Dapolsertib

Total operating revenues for the full year 2023 were $16.3M, compared to $15.8M for the same period in 2022. As of March 7, 2024, Ryvu's cash position was $57.2M, excluding the first tranche of €8M in venture debt from the EIB, expected imminently. Together with other already secured funding sources, this cash position provides a runway through Q1 2026. Ryvu will present preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the upcoming 2024 American Association for Cancer Research (AACR) Annual Meeting (April 5-10, San Diego, California). After announcing the hematology-focused RVU120 development plan in Q4 2023, Ryvu launched two Phase II studies in early 2024. An additional two Phase II clinical trials for RVU120 are expected to be launched in mid-2024. By the end of the year, the company plans to enroll over 100 patients across all RVU120 Phase II studies and aims to present initial Phase II data. KRAKOW, Poland, March 13, 2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small-molecule therapies that address emerging targets in oncology, summarizes its 2023 fiscal year and provides a corporate update. Pawel Przewiezlikowski, co-founder, largest shareholder, and Chief Executive Officer of Ryvu Therapeutics, said: - In 2023, we made significant progress in all key business areas and look forward to multiple catalysts in 2024. We have already started two Phase II studies of RVU120, and around mid-year, we plan to launch two more Phase II studies in hematology. By the end of the year, we plan to enroll more than 100 patients across these clinical trials. We also plan to launch a new Phase II study of MEN1703 (SEL24) in DLBCL, which is being developed under a license agreement with the Menarini Group. Study start-up activities for new trials of both RVU120 and MEN1703 are proceeding quickly. Krzysztof Brzozka, Ph.D., Executive Vice President, and Chief Scientific Officer, said: - We are pleased with the significant progress made in our early-phase projects. Among the most advanced projects from our synthetic lethality platform – PRMT5 and WRN – we plan to identify a clinical candidate in 2024. We are also seeing progress in the programs being developed by our partners – particularly BioNTech and Exelixis. We were excited to achieve the second milestone in the Exelixis collaboration, and we look forward to presenting data on our synthetic lethality assets and novel platform at AACR. 2023 SUMMARY AND RECENT CORPORATE EVENTS RVU120 clinical development plan In 2023 Ryvu prepared for the launch of two Phase II RVU120 trials, which then initiated in early 2024: 1) RVU120 as monotherapy in genetically defined cohorts of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS, RIVER-52 study), and 2) RVU120 in combination with venetoclax for patients with relapsed/ refractory AML (RIVER-81 study). Ryvu will financially support the REMARK study's Phase II clinical trial of RVU120 in patients with low-risk myelodysplastic syndromes (LR-MDS). REMARK will be conducted as an investigator-initiated study through the EMSCO network, with Prof. Uwe Platzbecker, a globally renowned expert in the field of LR-MDS, as the Coordinating Principal Investigator. Start-up activities have already been launched, and patient enrollment will start in mid-2024. Study start-up is also underway for POTAMI-61, a Phase II study evaluating the efficacy of RVU120 in patients with myelofibrosis (MF). Initiation of patient recruitment is scheduled for mid-2024. Translational research on RVU120 in solid tumors will continue, including combination studies, as well as academic collaborations in the areas of medulloblastoma (MB) and sarcoma-related research. The company plans to enroll more than 100 patients across all RVU120 Phase II trials this year and aims to present initial Phase II data by the end of 2024. RVU120's updated clinical development plan includes studies (RIVER-52, RIVER-81, and POTAMI-61) that could lead to three drug approvals between 2026 and 2027. Key data presented during 2023 conferences In 2023, Ryvu Therapeutics presented data from the RVU120 program at several international conferences, including EHA 2023, ESMO 2023, and ASH 2023: RVU120 monotherapy demonstrated clinical activity in a Phase Ib study in which 50% of evaluable patients with r/r AML or HR-MDS achieved clinical benefit, including a complete response, morphologically leukemia-free status, clinically significant reduction of blasts including reductions that allowed bridging to a bone marrow transplantation, two-year disease stabilization, hematologic improvements, as well as reduction in bone marrow fibrosis. In particular, early signs of efficacy were observed in patients with an NPM1 mutation, DNMT3a mutation, and HR-MDS. The recommended Phase II dose (RP2D) of 250 mg was found to be safe and well-tolerated, achieving RVU120 concentrations in the pharmacologically active range, with a level of target inhibition between 50% and 70%. This level of target inhibition is expected to result in therapeutic efficacy in selected patients or in combinations with synergistic therapies. RVU120 is emerging as a potential candidate in the first-line treatment of AML, supported by its activity against leukemic stem cells. RVU120 acts synergistically with venetoclax in both sensitive and venetoclax-resistant models. At the ENA conference in October 2023, Ryvu presented preclinical data for PRMT5 and the synthetic lethality platform, and Ryvu's partner – Menarini Group, presented preclinical data for MEN1703 in advanced diffuse large B-cell lymphoma (DLBCL). Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors with outstanding drug-like physicochemical properties and the ability to block methyltransferase activity of PRMT5 with nanomolar concentrations and bioavailable upon oral administration. The novel, optimized inhibitors exhibit a significantly improved pharmacokinetic profile. In addition, the compounds show antitumor efficacy and target engagement in vivo, providing a solid foundation for further development towards clinical trials. MEN1703 (SEL24) has shown promising antitumor activity in translational studies in various types of DLBCL. These data justify the development of MEN1703 in Phase II clinical trials in this indication. Expansion of MEN1703 (SEL24) development by Ryvu's partner – Menarini Group, to include a new Phase II clinical trial in DLBCL. In September 2023, Ryvu announced the Menarini Group's decision to expand the development of MEN1703 (SEL24) by initiating a new Phase II clinical trial in patients with DLBCL. A Phase II study in DLBCL is scheduled to begin in mid-2024. The goal is to evaluate the activity of MEN1703 (SEL24) as monotherapy and in combination with standard therapy in patients with DLBCL. The study will be initiated based on the potent activity of MEN1703 (SEL24) observed in preclinical lymphoma models. Clinical trials have confirmed the acceptable safety profile and early signs of activity of MEN1703 (SEL24) as a monotherapy. Based on the available data, further program development will continue in patients with DLBCL and potentially in additional indications. Recent financial events On February 3, 2024, Ryvu received notice that the second financial milestone was achieved under the collaboration agreement with Exelixis, resulting in a $2M payment to Ryvu. Ryvu and Exelixis are working under a research collaboration and license agreement to develop antibody-drug conjugates (ADCs) with Ryvu's portfolio of STING agonists. On March 5, 2024, Ryvu received notice from the European Investment Bank (EIB) that it had met the conditions for disbursement of the first venture debt tranche of €8M. These funds are not yet included in the cash balance reported in this press release, but Ryvu expects to receive the funds on March 13, 2024. As part of the agreement announced in August 2022, Ryvu still has access to an additional €14M in venture debt from the EIB. UPCOMING EVENTS Ryvu will attend the AACR Annual Meeting (San Diego, USA) from April 5-10, 2024, to present preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24). 2023 Fiscal Year Financial Update [1] Cash Position – On December 31, 2023, Ryvu Therapeutics held $63.7M in cash, cash equivalents, and bonds, compared to $23.2M at the end of 2022. On March 7, 2024, Ryvu Therapeutics held $57.2M in cash, cash equivalents, and bonds, which excludes €8M in venture debt from the EIB to be received imminently. Operating Revenues – In 2023, Ryvu recognized total operating revenues (including grants) of $16.3M, compared to 2022, when the total operating revenue amounted to $15.8M. Operating costs, excluding the non-cash cost of valuation of the Incentive Program ($2.0M) and valuation of NodThera shares ($0.9M) in the full year 2023, amounted to $37.6M, representing an increase compared to $26.4M in the previous year. Net Loss Attributable to Common Shareholders – In 2023, the net loss attributable to common shareholders, excluding the non-cash cost of valuation of the Incentive Program, amounted to $20.0M, compared to $13.8M in the previous year. About Ryvu Therapeutics Ryvu Therapeutics is a clinical-stage drug discovery and development company focused on novel small-molecule therapies that address emerging targets in oncology. Internally discovered pipeline candidates use diverse therapeutic mechanisms driven by emerging knowledge of cancer biology, including small molecules directed at kinase, synthetic lethality, and immuno-oncology targets. Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics has signed multiple partnering and licensing deals with global companies, including BioNTech and Exelixis. The Company was founded in 2007 and is headquartered in Kraków, Poland. Ryvu is listed on the Warsaw Stock Exchange and is a component of the mWIG40 index. For more information, please see . [1] USD figures are provided at a conversion rate of: for the period from 01/01/2023 – 31/12/2023: PLN 4.1823; for the period from 01/01/2022 – 31/12/2022: PLN 4.4679; as of 7/03/2024: PLN 3.9485 as of 31/12/2023: PLN 3.9350 as of 31/12/2022: PLN 4.4018 SOURCE Ryvu Therapeutics

Updated preclinical data will be presented from Ryvu's synthetic lethality pipeline, including PRMT5 inhibitors in MTAP-Deficient cancers, WRN inhibitors for the treatment of microsatellite unstable (MSI-H) tumors, and Ryvu's cutting-edge synthetic lethality platform based on primary cancer cells. Poster presentation to highlight the synergistic effects of RVU120 in combination with ruxolitinib in myeloproliferative neoplasms. Ryvu's partner Menarini to present data on MEN1703 (SEL24), demonstrating promising anti-tumor activity in preclinical models of myelofibrosis both as a single agent and combined with ruxolitinib. KRAKOW, Poland, March 6, 2024 /PRNewswire/ -- Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, announced today that preclinical data from its synthetic lethality pipeline and RVU120 project, as well as on MEN1703 (SEL24), will be presented at the upcoming 2024 AACR Annual Meeting, scheduled for April 5-10 in San Diego, California. "We are excited to present our latest preclinical data at the AACR Annual Meeting, showcasing our significant progress in advancing novel small molecule therapies for oncology. This year, we will present data from our most advanced preclinical project on MTA-cooperative PRMT5 inhibitors, the lead program within Ryvu's synthetic lethality pipeline. Our PRMT5 inhibitors have demonstrated remarkable efficacy and selectivity in preclinical models of tumors with MTAP gene deletion, providing a strong foundation for further development," said Krzysztof Brzózka, Ph.D., Chief Scientific Officer of Ryvu Therapeutics. "Our discovery platform continues to produce novel precision medicine targets and drugs, and we are proud to highlight platform data based on primary cancer cells, specifically in colorectal cancer models with broader applicability across cancers. " Details on the poster presentations are as follows: Abstract Title: "Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers." Session Name: HDAC and Methyltransferase Inhibitors Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4598 Co-deletion of MTAP is observed in approximately 80-90% of tumors with homozygous deletion of CDKN2A, representing 10-15% of all human tumors. These tumor types, including non-small cell lung cancer, pancreatic adenocarcinoma, glioblastoma, and mesothelioma, have a poor prognosis, highlighting the significant unmet medical need in this area. Deletion of MTAP leads to a significant accumulation of methylthioadenosine (MTA) in cells. MTA, at high concentrations, selectively inhibits the PRMT5 methyltransferase enzyme. As a result, the overall level of symmetric arginine dimethylation throughout the proteome is reduced, which makes cells with MTAP deletion more susceptible to therapeutic targeting of PRMT5. Ryvu has developed potentially best-in-class MTA-cooperative PRMT5 inhibitors showing favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding. Structure-based lead optimization has enabled rapid expansion and delivery of two independent chemical series with novel intellectual property, characterized by high target engagement in cells, and selective potency in MTAP-deleted cell lines, along with favorable DMPK profiles allowing an oral administration. The antitumor activities were compared in vitro and in vivo in MTAP null tumors. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Performed studies confirm that MTA-cooperative PRMT5 inhibitors exert a strong synthetic lethal phenotype in MTAP-deleted cancers, offering an exciting therapeutic opportunity for a large patient population. Abstract Title: "A comprehensive platform for identification of KRAS-specific synthetic lethal targets using patient-derived cells." Session Name: New Targets, Technologies, and Drug Delivery Systems Session date and time: Tuesday, April 9, 9:00 AM - 12:30 PM EST Poster Number: 4684 Ryvu's cutting-edge drug discovery platform uniquely combines high throughput capabilities with the precision and translational impact traditionally associated with later, lower throughput stages. Our approach taps into the power of primary cells to transform cancer treatment, focusing especially on colorectal cancer (CRC). By leveraging human stem cell derived model cells (PDC), patient-derived xenografts (PDXs) and clinical samples we have created a groundbreaking approach to identify synthetic lethal (SL) targets specific to oncogenic pathways. We integrate CRISPR/Cas9 technology, phenotypic screening, RNA-seq, and whole-exome sequencing (WES), enabling rapid identification of molecular vulnerabilities. We present results obtained in engineered intestinal primary models which represent frequently altered genes in CRC, including KRAS G12D mutation. Notably, our use of normal hISCs facilitates the identification of genes essential only for transformed cells, amplifying the precision tumor targeting of our novel discoveries. Beyond CRC, our platform could extend to personalized medicine approaches in various cancer types. By spearheading the identification of KRAS-specific SL inhibitors, we pave the way for novel, targeted therapies, offering hope to patients battling this heterogeneous malignancy and beyond. Abstract Title: "Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors." Session Name: Novel Antitumor Agents 4 Session date and time: Tuesday, April 9, 1:30 PM – 05:00 PM EST Poster Number: 5942 The synthetic lethality resulting from the inhibition of the WRN helicase protein has been observed in tumors characterized by high levels of microsatellite instability (MSI-H). This instability stems from a deficiency in the DNA mismatch repair (MMR) mechanisms, leading to the accumulation of DNA damage. This phenomenon is notably prevalent in 10-30% of colorectal, gastric, endometrial, and ovarian cancers. Structure-based optimization performed at Ryvu facilitated the rapid expansion and delivery of a compound library with novel intellectual property (IP), demonstrating target engagement in cells and selective potency over other RecQ family members. The pharmacokinetic properties of these compounds were favorable and allowed progressing to in vivo studies which confirmed efficacy of our compounds in xenograft MSI-H cancer models. These data provide pharmacological proof-of-concept for the synthetic lethal effect of our inhibitors and support WRN inhibition as a new, targeted oncological therapy. Abstract Title: "Combination JAK1/2 and CDK8/19 inhibition demonstrates enhanced efficacy in myeloproliferative neoplasms." Session Name: Targeted, Combination, and Differentiation Therapies Session date and time: Wednesday, April 10, 9:00 AM - 12:30 PM EST Poster Number: 7225 The presentation, prepared in collaboration with Prof. Raajit Rampal's group from Memorial Sloan Kettering Cancer Center, includes the assessment of RVU120, a highly selective and potent CDK8/19 inhibitor, both in monotherapy and combination with ruxolitinib (RUX), a JAK1/2 inhibitor, for the treatment of myeloproliferative neoplasms (MPN) and hydroxyurea-resistant/intolerant polycythemia vera (PV). The combination of RVU120 and RUX demonstrated biochemical synergy and differential inhibition of STAT5 phosphorylation in vitro. Further, in vivo treatment with RVU120/RUX+RVU120 resulted in significant reductions in disease manifestation (splenomegaly, WBC, fibrosis scoring, hematopoiesis) compared to VEH/RUX. These data suggest that JAK1/2 and CDK8/19 inhibition could be a potential novel therapeutic strategy in MPNs. Additional work on nascent RNA expression and cytokine profiles aims at elucidating the exact mechanism of synergy between tested compounds. Abstract Title: "MEN1703/SEL24 exhibits promising antitumoral activity in preclinical models of myelofibrosis both as single agent and combined with ruxolitinib." Session Name: Novel Antitumor Agents 2 Session date and time: Sunday April 7, 01:30 AM – 0500 PM EST Poster Number: 665 MEN1703 (SEL24) is an oral, first-in-class, dual PIM/FLT3 kinase inhibitor in development for hematologic malignancies. The presented study aims to investigate the efficacy of MEN1703 alone and in combination with the JAK inhibitor ruxolitinib (RUX) in preclinical models of myelofibrosis (MF) and to elucidate the underlying signaling pathways. MEN1703 demonstrated anti-tumoral efficacy in MF preclinical models, exhibiting in vitro activity at clinically relevant concentrations. Importantly, the combination of MEN1703 with the standard of care, RUX, exhibited synergistic effects, and molecular analyses confirmed the inhibition of downstream targets of PIM. The results support the therapeutic potential and relevance of MEN1703 in the treatment strategies for myelofibrosis. All abstracts are now available online and can be obtained from the conference site: About Ryvu Therapeutics Ryvu Therapeutics is a clinical-stage drug discovery and development company focused on novel small-molecule therapies that address emerging targets in oncology. Internally discovered pipeline candidates use diverse therapeutic mechanisms driven by emerging knowledge of cancer biology, including small molecules directed at kinase, synthetic lethality, and immuno-oncology targets. Ryvu's most advanced programs include RVU120, a selective CDK8/CDK19 kinase inhibitor with the potential to treat hematological malignancies and solid tumors, currently in Phase II development (i) as a monotherapy for the treatment of patients with relapsed/refractory acute myeloid leukemia (r/r AML) and high-risk myelodysplastic syndromes (HR-MDS) as well as (ii) in combination with venetoclax for the treatment of patients with r/r AML. Another clinical program, SEL24 (MEN1703), is a dual PIM/FLT3 kinase inhibitor licensed to the Menarini Group. Ryvu Therapeutics has signed multiple partnering and licensing deals with global companies, including BioNTech and Exelixis. The Company was founded in 2007 and is headquartered in Kraków, Poland. Ryvu is listed on the Warsaw Stock Exchange and is a component of the mWIG40 index. For more information, please see . SOURCE Ryvu Therapeutics