Slides
Page 1
Developing therapeutics at the forefront of oncology RVU120 Phase II Program: Progress and Data Update December 12, 2024 (Data updated with a cutoff of December 11)
Page 2
2 Note on the presentation and forward-looking statements This document does not constitute a public offering in the meaning of the Regulation (EU) 2017/1129 of the European Parliament and of the Council, or any other offer or invitation to acquire any Company's securities, nor the incentive to submit bids for the acquisition orsubscription of the Company's securities. This document does not constitute information about the Company's securities and the terms and conditions of their acquisition or offering sufficient grounds to decide whether to purchase or acquire such securities. In particular, the document does not constitute an offer ofsecurities for sale in the United States, nor may the securities be offered or sold in the United States absent registration under the Securities Act or in reliance upon an available exemption from the registration requirements of the U.S. Securities Act and in compliance with applicable state securities laws. The forward-looking statements contained in this document, such as those relating to the Company's income, results or development in particular in connection with the clinical development of company's projects, are based on a number of assumptions, expectations and projections, and are subject to uncertainty and may change as a result of external or internal factors and should not be treated as binding forecasts. Neither the Company nor the persons acting on its behalf, in particular the members of the Company's Management Board, the Company's advisers nor any other person, provide any assurance that future expectations will be fulfilled, and in particular do not guarantee the future results or events of such statements and that the future results of the Company will not differ materially from the forward-looking statements. The information in this document is subject to change. Neither the Company nor any other person is obligated to update them.
Page 3
AGENDA RVU120 program overview RIVER-52 RIVER-81 POTAMI-61 REMARK RVU120 outlook RVU120 PHASE II studies progress and data update Chief Executive Officer PAWEŁ PRZEWIĘŹLIKOWSKI HENDRIK NOGAI KAMIL SITARZ Chief Medical Officer Chief Operating Officer
Page 4
4 DISCOVERY PLATFORMFIRST-IN-CLASS CLINICAL PIPELINE RVU120 • First-in-class dual PIM/FLT3 kinase inhibitor in Phase II; DLBCL study to initiate with potential across hematology • Partnered with Menarini Group MEN1703 FULLY INTEGRATED RESEARCH & DEVELOPMENT ORGANIZATION • LISTING: WSE:RVU (mWIG40 index); cash runway to Q1 2026 • TEAM: >300 employees, including ~185 scientists (with ~100 PhDs) • SITE: Fully-owned, state-of-the-art 108,000 sq ft facility • First-in-class, oral CDK8/19 inhibitor • Four Ph II studies ongoing: mono and combo in AML/HR-MDS, LR-MDS, and MF • RVU305: best-in-class oral MTA-cooperative PRMT5 inhibitor in IND/CTA-enabling studies • WRN program • Novel SL targets SYNTHETIC LETHALITY IMMUNO-ONCOLOGY • BioNTech: STING standalone license and multi-target research collaboration • Exelixis: STING ADC collaboration Fully-owned Partnered Fully-owned Partnered Ryvu is developing novel therapies to address high-value emerging targets and pathways in oncology
Page 5
5 SYNTHETIC LETHALITY RVU305 (PRMT5) SOLID TUMORS IND/CTA submission in 2H25 WRN SOLID TUMORS In lead optimization NOVEL TARGETS ONCOLOGY IMMUNO-ONCOLOGY STING & MULTI-TARGET IMMUNE MODULATION COLLABORATION ONCOLOGY STING ADC ONCOLOGY PROGRAM INDICATION DISCOVERY PRECLINICAL PHASE I PHASE II PARTNER EXPECTED MILESTONES RVU120 (CDK8/19) R/R AML/HR-MDS (RIVER-52) (monotheraphy) Updated Ph II data in 2Q25 R/R AML (RIVER-81) (combo with venetoclax) Q Updated Ph II data in 2Q25 LR-MDS (REMARK) (monotherapy) Initial Ph II data in 2Q25 Myelofibrosis (POTAMI-61) (mono and combo with ruxolitinib) Initial Ph II data in 2Q25 Solid Tumors (AMNYS-51) Complete Ph I data & translational studies in 2024 MEN1703 (SEL24) (PIM/FLT3) DLBCL (mono and combo with glofitamab) Initiation of Ph II in 4Q24 Study start-up Broad pipeline addressing emerging targets in oncology
Page 6
6 RVU120 is an innovative dual CDK8/19 inhibitor designed to target the expression of genes crucial for cancer cell survival and differentiation RVU120 is a clinical-stage, first-in-class, small molecule CDK8/19 kinase inhibitor developed and fully-owned by Ryvu high selectivity low risk of DDI (esp antifungals) easy to formulate orally bioavailable favorable safety profile
Page 7
7 RVU120 development plan is focused on hematological malignancies Four Phase II studies ongoing RVU120: opportunities across a broad range of cancers AML High-risk MDS Low-risk MDS Myelofibrosis (MF) MDS/MPN overlap syndrome NHL Diamond-Blackfan Anemia Breast Sarcoma Medulloblastoma ACC ▪ Translational evidence in multiple tumor types, additional potential in combinations ▪ Single agent and combination potential across several solid tumors Blood Cancers & Disorders Solid Tumors • Signs of clinical activity in AML/HR-MDS • Broad potential across hematologic disorders • Responder hypothesis in AML – unmet need with no approved therapies • Synergy with standard-of-care in AML and MF • Next expected clinical data release – Q2 2025
Page 8
8 RVU120 Phase II development plan rationale: RIVER-51 clinical data 15 of 30 evaluable patients showed clinical benefit across dose levels Clinical benefits Favorable safety profile Target engagement levels between 50-70% at a dose of 250 mg – selected for Phase II development • 30 treated patients are evaluable for response (38 were treated in total) • 9 patients achieved clinically significant BM blast reduction • (including 1 CR, 1 MLFS, 3 marrow CRs) • 5 patients achieved erythroid hematological improvement (HI-E), 4 of those became transfusion-independent, of which 2 normalized also their Grade 3 thrombocytopenia NPM1 and DNMT3A mutations • An NPM1 mutation was identified in 2 pts – one patient achieved a CR, the other experienced an unrelated SAE in cycle 2 and progressed • Three additional patients had a DNMT3A mutation without NPM1 mutation and achieved significant blast reductions, long-term disease control, or hematologic improvement • 4 pts with HR-MDS treated were failing 1-5 prior lines of treatment • 3 of these pts had >10 % blasts at baseline, all of them met the Cheson criterion of marrow CR during treatment with RVU120 HR-MDS
Page 9
9 Data generated in RIVER-51 study support further development of RVU120 in AML, HR-MDS, LR-MDS and MF • Confirmed CR in NPM1/DNMT3A AML patient • Several patients with significant blast reduction • >20% patients, (all with AML-MR or HR-MDS), showed hematological improvement, meeting Cheson criteria for erythroid response • Signs of activity in secondary AML - reduction of fibrosis and hematologic impr. • Supported by non-clinical data in MF/MDS models P106-004 AML -MR • Mutations: GATA2, RUNX1, SF3B1,TET2, WT1 • Karyotype: 47,XY,+21; 3 prior treatment lines • 9U RBC/8 weeks; grade 4 Thrombocytopenia P108-002 HR-MDS • Mutations: MPL, DNMT3A, U2AF1 • Karyotype: 46XY, add (4)(q21); 1 prior treatment line • Best response: marrow CR P103-002 AML • NPM1, DNMT3A, FLT3-ITD.,NRAS • 46,XX, 3 prior treatment lines • 6U RBC/3 weeks and 6U Plts/4 weeks CR achieved end of C1 with persistent skin leukemia, resolved in C5 RBC-TI and Plt-TI on RVU120 treatment Reduction of fibrosis grade and marrow CR Significant blast reductions Transfusion independence Improvement of BM architecture C2D13 fibrosis grade 3 C6D1 fibrosis grade 2
Page 10
10 2024 2025 2026 2027 2028 I II III IV I II III IV I II III IV I II III IV I II III IV Phase II studies in hematologic malignancies • RIVER-52: AML/HR-MDS, monotherapy • RIVER-81: AML, combination with venetoclax • POTAMI-61: myelofibrosis (MF), monotherapy/combination with ruxolitinib • REMARK: LR-MDS, monotherapy, investigator-initiated trial (IIT) Current clinical development of RVU120 focuses on single agent trials in patients with AML, MDS, and MF and combinations in AML and MF Ph II Part 1 Ph II Part 1 Ph II Part 2 Ph II Parts 2 and 3 Ph II Phase III (potential for 1L) Phase III (potential for 1L) Approval process in selected regions Ph II Part 2 Ph II Part 1 Ph II Part 2 Phase III (potential for 1L) Beyond 2028
Page 11
11 1 4 9 14 16 20 23 25 28 42 66 78 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec(e) Total number of patients enrolled in all RVU120 Phase II clinical studies • RIVER-81: FPI in Jan’24 • RIVER-52: FPI in Feb’24 • REMARK: FPI in Sep’24 • POTAMI-61: FPI in Dec’24 Active enrollment in all four Phase II studies Expected number of patients enrolled in Q4 almost 3x higher than in Q1-Q3 combined 99(1) 2024 28 21 21 84 13 34 84 21 42 0 50 100 150 200 250 300 350 REMARK POTAMI-61 RIVER-81 RIVER-52 Screening First evaluation Second evaluation Time needed for screening and evaluating patients (days) Each next evaluation 42 42 84 RIVER-52 RIVER-81 POTAMI-61 REMARK IIT study with limited ongoing access of Ryvu to clinical results RVU120 Phase II studies progress and data update Summary of enrollment Note: Responses to targeted agents can occur up to 6 months after start of treatment 42 42 42 42 42 42 42 84 42 42 42 42 42 42 42 42 84 (1) expected as of December 31, 2024
Page 12
12 RVU120 Phase II studies progress and data update Summary of site activations 150% increase in the number of activated sites from Sep to Dec 2024(1) 32 28 20 2 22 2 Clinical program with a global footprint enabling accelerated enrollment 3 7 10 16 24 32 40 45 63 86 102 106 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec(e) 113(1) Total number of sites activated in all RVU120 Phase II clinical studies 2024 (1) expected as of December 31, 2024
Page 13
13 RVU120 Phase II studies progress and data update Studies summary RIVER-52 • 1 of 2 evaluable NPM1+ pts with 50% blast reduction • Disease stabilizations and reductions of peripheral blasts observed in DNMT3A+ pts • Data from the first 10+ evaluable patients in Cohorts 2-4 expected in Q1 2025 RIVER-81 REMARK • FPI on September 18, 2024; study in progress • First efficacy data expected in Q2 2025 First signs of efficacy in Phase II; number of evaluable patients expected to increase in H1 2025 (1) Estimated enrollment for December 31, 2024 Increasing enrollment from Q4 2024 Good enrollment and first data Promising start of enrollment • Dose escalation completed with tolerable safety for the full combination doses • 1 complete remission (CR) in a difficult to treat ven-refractory population, eight patients at RVU120 250 mg had at least one evaluable post-baseline assessment • Part 2 initiated; further development decision in H1 2025 POTAMI-61 • FPI on December 4, 2024; study in progress • First efficacy data expected in Q2 2025 Robust enrollment expected
Page 14
14 Initial combo opportunity in r/r AML could expand into a significantly larger opportunity in front-line AML Relapsed/ Refractory AML Newly Diagnosed AML (Unfit) Newly diagnosed AML cases US, 20301 RVU120 Path to Market US Market Opportunity 20k • Strong Phase II combo data could support a Phase III registration study with approval as early as 2029 • A first-line doublet or triplet could be an efficacious and safe alternative to ven+aza and triplet combos for patients unfit/ineligible for intensive chemo Patients ineligible for intensive induction US, 20302 12k Total US market size: 1L ineligible2 $1.2B+ High unmet medical need in patients failing first-line ven: nearly all ven patients relapse or become refractory with few treatment options Unfit venetoclax patients progressing to 2L US, 20302 4k Total US market size: 2L ineligible2 $400M+ (1) PharmaIntelligence, AML Epi Datapack, July 2023. (2) Datamonitor AML Patient-based Forecast Model, Dec 2024. 2L and 3L NPM1/DNMT3A patients US, 20302 2k Total US market size: 3L2 $200M+ Development of RVU120 towards earlier lines of therapy RIVER-52 RIVER-81 Patients with AML harboring NPM1/DNMT3A mutations have few options in second- or third-line after failing menin inhibitors, chemo, ven and other treatment Mutation- driven Venetoclax- refractory Commercial Opportunity for RVU120 in AML
Page 15
RIVER-52 RVU120 monotherapy in r/r AML and HR-MDS patients Phase II
Page 16
16 • Differential efficacy of RVU120 in AML models: • In vitro screening of AML patient-derived cells revealed differential efficacy of RVU120 and other CDK8 inhibitors in NPM1 and/or DNMT3A mutants • RVU120 as monotherapy demonstrated high efficacy in NPM1 or DNMT3A- mutated patient-derived xenografts • Transcriptomic profiling provides mechanistic rationale: Transcriptomic profiling indicated RVU120 represses MEIS1/HOXA/B gene expression programs, highly enriched in AML positive for NPM1 and DNMT3A mutations • Clinical Activity in Phase I: One of two NPM1 mutant patients recruited in Phase I achieved complete remission (CR); transcriptomic profiling demonstrated repression of MEIS1/HOXA/B genes, consistent with nonclinical findings PDC 30%0 5 10 15 20Samples DNMT3A & NPM1 NPM1 DNMT3A Other OHSU, Nature 2018 AML patients n=531 RIVER-52 Nonclinical Results and Signals of RVU120 Efficacy from Phase 1 (RIVER-51) Provide Rationale for Phase 2 study in NPM1 and DNMT3A Mutant Patients
Page 17
17 Results from the ongoing Part 1 will determine potential launch of Part 2 RIVER-52 • Primary endpoints: ― Rate of CR, CRh, CRi, with and without MRD, and DoR • Secondary endpoints: ― Transfusion independence, Progression-free survival, Relapse-free survival (RFS), Overall survival • For Part 2: including PRO and HRQoL change from baseline • Population: relapsed/ refractory AML or HR-MDS with no alternative treatment • Estimated enrollment: ~40-140 patients • Up to 80 clinical sites planned globally STUDY DESIGN PART 1 (N = ~40 pts) PART 2 (N = ~100 pts) Genetically defined and disease specific cohorts: • Pts with NPM1-mutated AML • Pts with DNMT3a-mutated AML • Pts with HR-MDS Clinical Benefit (CR/CRh/CRi/HI) in any of the cohorts Confirmatory Cohort Simon 2-stage design Pts selected based on Part 1 outcome RVU120 monotherapy Phase II study with RVU120 as a single agent in AML/HR-MDS
Page 18
18 S Swimmer Plot : 14 ongoing patients out of 30 enrolled overallRIVER-52 Data Cut-off: December 10, Preliminary data No new safety signal was identified Systemic exposure of RVU120 following oral dosing of 250 mg QOD was confirmed to be consistent with previous studies Data is immature for the interpretation of efficacy Reasons for study discontinuation: Adverse event Death (unrelated to study drug) Disease progression Patient withdrawal of consent Patient status Ongoing at data cut-off Response Blast reduction no response not evaluable
Page 19
19 Agent (#pts) Revumenib (N=94) Ziftomenib (N=83) RVU120 (N=20) Trial Phase 1/2 (AUGMENT-101) Phase 1/1b (KOMET-001) Phase 2 (RIVER-52) Company Syndax Kura Ryvu DLT Ph 1 QTc Pr Gr 3 Pneumonia Gr 4/5 DS No DS (all) 26 (28%) 12 (15%) 0 (0%) DS (≥ Gr3) 15 (16%) 10 (12%) 0 (0%) Neutropenia (≥ Gr3) 27 (29%) 7 (8%) 2 (10%) Febrile Neutropenia (≥ Gr3) 36 (38%) 18 (22%) 3 (15%) Thrombocytopenia(≥ Gr3) 20 (21%) 5 (6%) 3 (15%) Anemia 22 (21%) 20 (24%) 2 (10%) QTc prolongation (any) 24 (25%) 0 (0%) 1 (5%) QTc prolongation (≥ Gr3) 13 (14%) 0 (0%) 0 (0%) Transaminitis 27 (29%) 16 (19%) 1 (5%) Sepsis 11 (12%) 15 (18%) 1 (5%) RIVER-52 RVU120 appears to have a good safety profile, with the notable absence of QTc prolongation and differentiation syndrome Data cut-off 01 Nov 2024
Page 20
20 • 59yo Female, ECOG 1 • Comorbidities: degenerative spine disease with musculoskeletal and connective tissue disorders • AML with NPM1 mutation, May 2022 • Previous treatment: cladribine, daunorubicin, cytarabine (May-Sep 2022): CR • 4 completed cycles of RVU120 • SAEs Anemia/Fatigue Patient history C1D1 C2D13 C4D13 EoT 0 10 20 30 40 50 BM blasts central and local [%] 4.5% 17% 33.5% 43% 18% 9% Central Cytomorphology Central Flow Cytometry Local Cytomorphology NGS C1D1 15-May-2024 EoT 12-Sep-2024 C01D01 C01D13 C02D01 C02D13 C03D01 C03D13 C04D01 C04D13 EoT 0 1 2 10 20 30 40 WBC, ANC, PLTS [x109/L] Hgb [g/dL] WBC ANC PLT Hgb [g/dL] Hematology Bone Marrow WT1.1 – c.1110dup; WT1.2 – c.1249+2T>C; PTPN11.1 – c.766_768delinsAGGGTG; PTPN11.2 – c.854T>C An initial reduction of blasts of > 50% could be detected in this patient that has a highly heterogenic disease RIVER-52 Patient 524809-01 – Cohort 2 (NPM1+)
Page 21
21 The patients are ongoing on RVU120, and the treatment outcome has still to be assessed at later time points RIVER-52 Although not meeting objective response criteria, preliminary data in additional patients showed reduction of blasts with multiple patients ongoing Patients with DNMT3A mutated AML Patient with HR-MDS
Page 22
22 RIVER-52 31 patients enrolled, and 42 sites activated (as of Dec 11, 2024) PART1 Cohort 1 (AML WT) • Discontinued, data used to strengthen RVU120 safety database Cohort 2 (AML NPM1+) • Enrollment improved after initiation of new sites in Spain and France in Q4 2024 Cohort 3 (AML DNMT3A+) • Enrollment in line with the expectations Cohort 4 (HR-MDS) • Enrollment in line with the expectations • 42 out of 44 sites planned for this year have already been activated • Data from the first 10+ patients in Cohorts 3-4 (DNMT3A+, HR-MDS) are expected in Q1 2025 • Data from the first 10+ patients in Cohort 2 (NPM1+) are expected in Q22025 1 5 9 10 11 12 13 13 18 29 37 1 3 5 9 11 12 14 16 20 33 39 44 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec(e) Patients enrolled Sites activated 3 new NPM1+ pts 2024 Enrollment increasing with the activation of new sites, to yield preliminary data in H1 2025 (1) expected as of December 31, 2024 (1)
Page 23
23 RIVER-52 Summary PART 1 Cohort 2 AML NPM1+ Cohort 3 AML DNMT3A+ Cohort 4 HR-MDS N≤20 N≤20 N≤20 If observed CR rate ≥20% and/or evidence of anti-tumor or clinical activity PART 2: Simon 2-stage design Stage 1 N≤49 Stage 2 N≤45 If ≥4 CR Dose optimization (optional) N≤20 Phase II study with RVU120 as a single agent in AML/HR-MDS • The available patient data are still immature for evaluation of efficacy • 1 of 2 evaluable patients in Cohort 2 (AML NPM1+) with 50% blast reduction • Significantly improved enrollment in Cohort 2 from Q4 2024 • Preliminary data expected in H1 2025 Study/risk management
Page 24
RIVER-81 RVU120 combination with VEN in patients with r/r AML Phase II
Page 25
25 RVU120 + VENAZA + VEN MV4-11 RIVER-81 Strong nonclinical evidence for synergy between RVU120 and venetoclax providing rationale for a Phase II study in venetoclax refractory patients • True Synergy and Superiority: • RVU120 + ven demonstrates synergy across multiple AML cell lines and superiority over ven + aza • Remissions in Animal Studies: • RVU120 + ven achieves remissions in animal models at doses that allow hematological recovery • Mechanism of Synergy: • MCL-1 is a known mediator of ven resistance. RVU120 induces caspase-dependent degradation of MCL-1 • MCL-1 inhibitors were tested in this setting, but prohibitive cardiotoxicity prevented further development • The safety profile of RVU120 allows exploration of this concept • Effectiveness on Leukemic Stem Cells (LSCs)
Page 26
26 RVU120 + venetoclax • Primary endpoints: ― Rate of CR, CRh, CRi, with and without MRD, and DoR • Secondary endpoints: Transfusion independence, PFS, RFS, OS • For Part 2: including PRO and HRQoL change from baseline • Population: r/r ven-failed AML, no alternative treatments • Estimated enrollment: ~35-97 patients(1) • Up to 50 clinical sites planned globally STUDY DESIGN RIVER-81 RIVER-81 is supported in part by a €13.3M grant from the Polish Medical Research Agency (ABM) PART 1 (N = 17 pts) PART 2 (N = ~39 pts) Dose finding in patients with r/r AML after failing a venetoclax-based regimen Expansion Cohort at selected doses of RVU120 and venetoclax (Simon 2-stage design + optional enrichment cohort) (1) 35 patients for: Part 1 (N=17 pts) and Stage 1 of Part 2 (N=18 pts); 97 patients for: complete planned enrollment into Parts 1, 2 and 3, including optional additional enrichment cohort. Phase II study testing RVU120 in combination with venetoclax in ven-refractory patients with AML PART 3 (N = ~41 pts) Confirmatory Cohort at doses of RVU120 and venetoclax as in PART 2
Page 27
27 RIVER-81 PART 1 (dose escalation) has been completed, the study is currently enrolling into PART 2 at the highest dose from PART 1 Cohort 1 RVU120 125 mg Ven 200 mg N=5 PART 1: Dose finding Cohort 2 RVU120 250 mg Ven 200 mg N=7 Cohort 3 RVU120 250 mg Ven 400 mg N=5 RVU120 at a dose of 250 mg Stage 1 RVU120 250 mg Ven 400 mg N=18 Enrollment in Part 2 initiated based on the observed safety and the early signs of efficacy of the combination 11 of 18 patients have already been treated in Stage 1 of Part 2 PART 2: Simon 2-stage • Dose escalation successfully completed, no DLT was observed • No altered exposure when dosed in combination with venetoclax • Maximal anticipated RVU120 + ven combination dose (250 mg + 400 mg) achieved • Confirmed potential for RVU120 + ven doublet and possible triplet combinations in the future Clinical Benefit CR, blast reductions Nov 2024 Nov 2024 to Mar 2025
Page 28
28 RIVER-81 Cytomorphological decrease of bone marrow blasts to < 5% on C1D13 Decrease of bone marrow blasts from 20% to 9% in flow cytometry on C2D13 Eight patients treated with RVU120 at a dose of 250 mg (RP2D) had at least one evaluable post-baseline assessment One patient achieved a CR in a difficult to treat ven-refractory population Data Cut-off: December 10, Preliminary data
Page 29
29 C1D1 04-Jul-2024 EoS 10-Oct-2024RIVER-81 Patient 813405-01 – Cohort 2 (RVU120 250 mg + Ven 200 mg) Patient history Bone Marrow • 82yo Female, ECOG 2 (C2D1) • AML with myelodysplasia-related changes Oct-2022 • Previous treatment: venetoclax plus azacitidine (Oct-2022 to Mar-2024) • C1D1: 4-Jul-2024 • 250 mg RVU120 + 200 mg Ven • CR declared on C3D7 (27-Aug-2024); last drug administration on 2-Sep-2024; patient withdrew consent on 10-Oct-2024 C1D1 C2D13 unsch 30Sep 0 5 10 15 BM blasts central and local [%] 2% 11% 2% 7% 2% Central Cytomorphology Central Flow Cytometry Local Cytomorphology 0% NGS Hematology DNMT3A_17 – c.2063G>A ; DNMT3A_9 – c.1064del; IDH1 – c.394C>G SCREENING C1D1 C1D2 C1D3 C1D4 C1D5 C1D6 C1D7 C1D13 C1D14 C1D17 C2D1 C2D7 C2D13 C2D25 C3D7 C3D13 C3D24 C3D30 0 20 50 100 150 200 WBC, ANC, Mon,Lym, Blasts, PLTS [x109/L] Hgb [g/dL] 0.760 0.07 10.9 10 96.000 187.000 0.310 1.890 9.2 25.000 10.7 2.360 1.790 CRi CR C3D7-9 missed doses CRi C2D8- C2D26 drug interrupted for neutropenia C1D10-12 missed doses
Page 30
30 TIER MUTATION % VAF TIER 1 ASXL1 c.1913_1914del 36% U2AF1 c.470A>C 35% CUX1 c.2983C>T 9% STAG2 c.3277+1G>C 8% TP53 c.814G>A c.524G>A c.577C>T 25% 10% 2% TIER 2 TP53 c.434T>G c.650T>G 6% 5% RIVER-81 Patient 813904-02 – Cohort 3 (RVU120 250 mg + Ven 400 mg) C1D1 30-Oct-2024 Patient history Bone Marrow • 74yo Female, ECOG 1 • Comorbidities: type 2 diabetes mellitus, appedicectomy, tonsillectomy, hysterectomy • AML with myelodysplasia-related on Apr-2023, del5q31 and 17p13 (TP53) • Previous treatment: venetoclax and azacitidine (Apr-2023 to Aug-2024) • C1D1: 30-Oct-2024 • 250 mg RVU120 + 400 mg Ven • Completed 2 cycles of treatment C1D1 C1D13 0 20 40 60 80 100 BM blasts Central Cytomorphology Central Flow Cytometry Local Cytomorphology and Flow Cytometry 6% 3.5% 10% 17% NGS Hematology screening (1 RBC transfused/week) C1D1 C1D2 (RBC transfusion) C1D3 C1D4 C1D5 (RBC transfusion) C1D6 C1D7 C1D13 C1D14 (RBC transfusion) C1D17 (RBC transfusion) 0 20 40 60 80 100 WBC, ANC, Mon,Lym, Blasts, PLTS [x109/L] Hgb [g/dL] 3.880 10 49.000 0 9.4 7.6 4.470 0.09 0.000015 91.000 2.720 2.71 The bone marrow blasts decreased to < 5% on one timepoint, which was assessed as response by the investigator
Page 31
31 RIVER-81 • Dose escalation in Part 1 successfully completed • Enrollment in Part 2 initiated: 11 patients already treated, a total of 18 patients planned for Stage 1 of Part 2 28 patients enrolled, and 33 sites activated (as of Dec 11, 2024) 1 3 4 5 6 9 11 12 13 17 22 35 2 4 5 7 13 20 26 28 31 33 33 33 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec(e) Patients enrolled Sites activated 2024 All 33 clinical sites expected for this year have already been activated. Enrollment for Part 2 is ongoing at a high rate.
Page 32
32 2024 2025 2026 2027 2028 2029 I II III IV I II III IV I II III IV I II III IV I II III IV I II III IV RVU120 + venetoclax 2L+ AML (RIVER-81) 1L AML (+aza) Ph II Part 1 Ph II Part 2 Ph II Parts 2 and 3 Phase III Approval process in selected regions • Early signs of efficacy for RVU120 + ven in r/r AML (1 CR and 1 blast reduction) • Relapsed/Refractory (2L+): opportunity to resensitize patients to venetoclax treatment – ven rechallenge is not routinely done currently • Newly diagnosed (1L): Potential to move with combo into 1L to tap into larger commercial opportunity RIVER-81 Potential for accelerated approval in r/r AML and upside path to 1L combo
Page 33
33 RIVER-81 Summary PART 1 PART 2: Simon 2-stage design Stage 1 RVU120 250 mg + VEN 400 mg N≤18 Stage 2 RVU120 same dose selected for Stage 1 N≤11 Additional enrichment cohort (optional) RVU120 250 mg + VEN 200 mg or RVU120 125 mg + VEN 100 mg N≤10 PART 3: Confirmatory Confirmatory cohort Same dose as selected for enrichment stages 1 & 2 N≤41 • Part 1 (dose escalation) completed; safety profile confirmed • One patient in Part 1 achieved a CR • Part 2 initiated – 11 patients treated (as of December 11, 2024) • Next data release expected in H1 2025 Phase II study testing RVU120 in combination with venetoclax in AML Cohort 1 RVU120 125 mg Ven 200 mg N=5 Cohort 2 RVU120 250 mg Ven 200 mg N=7 Cohort 3 RVU120 250 mg Ven 400 mg N=5 Study/risk management
Page 34
34 An increasing volume of academic research confirms the interest in CDK8 inhibition and RVU120 in AML RIVER-52 RIVER-81
Page 35
POTAMI-61 RVU120 as a single agent and in combination with ruxolitinib in patients with myelofibrosis (MF) Phase II
Page 36
36 • Growing market with many patients undiagnosed or not treated due to lack of treatment options • Long durations of therapy and unmet medical need, for example, in patients with severe cytopenias • CDK8 kinase is an important player in MPN pathogenesis, and RVU120 disrupts the downstream signaling events, mitigating MPN symptoms • In preclinical studies, RVU120 effectively reduced splenomegaly, bone marrow fibrosis, and abnormal blood cell production. RVU120 has also demonstrated synergy in combination with JAK inhibitors • RVU120 has erythroid stimulating activity and demonstrated a favorable safety profile on normal hematopoiesis, making it a potential candidate for broad clinical use in treating MPNs RVU120 in myelofibrosis Mechanism of RVU120 in MF RVU120 reduces bone marrow fibrosis Opportunity in myelofibrosis RVU120 reduces splenomegaly RVU120 as a monotherapy and in combination with ruxolitinib reduces splenomegaly in a MPLW515L mouse model of MPN RVU120 as a monotherapy and in combination with ruxolitinib reduces bone marrow fibrosis while also increasing trilineage hematopoiesis in a MPLW515L mouse model RVU120 validated preclinically as a drug candidate in MFPOTAMI-61
Page 37
37 POTAMI-61 RVU120 attenuates MPN phenotypes relevant for accepted clinical endpoints, e.g., spleen volume reduction and survival
Page 38
38 Transcription initiation Epigenetic regulators CDK8 module Mediator complex CDK8 interactome in SET2 JAK V617F cells Synergistic interactions of RVU120 in SET2 JAK V617F cells JAK2, IRAK1 POTAMI-61 Validated synergy with SoC and advanced experimental therapies
Page 39
39 Patient with MDS and bone marrow (BM) fibrosis showed clinical evidence of activity: achieved marrow CR and BM fibrosis reduced from G3 to G2 on C6D1 biopsy C2D13 fibrosis grade 3 C6D1 fibrosis grade 2 POTAMI-61 Clinical evidence (Phase I in AML) of activity on bone marrow fibrosis
Page 40
40 Phase II study of RVU120 in myelofibrosis (MF) as mono and combo – first patient dosed in December 2024 • Population: • Primary or secondary MF; intermediate or high-risk MF per DIPSS; Cohort 1) previously treated with or ineligible for JAK inhibitor and Cohort 2) suboptimal response to RUX • Important: patients with thrombocytopenia can be included in Cohort 1 • Primary endpoints: spleen volume reduction at 24 weeks • Secondary endpoints: DoR, leukemic transformation, hematologic improvement, BM fibrosis reduction, PFS and OS • Estimated enrollment: ~20-230 patients(1) • Up to 50 clinical sites planned globally • Status as of December 11, 2024: first patient dosed, 5 patients in screening, 12 sites activated (17 sites planned by year-end) POTAMI-61 Part A (N = ~20 pts) Part B (N = ~210 pts) Expansion of Cohort 1 or 2 Cohort 3 (Frontline) STUDY DESIGN Cohort 2 (RUX add-on) Cohort 1 (Mono RUX-ineligible or RUX-failed) Confidential Initial opportunity in second line treatment with potential to move into frontline therapy (1) ~20 patients in Part A, ~210 patients in Parts B
Page 41
REMARK RVU120 as a single agent in patients with lower-risk myelodysplastic syndrome (LR-MDS) Phase II
Page 42
42 • A high unmet medical need remains in low-risk MDS (LR-MDS) after failure of available therapies • Transfusion burden remains high for patients with LR-MDS, resulting a poor quality of life • MDS pathogenesis is influenced by gene expression alterations that hinder the maturation of hematopoietic cells. • When aberrant stem cells from MDS patients are treated with RVU120, it triggers erythroid gene expression programs orchestrated by STAT5 and GATA1. • Importantly, RVU120’s activity does not lead to significant toxicity in the hematopoietic system. As a result, RVU120 emerges as a promising drug candidate for treating transfusion-dependent MDS patients. RVU120 in LR-MDS Mechanism of RVU120 in LR-MDS Clinical evidence of erythropoiesis demonstrated with RVU120 Opportunity in LR-MDS Several patients with AML and HR-MDS showed signs of hematological improvement, including an erythroid response in the RIVER-51 study. Induction of erythropoiesis was confirmed by flow cytometry. REMARK RVU120 validated preclinically as a drug candidate in LR-MDS
Page 43
43 Nonclinical rationale • Treatment of transformed CD34+ cells with RVU120 results in erythroid lineage commitment • Isolated CD34+ cells derived from MDS and Diamond-Blackfan anemia patients differentiate into erythrocytes in the presence of RVU120 • Increased red blood cell count and hemoglobin levels were observed in animal studies • Transcriptomic and chromatin studies identified that RVU120 can enhance GATA1-dependent transcription and reduce the expression of pro-inflammatory genes in MDS cells Related clinical observations • 4 AML/HR-MDS patients treated with RVU120 in Phase I showed hematological improvement • An increase in reticulocytes was also observed in patients with solid tumors REMARK RVU120 has strong erythroid-stimulating activity in nonclinical anemia models and selected patients with AML/HR-MDS in Phase I (RIVER-51), providing the rationale for the Phase II clinical study in patients with LR-MDS
Page 44
44 STUDY DESIGN IIT • Population: • Patients with relapsed/refractory LR-MDS • Primary endpoint: • Erythroid response (HI-E) according to IWG 2018 criteria after 8 cycles of treatment • Secondary endpoint: • RBC transfusion independence • Hb improvement • Quality of life (QoL) • Disease progression according to IWG 2018 criteria • Mutational pattern and burden of selected genes and their influence on response • First patient dosed in September 2024; 18 patients enrolled as of December 11, 2024 • Study conducted as an Investigator Initiated Trial with Prof. Uwe Platzbecker within EMSCO (European Myelodysplastic Neoplasms Cooperative Group) Prof. Uwe Platzbecker • Co-founder and chairman of EMSCO and co-chairman of the European Hematology Association Scientific Working Group on MDS • Primary focus on myelodysplastic syndromes (MDS) and its treatment • Worked on trials assessing luspatercept (Reblozyl) and imetelstat in patients with LR-MDS PHASE II ONGOING ASSESSMENT OF PHASE II WILL DRIVE FURTHER DEVELOPMENT EXPLORATORY RVU120 AS A SINGLE AGENT Patients failing available options Enrollment of ~40 patients planned REMARK RVU120 in LR-MDS – IIT conducted by Prof. Uwe Platzbecker and the EMSCO network
Page 45
45 • FPI on September 18, study progress in line with the schedule • Dosing optimization in progress – different tolerability/efficacy considerations in LR-MDS vs. AML • Initial study results expected in Q2 2025 (due to 16-week observation period needed) 18 patients enrolled, and 19 sites activated (as of Dec 11, 2024) 2 7 15 18 1 9 15 19 19 Aug Sep Oct Nov Dec(e) Patients enrolled Sites activated 2024 REMARK 19 of 24 sites planned for the study have already been activated. Efficient enrollment in the study supported by the EMSCO network. FPI
Page 46
RVU120 Outlook
Page 47
47 Part 1: exploratory data Planned locations for RVU120 Ph II studies: Part 2: expansion 4 Number of Ph II clinical trials initiated in 2024 6 Number of countries across studies 110+ Number of activated clinical sites globally ~100 Number of patients enrolled 20+ Number of clinical vendors managed 80+ Number of internal Ryvu team members in Clinical Development and Translational teams Global site locations and patient population Global CROs and clinical vendors Regulatory authorities worldwide Expected status as of December 31, 2024 Phase II clinical development with a global footprintRVU120
Page 48
48 2024 2025 2026 2027 2028 I II III IV I II III IV I II III IV I II III IV I II III IV Planned Ph II studies in hematologic malignancies • RIVER-52: AML/HR-MDS, monotherapy • RIVER-81: AML, combination with venetoclax • POTAMI-61: myelofibrosis (MF), monotherapy/combination with ruxolitinib • REMARK: LR-MDS, monotherapy, investigator-initiated trial (IIT) Ph II Part 1 Ph II Part 2 Phase III (potential for 1L) Approval process in selected regions Ph II Part 2 In H1 2025 Ryvu expects to have: • RIVER-52 / Part 1 completed (10+ evaluable patients in all three AML/NPM1+, AML/DNMT3A+ and HR-MDS cohorts) • RIVER-81 / Part 2 Stage 1 completed (30+ evaluable patients in RVU 250 mg + ven cohorts) • REMARK and POTAMI-61 / first efficacy data which will allow the pre-planned program review to focus on the most promising development paths All studies are in-line with the originally planned budgets. Q1 2026 cash runway remains unchanged. Ph II Part 1 Ph II Part 2/3 Ph II Part 1 Ph II Part 2 Phase III (potential for 1L) Ph II Phase III (potential for 1L) RVU120 Robust program progress without budget overruns allows for pre-planned program review and focusing on the best paths to approvals in H1 2025
Page 49
49 Market potential in hematological malignancies AML (Acute Myeloid Leukemia) MDS (Myelodysplastic Syndrome) MF (Myelofibrosis) • The most common, highly aggressive type of acute leukemia occurring in adults; unfavorable outcomes for most patients(1) • Annual incidence in the US at ~20,800 with an est. 11,220 deaths in the US in 2024 (2) • Venclexta (venetoclax) sales estimated to exceed USD 3.5 bn in 2025(3) • Kura licensed rights to ziftomenib to Kyowa Kirin for USD 330M upfront and USD 1.2 bn total milestones in Nov 2024 - Phase III asset - Part of a global collaboration • Disease leading to bone marrow damage, classified as cancer • Growing market due to faster diagnosis of the disease and potential new therapies • US incident cases expected to increase from 36,000 in 2018 to 46,000 in 2028 (4) • Reblozyl (luspatercept) projected peak sales of USD 3.2 bn by 2029(5) • Rytelo (imetelstat) projected peak sales of USD 1.2 bn(6) • MF is a bone marrow disease characterized by JAK mutations; often leads to severe anemia • Chronic disease with long duration of therapy; US prevalence is est. to be ~13,000 patients(7) • Jakafi (ruxolitinib) sales in 2023 – USD 2.6 bn • Morphosys acquired by Novartis for EUR 2.7 bn in Feb 2024 – primary asset is Phase III MF drug pelabresib Global AML Market (4) 2022 2031 USD 3.2 bn USD 6.6 bn 8.5% CAGR (2022-2031) Global MDS Market (4) 9.3% CAGR (2022-2030) Global MF Market (7) 2.6% CAGR (2022-2031) 2022 2030 USD 3.3 bn USD 6.6 bn 2022 2031 USD 2.3 bn USD 2.9 bn RVU120 1. Mayo Clinic 2. cancer.org January 2024 3. Biomedtracker 5 March 2023 4. GlobalData forecast 5. Goldman Sachs forecast 6. Coherent Insights
Page 50
50 Summary / Q&ARVU120 RVU120 Phase II Progress RIVER-52 RIVER-81 REMARK POTAMI-61 • Part 1 (combo dose escalation) completed – safety confirmed • One patient in Part 1 achieved a CR • Part 2 initiated; further development decision in H1 2025 • First patient dosed in Sep’24 • Initial efficacy data expected in Q2 2025 • First patient dosed in Dec’24 • Initial efficacy data expected in Q2 2025 • 1 of 2 evaluable NPM1+ pts with 50% blast reduction • 1 of 3 evaluable DNMT3A+ pts with disease stabilization • Data from the first 10+ evaluable patients in Cohorts 2-4 expected in H1 2025 Next steps and upcoming newsflow H1 2025 RVU120 program summary RVU120 development plan review based on: • Ongoing data analysis • Updated competitive analysis • KOL feedback Q2 2025 RVU120 Phase II data update: RIVER-52, RIVER-81, POTAMI-61, REMARK • Successful launch of all 4 Phase II studies: RIVER-52, RIVER-81, POTAMI-61, REMARK • Global clinical program with accelerating enrollment • Strong interest from the investigator community • Safety profile potentially better than in most drugs used in AML • Encouraging early signs of efficacy in Phase II • Numerous data readouts expected in 2025 • No budget overruns with cash runway still to Q1 2026 Next data in Q2 2025 Next data in Q2 2025 Enrollment ongoing; initial data in Q2 2025 Enrollment ongoing; initial data in Q2 2025 All studies on-track, efficacy analysis in H1 2025
Page 51
Thank you CONTACT DATA: Ryvu Therapeutics S.A. www.ryvu.com ryvu@ryvu.com ir@ryvu.com