On July 16, 2024 Oncodesign Precision Medicine (OPM) (ISIN: FR001400CM63; Mnemonic: ALOPM), a biopharmaceutical company specializing in precision medicine for the treatment of resistant and metastatic cancers, reported positive results of phase 1 trial testing the drug candidate OPM-101, administered orally in single ascending doses (SAD) and multiple ascending doses (MAD), in healthy volunteers (HV) (Press release, Oncodesign, JUL 16, 2024, View Source [SID1234644902]).

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OPM-101 is an experimental, powerful and selective small molecule inhibitor of the RIPK2 kinase. OPM-101 is designed to modulate the pro-inflammatory signal transmission pathway of this kinase, which is responsible for the development of inflammatory diseases, and has the potential to treat diseases in the fields of IBD (Chronic Inflammatory Bowel Disease) and immuno-oncology. RIPK2 is a key protein in the regulation of immune responses and inflammatory processes. Recent research highlighted its potential as a therapeutic target, both in chronic inflammatory disorders and in several types of cancer.

This randomized, double-blind, placebo-controlled phase 1 study was designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of OPM-101 (EudraCT: 2022-003122-50) in 104 healthy volunteers (78 HV with OPM-101 and 26 with placebo):

In the SAD part of the trial, 72 HV (mean age = 34 years) received a single oral dose of placebo or 5, 20, 60, 150, 300, 600 or 1,000 mg of OPM-101, with one cohort dedicated to the high-fat meal effect and another to the gender effect.
In the MAD part of the trial, 32 HV (mean age = 36 years) received an oral dose of 75, 150 or 300 mg of OPM-101 or placebo twice daily for 14 consecutive days, including a cohort dedicated to the gender effect.
This phase 1 trial, which began in February 2023, was completed on schedule in June 2024.

The results of the SAD and MAD administrations in the clinical trial demonstrated that OPM-101 is well tolerated and significantly inhibits the RIPK2 pathway at doses as low as 60 mg single administration and 75 mg b.i.d. (bis in die – Twice daily). Target engagement kinetics and pharmacodynamic results showed a fast development of inhibitory effect, already observed 2 to 4 hours after the first administration, and inhibition maintained for 14 days of administration. The mean level of target engagement was 65% (75 mg b.i.d), 75% (150 mg b.i.d) and 85% (300 mg b.i.d) over the 14 days of treatment.

Safety evaluations (vital signs, blood tests, ECG, holters) were carried out regularly throughout the trial. The trial also collects secondary pharmacokinetic measures, including half-life assessments. Exploratory measures to assess OPM-101 target engagement were calculated by tracking changes from baseline in L18-MDP-stimulated TNFα production ex-vivo in whole blood samples.

The results of the MAD cohorts demonstrated maximum target engagement by OPM-101, demonstrated by a 90 to 100% reduction in TNFα production, leading to complete inhibition of stimulated production and a return to basal levels of TNFα, thus showing immunomodulation rather than total suppression of immunity as observed with other IBD treatments. This maximum engagement of the target was observed, depending on the dose, between 2 and 6 hours after the first administration of the treatment. Residual target engagement prior to the next dose was maintained over the 14 days of administration at mean levels of 65%, 75% and 85% with the 3 dose levels tested in MAD, respectively.

Involvement of the target in the MAD part of the study (inhibition of TNFα production induced by L18-MDP, in % of predose)

In the MAD part of the study, on Day 15, i.e., 24 hours after the last administration, 50%, 55% and 80% of target engagement were still observed in the three doses of MAD tested. At 48 hours after the last administration, target engagement levels gradually decreased as expected. These results demonstrate time- and dose-dependent target engagement. These proof-of-concept results for the immunomodulatory mechanism were obtained with oral administration of OPM-101 for 14 consecutive days, which was also generally well tolerated in all SAD and MAD cohorts.

No serious adverse event was reported. All treatment-emergent adverse events considered to be at least possibly related to the drug and the study were mild to moderate in both the SAD and MAD cohorts. Twelve healthy volunteers (15%) reported a total of 15 adverse events considered to be related to OPM-101. 80% of these events were mild and 20% moderate. There was no clinically significant change in safety-related laboratory tests reported during the treatment periods for all dose cohorts of OPM-101 included in the analysis, except for one volunteer who experienced a moderate (3N) increase in ALT (liver enzyme) during MAD, resulting in discontinuation of treatment after 12 days.

The pharmacokinetic results in the MAD part are consistent with those observed in the SAD part of the study. The main pharmacokinetic characteristics of OPM-101 are: fast absorption with a Tmax observed between 2-4h, a terminal half-life estimated at 12-13h, a steady state reached after 3-4 days and a dose-dependent exposure.

On the basis of the PK/PD correlation determined from the results of the SAD part of the study, we anticipate that a very significant target engagement (≥80%) can be achieved and maintained with a plasma concentration of OPM-101 remaining above 150 ng/mL in the interval between 2 treatment administrations. This threshold was achieved with the 2nd and 3rd dose levels in the MAD part of the study.

OPM plans to present additional results from the phase 1 cohorts at a future medical meeting in Q4 2024, subject to acceptance of the abstract by the United European Gastroenterology Week (UEGW) organizing committee.

Based on the results presented today, OPM plans to initiate enrolment in a phase 1b/2a clinical trial in the fourth quarter of 2024.

"We are very pleased with the progress and results of this clinical trial with OPM-101, which provided convincing results for all primary, secondary and exploratory endpoints included in this study," said Philippe Genne, Chief Executive Officer of OPM. "We are pleased to demonstrate the safety of our candidate and the strong PK/PD correlation that exists. High target engagement is demonstrated at tolerated doses of OPM-101 throughout the treatment period. The modulation of TNFα production ex vivo can be considered as a key biomarker of target engagement for future clinical trials. The clinical results reported today not only highlight the consistency with the immunomodulatory effect of OPM-101 observed in preclinical studies, but also validate OPM-101 as a safe and effective inhibitor of the RIPK2 pathway. We are currently in the process of identifying with our clinical experts the first clinical indication that we will explore in a phase 1b/2a study before the end of the year in order to provide a first clinical proof of concept in a patient population capable of generating significant added value for our asset".

"These results validate OPM-101 as a highly specific, effective and well-tolerated inhibitor of the RIPK2 immune pathway," added Jan Hoflack, Deputy CEO and Chief Scientific Officer of OPM. "The field related to this therapeutic approach is currently booming with new high quality preclinical and clinical scientific publications mentioning a potential role for an inhibitor like OPM-101 in multiple immuno-oncology indications, in addition to the already well-established rational for the treatment of IBD and other inflammatory diseases. Our team is currently working to validate the different therapeutic options available for OPM-101, with the aim of launching a proof-of-concept clinical trial in relevant patients rapidly and efficiently before the end of the year. The current idea of a safe and effective RIPK2 inhibitor like OPM-101 suggests significant potential in both IBD and immuno-oncology, two of today’s largest pharmaceutical markets with significant unmet needs".

On July 16, 2024 Hoth Therapeutics, Inc. (NASDAQ: HOTH), a patient-focused biopharmaceutical company, reported that it has received written approval from the GW University Hospital, UC Irvine and Northwell Health to proceed with its First-in-Human (FIH) Phase 2a clinical trial of HT-001 for the treatment of skin toxicities associated with Epidermal Growth Factor Receptor Inhibitors (EGFRi) (Press release, Hoth Therapeutics, JUL 16, 2024, View Source [SID1234644901]).

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"We are very pleased to have received approval from these three world class medical centers for our FIH clinical trial," said Hoth Therapeutics Chief Executive Officer, Robb Knie. "We are hopeful that this trial will demonstrate successful delivery of our lead therapeutic candidate HT-001 and bring hope to cancer patients suffering from skin toxicities associated with EGFRi treatments."

This Phase 2a dose- ranging study to investigate the efficacy, safety, and tolerability of topical HT-001 for the treatment of skin toxicities associated with EGFRi. More information can be found at clinicaltrials.gov.

On July 16, 2024 Genomics plc (Genomics), a healthcare company transforming health through the power of genomics reported a three-year extension of the company’s collaboration with Vertex Pharmaceuticals Incorporated (Vertex) (Nasdaq: VRTX) to use human genetics and machine learning to improve the discovery and development of new precision medicines (Press release, Vertex Pharmaceuticals, JUL 16, 2024, View Source [SID1234644900]). The partnership, which began in 2018, was previously extended in 2021. The collaboration will now run until 2026.

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The companies have been working together to support Vertex’s efforts to develop transformative medicines for serious diseases. To date, Genomics’ work has focused on using improved understanding of human genetics to pinpoint causal disease pathways and processes, and to identify novel targets in known and newly identified pathways.

As part of the extension, Genomics will expand the range of genomic insights it uses to support this work and expand the number of therapeutic areas under study. The partnership will now also explore using Genomics’ proprietary genetic tools to improve identification of patient populations and to de-risk the selection of biomarkers for measuring early readout of drug efficacy.

Mark Bunnage, Senior Vice President and Head of Global Research, Vertex:

"Vertex’s leading-edge discovery teams and R&D capabilities, and Genomics’ world class scientists, are at the forefront of using insights into human genetics to identify the most promising targets and advance them into medicines for patients. This collaboration has been valuable and productive, and we’re excited to continue and expand our transformative work right across the drug development pathway."

Professor Sir Peter Donnelly FRS, FMedSci, Founder and Chief Executive Officer, Genomics plc:

"We are proud to extend our partnership with Vertex once again. Our unique genomic data platform has meant that together, we have discovered novel genetically-validated targets with the potential to address diseases of high unmet medical need. Vertex is rightly recognized for its innovative pipeline and track record in developing treatments for serious diseases, which benefit the patients, families, and healthcare systems coping with these often life-threatening conditions. We are delighted to continue working with them to drive precision medicine approaches where treatments are tailored and delivered to those most likely to benefit."

On July 16, 2024 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported that updated data from the ARROS-1 Phase 1/2 clinical trial of zidesamtinib and ALKOVE-1 Phase 1/2 clinical trial of NVL-655, will be presented during two oral presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 taking place September 13-17, 2024, in Barcelona, Spain (Press release, Nuvalent, JUL 16, 2024, View Source [SID1234644899]).

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Details for the presentations are as follows:

Title: Phase 1/2 ALKOVE-1 study of NVL-655 in ALK-positive (ALK+) solid tumors
Presentation Number: 1253O
Session Category: Proffered paper session
Session Title: NSCLC metastatic
Presentation Date and Time: Saturday September 14, 2024, 9:40 – 9:50 CEST
Location: Barcelona Auditorium – Hall 2
Presenter: Alexander Drilon, M.D. (Memorial Sloan Kettering Cancer Center, New York, USA)

Title: Phase 1/2 ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumors
Presentation Number: 1256MO
Session Category: Mini oral session
Session Title: NSCLC metastatic
Presentation Date and Time: Saturday September 14, 2024, 10:30 – 10:35 CEST
Location: Santander Auditorium – Hall 5
Presenter: Benjamin Besse, M.D., Ph.D. (Institut Gustav Roussy, Villejuif, France)

Additionally, the company will present new preclinical data further characterizing the intracranial activity of zidesamtinib during a poster session. The title is:

Title: Profiling of Zidesamtinib and Other ROS1 Inhibitors in an Intracranial CD74-ROS1 G2032R Preclinical Model
Abstract Number: 4811
Presenter: Anupong Tangpeerachaikul (Nuvalent, Inc., Cambridge, Massachusetts, United States)

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. 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.

About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor created with the aim 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 single or compound treatment-emergent ALK mutations such as G1202R. In addition, NVL-655 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. NVL-655 has received orphan drug designation for ALK-positive non-small cell lung cancer (NSCLC) and is currently being investigated in the ALKOVE-1 clinical trial (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.

On July 16, 2024 Biosyngen, a leading biotechnology company focused on the development of innovative cell therapies, reported that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) in China has approved the initiation of a pivotal Phase ll clinical trial evaluating BRG01, the company’s autologous Epstein-Barr virus (EBV) specific chimeric antigen receptor T-cell (CAR-T) therapy, for the treatment of patients with recurrent or metastatic EBV-positive nasopharyngeal carcinoma (Press release, BioSyngen, JUL 16, 2024, View Source [SID1234644898]). BRG01 is the world’s first CAR-T therapy for solid tumor to obtain clinical trial approvals from China and the U.S. and to advance to a pivotal Phase ll clinical trial, representing a significant milestone in the field of cell-based immuno-therapies for solid cancers.

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"The approval of the Phase ll clinical trial for BRG01 is a testament to the robust preclinical data and strong early clinical results observed with this innovative therapy" said Professor Zhang Li, Director of the Phase l Ward at the Sun Yat-Sen University Cancer Center and Deputy Director of the Lung Cancer Research Institute at Sun Yat-sen University, who is serving as the principal investigator for the BRG01 clinical trial. "BRG01 has the potential to be a first-in-class T-cell therapy for EBV-positive tumors, and we are confident in its ability to deliver meaningful clinical benefits to patients with this difficult-to-treat malignancy."

The Phase l clinical trial of BRG01 in China and the U.S. has completed patient enrollment in January this year. All participants have received BRG01 infusion as part of this registered clinical trial. The Phase l study has successfully completed assessments of dose-limiting toxicity (DLT) and preliminary efficacy in nine patients with advanced nasopharyngeal carcinoma who had previously been treated with at least one immune checkpoint inhibitor, such as a PD-1antibody.

Initial data from the study have demonstrated excellent safety and encouraging signs of clinical activity, with 75% of high-dose patients experiencing local tumor shrinkage and reduced metabolic activity on PET-CT scans, and some patients achieving complete remission of their tumor lesions. Additionally, BRG01 has shown potent anti-EBV activity, with significant reductions in peripheral blood EBV viral load observed following treatment.

These findings underscore BRG01’s potential in tumor therapy and highlight its dual benefits in antiviral treatment, establishing a robust foundation for future clinical applications. These results are likely pivotal in the CDE’s decision to advance BRG01 to phase II clinical trials.

BRG01 is an autologous T cell immunotherapy product that has been engineered to express chimeric receptors targeting the Epstein-Barr virus (EBV) antigen on the surface of T cells. This innovative therapy represents a new generation of CAR-T cell treatment specifically designed to target EBV. BRG01 received phase I clinical trial approval from the CDE in China in December 2022 and from the FDA in the United States in February 2023. Subsequently, it was granted orphan drug designation (ODD) and fast track designation (FTD) by the FDA in June and July 2023, respectively.

At the annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) in May, Biosyngen presented preclinical research on the therapy, and the data was published as an original study in Frontiers in lmmunology. In addition, at the Gordon Research Conference (GRC) on Nasopharyngeal Carcinoma held in Switzerland in early June this year, Biosyngen’s scientist and pipeline inventor, Chair of Translational Immuno-Oncology at the University of Cologne, Professor Renata Stripecke also presented the results of preclinical research and the latest clinical data of this therapy.

The development of cell therapy drugs for hematological malignancies has seen substantial progress, yet advancements in solid tumor treatments have lagged behind. The FDA’s accelerated approval of lovance’s tumor-infiltrating lymphocyte (TlL) therapy, lifileucel, for the treatment of advanced melanoma in February represents a significant milestone in the commercialization of solid tumor cell therapies. This milestone has bolstered confidence among companies engaged in the development of cell therapies for solid tumors. However, overcoming the challenges posed by solid tumors requires a unique and comprehensive approach from the outset. This approach must encompass considerations regarding technology, target selection, and indication, ensuring satisfaction of clinical needs and druggability of the therapeutic interventions.

As one of the most common head and neck tumors, nasopharyngeal carcinoma – an epithelial carcinoma arising from the nasopharyngeal mucosal lining, is closely related to EBV infection. According to WHO, an estimated number of 133,000 new cases of nasopharyngeal carcinoma worldwide was reported in 2020; 50% of which was diagnosed in China. South China provinces such as Guangdong and Guangxi provinces make up for more than 60% of nasopharyngeal carcinoma patient population in China. Though existing practice such as immune checkpoint inhibitor has been applied in second-line treatment of nasopharyngeal carcinoma, overall response rates were generally below 30%. In another words, more than 70% patients did not benefit from existing therapy. Therefore, it is imperative to explore new approaches to improve efficacy and satisfy unmet medical needs.

The emergence and progression of nasopharyngeal carcinoma are closely associated with Epstein-Barr virus (EBV) infection. EBV has infected about 95% of population worldwide. It has been listed as Group 1 carcinogen ("Carcinogenic to humans") by World Health Organization (WHO) and proved to be associated with a range of diseases including nasopharyngeal carcinoma, EBV-positive gastric cancers, lymphoma and lymphoproliferative diseases. Research indicates that tumor cells in nasopharyngeal carcinoma frequently exhibit EBV antigen expression, and EBV-positive tumor cells display target proteins for CD4+T cells and CD8+T cells, facilitating the infiltration of EBV-targeting CAR T cells into tumor tissue to exert a cytotoxic effect.

Leveraging this specific EBV target, CAR T-cell therapy developed by Biosyngen is also being explored for treating EBV-positive lymphoma. In April 2023, BRG01 obtained approval from the Drug Evaluation Center (CDE) and the Food and Drug Administration (FDA) for clinical trials in this new indication, with Phase I clinical studies currently ongoing.

Biosyngen has evolved into a biotechnology company specializing in three major cell therapies for solid tumors and hematologic malignancies, including CAR-T, TCR-T, and TIL. The company’s therapies utilizing these strategies have all been granted approvals for clinical trials, with its TCR-T and TIL therapies targeting various solid tumors such as lung and liver cancer.

"The approval of BRG01 for a pivotal Phase ll clinical trial is a major milestone for Biosyngen and underscores our commitment to developing innovative cell therapies to address significant unmet needs in solid tumors," said Dr. Michelle Chen, Co-Founder and CEO of Biosyngen. "We plan to continue investing in research and development to expedite the clinical progress and market availability of BRG01, offering more effective treatment options for patients worldwide."

With Biosyngen’s efficient operations and rapid research outcomes, there is optimism for significant advancements in solid tumor cell therapies within a shorter timeframe, potentially bringing new treatment possibilities and hope to patients.