On June 11, 2024 Asgard Therapeutics, a privately held biotech company pioneering in vivo direct cell reprogramming for cancer immunotherapy, reported that it selected Exothera S.A. ("Exothera"), a leading provider of nucleic acids and viral vector development and manufacturing services, for process development up to clinical Phases I/II manufacturing of its candidate AT-108, based on viral vector technology (Press release, Asgard Therapeutics, JUN 11, 2024, View Source [SID1234644248]).

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AT-108 is a first-in-class, off-the-shelf gene therapy that leads to personalized and potent anti-cancer immune responses. AT-108 reprograms cancer cells inside the patient’s body to become conventional Type 1 Dendritic Cells (cDC1s), a rare subset of immune cells, which are critical for effective anti-tumor immunity. These induced cDC1s present the individual’s specific cancer antigens to the immune system, triggering personalized and systemic anti-cancer immune responses.

Exothera will be entrusted with the development and scale-up of a manufacturing process for the drug candidate, including development of analytical methods, GMP-grade material production, and aseptic filling.

Exothera offers a full-service model for viral vector-based biotherapeutics thanks to state-of-the-art technologies, and one of the largest viral vector facilities in Europe (15 000 m² – 161 500 ft²).

Cristiana Pires, Co-founder and Chief Executive Officer of Asgard Therapeutics, said: Following our proof-of-concept studies supporting the lead candidate AT-108, we are very happy to reach process development phase and start CMC activities. We are looking forward to work with the very knowledgeable and skilled technical team at Exothera to progress our pioneering AT-108 towards clinical development.

Hanna Lesch, Chief Technology Officer at Exothera, mentioned: We are proud to support Asgard Therapeutics in bringing these revolutionary therapeutics closer to the patients. Over the years we gained extensive experience with virus-based therapeutics production – both in suspension and in fixed bed bioreactors – and we are confident that we will use this expertise to help Asgard Therapeutics achieve clinical phase success.

On June 11, 2024 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics and Orano Med, a clinical stage radiopharmaceutical company developing targeted alpha therapies with lead-212 (212Pb), reported the debut of their lead Radio-DARPin therapy (RDT) candidate MP0712, targeting DLL3, in an oral presentation (Press release, Molecular Partners, JUN 11, 2024, View Source [SID1234644228]). The data presented today provide strong support for MP0712’s clinical development in small-cell lung cancer (SCLC) and other DLL3+ neuroendocrine tumors. MP0712 features 212Pb as a potent therapeutic payload. The data were presented today at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2024 Annual Meeting taking place June 8-11 in Toronto, Canada.

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"Three years ago, we started our venture into the radiotherapy space. We have made tremendous progress with our Radio-DARPins and are proud to present MP0712, our first RDT development candidate targeting DLL3 delivering and 212Pb to kill the tumor, in partnership with Orano Med," said Patrick Amstutz, Ph.D., Molecular Partners’ Chief Executive Officer. "We have made key learnings how to reduce kidney accumulation and increase tumor uptake. We are now exploiting the long-known DARPin advantages to a full pipeline of candidates addressing high medical need. Kudos to both the Orano Med and Molecular Partners team for advancing the science to make this happen."

"We are extremely excited with the first preclinical results of the MP0712 program, which confirm the potential of the combination between Molecular Partners’ targeting technology and 212Pb, an isotope perfectly suited for targeted alpha therapy. We eagerly anticipate advancing the drug’s development and initiating clinical trials to provide solutions for patients with unmet medical needs," said Julien Dodet, CEO of Orano Med.

MP0712 is the first high-affinity DLL3-targeting RDT combining the advantages of DARPins as small protein-based delivery vectors and the short-lived alpha particle-emitting radioisotope 212Pb. DLL3 is expressed in >85% of SCLC patients and in other neuroendocrine tumors, while its expression in healthy tissues is low, making it a priority target for radiopharmaceutical therapy. SCLC is an aggressive form of lung cancer, with a poor five-year survival prognosis and a high unmet need for patients.

The preclinical package presented at SNMMI includes in vivo data demonstrating strong and homogeneous tumor uptake of 212Pb-DLL3 RDT, as well as significant and durable inhibition of tumor growth at clinically-relevant doses. The safety results seen across the tested dosing levels in mice suggest a favorable safety profile and potential for clinical use. 212Pb-DLL3 RDT candidates were engineered by tuning their biophysical properties to achieve an optimal safety/antitumor activity profile in vivo. The selected lead candidate, MP0712, demonstrated a promising biodistribution profile in mouse xenograft tumor models, with close to 60% of injected dose detectable in the tumor and encouraging tumor to kidney ratios over two. The replicable DARPin learnings from the development of MP0712, as well as additional platform improvements, are being taken forward to the broader RDT portfolio.

The intrinsic properties of DARPins, such as small size, high affinity and selectivity, and a broad range of potential targets, make them ideal vector candidates for radiopharmaceutical therapeutics. Historically, small protein-based vectors faced challenges with kidney accumulation and toxicity, as well as suboptimal tumor uptake. Molecular Partners has evolved its RDT platform to address these limitations with its half-life extension technologies and surface engineering approaches, while preserving the advantages of the small protein format. In addition, Molecular Partners’ DARPin candidates have been clinically validated with over 2500 patients treated worldwide and multiple DARPin mechanisms have been demonstrated as biologically active in for different indications, contributing to validation of the drug class and Molecular Partners as leader in the field of DARPin engineering and development.

Details of the presentation summarizing the MP0712 preclinical data at the SNMMI 2024 Annual Meeting can be found below. The presentation will be made available on Molecular Partners’ website after the presentation.

Presentation Title: Lead-212 Radio-DARPin Therapeutic (RDT) targeting delta-like ligand 3 (DLL3) shows promising preclinical antitumor efficacy and tolerability in small cell lung cancer (SCLC)
Session: IS09 Integrated Session: Radionuclides (CMIIT/RPSC);
Timing: 11 June 2024; 8:00–9:15 am EDT

On June 10, 2024 Pacylex Pharmaceuticals Inc. (Pacylex) is a clinical-stage pharmaceutical company developing N-myristoyltransferase (NMT) inhibitors to treat hematologic cancers and solid tumors, reported the publication of Phase 1 clinical trial results in the journal Investigational New Drugs (Press release, Pacylex Pharmaceuticals, JUN 10, 2024, View Source [SID1234645047]). The report, titled: "A First-in-Human Phase I Trial of Daily Oral Zelenirstat, a N-myristoyltransferase Inhibitor, in Patients with Advanced Solid Tumors and Relapsed/Refractory B-cell Lymphomas," describes effects of zelenirstat at various doses on cancer patients who exhausted all other therapeutic options.

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Myristoylation is a fatty acid modification critical to targeting certain proteins to cell membranes where they participate in activities essential to cancer cell survival and proliferation. Zelenirstat works by the unique mechanism of inhibiting the myristoylation required for the assembly, translocation, and function of EGFR, VEGFR, and the B-cell receptor. Last month Pacylex published in the Journal of Translational Medicine that zelenirstat also blocks Complex I formation in mitochondria of cancer cells to shut down oxidative phosphorylation, an energy generation process needed for metastases and cancer stem cell survival.

The Phase 1 dose escalation safety and tolerability study was conducted in 29 patients with refractory/relapsed (r/r) lymphoma and refractory solid tumors who averaged 4 lines of prior therapy. Zelenirstat, administered as a once daily oral medication, was well-tolerated in Phase 1 patients up to the recommended Phase 2 dose (RP2D) with no dose limiting toxicities observed in 6 dose levels. The most common treatment related adverse events were mild to moderate gastrointestinal side effects which were self-limiting and occurred in a minority of patients.

The study was designed and sponsored by Pacylex Pharmaceuticals and was conducted at the Cross Cancer Institute, Edmonton, AB, under the direction of Principal Investigator Dr. Randeep Sangha; the British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, BC, by Dr. Laurie Helen Sehn; Princess Margaret Cancer Centre, Toronto, ON by Dr. John Kuruvilla; and Université de Montréal’s hospital affiliated research centre, the CRCHUM, QC by Dr. Rahima Jamal.

The 7 patients receiving the recommended Phase 2 dose had significantly better progression free and overall survival than the 17 treated at lower doses; 57% had stable disease or better for six months or longer, including patients with ovarian, appendiceal, and colorectal cancer. The sole person with colorectal cancer receiving the RP2D had experienced only short-term benefit from any of the 6 prior lines of therapy, but continues to receive the zelenirstat 450 days after starting therapy and had reductions of approximately 50% in CEA (carcinoembryonic antigen) and tumor volumes.

"These Phase 1 results are as encouraging as any cancer study I have run with an oral cancer therapy", said Dr. Randeep Sangha. "The safety profile was consistent with long-term therapy and considering how many prior lines of therapy these patients had received, the signals of potential efficacy in several different types of solid tumor cancers was surprising."

"Given the outstanding safety of zelenirstat in Phase 1 and the prolonged stable disease or better seen in patients with refractory ovarian, appendiceal and colorectal cancer who received the RP2D, we are advancing zelenirstat into two Phase 2a studies that have begun dosing patients with refractory and relapsed B-cell non-Hodgkin’s lymphoma, and advanced refractory colorectal cancer", said Dr. John Mackey, CMO of Pacylex Pharmaceuticals.

"Zelenirstat is a very unique approach to treating cancer – it inhibits proteins that have been hijacked in cancer cells for survival and proliferation signaling, tumor blood supply, cell surface receptor recycling, and energy production, all with one drug", said Dr. Michael Weickert, CEO of Pacylex. "This explains how zelenirstat has potential as an important therapeutic option across many different cancers."

About zelenirstat (PCLX-001)

Zelenirstat (formerly identified as PCLX-001) is a first-in-class, oral, small molecule NMTi being developed to treat patients with leukemia, lymphoma, and solid tumors. Zelenirstat selectively killed cancer cells in vitro and in animal models has been shown to fully regress hematologic malignancies and inhibit the growth of lung and breast cancer tumors. In AML models, zelenirstat preferentially killed leukemic stem enriched cell populations and reduced the bone marrow leukemic burden.

About zelenirstat Phase 1 and 2 studies

Pacylex completed the dose escalation phase of a Phase 1 multiple ascending dose safety, tolerability, and pharmacokinetics study on zelenirstat in people with relapsed/refractory lymphoma and refractory solid tumors (NCT04836195). A recommended Phase 2 dose was determined. Zelenirstat demonstrated an acceptable safety and tolerability profile, pharmacokinetics consistent with once daily oral dosing, and early signs of efficacy.

Zelenirstat is currently being studied in a Phase 2a open-label study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of zelenirstat in patients with relapsed/refractory B-cell non-Hodgkin Lymphoma (NHL) and a separate Phase 2a cohort in patients with refractory metastatic colorectal cancer that has progressed despite all available standard therapies.

On June 10, 2024 NH TherAguix (NHT), a phase II clinical-stage biotechnology company specializing in the development of novel nanomedicine solutions applicable to precision radiotherapy in oncology, reported the publication in the peer-reviewed journal Scientific Reports, part of the Nature group, of an article describing a method for quantifying its next-generation radio-enhancer, AGuIX, after tumor targeting (Press release, NH TherAguix, JUN 10, 2024, View Source [SID1234644425]). The article highlights the MRI biomarker properties of AGuIX in addition to its radio-enhancing properties when combined with radiotherapy.

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The article, entitled "Quantifying gadolinium-based nanoparticle uptake distributions in brain metastases via magnetic resonance imaging", can be found on the Scientific Reports website: Link.

AGuIX nanoparticles offer a breakthrough in radiotherapy, addressing a key challenge by increasing efficacy while preserving surrounding healthy organs. Prior to treatment, AGuIX serves as a biomarker visible on MRI, allowing for dose customization and image-guided irradiation to precisely target tumors and optimize therapy delivery. With its gadolinium-based structure, AGuIX provides strong contrast imaging properties, while its capacity to amplify X-ray doses at the tumor site further enhances radiotherapy effectiveness.

The recently published article in Scientific Reports highlights AGuIX’s potential as a biomarker in a study involving 23 patients with brain metastases. Each patient received either a 100 mg/kg intravenous dose of AGuIX or a placebo, with subsequent biodistribution and quantification analyses conducted. This investigation is part of the ongoing randomized Phase II NANOBRAINMETS trial at theDana Farber Brigham Cancer Centre in Boston, USA. The trial aims to evaluate the efficacy of AGuIX combined with stereotactic radiotherapy compared to stereotactic radiotherapy alone in patients with brain metastases. Quantification of AGuIX on MRI images revealed that patients who received AGuIX had nanoparticle concentrations in their brain metastases ranging from 0.012 to 0.17 mg/ml, with a mean concentration of 0.055 mg/ml. Patients receiving placebo showed no significant absorption in their brain metastases. These results confirm AGuIX ability to infiltrate brain tumors in significant quantities.

Additionally, these data indicate that AGuIX uptake by brain metastases was 35% higher than data from the Phase I NANORAD-1 trial previously conducted by NH TherAguix on 15 patients. In this trial, only 3 of the 15 patients had received the highest dose of 100 mg/kg, confirming a dose effect.

"We are very pleased that our collaboration with the Dana Farber teams is regularly expanding and confirming the clinical evidence data for AGuIX in the best possible conditions," said Olivier de Beaumont, CMO of NH TherAguix. "This publication is an acknowledgement of the research efforts made by the Dana Farber Cancer Institute teams, in collaboration with NHT teams, for the clinical development of our innovative nanomedicine. I would like to thank the Dana Farber Cancer Institute teams for the confidence they have shown in our project from the outset, as well as for their collaborative spirit, enabling us to enrich our knowledge of AGuIX."

The AGuIX radio-enhancer is currently being evaluated in four Phase II trials in several types of solid tumors, in combination with radiotherapy. Three of these studies are expected to produce significant results by the end of 2024.

Although radiotherapy has experienced significant advancements in recent years, numerous challenges persist in providing patients with the most effective and precise treatment available. This publication, alongside our recent Fast Track designation by the US FDA, underscores the potential of our nextgeneration radio-enhancer for treating brain metastases and glioblastoma, among the most lethal cancers globally. We firmly believe that the forthcoming results from our clinical trials, anticipated later this year, will chart a new course in therapeutic approaches for these medically urgent conditions," concluded Vincent Carrère, CEO of NHT.

On June 10, 2024 Lixte Biotechnology Holdings, Inc. (the "Company") reported to have entered into a Clinical Trial Agreement (the "Agreement") with the Netherlands Cancer Institute ("NKI") to conduct a Phase 1b/2 clinical trial of the Company’s protein phosphatase inhibitor, LB-100, combined with atezolizumab, a PD-L1 inhibitor, the proprietary molecule of F. Hoffman-La Roche Ltd. ("Roche"), for patients with metastatic colon cancer (Filing, 8-K, Lixte Biotechnology, JUN 10, 2024, View Source [SID1234644326]). Under the Agreement, the Company will provide its lead compound, LB-100, and under a separate agreement between NKI and Roche, Roche will provide atezolizumab and financial support for the clinical trial. The Company has no obligation to, and will not provide any reimbursement of clinical trial costs. Pursuant to the Agreement and the protocol set forth in the Agreement, the clinical trial will be conducted by NKI at NKI’s site in Amsterdam by principal investigator Neeltje Steeghs, MD, PhD, and NKI will be responsible for the recruitment of patients. The Agreement provides for the protection of the respective intellectual property rights of each of the Company, NKI and Roche.

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This Phase 1b clinical trial will evaluate the side effects and optimal dose of LB-100 combined with atezolizumab for the treatment of patients with metastatic microsatellite stable colorectal cancer. Immunotherapy using monoclonal antibodies like atezolizumab can enhance the body’s immune response against cancer and hinder tumor growth and spread. LB-100 has been found to improve the effectiveness of anticancer drugs in killing cancer cells by inhibiting a protein called PP2A on cell surfaces. Blocking PP2A increases stress signals in tumor cells expressing the PP2A protein. Accordingly, combining atezolizumab with LB-100 may enhance treatment efficacy for metastatic colorectal cancer, as cancer cells with heightened stress signals are more vulnerable to immunotherapy.

This study comprises a dose escalation phase and a dose expansion phase. The objective of the dose escalation phase is to determine the recommended Phase 2 dose (RP2D) of LB-100 when combined with the standard dosage of atezolizumab. The dose expansion phase will further investigate the clinical activity, safety, tolerability, and pharmacokinetics/dynamics of the LB-100 and atezolizumab combination. The clinical trial is scheduled to open by June 30, 2024. Patient accrual is expected to take up to 24 months, with a maximum of 37 patients with advanced colorectal cancer to be enrolled in this study.

Additional information on the clinical trial is available on the clinicaltrials.gov website at View Source

The foregoing description of the terms of the Agreement does not purport to be complete and is subject to and qualified in its entirety by reference to the Agreement, a copy of which is filed with this Form 8-K and incorporated by reference.