Targeted therapeutics - at the forefront of oncology CORPORATE PRESENTATION - Ryvu Therapeutics
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Targeted therapeutics at the forefront of oncology CORPORATE PRESENTATION January 2022
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 or subscription 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 of securities 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, 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.
2
Ryvu at a glance
Clinical Pipeline Across Heme Small Molecule Discovery Platform; Fully Integrated Research
and Solid Tumors Novel Synthetic Lethality Targets Organization
• Wholly owned, first-in-class, Developing small molecule therapies which address • Team of ~150 scientists (with ~80 PhDs)
selective, oral CDK8/19 inhibitor high value emerging targets and pathways in international expertise in drug discovery and track
• Phase Ib study in AML/MDS: Early oncology record in delivering new clinical candidates
RVU120
signs of efficacy reported at
EHA/ASH 2021; further enrollment • State-of-the-art facility including HTS, medicinal
ongoing; Synthetic Lethality • WRN, PRMT5, chemistry, biology and
in vivo facilities
• Phase Ib study in solid tumors Novel SL targets
enrolling
• First-in-class dual PIM/FLT3 kinase Immuno-Oncology • HPK1, STING
SEL24 inhibitor for AML in Phase II;
partnered with Menarini;
• Single agent efficacy and acceptable
safety profile demonstrated in r/r Partnerships including Galapagos and Merck
AML; enrollment in IDH+ patients
ongoing
Listed on Warsaw Stock Exchange, market cap of $285m1
• One of the largest biotech companies in the region, headquartered in Krakow, Poland
• ~$21.3m cash position2 and significant non-dilutive grant funding (>$25m secured for the period 2021-2023)
3
1 As of market close on 04 January 2022. Exchange rate (NBP): $1=PLN4.0396
2 As of 31 October 2021
Team with strong track record of clinical development and shareholder value creation
PAWEL PRZEWIEZLIKOWSKI, MSc, MBA KRZYSZTOF BRZOZKA, Ph.D., MBA KAMIL SITARZ, Ph.D., MBA VATNAK VAT-HO, MBA
CEO and Founder CSO COO CBO
PETER LITTLEWOOD, MSc TOMASZ NOCUN, MSc, MBA MATEUSZ NOWAK, Ph.D., MBA TOMASZ RZYMSKI, Ph.D., MBA MARTIN SWARBRICK, Ph.D. JUSTYNA ZOLTEK
Director of DMPK Director of Research Financing Director of Early Discovery & Innovation Director of Biology Director of Chemistry Director of HR
Supervisory Board Scientific Advisory Board and industry collaboration history
PIOTR ROMANOWSKI, M.D. Ph.D., CHAIRMAN GREG NOWAKOWSKI, M.D.
AXEL GLASMACHER, M.D. ANTHONY TOLCHER, M.D. FRCPC
COLIN GODDARD, Ph.D. JOSEPH TABERNERO, M.D. Ph.D.
JARL ULF JUNGNELIUS, M.D. MICHAEL SAVONA, M.D.
RAFAL CHWAST, MSc CEZARY SZCZYLIK, M.D. Ph.D.
THOMAS TURALSKI JORGE CORTES, M.D.
TADEUSZ WESOLOWSKI, Ph.D PRZEMYSLAW JUSZCZYNSKI, M.D., Ph.D
4
Broad pipeline addressing emerging targets in oncology
5
Ryvu evolution
2007 2019 2020 - 2021
SEL24 RVU120
Selvita, a hybrid model Corporate spin-out of • Successfully completed Phase • Preliminary positive Phase I
biotech company, with joint Selvita (CRO) from Ryvu I in AML clinical & preclinical data
CRO and innovative drug Therapeutics completed • IDHm AML cohort expansion presented at EHA2021 and
discovery operations >$250m incremental ongoing ASH2021
value created for Ryvu • Positive Phase II clinical • First patient dosed in Phase I/II
shareholders data presented at EHA2021 solid tumor study
and ASH2021
6
Clinical Candidates in Hematology
and Solid Tumors
7
RVU120: Highly selective first-in-class CDK8/CDK19 inhibitor with potential in
hematological malignancies and solid tumors
RVU120 is a potent and selective CDK8/CDK19 inhibitor • CDK8 is a kinase subunit of the Mediator
Unique MOA complex involved in regulation of Pol II mediated
transcription, super enhancers (SE),
and cellular differentiation processes
Low nM activity on CDK8/CDK19
• Distinct from other CDK family members,
and excellent kinase selectivity (broad kinome)
does not interfere with cell cycle progression
(unlike CDK1, CDK2, CDK4/6 inhibitors)
• Lack of binding to off-targets potentially associated
Targeted/Safer with toxicity of pre-clinical EMD Serono CDK8/19
inhibitors (such as JNK1 or GSK3b)1
• Higher selectivity based on comparison
of gene expression effects2
• Developed internally at Ryvu
Wholly Owned
RVU120 • Composition of matter patents issued
Orphan drug designation in AML Therapy Acceleration Program (TAP) grant support
in 2020 Total funding: $3.25m
8
1Chenet al. 2019
2Rzymski et al. 2017
RVU120: Potential across a broad range of tumors
BLOOD CANCERS & DISORDERS SOLID TUMORS
• AML • MDS • Breast • HCC
• JAK2 mut AML/MPN • ALL, NHL • Colorectal • Neuroendocrine
• Diamond-Blackfan Anemia (DBA) • Rhabdomyosarcoma • Other
RVU120 induces complete regression RVU120 shows strong anticancer activity
and bone marrow recovery in AML PDX models in TNBC xenografts in vivo after oral administration
In CD34+ AML patient-derived xenografts: Activity of RVU120 has been tested in a subcutaneous xenograft of TNBC cell line
Complete regression Hematologic recovery MDA-MB468. Oral administration of RVU120 at 60mg/kg dose QD resulted in TGI
(peripheral blood) (bone marrow) -81%. Overall tolerability was superior vs cisplatin reference.
PERIPHERAL BLOOD M D A - M B - 4 6 8 t u m o r v o lu m e k in e t ic s
30
B o d y w e ig h t k in e t ic s
350
COLORECTAL CANCER MODEL
C o n tr o l
R V U 1 2 0 , 6 0 m g /k g , Q D , P O
C is p la tin , 8 m g /k g , E 2 W , IP 25
300
T u m o r v o lu m e ( m m 3 )
B o d y w e ig h t ( g )
250 20
200 15
150
10
100 C o n tr o l
5 R V U 1 2 0 6 0 m g /k g , Q D , P O
C is p la tin 8 m g /k g , E 2 W , IP
50
0
1 3 5 7 9 11 13 15 17 19 21 23 25
1 3 5 7 9 11 13 15 17 19 21 23 25 Days
Days d is c . d is c .
d is c . d is c .
9
Unmet needs in acute myeloid leukemia may be addressed with RVU120 and SEL24
Most common, highly aggressive type of acute leukemia in adults with poor outcomes in most patients1
~$1,300m
~20,000 new cases diagnosed
and >11,000 deaths in the US in 20182 AML Market5
~$600m
2020 2025
$8.0 billion ~$500m
AML makes up 1% of all cancers $1.2 billion
and 34% of all adult leukemia cases2,3 46%
~$400m
CAGR
~$300m
Occurs in a predominantly elderly, frail patient population;
75% of patients diagnosed with AML were aged >60 years4 ~$300m
RYVU CLINICAL PROGRAMS DESIGNED
Lowest survival among all blood cancers; TO FULFILL UNMET NEEDS IN AML
only 26% of patients survive 5 years after diagnosis
OVERCOMING RESISTANCE TO SINGLE-TARGET MUTATION-
SPECIFIC INHIBITORS
30% AML patients with an ITD mutation in the FLT3 gene
have a less favorable prognosis; 70% of patients are EFFICACY IN BROADER PATIENT POPULATIONS
refractory to current inhibitors targeting FLT3 mutation
REDUCING CHEMOTHERAPY-BASED TREATMENT REGIMENS
1 Mayo Clinic
2 Cancer.net FULLY ORAL REGIMEN
3 Leukemia & Lymphoma society
4 Walter, R; Leukemia 2015
5 Evaluate Pharma
10RVU120 Phase I AML/MDS study design
STUDY POPULATION: PRIMARY OBJECTIVE: SECONDARY OBJECTIVES: EXPLORATORY OBJECTIVE:
1 • Patients with relapsed
2 3 4
• Assess safety and tolerability • Evaluate pharmacokinetics • Exploratory biomarkers
/refractory AML or high risk MDS • Determine the recommended dose • Evaluate preliminary anti-leukemic
• No upfront patient stratification activity
5 SITES IN US H2 2019-2021 Q1-Q2 2022
PART 1: ESTABLISHING RECOMMENDED PHASE 2 DOSE (RP2D) EVALUATION PART 2: SAFETY EXPANSION
EXPANSION FROM SINGLE PATIENT SAFETY,
COHORTS TO A 3+3 DESIGN EFFICACY,
DLTs evaluated at completion of cycle 1 in each PK, PD
cohort
6 PATIENTS
2 SITES IN POLAND
COHORT 1
COHORT 2 ORAL DOSE RP2D SAFETY
MTD EXPANSION
COHORT 3 Three week cycle: Single dose
every other day for a total of
UP to 8 7 doses/cycle followed by
one week off
COHORTS
11Initial RVU120 Phase I data show acceptable safety and PK characteristics
As of data cutoff of November 16, 2021 for ASH 2021:
• 10 patients (8 AML and 2 HR-MDS), median age 69.5 years, were enrolled. All patients presented adverse biological characteristics of disease and
were failing after median 3 previous lines of therapy.
• 6 patients completed all safety evaluations for cycle 1 – no DLTs were reported. A total of 12 SAEs have been reported – no SAEs deemed related to
study drug.
• PK analysis performed using plasma samples collected at C1D1 and C1D13; PK data suggest exposure is linear up to the 75 mg dose level; above
75mg, non-linear PK can be explained by autoinhibition of the major RVU120 metabolizing enzyme (CYP1A2)
SAFETY
∫ pt103001 escalated from 50 mg to 75 mg dose of study drug after cycle 7.
*all the three events occurred after study drug termination for progression.** initially reported as possibly related, were then updated as unrelated, based on radiological evidence of Pancreatitis and
Grade 2 Pleural Effusion prior to study drug administration.
12
Source: C. Abboud et al, ASH 2021.RVU120 Phase I data show early signs of efficacy in AML and HR-MDS
ASH 2021: Data cutoff 16 November 2021
Clincially relevant responses were seen in patients in receiving the 75mg dose:
✓ Erythroid Response in Cohort 3 patient (50mg, escalated to 75mg): HR-MDS, demonstrated an erythroid response – patient continues on treatment for
more than 15 months
✓ Complete Remission in Cohort 4 patient (75mg): R/R AML, bone marrow response in C2 improved to Complete Remission (CR) in C7
13Case Focus: AML patient achieved Complete Remission despite poor prognostics,
including DNMT3A/NPM1 mutations
• AML with mutations in FLT3, DNMT3A, NPM1; failed 3 prior lines of therapy, including 2 FLT3 inhibitors and venetoclax + decitabine –
COHORT 4 known to be associated with poor prognosis (median OS 2.4 months1)
AML • Received 75mg dose of RVU120
PATIENT:
• Showed fast clearance of bone marrow blasts at C1D17, and recovery in platelets and absolute neutrophil count (ANC) from C2; skin
leukemia gradually improved under RVU120 treatment up to complete resolution in C7, achieving a Complete Remission (CR)
EFFICACY IN DNMT3A/NPM1 MUTATED AML COMPLETE REMISSION
• Efficacy of RVU120 in an DNMT3A/NPM1 mutant patient was associated
• RVU120 shows on-target efficacy in ~50% of tested PDCs, which is associated
with monocytic differentiation, pharmacodynamic effect observed in
with recurrent mutations of DNMT3A and/or NPM1, constituting together ~30%
preclinical profiling of PDCs
of all AML patients
RVU120 SENSITIVITY AML PDC PANEL (0.2µM)
14
1.Haematologica. 2021 Mar 1; 106(3): 894–898
Source: Angelosanto et al, EHA 2021, Poster EP480.Case Focus: HR-MDS patient achieved Erythroid Response,
remaining on treatment with RVU120 for more than 15 months
Anemia may occur due to ineffective Translational Data Correlate with Patient’s Erythroid Response
Anemia in Chronic erythropoiesis, and is a hallmark of
Hematological several diseases such as
Diseases myelodysplastic syndrome and
Diamond-Blackfan anemia • Failed 3 prior lines of therapy, including previous HMA, associated with median OS
of 4.5 months2; received 50mg dose of RVU120 and escalated to 75mg from C7
SD
RVU120 induces erythroid • Achieved an erythroid response (ER) according to Cheson Criteria1 from C5 to C7
RVU120 Induces differentiation in (Lin-) CD34+, that and again an erythroid improvement from C10 up to C12 and erythroid response
Erythroid acquired genetic abnormalities
characteristic for MDS/AML and from C18 to C20
Differentiation
DBA PD remains on treatment after more
• Patient was first dosed on August 26, 2020 and
than 15 months3 with SD
Rzymski et al, EHA 2021, S164, Oral Session
15
Source: Angelosanto et al, EHA 2021, Poster EP480. 1.Cheson, et al. 2006. Myelodysplasia.” Blood. https://doi.org/10.1182/blood-2005-10-414; 2.Nazha et al. Blood Cancer Journal (2017) 7:644.
3. Duration of therapy of greater than 15 months as of data cutoff of 16 November 2021RVU120: Solid tumor development
First patient dosed in August 2021. Enrollment ongoing; preliminary results in 2022
H2 2021 2022
PART 2: EFFICACY & SAFETY EXPANSION SIMON
PART 1: ESTABLISHING RECOMMENDED DOSE EVALUATION
2-STAGE
A 3+3 STUDY DESIGN STAGE 1 STAGE 2
18 PATIENTS 14 PATIENTS UP TO 20
DLTs evaluated at completion of cycle 1 in each cohort PATIENTS
ADULTS R/R + 10
COHORT 1 mTNBC PATIENTS
R/R SOLID TUMORS PFS at 9 months
SINGLE ORAL DOSE EOD
COHORT 2
RP2D
NO MORE THAN COHORT 3 7 DOSES/CYCLE determined Overall survival
3 PRIOR THERAPIES
3 WEEK CYCLE UP TO 3 follow-up:
FOR ENTRY DISEASE REMAINING
OTHER + 10 2 years
COHORTS
SOLID PATIENTS
SAFETY, TUMORS
EFFICACY,
PK, PD Go/no-go decision to enroll next 10 patients
based on RECIST ORR after cycle 3
16SEL24 (MEN1703) is a differentiated, first-in-class PIM/FLT3 dual kinase inhibitor
PIM and FLT3 Initial Ph I/II Study Results (ASH 2020, EHA 2021)
1 are oncogenes involved in AML
• As of January 21, 2021 (cut-off date), n=48 pts were
Dual targeting creates potential for broader activity, treated across the dose escalation (DE, n=25) and
2 more durable responses than selective FLT3 inhibitors Phase II cohort expansion (CE, n=23).
such as gilteritinib Initial Single
• Across DE and CE, 4 CR/CRi occurred, three of which
Agent Efficacy
Potential for treating patients that have relapsed on selective in pts with IDH mutations.
3 FLT3 inhibitors – PIM kinases are largely responsible
in IDHm AML
• A total of 3 out of 5 pts with IDH mutations treated
for the development of resistance to FLT3 inhibitors
at doses ≥75 mg achieved CR/CRi, including a CR in a
patient with IDH2 mutant AML relapsed on
enasidenib.
VALUE THROUGH
GLOBAL DEAL WITH
• Partnered globally with Menarini in 2017 ➢ Follow-up Ph II study in patients with IDHm AML
TOP 40 global pharma company, based in Italy
initiated in July 2021
• Menarini is fully responsible for clinical development
and funds translational research at Ryvu ➢ Orphan Drug Designation (ODD) by US FDA received in
• Ryvu eligible to receive >$100M in milestones and double-digit royalties Oct 2021
17SEL24 (MEN1703) Phase II data confirm manageable safety profile
RESULTS FROM DIAMOND-01 (CLI24-001) TRIAL: FIRST IN HUMAN STUDY OF SEL24/MEN1703, A DUAL PIM/FLT3 KINASE
INHIBITOR, IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
SCOTT SOLOMON,1 PAU MONTESINOS,2 AZIZ NAZHA,3 STEPHEN STRICKLAND,4 GIOVANNI MARTINELLI,5 ARMANDO SANTORO,6 ROLAND WALTER,7 RACHEL COOK,8 MARIA CALBACHO,9 SUSANA VIVES,10 SALMAN FAZAL,11 KRZYSZTOF BRZÓZKA,12 SETAREH SHAMSILI,12 SIMONE
BALDINI,13 DIRK LAURENT,13 ANDREA PELLACANI,13 FARHAD RAVANDI,14
DEMOGRAPHICS AND BASELINE
RESULTS PATIENT CHARACTERISTICS
All 125 mg
• 48 patients were treated: in DE (n = 25) and in CE (n = 23) part
(n=48) (n=30)
• Data cut-off date: April 19, 2021 Age (years)
Median (range) 69 (25-84) 69.5 (38-83)
Reason for inclusion, n (%)
Newly diagnosed AML 3 (6.3%) 2 (6.7%)
Primary refractory AML 16 (33.3%) 7 (23.3%)
SAFETY Relapsed AML 29 (60.4%) 21 (70.0%)
AML status, n (%)
De novo AML 27 (56.3%) 16 (53.3%)
• At RD, SEL24/MEN1703 showed a manageable safety profile with most Non De novo AML 21 (43.7%) 14 (46.7%)
Cytogenetics, n (%)
Grade ≥3 treatment-emergent AEs (TEAEs) being hematologic or infectious Favorable 7 (14.6%) 3 (10.0%)
Intermediate 6 (12.5%) 4 (13.3%)
Grade ≥3 TEAEs (incidence >10%) at RD (125 mg, N=30)
Unfavorable 22 (45.8%) 15 (50.0%)
Preferred Term (PT) Incidence
Unknown 11 (22.9%) 8 (26.7%)
Febrile neutropenia 9/(30.0%) Most frequent mutations, n (%)
Pneumonia 9/(30.0%) FLT3/ITD 12 (25.0%) 8 (26.7%)
Leukocytosis 6/(20.0%) FLT3/TKD 1 (2.1%) 1 (3.3%)
Sepsis 4/(13.3%) DNMT3A 7 (14.6%) 3 (10.0%)
Lymphocyte count decreased 4/(13.3%) IDH1 6 (12.5%) 2 (6.7%)
Neutrophil count decreased 4/(13.3%) IDH2 2 (4.2%) 0 (0.0%)
Platelet count decreased 4/(13.3%) NPM1 7 (14.6%) 5 (16.7%)
18
1 Northside Hospital Cancer Institute, Atlanta, GA, USA | 2 Hospital Universitari i Politècnic La Fe, Valencia, Spain | 3 Cleveland Clinic, Cleveland, OH, United States | 4 Vanderbilt University Medical Center, Nashville, TN, United States | 5 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori “Dino Amadori” IRST
IRCCS, Meldola, Italy, | 6 Humanitas University Humanitas Clinical and Research Milan, Center IRCCS Italy | 7 Fred Hutchinson Cancer Research Center, Seattle, WA, United States | 8 Oregon Health and Science University, Portland, OR, United States | 9 Hospital 12 de Octubre, Madrid, Spain | 10 ICO-Hospital Germans Trias i
Pujol, Badalona, Spain | 11 Allegheny Health Network, Pittsburgh, PA, United States | 12 Ryvu Therapeutics, Krakow, Poland | 13 Menarini Group, Florence, Italy | 14 MD Anderson Cancer Center, Houston, TX, United StatesSEL24 (MEN1703) showed single agent efficacy in R/R AML patients,
in particular in IDH+ population
EFFICACY
• Objective responses have been reported in 4 out of 48 patients (8%) across DE and CE phases, with 3 out of 4 responders harboring IDH mutations
• Median number of cycles in responding patients was 7 (Range 7-8)
• 3 out of 5 patients with IDH mutations treated at doses 75-125 mg achieved CR/CRi, including a CR in a patient relapsed on enasidenib
• 1 patient with IDH1 mutation achieved CRi and underwent allogeneic-HSCT
Characteristics of Responding patients and of their treatment
Dose Response
Patient ID Age AML Status Reason for inclusion Cytogenetics Mutations No of cycles
Level by cycle #
004-012 81 75 mg de novo AML Relapsed AML Intermediate DNMT3, IDH2 8 5
ASXL1, CUX1, DDX41
004-022 75 125 mg AML post MDS Relapsed AML Unfavourable (C.3G>A, R525H), EZH2, PRPF8 7 6
401-031 63 125 mg AML post MDS Relapsed AML Unfavourable IDH1 7 3
401-034 55 125 mg de novo AML Relapsed AML Unfavourable IDH1 7 3
• SEL24 (MEN1703) as single agent showed preliminary efficacy in R/R AML, particularly clustering in patients with IDH mutant disease
• FOLLOW-UP PHASE II STUDY IN PATIENTS WITH IDH MUTATION STARTED IN JULY 2021
• BROADER CLINICAL DEVELOPMENT PLAN in AML AND OTHER INDICATIONS AGREED WITH MENARINI
19RVU120 and SEL24 Clinical and Translational Updates
at ASH and SABCS 2021
RVU120 Clinical PH I AML/MDS CLINICAL • ASH 2021: CLI120-001 Phase Ib Study of RVU120(SEL120) in Patients with AML and High Risk
MDS: Updated Safety/Efficacy Results from Initial Dose Escalation (Publication Number:
Update STUDY UPDATE 3418), Camille Abboud Sr., MD (Washington University in Saint Louis/ Washington University
School of Medicine) et al.
• ASH 2021: Preclinical and Clinical Signs of Efficacy of RVU120 (SEL120), a Specific CDK8/19
DNMT3A-MUTATED AML Inhibitor in DNMT3A-Mutated AML (Publication Number: 2371), Tomasz Rzymski, PhD
(Ryvu Therapeutics) et al.
MDS AND ERYTHROID • ASH 2021: RVU120 (SEL120) CDK8/19 Inhibitor - a Drug Candidate for the Treatment of MDS
Can Induce Erythroid Differentiation (Publication Number: 1518), Tomasz Rzymski, PhD
DIFFERENTIATION (Ryvu Therapeutics) et al.
RVU120
Translational Data • ASH 2021: Inhibition of Cyclin Dependent Kinase 8 (CDK8): A Novel Approach to Target the
T-ALL AND LICS Leukemia Initiating Cells (LICs) in T-Cell Acute Lymphoblastic Leukaemia (T-ALL) (Publication
Number: 2250), Sujan Piya, PhD (MD Anderson Cancer Center) et al.
HORMONE-INDEPENDENT • SABCS 2021: Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-
independent breast cancer cells in vitro and in vivo (#1766), Tomasz Rzymski, PhD
BREAST CANCER (Ryvu Therapeutics) et al.
• SEL24(MEN1703) Inhibits PIM/FLT3 Downstream Target in Acute Myeloid Leukemia (AML)
SEL24 Patients: Results of the Pharmacodynamics (PD) Assay and Genomic Profiling in the First-in-
R/R AML, IDH MUTATION
Clinical Update Human Diamond-01 Trial (Publication Number: 3436), Alessandro Paoli (Menarini Group) et al.
20Small Molecule Platform
with Focus on Synthetic Lethality
21Integrated Ryvu Discovery Engine
TARGET IDENTIFICATION DRUG DISCOVERY RESEARCH PIPELINE
AND VALIDATION
✓ MultiDEP: proprietary bioinformatic ✓ Broad portfolio of synthetic lethal and
engine ✓ Integrated, multidisciplinary processes: immuno-oncology targets at various stages of
rapid lead identification/optimization with the cycle – clinical candidate selection to
• Discovery of novel synthetic lethal deep translational biology support target validation and hit finding
target pairs
• Enables multicomponent and multigene ✓ Platform has delivered 2 projects in clinical
analysis to provide comprehensive, development; multiple projects in
large-scale analysis, unprecedented discovery/research Synthetic • WRN, PRMT5,
among competitors
✓ Team of ~150 scientists (with ~80 PhDs) with Lethality Novel SL targets
international expertise in drug discovery and
track record in delivering new clinical
candidates Immuno-
• HPK1, STING
Oncology
22Ryvu strategically utilizes synthetic lethality phenomenon to access
new treatment modalities
~40K PROTEINS IN HUMAN LOSS-OF-FUNCTION MUTATION IN GENE X LEADS TO GENE Y ADDICTION IN
GENOME (Gencode/NCBI) CANCER CELLS
~20K PROTEIN-CODING GENES
CANCER CELL
CANCER CELLS GENE X GENE Y
PHENOTYPE
~2K DRUGGABLE GENOME VIABLE
~60 DRUG TARGETS
VIABLE
~293 CANCER DRIVER GENES
(Bailey, Cell 2018)
LETHAL
>99% SNVs PASSENGER
MUTATIONS
Synthetic lethal compounds selectively kill cancer cells by targeting tumor cell-
essential processes, but leave healthy cells unharmed.
LACK OF RATIONAL OPTIONS
PREDOMINANTLY ONCOGENES
FOR CANCERS DRIVEN BY:
Neomorphic activity Unclear dominant oncogenic event
Hyperactivity Non-druggable oncogenes
Aberrant expression Mutations in tumor suppressors/
loss of function mutations
23Small molecule inhibitors of WRN
WRN INHIBITORS PROGRAM IN RYVU WRN INHIBITORS OF ATPase ACTIVITY SELECTIVELY TARGETING TUMORS
WITH MICROSATELLITE INSTABILITY
Synthetic lethality of WRN with INHIBITORS
KEY RATIONALE
microsatellite instability (MSI-high)
WRN inhibitors of ATPase activity selectively
targeting tumors with microsatellite Helicase function validated
MoA
instability (MSI) in vitro as critical requirement
First or best-in-class potential
NOVELTY 1
Focus on anti-targets selectivity (RecQ) Ryvu identified several
preliminary small molecule hits
Tumor agnostic with MSI-high vulnerability WRN confirmed as specific vulnerability of MSI-H cell lines
TOP TUMOR – first-in-class inhibitors
(~10-30% of colorectal, endometrial, in several genome-wide screens
INDICATIONS of WRN ATPase activity
gastric, ovarian cancers)
2
Distal PD biomarker developed,
BIOMARKERS Distal biomarker developed battery of in vitro assays being
developed
3
DEVELOPABILITY Target druggable with small molecules Discovery engine:
Multiple hits identified from HTS Rational med.-chem hit-to-lead
expansion
STATUS Hit ID and Hit to lead generation ongoing
Chan 2019
24MTAPdel cancers – PRMT5 MTA-cooperative inhibitors
PRMT5 SL INHIBITORS PROGRAM IN RYVU RYVU HAS SL PRMT5 INHIBITORS WITH BEST-IN-CLASS POTENTIAL
RYVU compound exhibits synthetic lethal phenotype: 1
KEY PRMT5 MTA-cooperative inhibitors exert Patentable chemical series, confirmed
differential PD biomarker inhibition in isogenic pair in HCT116 (3D)
RATIONALE synthetic lethal phenotype in MTAP deleted biomarker inhibition
cells
2
MTA-cooperative inhibitors EC50 (MTAP KO) = 7 nM
MoA Immediate program kick-off: full in vitro
pharmacology cascade in place, PRMT5
crystallography and in vivo pharmacology
up and running
NOVELTY Best-in-class potential (vs Mirati, Tango)
3
MTAP deletions, up to 15% of all cancers, one of
Fast progress possible due to fully
TOP TUMOR the largest genetically defined population: developed cascade and chemical
INDICATIONS pancreatic, lung, DLBCL, bladder, oesophageal properties of hit series.
(by %: mesothelioma, GBM)
DATA FROM COMPETITORS
BIOMARKERS MTAP and p16 status
SAM (plasma), SDMA (tissue) levels
DEVELOPABILITY Target druggable with small molecules
Ryvu SL PRMT5 inhibitors identified
VALUE 2021: Hit-to-lead
INFLECTION 2022: Lead, in vivo PoC
POINTS 2023: Preclinical candidate
AACR 2021
SEC 2021
25Ryvu has selective, potent HPK1 inhibitors with anti-tumor efficacy in mice
RYVU INHIBITORS BLOCK HPK1 KINASE ACTIVITY AND Ser376
PHOPHORYLATION OF SLP-76 ADAPTOR PROTEIN IN NANOMOLAR
RYVU APPROACH CONCENTRATION RANGES
LEAD OPTIMIZATION
STATUS ▪ 2022: preclinical candidate
▪ 2023: IND RVU-578 RVU-834 BMS BeiGene UHN
IC50 human HPK1 [nM]* 0.45 0.58 165 65.2 55.9
▪ Small molecule, selective, orally bioavailable
APPROACH IC50 mouse HPK1 [nM] ** 0.47 0.35 20.4 1.34 3.69
inhibitors of HPK1 kinase activity
IC50 Jurkat E6.1 pSLP76 [nM] 28.8 69.5 334 150 313
IC50 human PBMC pSLP76 [nM] 24.5 39.6 202.4 - 67.9
▪ High selectivity against kinases from TCR pathway
IC50 murine Splenocytes pSLP76 [nM] 26.3 70.1 207 75.7 77.7
DIFFERENTIATION ▪ Immunostimulatory activity in immunosuppressed,
resistant hPBMC and T cells across species * At 800µM ATP, ** AT Km ATP
▪ RYVU HPK1 inhibitors are ATP-competitive, direct binders of human ▪ RYVU HPK1 inhibitors overcome ▪ Enhanced OT-1 cells specific
▪ Target engagement in vivo in mice
HPK1 protein occupying active site of both monomers (X-ray crystal PGE2-mediated immunosuppression killing of MC38.OVA in the
treated with anti-CD3 antibody
structure) in human PBMCs presence od RVU-578
% inh. pSLP-76 in splenic T cells RVU-578
OT-1 T cells specific killing of MC38.OVA colon carcinoma
[%ctrl]
-40
[%] inh. pSer376 SLP-76
50
50
[%ctrl]
0% RVU-578 RVU-578
%inh. pSer376 SLP-76
-20 RVU-28578-02 IL-2 PBMC +PGE2
40
killing
40
0 4000
4000
IL-2 conc. [pg/mL]
specifickilling
33% 40% EC50 = 9.91 nM -PGE2
IL-2 conc. [pg/mL]
20 30
-PGE2
3000
3000 30
40
cell specific
60 78% 2000
2000 20
20
80 100%
104% 104% 1000 10
10
T cell
1000
100
T
120 stim
00 00
20 67 22 4 25 2 7 91 im
SO
0
0
3
SO
07 08 02
30
10
03
0,
8
8
8
F
EF
st
pe
e
,0 ,0 00 00
M
M
7
7
7
,0
l
00 00
0,
0,
0,
RE
0 0 0,
ic
00
D
D
-5
-5
-5
y
0 0, 0,
R
5%
5%
0,
h
ot
VU
VU
VU
pk
pk
Ve
0.
0.
is
RVU-578 [uM]
R
R
R
m
m
75
25
pk
pk
pk RVU-578 [µM]
+PGE2 -PGE2
m
m
m
Concentration [µM]
aCD3
10
30
75
aCD3
+PGE2 -PGE2
26Small molecule, direct, systemic STING agonists with strong anti-tumor efficacy
RYVU APPROACH
STATUS PRECLINICAL CANDIDATE
▪ Small molecule, systemic, direct STING
APPROACH
agonists amenable to ADC technology
▪ Superior in vitro activity and anti-tumor efficacy
DIFFERENTIATION
▪ Suitable either for systemic or targeted delivery
IP RIGHTS STATUS ▪ Several patent applications covering broad
chemical estate filed, initial FTO confirmed
KEY DIFFERENTIATION
Small molecule, direct, systemic STING agonists with multiple routes
of administration (IV, SC, IT) allowing two tracks of development:
standalone systemic treatment
Vehicle control R V U -2 7 0 6 5 , 1 5 m g /k g , E 5 D * 4 , iv
using targeted delivery as payload for antibodies 3000 3000
2500
T u m o r v o lu m e ( m m 3 )
(antibody-drug conjugates ADC approach)
2500
Tumor volume (mm3)
RVU-27065
Vehicle
2000 2000
1500 1500 15 mg/kg
Systemic efficacy in mouse models on par with GSK reference (IV) and outperforming 1000 1000 CR 7/10
Aduro/Novartis agonist (IT) accompanied with favorable safety profile 500 500
0 0
0 5 10 15 20 25 30 35 40 45 50 55 60 0 10 20 30 40 50 60 70 80 90
Active across multiple STING haplotypes to target broad patient population Day post randomization D a y p o s t r a n d o m iz a tio n
Well protected IP and confirmed initial FTO space
27Corporate Progress
28Financial results & employment
Q1-Q3 Q1-Q3
$ million
2020 2021 # of employees
Revenues, incl.: 7.6 5.1 Cash position
October 31, 2021
Partnering 3.8 0.1
$21.3M
Grants 3.7 4.8
Costs* 13.8 17.4 Available grant funding
EBIT* -6.1 -12.2 >$25M
> 170 employees
EBITDA* -4.1 -9.8
Financing secured until
CAPEX -7.9 -3.5
* excluding the impact of the non-dilutive, cash-neutral
Employee Incentive Scheme (of $3.9m)
Q1 2023
> 80 PhDs
29Broad pipeline addressing emerging targets in oncology
Ryvu drives value creation from its multiple data readouts
Anticipated Milestones
Program/ Partners / 2021 2022+
target name Indication Discovery and preclinical Phase I Phase II Collaborators
SEL24
• Ph. II
(MEN1703) AML • Ph. II complete
interim data
PIM / FLT3
AML /
• Initial Ph. Ib data • Ph. II initiation
RVU120 MDS
CDK8 • Ph. I Interim data
Solid tumors • Ph. I Initiation
• Ph. II initiation
• Lead optimization
MTAP Solid tumors • Hit-to-lead
• Non-GLP tox
• Lead optimization
WRN Solid tumors • Hit-to-lead
• Non-GLP tox
• Lead
HPK1 Solid tumors • Non-GLP tox
optimization
• Candidate
STING Solid tumors • Ph. I initiation
nomination
2021 2022+
2 Clinical stage assets 3+ Clinical stage assets
2 Human PoCs 3+ Human PoCs
7+ Early pipeline programs 10+ Early pipeline programs
30Ryvu investment highlights
Developing small molecule therapies which address high value emerging
targets and pathways in oncology Near term milestones
RVU120
Diverse pipeline targeting kinases, synthetic lethality and immuno-oncology Additional Phase I data in AML at ASH2021
Initial solid tumor data in H1 2022
First-in-class selective CDK8 inhibitor (RVU120) with potential across
multiple indications
SEL24(MEN1703)
Validation from strategic collaborations including Phase II – new data at ASH2021
partnership with Menarini on SEL24(MEN1703)
NEAR TERM MILESTONES:
New programs expected to enter
Extensive early stage pipeline delivering near term clinical candidates the clinic in 2022+
Robust internal drug discovery engine and partnership options Additional near-term PC and late
for early-stage candidates discovery targets
Limited cash burn thanks to non-dilutive grants and cost-efficient discovery Partnering deals in the early pipeline
platform, significant resources located in Poland
31Appendix
32Excellent on-target activity of RVU120 in pSTAT positive AML cell models
RVU120 is a potent and selective CDK8/CDK19 inhibitor pSTAT1/pSTAT5 levels discriminate responder/ non-responder
p-STAT5 Ser726
Low nM activity on CDK8/CDK19
and excellent kinase selectivity (broad kinome)
RESPONDERS NON-RESPONDERS
(WESTERN BLOT, PROTEIN QUANTIFICATION)
p-STAT1 Ser727
RELATIVE INTENSITY
• Spares CDK2, CDK4, CDK6, CDK7, CDK9, etc.
• Type I, ATP-competitive mechanism of binding and inhibition RESPONDERS NON-RESPONDERS
of CDK8/19 activity
• Lack of binding to off-targets potentially associated
with toxicity of pre-clinical EMD Serono CDK8/19 inhibitors
(such as JNK1 or GSK3b)1
• Higher selectivity based on comparison of gene expression effects2
• Composition of matter patents granted in 2017
1Chen et al. 2019
2Rzymski et al. 2017
33RVU120 induces complete regression and bone marrow recovery in AML
In CD34+ AML patient-derived xenografts
PDX cells NSG mice
Vehicle / RVU120
Dose: 45mg/kg
Leukemia burden analysis
17 days latency Daily treatment 29/30 days
P20: CD34+ NPM1wt
COMPLETE REGRESSION HEMATOLOGIC RECOVERY REDUCED
(PERIPHERAL BLOOD) (BONE MARROW) SPLENOMEGALY
TUMOR GROWTH KINETICS BONE MARROW SPLEEN
PERIPHERAL BLOOD
SPLEEN WEIGHT [mg]
%mCD45+
%hCD45+
RVU
120
CONTROL RVU120 CONTROL RVU120
DAYS
Research performed at:
34RVU120 strongly synergizes with venetoclax
RVU120 potentially addresses
treatment resistant disease through
safe, indirect MCL-1 downregulation in cancer cells MV-4-11 cells IV NSG mice RVU120+Venetoclax
Daily, PO, 21 days
Leukemia burden
analysis
HEMATOLOGIC RECOVERY
COMPLETE REGRESSION
(BONE MARROW)
Compelling potential
for RVU120 in combination
with Venetoclax
35Contact data
Ryvu Therapeutics S.A.
www.ryvu.com
ryvu@ryvu.com
36You can also read
