On April 28, 2025 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported the presentation of a poster at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, highlighting preclinical data on ORIC-944, a potent, highly selective, orally bioavailable allosteric inhibitor of PRC2, which demonstrated synergistic activity and improved progression-free survival (PFS) when combined with androgen receptor pathway inhibitors (ARPIs) in models of prostate cancer (Press release, ORIC Pharmaceuticals, APR 28, 2025, View Source [SID1234652240]).

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"We are excited by the potential of ORIC-944 to be a best-in-class PRC2 inhibitor for the treatment of prostate cancer," said Lori Friedman, PhD, chief scientific officer. "The data presented at AACR (Free AACR Whitepaper) demonstrate the strong synergy of ORIC-944 when combined with standards of care, reversing the evolution of prostate cancer, and improving progression-free survival in both castration-resistant and castration-sensitive prostate cancer models – validating the clinical exploration of ORIC-944 across the continuum of prostate cancer."

Poster presentation:

ORIC-944, a PRC2 inhibitor with best-in-class properties, restores luminal features and restricts adaptation in prostate cancer models, conferring synergy with AR pathway inhibitors

Key findings of the presentation:

ORIC-944 increased progression-free survival (PFS) when combined with ARPIs in both castration-sensitive and castration-resistant prostate cancer models.
ORIC-944 demonstrated transcriptional synergy and antitumor synergy when combined with ARPIs in prostate cancer cells.
In preclinical prostate cancer models, ORIC-944 demonstrated robust inhibition of PRC2, enhanced luminal cell state, and consistently restricted lineage transcription factor accessibility through chromatin remodeling, ​thereby reenforcing the luminal state and preventing access to plasticity programs.
Results position ORIC-944 as a potential best-in-class PRC2 inhibitor that, through both transcriptional and chromatin mechanisms, blocks prostate tumor adaptation, restores luminal features, and sensitizes tumors to ARPIs.
ORIC-944 is currently being evaluated in combination with ERLEADA (apalutamide) and in combination with NUBEQA (darolutamide) in an ongoing Phase 1b trial for prostate cancer.
About ORIC-944
ORIC-944 is a potent and selective allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the embryonic ectoderm development (EED) subunit that demonstrates best-in-class drug properties in preclinical studies, including potency, solubility, and pharmacokinetics, with half-life supporting once daily dosing. ORIC-944 was initially evaluated as a single agent in a Phase 1b trial in patients with advanced prostate cancer and demonstrated potential best-in-class drug properties, including clinical half-life of approximately 20 hours, robust target engagement and a favorable safety profile. ORIC-944 is currently being evaluated in combination with ERLEADA (apalutamide) and in combination with NUBEQA (darolutamide) in an ongoing Phase 1b trial for prostate cancer (NCT05413421).

On April 28, 2025 Nurix Therapeutics, Inc. (Nasdaq: NRIX), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of targeted protein degradation medicines, reported data that demonstrate the potential of its DEL Foundation Model to enable the rapid in silico identification of novel binders for a broad range of therapeutically relevant proteins, addressing a key barrier in the discovery and development of small molecule drugs (Press release, Nurix Therapeutics, APR 28, 2025, View Source [SID1234652239]). These results were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, IL, which is being held from April 25-30, 2025.

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"Nurix’s DEL-AI platform has the potential to accelerate the discovery of breakthrough small molecule drugs—whether they be protein degraders, molecular glues, or inhibitors—by enabling ready-access to tractable chemical matter for an expansive set of proteins, especially those previously considered beyond the reach of drug discovery organizations," said Gwenn M. Hansen, Ph.D., chief scientific officer of Nurix. "Our team has leveraged the rich datasets generated from rigorously controlled screenings of our customize collection of over five billion unique DEL compounds against hundreds of disease targets and E3 ligase proteins to construct a powerful suite of machine learning models and tools. By directly integrating the sampling density provided by DEL compound repertoires with primary protein sequence information, our model can learn a generalizable structure activity relationship capable of predicting novel binders for nearly any disease-relevant protein target."

"Our DEL-AI engine is a potential game changer, allowing us to substantially accelerate drug discovery workflows and efficiently identify therapeutic candidates for our wholly owned pipeline and our current and future discovery partnerships," said Arthur T. Sands, M.D., Ph.D., president and chief executive officer of Nurix. "This powerful research engine is a result of our significant expertise and strategic investments in DEL methodology and our machine learning platform."

Nurix’s presentation at the AACR (Free AACR Whitepaper) 2025 Annual Meeting, titled: "DEL-AI: Proteome-wide in silico screening of multi-billion compound libraries using machine learning foundation models," described the development of a first-in-class foundation model that was trained on the Company’s high quality, proprietary DEL data. Nurix’s DEL Foundation Model is able to perform virtual DEL experiments on prospective protein target sequences to accurately predict novel binders to a large proportion of therapeutically relevant targets, including many targets considered undruggable. In plots of virtually predicted vs. experimentally-derived DEL screens against therapeutically relevant proteins, Nurix’s DEL Foundation Model demonstrated the ability to accurately predict the experimental results, including experimentally validated binders. Success of the DEL Foundation Model was found to correlate to the degree of similarity of query sequences to proteins within the DEL training set, and data demonstrated that the current model requires as little as 50% amino acid sequence similarity of a query protein to training data to enable binder prediction. Nurix’s model was also capable of inferring binders from chemical space not represented in the training set, suggesting that the model is capable of both protein sequence and chemical structure generalizations.

The development of the DEL Foundation Model was led by Nurix in collaboration with Loka, a Silicon Valley-based software development firm, and supported by Amazon Web Services (AWS), leveraging AWS SageMaker and AWS managed MLflow to provide enterprise-grade reliability and scalable infrastructure.

About DEL-AI

DEL-AI is Nurix’s discovery platform which employs advanced machine learning to enable all aspects of Nurix’s discovery engine, starting with DNA encoded library (DEL) hit-finding and degrader design, followed by automated chemistry synthesis and direct-to-biology screening and optimization, to rapidly generate degraders and degrader antibody conjugates (DACs) as new chemical entity drug candidates. By leveraging hundreds of billions of DEL compound binding signatures derived from thousands of DEL affinity screens collected from a diverse set of highly validated protein targets, Nurix’s DEL-AI platform can prospectively identify binders as starting points for drug discovery for virtually any pharmaceutically relevant target.

On April 28, 2025 Nerviano Medical Sciences S.r.l. (NMS), a clinical-stage oncology company developing targeted therapies across DNA damage response and kinase pathways, reported the initiation of two Phase 1 clinical trials evaluating its unique non-trapping, highly specific and brain penetrant PARP1 inhibitor NMS-293 in combination therapies for relapsed small cell lung cancer (SCLC) and BRCA wild-type ovarian cancer (Press release, Nerviano Medical Sciences, APR 28, 2025, View Source [SID1234652238]). NMS-293 represents a third generation of PARP1 inhibitor using non-trapping as a way to combine with DNA-damaging therapies while preserving bone marrow safety. In this way, NMS-293 addresses tumors outside of BRCA or homologous recombination (HR) repair mutations which is unique. BRCA/HR mutation therapies represent only a small minority of tumors, mainly subsets of pancreatic, breast, prostate and ovarian cancers. Thus, therapies that leverage DNA damage response but are not limited to synthetic lethality of BRCA/HR mutations such as NMS-293 combinations with DNA damaging agents could address many tumor types in the future.

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PARPA-293-004: NMS-293 with Temozolomide in Relapsed SCLC

This open-label, single-arm Phase 1 trial will enroll approximately 10 patients with relapsed SCLC who have progressed after platinum-based chemotherapy, immunotherapy and other standards of care. The objectives include safety and preliminary anti-tumor activity. This regimen is similar to the ongoing Phase 2 -002 study in relapsed high-grade glioma. Boosting temozolomide activity in this relapsed setting of SCLC could lead to accelerated registration pathways and future early line combination study options with a variety of DNA-damage modalities.

ClinicalTrials.gov Identifier: NCT06931626

PARPA-293-003: NMS-293 with Topotecan in BRCA Wild-Type Ovarian Carcinoma
This open-label Phase 1 study will enroll approximately 24 patients with recurrent ovarian cancer who have received platinum-based treatments and other standards of care, including patients with platinum resistance. The objectives include safety, dose-finding and preliminary anti-tumor activity. Boosting topotecan activity in patients with relapsed ovarian cancer could lead to accelerated registration pathways as well as various DNA-damaging modality combination options for future early line studies.

ClinicalTrials.gov Identifier: NCT06930755

The rationale for initiating these trials is supported by both preclinical evidence and emerging clinical data from temozolomide combination studies which revealed an unprecedented combination safety profile coupled with preliminary antitumor efficacy in high grade gliomas (Mahnke, DDR Summit 2025 and Guerts et al, AACR (Free AACR Whitepaper)-NCI-EORTC 2023) including glioblastoma (unpublished). NMS-293 is a highly novel third generation PARP1 inhibitor distinguished by non-trapping as shown preclinically with high potency, selectivity and brain penetrance. Taken together, the profile improves on poor bone marrow features of first and second generation trapping PARP1 inhibitors (Yap et al AACR (Free AACR Whitepaper) 2024) and thus removes traditional barriers of combining a DNA damage repair inhibitor with a DNA damaging agent to address non-BRCA mutation tumors.

"These trials represent our focused, mechanism-driven approach to improving treatment outcomes in areas of high unmet medical need including relapsed small cell lung and BRCA wild type ovarian cancers," said Lisa Mahnke, MD, PhD, Chief Medical Officer of NMS. "NMS-293 has the potential to establish a new third generation of PARP1 inhibitor and which is not being developed as a classical PARP1 inhibitor due its unique chemotype. NMS-293 is a highly potent, highly selective, non-trapping PARP1, inhibitor which is highly brain penetrant and which can be developed across many tumor types including brain tumors like GBM or others with or without brain metastases in combination with a variety of DNA-damaging modalities such as chemotherapies or ADC payloads to reach many non-BRCA-mutation tumors in the future."

On April 28, 2025 Mythic Therapeutics, a clinical-stage biotechnology company developing next-generation antibody-drug conjugate (ADC) therapies for the treatment of a wide range of cancers, reported preclinical data demonstrating the potential of MYTX-011 to treat multiple tumor types, regardless of mutation status or cMET expression level, in a poster session at the AACR (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Mythic Therapeutics, APR 28, 2025, View Source;utm_medium=rss&utm_campaign=mythic-therapeutics-presents-preclinical-data-demonstrating-potent-efficacy-of-mytx-011-across-a-broad-range-of-tumor-xenograft-models-harboring-clinically-relevant-mutations-at-the-american-associati [SID1234652237]).

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"These findings highlight the broad therapeutic potential of MYTX-011 across a variety of cMET-expressing cancers and the opportunity to expand the treatable patient population to patients with EGFR, KRAS and MET mutations, which have shown reduced response rates in clinical studies of other anti-cMET ADCs in development," said Brian Fiske, Ph.D., chief scientific officer and co-founder of Mythic. "These preclinical data reinforce our confidence in the ongoing Phase 1 dose escalation trial of MYTX-011. Building on last year’s promising preliminary data, we remain highly optimistic and eagerly await additional readouts."

MYTX-011 is a novel cMET-targeted DAR 2 vcMMAE ADC with an antibody that has been engineered to have pH-dependent binding, which results in higher internalization and payload delivery to tumor cells with a range of cMET expression.

In the study, pH-dependent binding of MYTX-011 translated to potent efficacy in tumor xenografts regardless of mutation status, including models harboring MET exon 14 skipping, KRAS and EGFR mutations. Notably, MYTX-011 demonstrated anti-tumor activity in low or moderate cMET-expressing non-small cell lung cancer (NSCLC) KRAS G12C xenografts as well as tyrosine kinase inhibitor-resistant xenografts bearing EGFR T790M mutations. Additionally, live cell imaging studies demonstrated how FateControl technology drives increased uptake of MYTX-011 antibody in cMET-expressing tumor cells compared to a non-engineered parent antibody. In previous studies, a benchmark ADC was either inactive or had greatly reduced efficacy.

These findings support the continued clinical advancement of MYTX-011, which is currently being evaluated in the ongoing Phase 1 KisMET-01 trial in NSCLC.

The Company will present additional data from its Phase 1 KisMET-01 study at an upcoming major medical conference.

About MYTX-011

MYTX-011, an investigational cMET-targeting ADC, leverages Mythic’s innovative FateControl technology which is designed to allow ADCs to actively navigate inside of cells, potentially increasing delivery of anti-cancer agents to tumor cells with less impact on healthy cells. This breakthrough approach takes the next step beyond linker-payload technologies and is designed to improve ADC efficacy against a broad set of molecular targets and patient profiles. MYTX-011 is currently being evaluated in the Phase 1 KisMET-01 clinical trial, a first-in-human, open-label, multi-center, dose escalation and dose expansion study enrolling patients with locally advanced, recurrent or metastatic NSCLC (NCT05652868).

On April 28, 2025 MaaT Pharma (EURONEXT: MAAT – the "Company"), a clinical-stage biotechnology company and a leader in the development of Microbiome Ecosystem TherapiesTM (MET) dedicated to enhancing survival for patients with cancer through immune modulation, reported new preclinical data for MaaT034, the Company’s next generation product, showing compelling anti-tumor efficacy results in germ-free mice at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 in Chicago, Illinois, taking place from April 25 to 30, 2025 (Press release, MaaT Pharma, APR 28, 2025, View Source [SID1234652236]).

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MaaT Pharma has built a versatile platform combining two complementary approaches. The first one leverages a GMP-compliant approach to produce standardized donor-derived therapies (MaaT013, MaaT033) using pooled donations, proven to restore a rich and diverse gut microbiome for patients with severe dysbiosis and currently in late-stage of clinical evaluation (Phases 2 and 3). In parallel, the Company is advancing a next-generation, AI-driven co-culture technology to develop a donor-independent synthetic microbiome ecosystem at large industrial scale targeting indication-specific diseases. MaaT034, the first-in-class co-cultured product, aims to optimize intestinal microbiome functions and to improve patient responses to immunotherapy in combination with Immune Checkpoint Inhibitors.

Below are the key results presented at AACR (Free AACR Whitepaper) for MaaT034:

Metagenomic analysis shows that MaaT034 reproduces the microbial functions of MaaT013 – the Company’s lead asset, currently evaluated in the randomized Phase 2 PICASSO trial in combination with immune checkpoint inhibitors (ICI), ipilimumab (Yervoy) and nivolumab (Opdivo) for unresectable or metastatic melanoma.
MaaT034 improves DC-mediated T cell activation and potentiates anti-tumor effects mediated by anti-PD-1 checkpoint blockade in vitro.
70% of MaaT034 microbial species engraft in mice, ensuring an enduring presence of beneficial bacteria in the gut environment.
MaaT034 increases the production of key microbial-derived metabolites such as short-chain fatty acids in germ-free mice. This translates into an improved gastrointestinal physiology as evidenced by gut mucosal restoration.
MaaT034 optimizes anti-PD1 mediated activity in tumor-bearing, germ-free mice. While anti-PD1 alone reduced tumor growth by 10%, the combination of anti-PD1 and MaaT034 resulted in a 83.7% tumor growth reduction (compared to a 24.2% reduction when using a single strain of Akkermansia muciniphila bacteria). These results demonstrate that improved tumor control is achieved with anti-PD1 in combination with MaaT034, as compared to PD-1 alone or in combination with a reference single bacterial strain.
"These positive data in tumor-bearing mice demonstrate the significant potential of MaaT034 as a microbiome ecosystem therapy candidate and provide a robust basis for the progression of this therapy into clinical development for solid tumors. We look forward to further evaluating the potential benefits of MaaT034 in the next phases of our research," said Gianfranco Pittari, MD PhD, Chief Medical Officer, MaaT Pharma.

Upcoming conferences participation

May 5-6, 2025 – Swiss Biotech Day, Basel
May 13, 2025 – Forum Midcaps Gilbert Dupont, Paris
June 12-15 – European Hematology Association (EHA) (Free EHA Whitepaper) Congress, Milan, IT
June 16-19, 2025 – Bio International Convention, Boston, MA – Company Presentation
June 18-19, 2025 – Portzamparc Conference Mid & Small Caps 2025, Paris
September 25, 2025 – KBC Healthcare Conference, Brussels
About MaaT034

MaaT034, currently in preclinical development, is a next-generation donor-independent full ecosystem synthetic microbiome therapy, dedicated to improving patient responses to immunotherapy in combination with Immune Checkpoint Inhibitors. Developed using the Company’s co-culturing proprietary MET-C platform, MaaT034 is optimized for large-scale production in oncology. Previous presented preclinical data showed that MaaT034 produced key metabolites, recognized as promoting gut barrier restoration and modulating immune responses, such as Short-Chain Fatty Acids (SCFA), secondary bile acids, and tryptophan derivatives. These data support the role of MaaT034 in gut barrier repair and in T cell reactivation either in combination with anti-PD1 or with anti-PD-L1. By enhancing gut barrier repair and modulating immune responses, MaaT034 is expected to complement the action of these immunotherapeutic agents, potentially improving their efficacy in treating solid tumors cancer.