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).

On June 13, 2024 LG Chem and AVEO Oncology, an LG Chem company, reported that it has enrolled the first patient in the United States for a Phase 1 clinical study of LB-LR1109 (NCT06332755; LG project code LR19155), LG Chem’s first proprietary anti-cancer investigational drug candidate (Press release, LG Chem, JUN 13, 2024, View Source [SID1234644316]). LG Chem will be collaborating closely with AVEO Oncology, its wholly owned subsidiary, that specializes in oncology development and commercialization, to advance strategies for late-stage clinical development and regulatory approval.

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This is a Phase 1, multi-center, open-label, non-randomized, dose escalation study designed to determine the recommended Phase 2 dose of LB-LR1109 and to evaluate safety, tolerability, preliminary efficacy, pharmacokinetics, immunogenicity, and pharmacodynamics of LB-LR1109, and its potential impact on quality of life. The study is evaluating participants with unresectable and metastatic non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma, or malignant melanoma who have progressed on standard of care treatment options.

In preclinical studies of LB-LR1109, LG Chem observed dose-dependent anti-cancer effects. Subsequently, the company received approval for an Investigational New Drug application from the U.S. Food and Drug Administration (FDA) in December last year.

Leukocyte Immunoglobulin Like Receptor B-1 (LILRB1), a protein released by cancer cells to prevent immune cell attacks, is commonly expressed on the surfaces of several immune cells, including T cells, natural killer cells (NK cells), and macrophages (phagocytic cells). This mechanism is believed to work by activating the tumor-eradicating cells such as T cells, NK cells, and macrophages simultaneously.i This simultaneous activation of overall immune cell functions may differentiate it from existing therapies that focus on single immune cells like T cells.

"We are excited to partner with LG Chem on their first proprietary anti-cancer compound," said Dr. Alex Spira, Director of Next Oncology of Virginia Cancer Specialists Research Institute and the Phase 1 Trial Program. "There is a high unmet need for patients that have progressed on standard of care treatment which necessitates the need to explore novel immune checkpoint inhibitors such as LB-LR1109."

Jeewoong Son, MD, President of LG Chem Life Sciences Company, stated, "We are focusing all our capabilities to provide innovative treatments that will be recognized by medical professionals and patients, as we aim to improve the lives of patients with cancer. While this is the first oncology compound from LG Chem, we are developing a robust pipeline that target novel oncology targets. We will continue to offer differentiated treatment options in the oncology field, where there is the greatest unmet medical need."

The advancement of this program into the clinic brings LG Chem and AVEO Oncology one step closer to realizing our vision of becoming one of the world’s leading oncology companies with a robust clinical pipeline of innovative therapies.

On June 13, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that clinical data of IBI363 (first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein) in advanced solid tumors are presented at the 2024 ESMO (Free ESMO Whitepaper) Virtual Plenary (ClinicalTrials.gov, NCT04085185) (Press release, Innovent Biologics, JUN 13, 2024, View Source [SID1234644315]).

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Dr. Hui Zhou, Senior Vice President of Innovent, stated: "IBI363, as a first-in-class molecule, represents Innovent’s continuous innovation and advancement in the immunotherapy field. Starting from molecular design, the unique approach of α bias with β and γ attenuated were creatively adopted, which greatly improved the therapeutic window of IL-2. Meanwhile, through the specific traction of PD-1, tumor-specific T cells expressing both PD-1 and CD25 can be selectively stimulated and amplified, thus exerting anti-tumor effects. IBI363 has demonstrated excellent druggability with antibody-like pharmacokinetics (IgG-like PK) and low immunogenicity. On top of the preliminary data reported at ASCO (Free ASCO Whitepaper), we presented more informative data at the ESMO (Free ESMO Whitepaper) virtual plenary. Especially in the IO-treated squamous NSCLC, IBI363 has demonstrated strong anti-tumor effects, which could potentially be the next breakthrough in this area. Moreover, a promising efficacy signal was shown in IO-naïve mucosal melanoma, a relatively ‘cold’ tumor, which brings us great confidence in the next step to expand the IO-naïve population, and also indicates the broad application potential of IBI363."

First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein IBI363 in patients with advanced solid tumors: Results from Phase 1 study

This Phase 1a/1b Study was conducted to evaluate the safety, tolerability and preliminary efficacy of IBI363 in subjects with advanced solid tumors.

Over 300 subjects received IBI363 monotherapy treatment, unprecedented dosing level compared with traditional IL-2 therapy, with good tolerability and safety

As of the data cutoff date (Apr 16, 2024), 347 subjects with advanced solid tumors received IBI363 monotherapy (0.2μg/kg QW~3mg/kg Q3W). The tumor types included NSCLC (N=100), melanoma (N=89), colorectal cancer (N=102) and others (N=56). 81.8% of subjects had 2 or more lines of prior systemic therapy. In patients with solid tumors other than CRC (N=245), 84.1% received prior immunotherapy.
As for safety, the most common treatment related adverse events (TRAEs) were arthralgia, anaemia, hyperthyroidism and hypothyroidism. The total incidence of TRAEs ≥ grade 3 was 23.9%. Immune related adverse events (irAEs) ≥ grade 3 occurred in 10.4% of subjects. In the 38 subjects of 3mg/kg Q3W dose group, 13.2% had TRAEs ≥ grade 3, the safety profile was similar to that of the total population, and no new safety signals were identified.
Broad anti-tumor activity and applicability across tumor types, dose-dependent efficacy observed as dose reached 3mg/kg

As for efficacy, 300 subjects received IBI363 ≥0.1mg/kg and had at least one post-baseline tumor assessment. 3 subjects achieved complete response (CR) and 49 subjects had partial response (PR). As of the data cutoff date, 38 responders are still free of disease progression (PD). The duration of response (DoR) was immature. In 204 IO-treated subjects, the ORR was 17.6%.
In 15 subjects who received IBI363 3mg/kg and had at least one post-baseline tumor assessment, the ORR was 46.7% and DCR was 80.0%.
Promising efficacy signals in driver gene wild-type non-small cell lung cancer

– 70 subjects received IBI363 ≥0.3mg/kg and had at least one post-baseline tumor assessment. 77% of them had 2 or more lines of prior systemic therapy, and only 1 subject was IO-naïve. The overall ORR was 27.1%, and DCR was 72.9%.

– In the 37 subjects with squamous cell carcinoma (36 received prior PD-(L)1 treatment, 1 received prior TCE treatment), 13 achieved PR. The ORR was 35.1%, and DCR was 75.7%. As of the data cutoff date, the median follow up time was 5.7 months and the median PFS was 5.5 months (95% CI, 3.2-6.9). 11 of 13 responders are free of disease progression.

– A total of 9 NSCLC subjects (8 received prior PD-(L)1 treatment, 1 received prior TCE treatment) received IBI363 at 3mg/kg Q3W and had at least one post-baseline tumor assessment, including 6 squamous and 3 driver gene wild-type adeno NSCLC. All of the 6 patients with squamous NSCLC and 1 patient with adeno NSCLC achieved PR. The ORR was 100% and 33.3%, respectively, and the DCR were both 100%.

Promising efficacy signals in IO-treated melanoma and IO-naïve mucosal melanoma

– 37 IO-treated melanoma subjects received IBI363 1mg/kg and had at least one post-baseline tumor assessment. There were 11 responders, including 1 CR and 10 PR. The ORR and DCR was 29.7% and 73.0%, respectively.

– In 8 IO-naïve mucosal melanoma subjects, 1 patient achieved CR and 5 patients had PR. The ORR was 75.0%, and DCR was 100%.

As IBI363 has shown encouraging efficacy signals and good tolerability, this study is continuing to further explore the anti-tumor activity of IBI363 in NSCLC, melanoma and other tumors. Relevant data and analysis results will be updated in future academic conferences or journals.

Professor Xueli Bai, The First Affiliated Hospital, School of Medicine, Zhejiang University, stated: "Lung cancer is the leading cause of cancer death worldwide, of which non-small cell lung cancer accounts for about 80%[1]. In recent years, PD-1/PD-L1 inhibitors have shown promising efficacy in non-small cell lung cancer. However, most patients developed primary or secondary resistance to immune checkpoint inhibitors after treatment. IO-failed patients with NSCLC always suffer from a lack of effective treatment, and chemotherapy such as docetaxel elicits an ORR of only about 10% and a median PFS of less than 4 months[2]. As an important cytokine activating tumor-specific CD8+T cells, IL-2 is complementary to immune checkpoint inhibitors in MOA. The combination of PD-1 and IL-2 may reverse the exhaustion of tumor-specific CD8+ T cells, thereby overcoming immune resistance. As a PD-1/IL-2α-bias bispecific molecule, IBI363 showed promising antitumor activity in IO-resistant driver gene wild-type NSCLC, and clinical benefits were demonstrated by both ORR and PFS. At the same time, the safety is manageable, without new safety signals at high dose level, which gives us more confidence."

Professor Yu Chen, Fujian cancer hospital, stated: "Melanoma is a rare tumor in China, and the majority of patients are acral or mucosal subtypes (about 60%-70%[3]), which are not sensitive to immunotherapy. IL-2, as an important cytokine that activates tumor-specific CD8+ T cells and mechanistically complementary to immune checkpoint inhibitors, has long become a well-established target in melanoma. As a novel PD-1/IL-2α-bias bispecific molecule, IBI363 demonstrates significantly higher response rate than the current standard of care in IO-failed melanoma, and the response is durable. Encouraging high ORR and DCR have been observed in mucosal melanoma, a subtype known to be insensitive to immunotherapy. IBI363 is well tolerated, and the toxicity is manageable. The current safety profile is similar to that of previous anti-PD-1 monoclonal antibodies. The clinical data suggest that IBI363 has great development potential in melanoma population. Clinical trials are ongoing for further confirming the clinical benefits of IBI363 in melanoma population."

About IBI363 (First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein)

IBI363 is a First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein independently developed by Innovent Biologics, which has two functions: blocking the PD-1/PD-L1 pathway and activating the IL-2 pathway. The IL-2 arm of IBI363 was modified to retain its affinity for IL-2Rα, but weakened its binding ability to IL-2Rβ and IL-2Rγ, thereby reducing toxicity. The PD-1 binding arm can simultaneously block PD-1 and selectively deliver IL-2. Since the newly activated tumor specific T cells express both PD-1 and IL-2α, this differential strategy allows for more precise and effective targeting and activation of this T cell subpopulation. IBI363 not only showed good antitumor activity in a variety of tumor-bearing pharmacological models, but also showed outstanding efficacy in PD-1 resistance and metastasis models. Starting from the urgent clinical needs, Innovent Biologics is conducting clinical studies in China, the United States and Australia to explore the efficacy and safety of IBI363 in advanced tumors.