On March 13, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small-molecule therapies that address emerging targets in oncology, reported its 2023 fiscal year and provides a corporate update (Press release, Ryvu Therapeutics, MAR 13, 2024, View Source [SID1234641124]).

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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 (Free AACR Whitepaper).

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 (Free EHA Whitepaper) 2023, ESMO (Free ESMO Whitepaper) 2023, and ASH (Free ASH Whitepaper) 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 (Free AACR Whitepaper) 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.