What to Expect at AACR 2025: Ryvu Therapeutics to Present Preclinical Data on Synthetic Lethality

During the upcoming annual meeting American Association of Cancer Research (AACR) Annual Meeting, April 25-30, 2025, in Chicago, IL., Ryvu Therapeutics will present preclinical data from its synthetic lethality pipeline.

“We are excited to see continued progress across our preclinical pipeline. Our proprietary ONCO Prime platform has identified several novel synthetic lethal targets, including targets for KRAS-driven tumors, which offer immense potential to transform cancer treatment,” noted Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics.

“Our work on next-generation antibody-drug conjugates (ADCs) targeting both synthetic lethality and immunocytotoxic mechanisms is advancing rapidly. At the same time, we continue to make significant strides in developing RVU305, our potentially best-in-class, brain-permeable MTA-cooperative protein arginine methyltransferase 5 (PRMT5_ inhibitor, with IND/CTA-enabling studies on track for completion in H2 2025.

“We are thrilled to present these advancements at the AACR Annual Meeting this year and look forward to engaging with the oncology community,” Brzózka conclued.

Lead Product
Ryvu’s most advanced program is RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies.

RVU120 is currently in Phase 2 development n combination with venetoclax (Venclexta®; Genentech/AbbVie) for the treatment of patients with r/r AML – the RIVER-81 study, as a monotherapy for the treatment of patients with lower-risk myelodysplastic syndromes (LR-MDS) – the REMARK study, as a monotherapy and in combination with ruxolitinib (Jakavi®; Incyte/Novartis) for the treatment of patients with myelofibrosis (MF) – the POTAMI-61 study.

Brain-permeable PRMT5 inhibitor
RVU305, a potentially best-in-class, brain-permeable MTA-cooperative PRMT5 inhibitor, demonstrates significant potential in targeting MTAP-deleted cancers. In preclinical studies, RVU305 effectively inhibited tumor growth in MTAP-null cancer models without affecting normal cells. Co-treatment with an anti-PD-1 antibody was well tolerated and resulted in antitumor activity in an MTAP-deleted, immune checkpoint inhibitors resistant model. The effects of RVU305, both alone and in combination with anti-PD-1, were supported by pharmacodynamic changes observed in tumor tissue. These results position RVU305 as a promising therapeutic option for patients carrying MTAP-deleted cancers resistant to immune checkpoint inhibitors treatment.

RVU305, a potentially best-in-class, brain-permeable PRMT5 inhibitor aiming to treat multiple solid tumors, is currently in IND/CTA-enabling studies.

Treating Colorectal Cancer
One of the study results presented highlights the discovery and validation of novel therapeutic targets for colorectal cancer (CRC) through synthetic lethal (SL) interactions, aiming to address the urgent need for more effective treatments. By using advanced models, including genetically engineered human intestinal stem cells (hISCs) and patient-derived xenografts (PDXs), combined with CRISPR/Cas9 technology, the team identified key vulnerabilities in CRC cells. Genome-wide screens revealed SL targets, particularly in genes associated with APC and KRAS mutations. These findings were validated both in vitro and in vivo, paving the way for the development of new, targeted therapies for CRC patients based on their unique mutational profiles.

Dual PIM/FLT3 kinase inhibitor
Dapolsertib (MEN1703, SEL24) is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group that is currently being investigated in a Phase 1 study in diffuse large B-cell lymphoma (DLBCL) – the JASPIS-01 study. [1]

BioNTech and Exelixis
In 2022 Exelixis and Ryvu entered into an exclusive license agreement focused on the development of novel targeted therapies using Ryvu’s STING (STimulator of INterferon Genes) technology. The agreement expands Exelixis’ portfolio of biotherapeutics by combining Ryvu’s proprietary small molecule STING agonists and STING biology know-how with Exelixis’ network of expertise and resources in antibody engineering, antibody-drug conjugate (ADC) technologies, and proven history of developing and commercializing oncology therapeutics.

The STING pathway can be activated in immune cells in the tumor microenvironment and in tumor cells, and induces innate and adaptive immunity via activation of antigen presenting cells (APCs), cytotoxic T cells and natural killer (NK) cells. Targeted delivery of Ryvu’s STING agonist payloads could provide a differentiated and novel mechanism of action for killing cancer cells. Ryvu’s STING agonists have been rationally designed for differentiation from competitor compounds and have demonstrated STING-dependent, durable anti-tumor activity and cytokine release in preclinical models. The company’s pipeline includes small molecule agonists with demonstrated activity against all STING variants that are suitable for incorporation into ADCs.

In a separate transaction the same year, Ryvu and BioNTech entered into a multi-target research collaboration for several small molecule immunotherapy programs as well as an exclusive license agreement for Ryvu’s STING agonist portfolio as standalone small molecules.

Presentation during the upcoming annual AACR meeting include:

Clinical trials
RVU120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome – ClinicalTrials.gov ID NCT04021368
RVU120 (SEL120) in Patients with Relapse/​Refractory Metastatic or Advanced Solid Tumors – ClinicalTrials.gov ID NCT05052255
RVU120 for Treatment of Anemia in Patients With Lower-risk Myelodysplastic Neoplasms ((MDS)) – ClinicalTrials.gov ID NCT06243458
Safety and Efficacy of RVU120 Combined with Venetoclax for Treatment of Relapsed/​Refractory AML (RIVER-81) – ClinicalTrials.gov ID NCT06191263
Safety and Efficacy of RVU120 for Treatment of Relapsed/​Refractory AML (RIVER-52) – ClinicalTrials.gov ID NCT06268574
RVU120 in Patients With Intermediate or High-risk, Primary or Secondary Myelofibrosis (POTAMI-61) -ClinicalTrials.gov ID NCT06397313
MEN1703 (SEL24) to Treat Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma (JASPIS-01) (JASPIS-01) – ClinicalTrials.gov ID NCT06534437
SEL24/​MEN1703 in Patients With Acute Myeloid Leukemia – ClinicalTrials.gov ID NCT03008187

Highlights of Prescribing Information
Venetoclax (Venclexta®; Genentech/AbbVie)[Prescribing Information]
Ruxolitinib (Jakavi®; Incyte/Novartis)[Prescribing Information]

References
[1] Szydłowski M, Garbicz F, Jabłońska E, Górniak P, Komar D, Pyrzyńska B, Bojarczuk K, Prochorec-Sobieszek M, Szumera-Ciećkiewicz A, Rymkiewicz G, Cybulska M, Statkiewicz M, Gajewska M, Mikula M, Gołas A, Domagała J, Winiarska M, Graczyk-Jarzynka A, Białopiotrowicz E, Polak A, Barankiewicz J, Puła B, Pawlak M, Nowis D, Golab J, Tomirotti AM, Brzózka K, Pacheco-Blanco M, Kupcova K, Green MR, Havranek O, Chapuy B, Juszczyński P. Inhibition of PIM Kinases in DLBCL Targets MYC Transcriptional Program and Augments the Efficacy of Anti-CD20 Antibodies. Cancer Res. 2021 Dec 1;81(23):6029-6043. doi: 10.1158/0008-5472.CAN-21-1023. Epub 2021 Oct 8. PMID: 34625423.

Featured image: Chicago, Ill. Millenium Park/Bean, Chicago. Courtesy: © 2017 – 2025. Fotolia/Adobe

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