On April 8, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the presentation of new preclinical data for its novel HER2-selective inhibitor, NVL-330, and novel ROS1-selective inhibitor, zidesamtinib (NVL-520) (Press release, Nuvalent, APR 8, 2024, View Source [SID1234641901]). The two posters will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place from April 5 – 10 in San Diego. The posters will also be available on the Nuvalent website at www.nuvalent.com following the presentations.

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"Today’s presentations continue to reinforce the differentiated profiles of our drug candidates," said Henry Pelish, Ph.D., Senior Vice President of Drug Discovery at Nuvalent. "In comparative in vitro and in vivo analyses of NVL-330 with currently approved and investigational HER2-targeting agents, NVL-330 demonstrated a differentiated preclinical profile by achieving higher CNS penetration and deeper intracranial response. Importantly, in these preclinical studies, NVL-330 also demonstrated potency against a broad range of HER2 oncogenic alterations and selectivity over wild-type EGFR, in line with our goal of designing molecules that can thread the needle between multiple competing challenges."

Dr. Pelish continued, "In our ongoing ARROS-1 clinical trial of zidesamtinib, preliminary Phase 1 data has demonstrated a differentiated profile combining activity against ROS1 resistance mutations, CNS penetrance, and TRK avoidance which we believe has the potential to translate to deep, durable responses for patients with ROS1-driven cancers. A new preclinical mutagenesis screen reinforces this potential, showing that on-target resistance is unlikely following treatment with zidesamtinib at its average observed clinical concentration."

In 2024, the company expects to initiate a Phase 1 trial for its HER2 program and to share updated data from the ARROS-1 trial at a medical meeting.

AACR Presentation Overviews:

Title: Preclinical characterization of NVL-330, a selective and brain penetrant HER2 tyrosine kinase inhibitor with broad activity on HER2 oncogenic alterations
Authors: Yuting Sun*1, Kristin L. Andrews1, Anupong Tangpeerachaikul1, Tuan M. Nguyen1, Baudouin Gerard1, Nancy E. Kohl2, Joshua C. Horan1, Henry E. Pelish1
Abstract Number: 1979
Session Category: Experimental and Molecular Therapeutics
Session Title: Kinase and Phosphatase Inhibitors 2
Session Date and Time: Monday April 8, 2024, from 9:00 – 12:30 p.m. PT
Location: Poster Section 25

Presentation summary:

NVL-330 had broad preclinical activity on HER2 oncogenic alterations, including HER2 exon20ins, HER2 activating point mutations, and amplified wild-type HER2.
In a preclinical comparison with the selective tyrosine kinase inhibitor, zongertinib, NVL-330 demonstrated:
Similar potency and selectivity over wild-type EGFR; and,
Higher CNS penetrance.
In a preclinical comparison with antibody drug conjugate, T-DXd (Enhertu), NVL-330 demonstrated:
Deeper response and higher CNS penetrance in an intracranial tumor model; and,
Activity in cells with acquired resistance to T-DXd.
Title: Mutagenesis screens support potential best-in-class profile for selective, brain-penetrant, and TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520)
Authors: Anupong Tangpeerachaikul*1, Franklin Gu1, Henry E. Pelish1
Abstract Number: LB182
Session Title: Late-Breaking Research: Experimental and Molecular Therapies 2
Session Date and Time: Monday April 8, 2024, from 1:30 – 5:00 p.m. PT
Location: Poster Section 52

Presentation summary:

Comparison of the clinical concentration of zidesamtinib to its efficacious in vitro concentration suggests a potential for a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in humans, including in the CNS.
Zidesamtinib effectively suppressed on-target resistance in ENU mutagenesis screens with both ROS1 and ROS1 G2032R fusions, predicting that on-target resistance is unlikely when used as either a first-line or a later-line therapy.
On-target resistance is predicted to be more likely for earlier-generation ROS1 inhibitors crizotinib, entrectinib, and potentially repotrectinib as a first-line therapy.
These mutagenesis screens provide additional preclinical support for zidesamtinib’s potential to drive deep and durable responses for patients with ROS1-driven cancers.
*Presenter, corresponding author; 1Nuvalent, Inc., Cambridge, MA, USA; 2Kohl Consulting, Wellesley, MA, USA

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.

About zidesamtinib (NVL-520)
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. Zidesamtinib is currently being investigated in the ARROS-1 trial (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC and other solid tumors.

On April 8, 2024 GV20 Therapeutics, a clinical-stage biotechnology company integrating AI, genomics, and disease biology to create next-generation antibody therapeutics for cancer, reported preclinical data on it GV20-0251 program during an oral presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego, CA (Press release, GV20 Therapeutics, APR 8, 2024, View Source [SID1234641900]).

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"I am honored to showcase our novel technology platform and present the previously unknown immune function of IGSF8 at AACR (Free AACR Whitepaper) 2024. GV20-0251 is the first ever AI-designed antibody against an AI-predicated target to advance into the clinic and can potentially bring significant benefits to patients with solid tumors," said Shirley Liu, CEO of GV20 Therapeutics. "We have made great progress on GV20-0251 Phase I dose escalation and look forward to advancing into monotherapy cohort expansion and combination studies later this year."

The oral presentation at AACR (Free AACR Whitepaper) included an overview on the company’s novel discovery and development process of its lead antibody, GV20-0251, which antagonizes a novel cancer immunotherapy target, IGSF8. Many cancer patients’ immune systems make anti-PD1/anti-PDL1 antibodies, however the patients do not make enough and have the wrong IgA Fc to completely kill the tumors. GV20 uses tens of thousands of tumors as experimental systems and leverages artificial intelligence (AI) to mine big data from large tumor profiles to predict the antibodies in patient tumors that can be developed into cancer drugs. Through this modeling, GV20 discovered that IGSF8 is a novel innate immune checkpoint highly expressed on malignant cells with antigen presentation defects. Anti-IGSF8 enhances NK cell killing, antigen presentation, and turns immune-cold tumors hot. In addition, anti-IGSF8 alone or in combination with anti-PD1 inhibits tumor growth in multiple models, including some known to resist anti-PD1 therapy.

GV20’s in-house STEAD platform (Simultaneous Target Evaluation and Antibody Discovery), which integrates AI, genomics, and disease biology, can not only identify novel drug targets, but also create next-generation therapies against these targets, like GV20-0251. The ongoing Phase I study in solid tumors (NCT05669430) is advancing and GV20-0251 is demonstrating promising early clinical activities.

Details of the oral presentation at AACR (Free AACR Whitepaper) are below:

Title: "IGSF8 is a novel innate immune checkpoint and cancer immunotherapy target"

Session Type: Minisymposium
Session Category: Immunology
Session Title: Immune Targets and Therapies
Session Date/Time: Monday Apr 8, 2024, 2:30 PM – 4:30 PM
Abstract Presentation Number: 3914

On April 8, 2024 Abbisko Therapeutics Co., Ltd. (Abbisko Therapeutics) reported the completion of patient enrollment for its pivotal Phase III trial, MANEUVER (ABSK021-301) STUDY, for evaluating the efficacy and safety of pimicotinib in patients with tenosynovial giant cell tumor (TGCT) (Press release, Abbisko Therapeutics, APR 8, 2024, View Source;pimicotinib-302111016.html [SID1234641899]). A total of 94 patients were enrolled and exceeded the original target of 90 patients. The study is being conducted across more than 30 investigational sites worldwide, with European and North American patients accounted for more than half of the total enrollment. This study is a Phase III, randomized, double-blind, placebo-controlled, multicenter trial, which is the first global Phase III trial of TGCT simultaneously conducted in China, the U.S., Canada and Europe. The approval to conduct this Phase III trial was received by the China NMPA in October 2022, the U.S. FDA in March 2023, and the EMA in September 2023.

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Pimicotinib is a novel, orally available, highly selective, and highly potent small molecule inhibitor of CSF-1R independently discovered and developed by Abbisko Therapeutics. It has obtained the Breakthrough Therapy Designation (BTD) from China NMPA and the U.S. FDA, as well as the PRIME designation from EMA. Furthermore, the U.S. FDA granted Fast Track Designation (FTD), and Orphan Drug Designation (ODD) granted by EMA in January 2024, for the treatment of TGCT patients who are not amenable to surgery. The designations are poised to accelerate the global development and commercialization of pimicotinib.

In early December 2023, Abbisko Therapeutics entered into a license agreement with Merck. Under the terms of the agreement, Abbisko Therapeutics has granted Merck an exclusive license to commercialize products comprising or containing pimicotinib in the Chinese mainland, Hong Kong, Macau and Taiwan, and an exclusive option for global commercial rights of pimicotinib.

TGCT, a locally aggressive neoplasm which affects synovial joints, mucous sacs, and tendon membranes, resulting in swelling, pain, stiffness, and decreased activity of the affected joints which seriously affect patient’s quality of life. Currently, there is no systemic therapy approved in China and Europe, and only one in the U.S. There are unmet medical needs of TGCT patients in the regions of China, the U.S. and Europe.

In addition to TGCT, Abbisko is actively exploring the potential of pimicotinib in treating other indications. The company has obtained approval from China NMPA to conduct Phase II clinical studies in chronic graft-versus-host disease (cGVHD) and advanced pancreatic cancer.

PHASE III MANEUVER (ABSK021-301) STUDY

The Phase III MANEUVER (ABSK021-301) study is a randomized, double-blind, placebo-controlled, multi-centered clinical trial designed to evaluate the safety and efficacy of pimicotinib in patients with TGCT. This study consists of two parts. Part 1 is a double-blinded phase, in which eligible patients were randomized to the pimicotinib treatment group or matching placebo group and receive 50mg QD of pimicotinib or matching placebo (28 days/cycle) until completion of 24 weeks of dosing (Part 1). Patients who complete Part 1 were eligible to continue in Part 2 of the study. Part 2 is an open-label treatment phase, and all patients entering this phase received 50mg QD of open-label pimicotinib until 24 weeks of dosing or withdrawal from the study. Approximately 90 patients were planned to be enrolled, and the primary endpoint is 25-Week ORR by the Blinded Independent Review Committee(IRC).

On April 8, 2024 D3 Bio, an emerging global biotechnology company that focuses on discovery, development, and registration of innovative cancer drugs reported its closing of Series A+ financing round led by Medicxi, a leading European life sciences investment firm (Press release, D3 Bio, APR 8, 2024, View Source [SID1234641898]). D3 Bio’s existing investors, Matrix Partners China and WuXi AppTec’s Corporate Venture Fund also participated.

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The substantial investment of US$62M in this round underscores D3 Bio’s steadfast commitment to advancing its pioneering oncology pipeline. The funding will be allocated to expedite the development of D3 Bio’s assets through preclinical and clinical stages, with a particular focus on accelerating the global clinical trial of D3S-001, a new generation small molecule KRAS G12C inhibitor with the best-in-class potential. D3S-001 is currently in phase II development in non-small cell lung cancer, colorectal cancer and pancreatic cancer.

"D3 Bio has built a pipeline of multiple oncology programs, which hold significant promise for developing future therapies across various indications. We are delighted to have Medicxi as both a new investor and a partner. This partnership not only validates the potential of our portfolio but also furnishes resources to propel our mission to advance breakthroughs in cancer treatment to transform the lives of patients across the globe." remarked Dr. George Chen, Chairman, and CEO of D3 Bio.

Francesco De Rubertis, Co-founder and Partner at Medicxi, commented: "Our mission is to support the innovative genius of entrepreneurs by providing the critical capital, expertise and experience that form the all-important ‘bridge’ to pharma. George and his team are exceptional drug innovators focused on developing new treatments where there are enormous unmet patient and market needs."

On April 8, 2024 Calliditas Therapeutics AB (NASDAQ: CALT) (NASDAQ Stockholm: CALTX) ("Calliditas") reported that the Company has received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for patent application no. 16/760,910 entitled "Use of NOX Inhibitors for Treatment of Cancer" (Press release, Calliditas Therapeutics, APR 8, 2024, View Source [SID1234641897]). This Notice of Allowance is expected to result in the issuance of a U.S. patent once administrative processes are completed.

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The allowed claims cover a method of treating a solid tumor presenting resistance to PD-1 inhibitor immunotherapy by administering setanaxib in combination with a PD-1 inhibitor. The patent, when issued, will have an anticipated expiration date in 2038.

"This is a significant value enhancing event for the global setanaxib franchise and we are delighted that we are able to expand product protection for setanaxib in the important area of oncology," said CEO Renée Aguiar-Lucander.

Calliditas has corresponding applications in several additional territories around the world, including a pending patent application in Europe.