On June 14, 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, reported preclinical proof-of-concept data from MP0621, a multispecific cKit x CD16a x CD47 Switch-DARPin program (Press release, Molecular Partners, JUN 14, 2024, View Source [SID1234644312]). The data validates the Switch-DARPin concept in vivo and MP0621’s potential as a next-generation therapeutic supporting hematopoietic stem cell transplantation (HSCT), initially for the treatment of acute myeloid leukemia (AML) patients. The data will be presented today in a poster session at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress taking place June 13-16 in Madrid, Spain.

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"We designed our Switch-DARPin platform to unlock undruggable targets and enable safe use of powerful immune activators via logic-gated and reversible immune activation," said Anne Goubier, Ph.D., SVP Research & Early Development. "MP0621 is our first candidate in this series, with the aim to clear HSCs effectively and safely, by targeting cKit, engaging innate immune cells via CD16a, and blocking CD47 only on cKit+ cells. We’re thrilled by these results, which validate our Switch-DARPin platform in vitro and in vivo and pave the way for a new generation of conditionally activated T cell engagers, with the potential to revolutionize therapy in areas of unmet need, such as solid tumors".

HSCT offers a potential cure for patients with AML and other malignant and non-malignant diseases. However, the toxicity of pre-HSCT conditioning often requires that it is carried out with reduced intensity, increasing the likelihood that diseased cells remain in the bone marrow and lead to relapse. Safer and more efficacious treatments are needed to improve HSCT outcomes for more patients with AML and other diseases requiring HSC transplant. MP0621 is intended to maximize the therapeutic potential of HSCT for AML patients, including those with poor cytogenetic risk profile, to extend the access to potentially curative HSCT for more patients, and to increase long term disease control post HSCT.

MP0621 is designed to induce eradication of HSCs while avoiding the toxicity associated with current high-intensity conditioning regimens. MP0621 engages natural killer cells and macrophages via CD16a to selectively kill targeted cKit-positive cells. cKit is critical for stem cell maintenance and renewal and thus an attractive target to select for HSCs as well as leukemic stem cells in AML. CD47 is widely expressed as "don’t-eat-me" signal and prevents killing of cells, including HSCs/LSCs. Blocking CD47 can enhance damage to bound stem cells; however systemic anti-CD47 blockers cause significant toxicity, highlighting the need for conditional and targeted blockade of CD47.

The Switch-DARPin platform provides a logic-gated "on/off" function (the "Switch") to multispecific DARPin candidates leading to target activation only in the presence of defined antigens. In MP0621, the Switch-DARPin binds to either cellular cKit or to the anti-CD47 DARPin binder. Upon MP0621 binding to cKit on cells, the Switch-DARPin will unmask the anti-CD47 DARPin, which in turn will bind CD47 and block the "don’t-eat-me" signal, leveraging the power of CD47 inhibition without its associated toxicity to healthy cells. The Company is presently conducting preclinical efficacy and safety studies for MP0621 with data expected in H2 2024.

In the poster presented, preclinical studies demonstrate that:

MP0621 selectively blocks CD47 on cells expressing cKit
Conditional blockade of CD47 enhances efficacy of cKit targeting, with phagocytosis comparable to a combo of anti-cKit and anti-CD47 monoclonal antibodies
MP0621 depleted cKit+ cells in bone marrow of humanized mice without affecting circulating immune cells
PK profile of MP0621 is suitable for HSCT therapy in humans
Poster details can be found below. The full poster will be made available on Molecular Partners’ website after the presentation.

Title: C-KIT X CD16A X CD47 Switch-DARPin with Conditional Blockade of CD47: A Next-generation Targeted Conditioning for Hematopoietic Stem Cell Transplantation
Session Title: Stem Cell Transplantation – Experimental
Abstract Number for Publication: P1294
Poster Session Timing: June 14, 2024; 6-7 pm CET

On June 13, 2024 Brenus Pharma, French biotech developing its proprietary discovery platform: "Stimulated-Tumor-Cell" (STC), reported it has presented the study design of "BreAK-CRC" First-in-human of STC-1010, Brenus’ lead candidate, during ASCO (Free ASCO Whitepaper) annual meeting (31st May – 4th June 2024) – Trials in Progress poster session, in Chicago (Press release, Brenus Pharma, JUN 13, 2024, View Source [SID1234644321]).

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Poster here. | Benoit You et al. Journal of Clinical Oncology 42, TPS3635-TPS3635(2024). DOI:10.1200/JCO.2024.42.16_suppl.TPS3635
Authors information’s: here.

Based on STC-1010’ robust preclinical package in vivo, in ovo, ex vivo, BreAK-CRC study will be launched in 9 oncology early phase centers (EU, US) with expert investigators in immunotherapy:

"Cancer vaccines continue to show promising clinical results in solid tumors. STC-1010, is a new immunotherapeutic approach based on cancer vaccine mechanism of action for colorectal cancer patients. In that, "BreAK-CRC" Study is eagerly expected. CRC is still challenging as current immunotherapies were found only active in dMMR/MSI-H "hot" CRC. For the pMMR/MSS population, representing 95% of patients with CRC, there is an important medical need for drugs likely to heat up "cold" tumors and have a real impact for the patient." François Ghiringhelli (M.D,PhD) Director of early clinical unit CLIPP2 and BreAK-CRC study coordinator, Centre Georges-François Leclerc, University of Burgundy, Dijon, France.

BreAK-CRC trial protocol has been reviewed in pre-submission meeting with the French National Health Authority. The submission of the CTA through the clinical trial information system of the European union is ongoing.

The Phase I/IIA clinical trial, aims to evaluate the safety and efficacy of STC-1010 in patients with unresectable advanced or metastatic colorectal cancer, 2nd cause of cancer mortality worldwide.

The Phase I will assess the tolerability of two dose levels of STC-1010, combined with low-dose immunostimulants and standard of care chemotherapy (SoC). The Phase IIA will enroll patients to further evaluate the treatment’s efficacy, particularly focusing on 12-month non-progression rate.

Exploratory analysis will evaluate the immune response and the ctDNA dynamic.

On June 13, 2024 InduPro, Inc., a biotechnology company defining protein spatial relationships to create novel therapeutics for the treatment of cancer and autoimmune diseases, reported an $85 million Series A financing co-led by The Column Group and Vida Ventures with participation from investors, including MRL Ventures Fund (the therapeutics-focused venture fund of Merck & Co, Inc.), Emerson Collective and Euclidean Capital (Press release, InduPro, JUN 13, 2024, View Source [SID1234644320]). The financing will support the advancement of the first expected clinical product candidate targeting cancer tissue based on the proximity of co-targeted pairs, from preclinical development to an expected IND filing in Q4 2025 for a Phase 1 clinical trial. It will also fuel a pipeline of novel bispecific antibodies and antibody drug conjugates (ADCs) that utilizes protein proximity for identification of novel tumor selective target pairings.

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Prakash Raman, Ph.D. joins as Chief Executive Officer of InduPro with more than two decades of biopharmaceutical business development and executive leadership experience, blending his scientific background, program and portfolio management and strong business development experience to lead and support biopharma companies.

InduPro therapeutically targets cell surface proteins in a variety of disease contexts by leveraging inherent or induced protein proximity. Through precise mapping of protein neighborhoods using its proprietary, high resolution proximity labeling technology, the Company is discovering novel co-target pairs that are highly selective for specific disease biology. Additionally, since protein proximity influences signals in cells that are critical for cellular health, proximity can be induced to modify cellular signaling and interactions in disease. InduPro’s approach relies on a unique discovery engine (ProXiMATE) to generate potential first-in-class and best-in-class novel therapeutic candidates across multiple indications and modalities.

"Our team is highly focused on precisely defining the spatial proximity of proteins on the surface of cells with high therapeutic potential across a broad range of indications and applications," said Dr. Raman. "Instead of a limited subset of targets with known disease biology, we are discovering novel targets and best-in class approaches for areas of high unmet need for many cancer and autoimmune patients."

The lead bispecific ADC program uses the Company’s Tumor Associated Proximity Antigen (TAPA) therapeutic approach to specifically target cancer tissue based on the proximity of co-targeted pairs discovered. In a separate ‘immunological synapse modulation’ approach, multi-specific antibodies are directed against targets whose induced proximity recruits and activates (or sequesters) proteins on the surface of immune cells in the treatment of autoimmune disease or immuno-oncology.

"Our approach provides unique insight into novel targets and mechanisms of biology by which to target and manipulate disease biology. This approach creates high patient impact and enables our first- and best-in class programs," said Scott Lesley, Ph.D., President & Chief Scientific Officer. "Our ProXiMATE platform leverages deep learning analysis of protein microenvironment and membrane proteomic data to create an extensive knowledge base of highly-tuned protein proximity maps that continually generate novel and high-value tumor selective targets for ADCs and T cell engagers."

"We are delighted that InduPro’s unique discovery engine is driven and supported by a talented team led by Prakash and will provide a strong foundation for a robust pipeline of potentially transformative therapeutics with opportunities for expansion and partnership," said Sarah Hymowitz, Ph.D., partner at The Column Group and Board Chair of InduPro. "We look forward to collaborating with the InduPro team to bring novel and highly promising therapies to patients living with a wide range of cancers and autoimmune diseases."

Dr. Raman previously served as President and CEO of Ribon Therapeutics, a biotech company focused on first-in-class small molecule drugs for Oncology and Immunology targeting the PARP family of enzymes. Prior to joining Ribon, Dr. Raman was a Senior Partner, Chief Business Development Officer at Flagship Pioneering, and held senior roles at Novartis for nearly 14 years, most recently as Vice President, Global Head of Novartis Institutes for Biomedical Research (NIBR) Business Development and Licensing. Dr. Raman completed his undergraduate work at the Indian Institute of Technology, Bombay, and received his Ph.D. in Organic and Medicinal Chemistry from the University of Wisconsin-Madison.

Formed in 2022 by Scientific Founder and recent Passano Award winner Chris Garcia, Ph.D., CSO Scott Lesley, Ph.D., and inventors of the protein proximity-based mapping technology, Rob Oslund Ph.D. and Niyi Fadeyi Ph.D., InduPro is led by a dedicated Board of Directors that includes Sarah Hymowitz, Ph.D., Board Chair from The Column Group, Helen Kim and Rajul Jain, M.D. from Vida Ventures, Peter Dudek, Ph.D. from MRL Ventures Fund, Rahul Ballal, Ph.D. CEO from Mediar Therapeutics, Craig Parker CEO from Surrozen, and InduPro CEO Prakash Raman, Ph.D.

On June 13, 2024 Remix Therapeutics (Remix), a clinical-stage biotechnology company developing small molecule therapies to modulate RNA processing and address underlying drivers of disease, reported that it will deliver a poster presentation demonstrating the therapeutic potential of REM-422, a potent, selective, oral small molecule MYB mRNA degrader for the treatment of acute myeloid leukemia (AML), at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Hybrid Congress in Madrid, Spain (Press release, Remix Therapeutics, JUN 13, 2024, View Source [SID1234644319]).

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The poster presentation will include preclinical data from MYB-dependent AML cell lines and human leukemia xenograft models showing REM-422 is broadly active across various AML models. Furthermore, REM-422 induces tumor regressions in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of AML at well-tolerated doses. In vitro and in vivo studies show that REM-422 functions by inducing incorporation of a poison exon into the MYB mRNA transcript resulting in mRNA degradation and inhibition of MYB protein expression.

"We’ve built a robust package of preclinical data across various models that reinforces the therapeutic potential of REM-422 for the treatment of AML and other MYB-dysregulated cancers," said Peter Smith, Ph.D., Co-Founder and Chief Executive Officer of Remix Therapeutics. "The ability to successfully target a previously undruggable transcription factor is encouraging as we continue to investigate REM-422 in our ongoing clinical trials."

The dysregulation of MYB, an oncogenic transcription factor, has been linked to numerous cancers including AML, myelodysplastic syndromes (MDS) and lymphoma. REM-422 is a potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression, resulting in antitumor activity in MYB-dependent human tumor models.

REM-422 is currently being investigated as a potential treatment for AML/HR-MDS and adenoid cystic carcinoma (ACC) in two, phase 1 clinical trials.

Details for the poster presentation are as follows:

Title: REM-422, a potent, selective, oral small molecule mRNA degrader of the MYB oncogene, demonstrates anti-tumor activity in mouse xenograft models of AML
Abstract Number: P531
Session Date and Time: June 14 at 6:00 PM CEST
Session Location: Poster Hall

About REM-422

REM-422 is a first-in-class, potent, selective, and oral small molecule mRNA degrader that induces the reduction of MYB mRNA and subsequent protein expression. REM-422 functions by facilitating the incorporation of poison exons within the mRNA transcript, leading to nonsense-mediated decay (NMD) of the transcript. REM-422 addresses MYB dysregulation, a driver of oncogenesis, upstream of protein expression.

About ACC

Adenoid cystic carcinoma (ACC) is a rare cancer that commonly develops in glandular tissues in the head and neck. It is caused by genetic mutations, likely developed over a patient’s lifetime, with the majority of ACC cases linked to an overexpression of the MYB protein. Depending on the location of the tumor, symptoms may include numbness of the face, difficulties swallowing, changes in vision, or difficulty breathing, among others. Current treatment solutions include surgery, radiation therapy, and chemotherapy.

About AML/HR-MDS

Acute myeloid leukemia (AML), a rare cancer of the blood and bone marrow, is the most common type of acute leukemia in adults. AML is caused by genetic mutations within bone marrow cells, which in turn causes the production of leukemic white blood cells that crowd out healthy blood cells. This may cause problems with bleeding, infection, and anemia. Myelodysplastic Syndromes (MDS) are disorders of blood-forming units in the bone marrow. High-risk (HR)-MDS patients have a higher percentage of blast cells in the bone marrow and that, in many cases, progresses to AML. There are several approved agents to treat AML, however, many patients relapse after achieving a response, underscoring the need for new therapies.

On June 13, 2024 Sirnaomics Ltd. (the "Company"; together with its subsidiaries, "Sirnaomics" or the "Group"; stock code: 2257), a leading biopharmaceutical company in discovery and development of RNAi therapeutics, reported that the Group has published a major advancement of its novel Oligonucleotide-Chemodrug Conjugate (ODC) agent (Press release, Sirnaomics, JUN 13, 2024, View Source [SID1234644317]). The ODC demonstrated potent antitumor activity in multiple tumor cell lines and a pancreatic tumor model in mice. The work was published in the latest issue of Journal of Oncology Research and Therapy (06, 2024: p1-16, Volume 9, issue 02). This groundbreaking work creates a solid foundation for the Company’s RNAi-based cancer therapeutic program using a proprietary Antibody-Oligonucleotide-Chemodrug Conjugate (AODC) modality.

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The published results are the extension of prior work (NAR Cancer, 2020, Vol. 2, No. 3. p1-12) using a proprietary anticancer ODC agent comprising a double-stranded siRNA targeting CHK1 mRNA incorporating gemcitabine into its Sense Strand in place of Cytidines. Gemcitabine (a small molecule anticancer drug) is synergistic with CHK1 inhibition increasing the IC50 of the combination about 100-fold in different cell lines. In the latest work, the ODC construct contained chemically modified bases to improve stability and this construct improved potency and efficacy against CHK1 gene expression. In vitro tests have shown potent antitumor activities of gemcitabine containing CHK1 specific siRNA validated using Pancreatic, NSCLC, TNBC and Ovarian cell culture models. The construct also provides efficacy against a pancreatic tumor in a xenograft model in mice, ablating the tumor upon Intravenous administration using Sirnaomics proprietary polypeptide nanoparticle formulation.

"Antibody Drug Conjugates (ADCs) have demonstrated exceptional specificity and efficacy for cancer treatment. Sirnaomics expects to harness similar benefits with its ODC constructs, to improve potency or duration of effect of small molecule therapeutics. Many small molecule drugs show efficacy initially but encounter drug resistance later due to upregulation of certain protein expression by tumor cells. Identifying those proteins and designing specific siRNAs against these targets provides a powerful approach to overcome these chemodrug induced resistances." Dr. David Evans, Head of Discovery Research of Sirnaomics and the corresponding author of the publication, indicated, "Building an oligonucleotide-drug conjugate (ODC) construct will minimize resistance and potentiate chemodrug efficacy, while reducing systemic toxicity of the chemodrug. Together with an antibody derived targeting property, this will provide a novel drug modality Antibody Oligonucleotide Drug Conjugate (AODC) for improvement of cancer treatment."

Dr. Patrick Lu, the founder, Chairman and CEO of Sirnaomics, comments, "The latest advancement of Sirnaomics proprietary ODC agent demonstrates the Company’s continuing innovative effort for novel cancer RNAi therapeutics, while pushing our clinical studies of STP705 for the treatment of skin cancer, STP707 for the treatment of solid tumors and STP122G for anticoagulation therapy. We expect Sirnaomics’ AODC agents will provide an alternative approach to treat various cancers based on tremendous success of ADCs and bring broad partnership opportunities."

About STP888

An example of an Oligonucleotide-Drug Conjugate (ODC) – CHK1 siRNA duplex containing Gemcitabine (STP888) targets the gene CHK1 which has been shown to synergize with the small molecule Gemcitabine in inducing anticancer efficacy. Upon binding, the mRNA is degraded and eventually the protein level of CHK1 is reduced. The Sense strand is degraded, releasing the gemcitabine and allowing the synergistic effect to be observed. The chemically stabilized construct will allow direct targeting to tumor cells (leaving adjacent normal cells) which will improve efficacy and reduce toxicity. Sirnaomics will pursue delivery using this construct coupled to an antibody against markers upregulated in the tumor but not in normal cells. This will be the foundation of Antibody Oligonucleotide-Drug Conjugates (AODC).