On April 18, 2023 Juntendo University, Sysmex Corporation, and ThinkCyte K.K. have reported a collaborative research partnership to advance the early detection and treatment of chronic myelogenous leukemia (CML) (Press release, Juntendo University, APR 18, 2023, View Source [SID1234630283]). The joint research program aims to develop a sensitive diagnostic approach for blood cancers and deliver critical new cellular insights to advance the treatment of CML using Ghost Cytometry, ThinkCyte’s artificial intelligence (AI)-driven cell characterization and sorting technology.

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Under the partnership, the research teams will apply a novel approach that captures high-resolution information about the structure, shape, and size of cells (morphology) at high speed. By generating ‘morphometric signatures’ directly from CML patient samples, the research teams seek to identify, isolate, and characterize disease-driving cells. Detecting small numbers of disease-driving tumor cells in CML can aid in the early diagnosis and intervention of disease; a crucial factor affecting long-term outcomes. By isolating these cells, researchers will also be able to advance the development of CML treatments by gaining a better understanding of how patients develop resistance to existing drugs and identifying new approaches to treating the disease.

"Although the development of tyrosine kinase inhibitors (TKIs) has greatly improved the prognosis of patients with CML, the rate of disease relapse after stopping TKI therapy is still very high," said Dr. Tomoiku Takaku MD, Ph.D., Associate Professor of Hematology at Juntendo University. "The development of new rapid and minimally invasive tools to diagnose the disease early and guide our understanding of how therapeutic agents targeting leukemia stem cells is key to advancing patient care. We believe this research will lead to findings that help reduce the burden of high drug costs and unwanted daily side effects that many CML patients face."

The three organizations have been jointly developing approaches to capture unique, disease-specific morphological differences between blood cancer cells and normal white blood cells using Ghost Cytometry.

"Ghost Cytometry has the potential to be a powerful new cell analysis technology for many hematological conditions. Starting with CML, we believe that the diagnosis and treatment of blood cancer be greatly advanced by this joint research program," said Tomokazu Yoshida, Member of the Managing Board and Senior Executive Officer Managing Director, CTO at Sysmex Corporation. "Sysmex has a rich history of expertise in cellular measurement technology cultivated in the diagnostic field and we are proud to contribute our research and development expertise to Juntendo University and ThinkCyte to provide direct impact to CML patients."

The research is supported in part by Japan’s Small and Medium Enterprise Agency’s "Go-Tech Project," which seeks to advance technologies with a demonstrated ability to modernize basic research in future high-growth industries.

"We are very excited about the research partnership with Juntendo University and Sysmex, who were quick to focus on our technology’s potential to advance research in areas of unmet medical need," said Waichiro Katsuda at ThinkCyte. "We believe that Ghost Cytometry can be an innovative approach to developing new diagnostic and therapeutic methods for many indications and look forward to the results of this joint research effort."

On April 18, 2023 Nordic Nanovector ASA (OSE: NANOV) ("Nordic Nanovector" or the "Company") reported that full results from its Phase 2 clinical trials of Betalutin (177 Lu lilotomab satetraxetan) in resistant/refractory (R/R) indolent non-Hodgkin’s lymphoma (NHL) have been published at EudraCT, the European Union Drug Regulating Authorities Clinical Trials Database (the database for all interventional clinical trials on medicinal products submitted to the National Competent Authorities (NCAs) of the European Union) (Press release, Nordic Nanovector, APR 18, 2023, View Source [SID1234630284]). The data from the Phase 1b/2a LYMRIT 37-01 and the Phase 2b PARADIGME studies can be found via this link:

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EU Clinical Trials Register

As previously announced on 5 July 2022, the PARADIGME trial of Betalutin in 3rd-line follicular lymphoma patients refractory to rituximab/anti-CD20 (3L R/R FL) was discontinued following a comprehensive review and independent data evaluation and a subsequent request for regulatory agency interaction. The data from the 109 patients enrolled in PARADIGME up until its discontinuation show:

Overall response rate (ORR) was 38.9% and 32.1%; complete response (CR) rate was 20.8% and 14.3% in participants receiving doses of 40/15 (Betalutin dose of 15 MBq/kg after a pre-dose of 40 mg lilotomab) and 100/20 (Betalutin dose of 20 MBq/kg after a pre-dose of 100 mg lilotomab), respectively.
Median duration of response (DoR) was approximately 8.5 months for the 40/15 dose and 3.4 months for the 100/20 dose. Median duration of complete response (DoCR) was 8.5 months for 40/15 and 9.2 months for 100/20. DoR and DoCR are difficult to interpret due to the small number of responders.
Over half the participants had progressed 6 months following treatment. The median progression-free survival (PFS) was 5.9 months versus 5.8 months with 40/15 and 100/20, respectively.
The majority of treatment emergent adverse events (TEAEs) were due to cytopenias, most notably decreases in platelets (thrombocytopenia was observed in 19 [16.8%] and platelet count decreased in 11 [9.7%] participants) and neutrophils (neutropenia in 18 [15.9%] and decreased neutrophil count in six [5.3%] participants). Anaemia and fatigue were also reported in >10% of participants.
As previously communicated in the 5 July 2022 announcement, the former Board of Directors of Nordic Nanovector took the decision to wind-down PARADIGME in a structured manner while ensuring that patients received the best possible care during this period, as the observed profile did not fully meet the objectives set out for the study. As a result, the former Board was of the opinion that the demonstrated profile was no longer sufficiently competitive to bring Betalutin to the market in 3L R/R FL within a timeframe that made financial and commercial sense for the Company. The current board and management concurs with the decision to discontinue PARADIGME and Betalutin development in the 3L R/R FL indication.

The Company still believes there could be a market for Betalutin in light of its safety profile, promising efficacy in earlier lines of therapy and unique feature of being delivered as a one-time dose. However, a potential new development programme would need to be conducted in a different patient population and line of treatment and would require significant financial resources.

The Company is exploring all strategic options including potential partnerships to see if there is a possible way forward for Betalutin in an alternative setting.

Pipeline update:

The rest of Nordic Nanovector’s pipeline consists of:

1. Humalutin: a radioimmunotherapy candidate based on a chimeric anti-CD37 antibody and the beta-emitting radionuclide lutetium-177 for NHL. The project has been on hold since 2016 and all preclinical data have been published in the following journals:

· The European Journal of Nuclear Medicine and Molecular Imaging
· Nature Scientific Reports
· PLOS ONE
2. Alpha37: an alpha-emitting radioimmunotherapy candidate based on a chimeric anti-CD37 antibody conjugated to lead-212. The project is a collaboration with partner OranoMed and has been on hold since 2021. All preclinical data has been published in:

PLOS ONE
3. Fully humanized anti-CD37 antibodies with potential in haematological cancers and autoimmune diseases. Preclinical data were presented in two posters at ASH (Free ASH Whitepaper), both available on the Nordic Nanovector website:

ASH posters
The project has been on hold in 2023.

4. CD37 DOTA CAR-T cell opportunity in haematological cancers is a research collaboration with the University of Pennsylvania. Data from preliminary investigations were inconclusive and the project has been put on hold.

5. Solid tumour radioimmunotherapy: a project directed at radioimmunotherapy for solid tumours, where target identification has been concluded and several interesting molecular targets for solid tumour indications have been identified. Validation of targets and testing of minimal viable products are being evaluated.

The Board continues to focus on reducing costs where necessary to enable the Company to minimise cash burn until a strategic partner can be found.

No assurances can be given as to the outcome or timing of the ongoing strategic review process. The Company will put forward any recommended proposals for resolution by shareholders in due course.

On April 18, 2023 OnQuality Pharmaceuticals ("OnQuality"), a targeted oncology supportive therapy company developing innovative medications to address unmet needs in oncodermatology and oncogastroenterology (cancer therapy-induced toxicities occurring in the skin and gastrointestinal tract) and to improve the quality of life for patients receiving anticancer medications, reported that it has presented preclinical data on OQL025 and OQL06x, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting (Press release, OnQuality Pharmaceuticals, APR 18, 2023, View Source [SID1234630282]). The conference is being held in Orlando, FL, April 14-19, 2023.

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EGFR inhibitors are commonly used for the treatment of various cancers, including lung and colorectal cancers. However, dose-limiting skin toxicities and diarrhea are frequently associated with the use of this class of anticancer therapies. Management of these toxicities includes specific guidance for dosage adjustment/therapy interruption to realize the benefit of EGFR inhibitor treatment and to minimize negative effects on patient’s quality of life.

EGFR inhibitor-induced acneiform rash frequently appears on the face, neck, upper chest and back with an incidence of 20% to over 90%. The incidence of EGFR inhibitor-induced diarrhea can be as high as 90%. Moderate or severe diarrhea can lead to dehydration, electrolyte imbalances, infection, and other serious complications. Patients experiencing diarrhea have a 40% higher rate of cancer therapy discontinuation.

OnQuality is developing OQL025, a Janus Kinase (JAK) inhibitor administered as a topical cream, and OQL06x, an oral gut-restricted JAK inhibitor. Topical OQL025 delayed the onset and the severity of EGFR inhibitor-induced rash with low systemic exposure in preclinical models. In murine models of diarrhea caused by afatanib, orally administered OQL06x reduced the severity of EGFR inhibitor-induced diarrhea when compared to placebo. The improvement was accomplished with minimal systemic exposure, as OQL06x has been designed to have gut-restrictive properties, reducing the potential to cause systemic toxicities and interference with EGFR inhibitor anti-cancer efficacy.

At AACR (Free AACR Whitepaper), OnQuality presented:
Title: OQL025, a topical cream for the prevention of epidermal growth factor receptor inhibitor-induced skin rash
Presenter: Robert C. Tyler, Ph.D.
Session Category: Clinical Research Excluding Trials
Session Title: Cancer Outcomes 1
Session Date and Time: Monday Apr 17, 2023 1:30 PM – 5:00 PM
Abstract Number: 3211

Title: OQL06x, a gut-restricted janus kinase inhibitor to control epidermal growth factor receptor inhibitor-induced diarrhea
Presenter: Robert C. Tyler, Ph.D.
Session Category: Clinical Research Excluding Trials
Session Title: Cancer Outcomes 1
Session Date and Time: Monday Apr 17, 2023 1:30 PM – 5:00 PM
Abstract Number: 3212

"OnQuality is committed to developing OQL025 and OQL06x for the prevention of EGFR inhibitor-induced acneiform rash and diarrhea, improving quality of life and potentially treatment outcomes for cancer patients. Our preclinical data demonstrated our novel approaches of OQL025 and OQL06x reduced specific EGFR inhibitor-induced toxicities while minimizing the potential to interfere with systemically administered anti-cancer regimens," said Robert C. Tyler, Ph.D., Senior Medical Director of OnQuality. "It was exciting to share these data and engage in meaningful scientific discussions about the unmet need for EGFR inhibitor-induced acneiform rash and diarrhea at the conference."

Details regarding the poster presentations can be found on the AACR (Free AACR Whitepaper) website.

On April 18, 2023 Turn Biotechnologies, a cell rejuvenation company developing novel mRNA medicines for untreatable, age-related conditions, reported immunology data that demonstrate its ERA technology enhances T cell performance against tumor cells (Press release, Turn Biotechnologies, APR 18, 2023, View Source [SID1234630281]).

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The findings are expected to improve the efficacy of CAR-T cell therapies.

Data will be shared at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held at the Orange County Convention Center in Orlando, Florida, from April 14 to 19.

The Turn Bio data will be shared on a poster, "Transient Epigenetic Reprogramming Enhances T-Cell Proliferation and Tumor Clearance," to be presented by Mustafa Turkoz, PhD, Turn Bio Immunology. An abstract of the poster was published in the AACR (Free AACR Whitepaper) journal "Cancer Research" on March 31.

Presentation details:

Title: "Transient Epigenetic Reprogramming Enhances T Cell Proliferation and Tumor Clearance".
Location: Section 23, Board number 27, in the Orange County Convention Center, during the CAR-T Cell Therapy session.
Date and Time: Tuesday, April 18, 2023, at 9 a.m. Eastern Time.
The AACR (Free AACR Whitepaper) Annual Meeting is one of the most important cancer meetings in the world, attracting key stakeholders in all areas of cancer research to connect, collaborate, and expand the frontiers of integrative cancer science and medicine. Last year’s meeting attracted more than 20,000 scientists, clinicians, other health care professionals, survivors, patients, and advocates.

On April 18, 2023 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 supporting the intracranial activity NVL-655 (Press release, Nuvalent, APR 18, 2023, View Source [SID1234630280]). NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to maintain activity against ALK and ALK mutations that confer resistance to currently approved therapies, and to avoid neurological adverse events and dose-limiting toxicities associated with TRK inhibition.

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The data result from a collaboration with Yonsei University College of Medicine and will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place April 14-19 in Orlando, Florida. The poster will also be available on the Nuvalent website at www.nuvalent.com following the presentation.

"Brain penetrance is a critical medical need for ALK TKIs due to the high incidence of brain metastases in ALK-positive non-small cell lung cancer (NSCLC), both at initial diagnosis and upon progression with currently available therapies. Treatment-emergent ALK resistance mutations as well as the structural similarity between the ALK and TRK kinases pose additional challenges for development of brain penetrant TKIs," said Professor Byoung Chul Cho, M.D., Ph.D., Yonsei University College of Medicine. "Careful design of highly potent ALK-selective compounds is needed to inhibit treatment-resistant ALK-driven disease while avoiding neurological effects associated with inhibition of TRK in the brain."

Professor Cho continued, "The potent preclinical efficacy of NVL-655 in a challenging patient-derived model of treatment-resistant intracranial ALK NSCLC was consistent with its design as a brain-penetrant ALK-selective TKI with activity against the G1202R mutation, and supportive of a differentiated preclinical profile for NVL-655 compared with approved and other investigational ALK TKIs."

The YU-1077 patient-derived cell line was developed from a patient with alectinib-resistant NSCLC harboring an EML4-ALK fusion with the G1202R resistance mutation. Cell viability and ALK signaling assays confirmed potent in vitro activity of NVL-655 and limited sensitivity to first- and second-generation ALK TKIs, consistent with prior relapse on alectinib and the G1202R resistance mutation. A mouse model of drug-resistant lung cancer that had metastasized to the brain was established through intracranial injection of YU-1077 cells. Upon treatment with NVL-655, intracranial efficacy was confirmed via MRI.

"This study marks the first utilization of a patient-derived model to assess the preclinical intracranial activity of NVL-655 and represents an enhancement in physiological relevance over our previous preclinical experiments," said Henry Pelish, Ph.D., Senior Vice President of Drug Discovery at Nuvalent. "The resulting data are an important addition to the growing body of preclinical evidence demonstrating NVL-655’s differentiated ability to target ALK and display intracranial activity against brain tumors bearing resistance mutations."

NVL-655 has previously demonstrated preclinical efficacy in a cell line model of intracranial disease, as well as broad preclinical activity across diverse ALK resistance mutations and tumor types while maintaining strong selectivity for ALK over TRKB. NVL-655 is currently being investigated in the ALKOVE-1 study (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.

AACR Presentation Overview:
Title: Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation
Authors: Jii Bum Lee1*, Mi Ra Yu1*, Mi Ran Yun1, You Won Lee1, Seung Yeon Oh1, Eun Ji Lee1, Anupong Tangpeerachaikul2+, Henry E. Pelish2, Byoung Chul Cho1
Permanent Abstract: 4022
Session Category: Experimental and Molecular Therapeutics
Session Title: Tyrosine Kinase and Phosphatase Inhibitors 1
Session Date and Time: Tuesday April 18, 2023 from 9:00 a.m. – 12:30 p.m. ET
Location: Orange County Convention Center, Poster Section 20
1Yonsei University College of Medicine, Seoul, Republic of Korea 2Nuvalent Inc., Cambridge, MA, USA
*Equal contributions
+Presenter

Summary of Presentation:
In the YU-1077 intracranial tumor model derived from a patient with alectinib-resistant lung cancer, NVL-655 showed potent preclinical efficacy, consistent with its design as a brain-penetrant ALK TKI with activity against the G1202R mutation.

These results—together with broad ALK mutational coverage, brain penetrance, and sparing TRK—further support NVL-655’s preclinical profile that is differentiated from that of FDA/EMA-approved and other investigational ALK TKIs.
About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M ("GRLM"), G1202R / G1269A ("GRGA"), or G1202R/L1198F ("GRLF"). NVL-655 has been optimized for CNS penetrance to improve treatment options for patients with brain metastases. NVL-655 has been observed in preclinical studies to selectively inhibit wild-type ALK and its resistance variants over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and drive more durable responses for patients. NVL-655 is currently being investigated in the ALKOVE-1 study (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.