plan to report pivotal data from both programs this year. We believe this enthusiasm is a clear demonstration of the medical need for patients with ROS1- and ALK-positive NSCLC, and of our responsibility to bring new treatment options to TKI pre-treated patients as quickly as possible."

"Parallel development paths are in place towards our ultimate goal to provide new, potential best-in-class treatment options to all patients with ROS1- or ALK-positive NSCLC," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent. "For zidesamtinib, we plan to submit an NDA this year with an initial target indication for TKI pre-treated patients with ROS1-positive NSCLC, where we believe zidesamtinib has demonstrated the potential to address a medical need. We expect to report topline pivotal data from this population in the first half of 2025. In parallel, we continue a collaborative dialogue with the FDA on accelerated opportunities towards a potential line-agnostic indication supported by our ongoing TKI-naïve cohort in the Phase 2 portion of our ARROS-1 trial."

Ms. Noci continued, "Similarly for neladalkib, we expect our initial NDA submission to be for TKI pre-treated patients with ALK-positive NSCLC, supported by topline pivotal data from the ALKOVE-1 trial that we expect to report by year-end 2025. Additionally, we remain on-track to initiate the Phase 3 randomized, controlled ALKAZAR trial for TKI-naïve patients in the first half of this year, a critical step towards our ultimate goal of moving neladalkib up the treatment paradigm."

"We believe we have the right team in place and are well resourced with cash runway into 2028 to support the advancement of our clinical programs and ongoing buildout of a commercial infrastructure," said Alexandra Balcom, Chief Financial Officer at Nuvalent. "Beyond our parallel-lead programs, we remain committed to advancement of our HEROEX-1 Phase 1a/1b trial and robust discovery pipeline for sustainable long-term growth."

Enrollment Updates for ARROS-1 and ALKOVE-1

ARROS-1 for ROS1-positive NSCLC

•As of December 31, 2024, a total of 430 Phase 1 and Phase 2 patients had been enrolled in the ongoing ARROS-1 Phase 1/2 trial of zidesamtinib for patients with advanced ROS1-positive NSCLC and other solid tumors, which is designed with registrational intent for TKI pre-treated and TKI-naïve patients with advanced ROS1-positive NSCLC. Updated Phase 1 data were presented in September 2024 at the ESMO (Free ESMO Whitepaper) Congress.

ALKOVE-1 for ALK-positive NSCLC

•As of December 31, 2024, a total of 596 Phase 1 and Phase 2 patients had been enrolled in the ongoing ALKOVE-1 Phase 1/2 trial of neladalkib for patients with advanced ALK-positive NSCLC and other solid tumors, which is designed with registrational intent for TKI pre-treated patients. Updated Phase 1 data were presented in September 2024 at the ESMO (Free ESMO Whitepaper) Congress.

Presentation at 43rd Annual J.P. Morgan Healthcare Conference

Dr. Porter will present at the 43rd Annual J.P. Morgan Healthcare Conference in San Francisco on Tuesday, January 14, 2025 at 9:00 a.m. PT. A live webcast will be available in the Investors section of Nuvalent’s website at www.nuvalent.com, and will be archived for 30 days following the conference.

About Zidesamtinib

Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.

About Neladalkib (NVL-655)

Neladalkib is a novel brain-penetrant ALK-selective inhibitor created with the aim to overcome limitations observed with currently available ALK inhibitors. Neladalkib is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations such as G1202R. In addition, neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and to drive deep, durable responses for patients across all lines of therapy. Neladalkib has received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ALK tyrosine kinase inhibitors and orphan drug designation for ALK-positive NSCLC.

About NVL-330

NVL-330 is a novel brain-penetrant HER2-selective tyrosine kinase inhibitor designed to address the combined medical need of treating HER2-mutant tumors, including those with HER2 exon 20 insertion mutations, avoiding treatment related adverse events due to off-target inhibition of wild-type EGFR, and treating brain metastases.

On January 14, 2025 LifeArc and Cleveland Clinic, a nonprofit, multispecialty academic medical centre, reported the companies have signed a new 10-year Master Services Agreement (MSA) for the development of novel monoclonal antibody-based therapeutics for patients with unmet medical needs (Press release, LifeArc, JAN 14, 2025, View Source [SID1234649709]).

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LifeArc will provide its expertise in humanisation of monoclonal antibodies (mAbs) to target key drivers of conditions identified by Cleveland Clinic including cancer and complement-mediated diseases. This MSA builds on a successful track record of the two organisations working together since 2019 on four humanisation projects, with a fifth project for 2025 already underway.

Professor Feng Lin, Lerner Research Institute, Cleveland Clinic said: "Working with LifeArc is a collaboration. Both sides of the team come together and bring their respective expertise to take the project forward."

Dr. Jason Slingsby, Chief Business Officer at LifeArc said: "This collaboration with Cleveland Clinic is a groundbreaking moment for research into the development of monoclonal antibodies. Combining our expertise could lead to the development of new clinical candidate mAbs and give hope to patients who need it the most. Monoclonal antibodies are offering us new ways to target a wide range of conditions and I’m excited to see what our collaboration will develop over the next 10 years.

The agreement brings together two leading innovators in monoclonal antibody development to deliver new treatments for patients with unmet medical needs. Cleveland Clinic, based in Cleveland, Ohio, with locations around the world, is renowned for delivering high-quality research and cutting-edge treatments to patients. LifeArc brings over 30 years of expertise in antibody humanisation and engineering, which has seen five licensed medicines on the market including Keytruda (pembrolizumab), one of the best-selling cancer treatments in 2024, and Leqembi(lecanemab), a new treatment for early-stage Alzheimer’s disease.

On January 14, 2025 Instil Bio, Inc. (Nasdaq: TIL, "Instil"), reported clinical progress of IMM2510/SYN-2510 in China by its collaborator, ImmuneOnco Biopharmaceuticals (Shanghai) Inc. (HKEX Code: 1541.HK, "ImmuneOnco") (Press release, Instil Bio, JAN 14, 2025, View Source [SID1234649708]).

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ImmuneOnco announced that the first patient has been dosed in its phase 1b/2 clinical trial of IMM2510/SYN-2510 in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) in China. ImmuneOnco announced it plans to enroll first-line patients in this trial and anticipates presenting initial clinical data, including data for first-line NSCLC patients, from this trial as soon as the second half of 2025.

Additionally, Instil announced that for its anticipated initial U.S. clinical trial of SYN-2510/IMM2510 in lung cancer, it plans to target enrollment of first-line patients with NSCLC in combination with chemotherapy with an expected initiation in the second half of 2025, assuming the necessary regulatory approvals are obtained.

"We anticipate that ImmuneOnco’s initial clinical data of IMM2510/SYN-2510 in combination with chemotherapy in patients with front-line NSCLC could be extremely valuable in advancing our development of IMM2510/SYN-2510 in NSCLC," said Bronson Crouch, CEO of Instil. "The data generated, if positive, could position us to open a potential global registrational study in front-line NSCLC."

About SYN-2510/IMM2510

SYN-2510/IMM2510 is a PD-L1xVEGF bispecific antibody in development for the treatment of multiple solid tumor cancers. SYN-2510/IMM2510 is differentiated from other PD-(L)1xVEGF bispecific antibodies by its VEGF trap, which binds multiple VEGF receptor ligands beyond VEGF-A, a bispecific structure which leverages PD-L1 as an anchor in the tumor microenvironment (TME), and enhanced antibody-dependent cellular cytotoxicity (ADCC) to direct killing of PD-L1-positive tumor cells.

On January 14, 2025 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported that the supplemental New Drug Application for ORPATHYS (savolitinib) has been granted approval by the China National Medical Products Administration ("NMPA") for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer ("NSCLC") with MET exon 14 skipping alteration (Filing, 6-K, Hutchison China MediTech, JAN 14, 2025, View Source [SID1234649706]). The NMPA has also converted the prior conditional approval of ORPATHYS in the previously treated patient population to full approval. The new label indication for ORPATHYS will now include both treatment-naïve and previously treated patients in China.

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The approval by the NMPA was based on data from the confirmatory Phase IIIb clinical trial in patients with MET exon 14 skipping alteration NSCLC (NCT04923945). Preliminary efficacy and safety data from the first-line cohort were presented during the IASLC World Conference on Lung Cancer (WCLC) in September 2023. Final data from the confirmatory Phase IIIb trial were presented at the European Lung Cancer Congress in March 2024.

In treatment-naïve patients, objective response rate ("ORR") was 62.1%, disease control rate ("DCR") was 92.0% and median duration of response ("DoR") was 12.5 months, as assessed by an independent review committee. Median progression free survival ("PFS") was 13.7 months and median overall survival ("OS") was not reached with median follow-up of 20.8 months. In previously treated patients, ORR was 39.2%, DCR was 92.4% and median DoR was 11.1 months, as assessed by an independent review committee. Median PFS was 11.0 months and median OS was not mature with median follow-up of 12.5 months. Responses occurred early (time to response 1.4-1.6 months) in both treatment-naïve and previously treated patients. The safety profile was tolerable and no new safety signals were observed. The most common drug-related treatment-emergent adverse events of Grade 3 or above (5% or more of patients) were abnormal hepatic function (16.9%), increased alanine aminotransferase (14.5%), increased aspartate aminotransferase (12.0%), peripheral oedema (6.0%) and increased gamma-glutamyltransferase (6.0%).

"This Phase IIIb confirmatory study of ORPATHYS is one of the largest Phase III clinical trials conducted in China for this patient population to date. ORPATHYS has demonstrated clear efficacy and tolerability in both first-line and second-line settings, underscoring its potential as a standard treatment option for NSCLC with MET exon 14 skipping alterations," said Prof. Shun Lu, Chief of the Shanghai Lung Cancer Center at Shanghai Chest Hospital, School of Medicine, Shanghai Jiaotong University, and Principal Investigator of the confirmatory Phase IIIb study. "By making ORPATHYS available as a first-line treatment, we are able to provide our patients with an effective targeted therapy earlier in their treatment journey. We look forward to introducing this novel treatment and optimizing the treatment strategy for this challenging patient population to improve their outcomes and quality of life."

"The approval marks an exciting step forward in addressing the unmet needs of NSCLC patients with MET exon 14 skipping alteration. It not only validates our research but also emphasizes our dedication to addressing unmet medical needs through targeted drug development," said Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED. "We are focused on advancing our research and expanding access to ORPATHYS, ultimately improving the treatment landscape for those affected by this challenging form of lung cancer. We also remain committed to further exploring ORPATHYS in other MET driven diseases in order to help more patients who may benefit from this targeted treatment."

"Today’s approval reinforces ORPATHYS as a transformative option for the treatment of biomarker-driven lung cancer, and we are proud that we can now offer this therapy to both first-line and second-line patients in China with advanced NSCLC with MET exon 14 skipping alterations," said Ms. Mary Guan, General Manager of AstraZeneca China Oncology Business. "Through our partnership with HUTCHMED, we are advancing ORPATHYS to address resistance to EGFR-TKIs1, unlocking new possibilities for treating MET-altered and amplified cancers, and expanding the reach of this innovative therapy to even more patients with this form of lung cancer."

Savolitinib was launched and is marketed under the brand name ORPATHYS by our partner, AstraZeneca, for this patient population, representing the first selective MET inhibitor approved in China.

About NSCLC and MET aberrations

Lung cancer is the leading cause of cancer death, accounting for about one-fifth of all cancer deaths.2 More than a third of the world’s lung cancer patients are in China. Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.3 The majority of NSCLC patients (approximately 75%) are diagnosed with advanced disease, and approximately 10-15% of NSCLC patients in the US and Europe and 30-40% of patients in Asia have EGFR-mutated NSCLC.4,5,6,7

MET is a tyrosine kinase receptor that has an essential role in normal cell development.8 MET overexpression and/or amplification can lead to tumor growth and the metastatic progression of cancer cells, and is one of the mechanisms of acquired resistance to EGFR TKI for metastatic EGFR-mutated NSCLC.8,9 Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.10 MET aberration is a major mechanism for acquired resistance to both first/second-generation EGFR TKIs as well as third-generation EGFR TKIs like osimertinib. Among patients who experience disease progression post-osimertinib treatment, approximately 15-50% present with MET aberration.11,12,13,14,15 The prevalence of MET aberration depends on the sample type, detection method and assay thresholds used.16

About ORPATHYS (savolitinib)

ORPATHYS is an oral, potent and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations), gene amplification or protein overexpression.

ORPATHYS was previously granted conditional approval in China in June 2021 for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. ORPATHYS is the first selective MET inhibitor approved in China. It has been included in the National Reimbursement Drug List of China (NRDL) since March 2023. It is also currently under clinical development for multiple tumor types, including lung, kidney and gastric cancers, as a single treatment and in combination with other medicines.

In 2011, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize ORPATHYS. Joint development of ORPATHYS in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of ORPATHYS in China. AstraZeneca is responsible for the commercialization of ORPATHYS in China and worldwide. Sales of ORPATHYS are recognized by AstraZeneca.