Targeted therapeutics - at the forefront of oncology CORPORATE PRESENTATION - Ryvu Therapeutics
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Targeted therapeutics
at the forefront of oncology
CORPORATE PRESENTATION
April 2021
Note on the presentation and forward looking statements
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2
Ryvu at a glance
Developing small molecule therapies which address high value emerging targets and pathways in oncology
• Diverse pipeline with mechanisms of action spanning kinase inhibition, RNA transcription, synthetic lethality (WRN, cancers with MTAP-deletion)
and immuno-oncology (STING, HPK1)
• Initial focus of pipeline on hematological malignancies, with near term expansion planned in solid tumors
Wholly owned, first-in-class, selective oral CDK8/19 inhibitor (RVU120) with therapeutic potential in multiple indications and clinical
data in 2021 in Phase Ib study
• Applicable across indications: acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), hematological and solid tumors
• Trial in lead indication (AML/MDS) enrolling across 6 sites in USA with first data available in H1 2021, solid tumor study starting in H1 2021
First-in-class dual PIM/FLT3 kinase inhibitor (SEL24) for Acute Myeloid Leukemia (AML) in Phase II - partnered with Menarini
• Dual-targeting of PIM and FLT3 designed to facilitate broader activity and potentially more durable responses
• Single agent efficacy shown in relapsed/refractory AML patients with acceptable safety profile demonstrated in Phase I
Broad early-stage pipeline delivering potential near-term clinical candidates and robust internal drug discovery engine (130 FTEs)
• Significant pipeline momentum with strong bet on synthetic lethality (first-in-class and best-in-class) targets and two I-O programs (STING, HPK1)
• Deep discovery capability and track-record in generating clinical candidates; validated by partnerships including Galapagos and Merck
Listed on Warsaw Stock Exchange, market cap of $257m1
• One of the largest drug discovery companies in the region, headquartered in Kraków, Poland
• ~$40m cash position2 and significant non-dilutive grant funding (>$25m secured till 2023)
3
1 24 March 2021. Exchange rate (NBP): $1=PLN3.90
2 10 March 2021
Broad pipeline addressing emerging targets in oncology
4
Strong momentum continues since the current strategy was adopted
2019
OCTOBER Corporate spin-out of Selvita (CRO) from Ryvu Therapeutics completed, >$100m incremental value created
for Ryvu shareholders
MARCH SEL24 – successfully completed Phase I in acute myeloid leukemia patients, FDA approval for Phase II
MARCH RVU120 – orphan drug designation in AML by FDA
APRIL Collaboration with Galapagos in inflammatory disorders announced
JUNE
Ryvu spin-out company NodThera raises $55m Series B funding
2020
JUNE SEL24 Phase I data at EHA 2020, RVU120 and pre-clinical posters at EHA and AACR 2020
JULY Completed construction and move into a new fully-owned $20m research center in Krakow
JULY PLN143m ($38m) raised in a follow-on public offering
SEPTEMBER First patient dosed in Europe with SEL24 in Phase II study
JANUARY Clinical Trial Application filed for RVU120 study in solid tumors in Europe
2021
JANUARY Clinical Trial Application approved for RVU120 AML/MDS Phase Ib sites in Europe
FEBRUARY Secured $5.5m non-dilutive grant funding for RVU120 in solid tumors
5
RVU120: Highly selective first-in-class CDK8/CDK19 inhibitor
with broad potential in hematological malignancies and solid tumors
Orphan drug designation in AML Therapy Acceleration Program
in 2020 (TAP) grant support
Total funding - $3.25m
RVU120
New treatment options Emerging therapeutic opportunities
in hematological disorders in solid cancers
BLOOD CANCERS BLOOD
• Direct cytotoxicity (induction of apoptosis) SOLID TUMORS
DISORDER • Precise, targeted mode of action
• Eradication of Leukemic Stem Cells (LSC) by transcriptional regulation
known to be responsible for tumor relapse AML DIAMOND-BLACKFAN BREAST of cancer-dependent genes
ANEMIA
in AML • Preclinical data to support broad
JAK2 mut
• Preclinical data indicate safe COLORECTAL potential in multiple solid tumors
AML/MPN
and synergistic combination with unmet medical needs
with standard-of-care chemotherapy • Modulation of immune cell activity
MDS PROSTATE
and approved targeted therapies (NK cells) as additional component
• Opportunity in another orphan indication of anticancer activity
(Diamond-Blackfan anemia) ALL, NHL OTHER
6
First therapeutic area of Ryvu focus: acute myeloid leukemia
Most common, highly aggressive type of acute leukemia in adults with poor outcomes in most patients1
~20,000 new cases diagnosed
Only
and >11,000 deaths in the US in 20182 AML
34%3 20%
patients
aged >80 receive
AML makes up 1% of all cancers Leukemia intensive
therapy5
and 34% of all adult leukemia cases2,3 61,000 US pts / yr3
Occurs in a predominantly elderly, frail patient population;
75% of patients diagnosed with AML were aged >60 years4
~$1,300m
Lowest survival among all blood cancers;
AML Market5
~$600m
only 26% patients surviving 5 years after diagnosis
2020 2025
$8.0 billion ~$500m
$1.2 billion
30% AML patients with an ITD mutation in the FLT3 gene 46%
have a less favorable prognosis, 70% of patients refractory ~$400m
CAGR
to current inhibitors targeting FLT3 mutation
~$300m
1 Mayo Clinic
2 Cancer.net ~$300m
3 Leukemia & Lymphoma society
4 Walter, R; Leukemia 2015
5 Evaluate Pharma
7
Clinical landscape: targeted small molecule therapies for AML
CDK8/CDK19 • RVU120 IS THE ONLY CDK8/CDK19
INHIBITOR IN CLINICAL DEVELOPMENT
FLT3
• SEL24(MEN1703) IS A UNIQUE,
Dual PIM/FLT3 CLINICAL-STAGE DUAL PIM/FLT3
INHIBITOR
PIM
RYVU CLINICAL PROGRAMS DESIGNED
IDH1 or IDH2
TO FULFILL UNMET NEEDS IN AML
OVERCOMING RESISTANCE TO SINGLE-TARGET
MUTATION-SPECIFIC INHIBITORS
Others
EFFICACY IN BROADER PATIENT POPULATIONS
REDUCING CHEMOTHERAPY-BASED
Phase 1/2 Phase 3 Approved TREATMENT REGIMENS
FULLY ORAL REGIMEN
8
RVU120: potential role of CDK8/CDK19 in AML treatment
RATIONALE FOR CDK8/CDK19 INHIBITORS IN AML
o Transcriptional deregulation is a hallmark of AML
o CDK8 is a kinase subunit of the Mediator complex serving as a bridge
between basal transcription and regulatory elements involved in:
⁻ Deregulation of super enhancers (SE)
⁻ Affected differentiation and pro/anti-apoptotic genes
EFFICACY OF RVU120 - CDK8/CDK19 INHIBITOR - IN AML
o Selectively targets leukemic cells, sparing normal blood cells
(unaffected normal hematopoiesis)
o Promotes cell death (differential cytotoxicity on STAT5+ AML)
o Represses increased levels of anti-apoptotic proteins
and induces lineage commitment genes in undifferentiated AML
cells
9
Excellent 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
10RVU120 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 BODY WEIGHT SPLEEN
Body Weight CHANGE
Change BONE MARROW
± SEM
PERIPHERAL BLOOD
SEM
5
[%]
change [%]
SPLEEN WEIGHT [mg]
0
weightCHANGE
%mCD45+
%hCD45+
-5
WEIGHT
-10
RVU
body
120
BODY
-15
Vehicle, QD, po
Mean
SEL120, 45 mg/kg QD, po
MEAN
-20
0 5 10 15 20 25 30
CONTROL RVU120 CONTROL RVU120
DAYS DAYS
Day of administration
Research performed at:
11RVU120 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
12RVU120: Phase Ib study – first patient dosed in September 2019
Phase 1b Study of RVU120 in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome
STUDY POPULATION: PRIMARY OBJECTIVE: SECONDARY OBJECTIVE: EXPLORATORY OBJECTIVE:
1 • Patients with relapsed 2 3 • To evaluate pharmacokinetics
4
• To assess safety and tolerability • To evaluate pharmacodynamics
/refractory AML or high risk MDS • To determine the recommended dose • To evaluate the preliminary
• No upfront patient stratification anti-leukemic activity
PROJECT MILESTONES STATUS AND PLANS
INITIAL RESULTS FROM PHASE Ib 6 ACTIVE SITES IN USA IN 2020 SITE EXPANSION
H1 2021
• 2 SITES IN POLAND – CTA APPLICATION APPROVAL
OBTAINED IN JANUARY 2021
H2 2021 FINAL RESULTS FROM PHASE Ib • EU & ASIA-PACIFIC SITES UNDER CONSIDERATION
H1 2022 PHASE II IN AML/MDS
2022+ INTERIM RESULTS FROM PHASE II
13RVU120 study design in AML/MDS and further plans
H2 2019-2020 Q1-Q3 2021 2022 START
PART 1: ESTABLISHING RECOMMENDED PHASE 2 DOSE (RP2D) EVALUATION PART 2: SAFETY EXPANSION PHASE II
EXPANSION FROM THE SINGLE PATIENT SAFETY, 6
COHORT TO A 3+3 DESIGN EFFICACY, PATIENTS AML SINGLE AGENT
DLTs evaluated at completion of cycle 1 in each cohort PK, PD
AML COMBINATION
Average of 24 PATIENTS
Front line : Triplet with Venetoclax
COHORT 1 MDS SINGLE AGENT
COHORT 2 SINGLE ORAL DOSE, EOD RP2D SAFETY
MDS COMBINATION
7 DOSES/CYCLE MTD EXPANSION Front Line with SOC HMAs
COHORT 3
3 WEEKS CYCLE
UP to 8
COHORTS
14Positioning of RVU120 in AML treatment regimen and strategic expansion
AML TREATMENT PROTOCOL RYVU STRATEGY FOR DEVELOPMENT
UNFIT PATIENTS OF RVU120 IN AML/MDS
RYVU STRATEGY
NO RELEVANT MUTATION - POSITIONING IN THIRD+ LINE TREATMENT
MUTATIONS DRIVEN • Monotherapy
STAGE 1
• Patients unfit for intensive chemotherapy
• Relapsed/refractory AML, high risk MDS
LOW LOW TARGETED
FIRST LINE INTENSITY INTENSITY OR
THERAPY
CHEMOTHERAPY CHEMOTHERAPY POSITIONING IN SECOND/THIRD LINE
• Monotherapy and combination with SoC
• Combo with Venetoclax or chemotherapies
LOW STAGE 2
RELAPSED/REFRACTORY • Patients unfit for intensive chemotherapy
INTENSITY TARGETED THERAPY
CHEMOTHERAPY
• Relapsed/refractory to frontline or follow up
treatment AML, high risk MDS
RVU120 RVU120 RVU120 POSITIONING IN FIRST LINE TREATMENT
+ + • Combination (doublet or triplet) with SoC
LOW INTENSITY TARGETED STAGE 3 • Regimen e.g. with Venetoclax+Azacitidine
CHEMOTHERAPY THERAPY • Patients unfit for intensive chemotherapy
(e.g. Azacitidine) (e.g. Venetoclax) • First line, treatment naïve, AML/MDS
15RVU120 beyond blood cancers: potential role of CDK8/CDK19 in solid tumors
TNBC BREAST AND COLORECTAL CANCER MODELS
RVU120: expansion plan in multiple solid tumors and
other heme malignancies
Phase I start: 2021, preliminary results: 2022
AML AML/MPN
Mediator
complex JAK2
Gene mutation
transcription NK cells and CDK8/CDK19 inhibitors have potential in multiple solid tumors
macrophage • Ryvu confirmed in vitro or in vivo potential in breast, colorectal and prostate cancer
T-ALL Notch JAK/STAT response against
Unique MoA differentiates CDK8/CDK19 from other CDK family members
signaling STAT1 multiple tumors
STAT3 • Do not interfere
COLORECTAL CANCER
with cell cycle MODEL
progression (like CDK1, CDK2, CDK4/6)
CDK8 STAT5 • Unique across family mediator of transcriptional reprogramming (induction of silent genes,
not physiological transcription) preventing metastasis and drug-resistance
• Different stratification of responders and biomarkers of response
SOX4 • First generation of CDK8/19 inhibitors unsuccessful due to toxic off-target effects and
WNT/ TNF/NFKB suboptimal PK/PD profile
β-catenin ER-
dependent
Pancreatic TGFβ/BMP genes Breast CDK8/19 inhibitors designed to provide targeted and safer treatment options
colorectal ->SMAD cancer • Selective targeting cancer cells while sparing healthy ones
cancer • (e.g. CDK4/6, CDK9 affect both normal and cancer cells – possible cytopenias, no bone marrow
recovery)
• Selective regulation of transcription in a cancer gene specific context
Prostate, • (e.g. CDK7/9 involved in general transcriptional programs of normal genes)
colorectal,
breast cancer
16
Chart inspired by Pharmaceuticals 2019, 12,92 + Ryvu dataRVU120: expansion plan in multiple solid tumors and other heme malignancies
– preliminary plan
Phase I start: 2021, preliminary results: 2022
H2 2020 2021 2022
PART 2: EFFICACY & SAFETY EXPANSION
SCREENING PART 1: ESTABLISHING RECOMMENDED DOSE SIMON 2-STAGE
EVALUATION
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 ALL ST COMERS PFS at 9 months
SINGLE ORAL DOSE EOD
COHORT 2
+NHL RP2D
COHORT 3 7 DOSES/CYCLE determined Overall survival
NO MORE THAN
3 WEEK CYCLE follow-up:
3 PRIOR THERAPIES REMAINING UP TO 3
+ 10 2 years
FOR ENTRY DISEASE COHORTS OTHER ST
PATIENTS
TYPES
SAFETY, Go no go decision to enroll next 10 patients
EFFICACY,
based on RECIST ORR after cycle 3
PK, PD
17SEL24(MEN1703) is a differentiated, first-in-class PIM/FLT3 dual kinase inhibitor
Dual targeting creates potential for broader activity, Potential for treating patients that have relapsed on selective
PIM and FLT3 are
1 2 more durable responses than selective FLT3 inhibitors 3 FLT3 inhibitors - PIM kinases are largely responsible
oncogenes involved in AML
such as gilteritinib for the development of resistance to FLT3 inhibitors
VALUE THROUGH
ONGOING CLINICAL TRIALS
GLOBAL DEAL WITH
DEVELOPED BY RYVU UP TO INITIATION Study title: A Phase I/II Study of SEL24 in Patients
OF CLINICAL STUDIES AND OUT-LICENSING With Acute Myeloid Leukemia
• Partnered globally with Menarini in 2017
TOP 40 global pharma company, based in Italy INITIAL RESULTS OF THE PHASE I STUDY:
• Menarini is fully responsible for clinical development • Determined the recommended Phase II dose (RP2D), the PK profile and the single
and funds translational research at Ryvu agent activity in R/R or newly diagnosed AML patients
• Study results published at EHA 2020 Conference in June 2020
$5.6m UPFRONT PAYMENT • Ryvu has received $1.9m milestone payment for successful completion
of Phase I studies
TOTAL POTENTIAL VALUE OF MILESTONES PHASE II PROGRESS
$104m & REFUND OF R&D COSTS • Ongoing cohort expansion at the recommended dose to confirm the safety profile
and assess drug efficacy at 14 clinical sites in the U.S. and in Europe (Poland, Italy,
UP TO DOUBLE-DIGIT ROYALTIES FOR RYVU
xx% FROM MENARINI
Spain)
• First patients dosed in the US. (July 2020) and Europe (September 2020)
• Planned study completion in 2021
18Initial Phase I data for SEL24(MEN1703) demonstrates compelling single agent efficacy
Acceptable safety data with complete responses observed
ESTABLISHED RECOMMENDED PHASE II DOSE RESULTS
EXPANSION FROM THE SINGLE PATIENT COHORT TO A 3+3 DESIGN
Establishment of recommended dose and evaluation
DLTs evaluated at completion of cycle 1 in each cohort of safety profile
INDIVIDUAL TREATMENT DURATION • SEL24 has acceptable safety profile up to 125mg
• RD defined at 125mg
25mg 001–001
003–002 CRi—CR with incomplete hematologic recovery • Treatment-Emergent Adverse Events – mostly
003–003
50mg 003–009 CR—Complete Remission hematologic or infectious. Transient peak in
003–010
002–004
75mg 004–011 transaminases was detected by C1 D14 in almost all
004–012
003–005 cohorts (Grade ≤2 and reversible in the 7 days OFF
004–013
100mg 005–014 treatment period up to the RP2D )
002–015
003–016
004–017
003–018
004–019
004–020
Objective response / single agent efficacy
125mg 003–021
004–022 in patients without FLT3 mutation
004–023
004–024
001–006
• Complete remission at 75mg in a 81 y.o. patient, with
002–007
150mg 003–008 DNMT3A/IDH2 mutant AML progressed on enasidenib
005–025
• Complete response with incomplete hematological
0 1 2 3 4 5 6 7 8
(Number of Cycles Completed) recovery at 125mg in a 75 y.o. patient with ASXL1/EZH2
PATIENTS mutant AML relapsed after chemotherapy and decitabine
N=25 patients treated FREQUENT MUTATIONS
22 patients evaluable • 2 newly diagnosed ▪ 5 (20%) FLT3/ITD.
(cut-off date 11-Feb-20) • 11 primary refractory AML ▪ 4 (16%) DNMT3A
• 12 relapsed AML ▪ 4 (16%) IDH1 Confirmed pS6 biomarker inhibition
68 years median age ▪ 2 (8%) IDH2
(range 25-84) ▪ 2 (8) NMP1
19Differentiated internally discovered small-molecule drug candidates and new programs
BEST IN CLASS FIRST IN CLASS
STING HPK1 SYNTHETIC LETHALITY
Novel Biology Insights
Current challenges
• First generation intratumoral STING agonists provided • Unique dual potential to modulate both innate
limited signs of clinical efficacy and adaptive anti-cancer immunity • Synthetic lethality arises when simultaneous
• Limited possibilities to reach multiple metastasis • Synergistic enhancement of T and DC cells mutations of gene pairs lead to cell death, whilst
with IT agonists function simultaneously making T cells resistant individual mutations does not cause a lethal
• Refractory STING alleles to first generation STING agonists to immunosuppression effects
do not cover whole patient population
Differentiation
Cancer Targets
• Direct, small molecule STING agonists • Hematopoietic progenitor kinase 1 • MTAP deletion cancers
• Active in multiple human STING haplotypes (HPK1, MAP4K1) • WRN helicase in MSI high and other tumors
• Anti-tumor efficacy after systemic administration • Important in regulation of the signaling cascade • Multiple other undisclosed targets
in preclinical mouse models on par or superior to competitors triggered by TCR activation in lymphocytes T
• Potentially multiple tumor types
Competitive
Competitive
agents
agents
milestone
milestone
Next
• Initiate IND enabling studies (2021) • Non-GLP toxicology (H1 2022) • Lead selection (>2021)
Next
• File IND (2022)
20Small molecule, direct, systemic STING agonists with strong anti-tumor efficacy
EXPECTED VALUE
RYVU APPROACH INFLECTION POINTS
STATUS CANDIDATE SELECTION STAGE PRECLINICAL CANDIDATE
H1 2021
SELECTION
▪ Small molecule, systemic, direct STING
APPROACH H2 2021 INITIATION OF IND STUDIES
agonists amenable to ADC technology
CURRENT DIFFERENTIAL ▪ Superior in vitro activity and anti-tumor efficacy
FACTORS ▪ Suitable either for systemic or targeted delivery H1 2022 IND FILING
IP RIGHTS STATUS ▪ Several patent applications covering broad 2022+
chemical estate filed, initial FTO confirmed CLINICAL TRIALS
KEY DIFFERENTIATION
Small molecule, direct, systemic STING agonists with multiple routes
of administration (IV, SC, IT) allowing two tracks of development:
standalone systemic treatment
using targeted delivery as payload for antibodies
(antibody-drug conjugates ADC approach)
Systemic efficacy in mouse models on par with GSK reference (IV) and outperforming
Aduro/Novartis agonist (IT) accompanied with favorable safety profile
Active across multiple STING haplotypes to target broad patient population
Well protected IP and confirmed initial FTO space
21RVU-24024 lead compound shows superior in vivo efficacy
22Ryvu has selective, potent HPK1 inhibitors with anti-tumor efficacy in mice
RYVU APPROACH
RYVU SMALL MOLECULE HPK1 INHIBITORS SHOW EFFICACY IN MOUSE
STATUS LEAD OPTIMIZATION SYNGENEIC MODEL COMPARABLE TO CLINICAL REFERENCE COMPOUND
▪ Small molecule, selective, orally bioavailable
APPROACH inhibitors of HPK1 kinase activity
TAKEDA/
RVU-918 RVU-293 UHN GENENTECH INCYTE BAYER
ARIAD
▪ High selectivity against kinases from TCR pathway IC50 [nM] 1.0 1.4 2.7 0.55 4.5 33 2.9
CURRENT DIFFERENTIAL hHPK1
▪ Immunostimulatory activity in immunosuppresed, Ki [nM] 0.1 0.3 0.7 0.1 1.6 20.7 0.4
FACTORS resistant hPBMC and T cells across species
EFFICACY IN CT26 (MOUSE MODEL OF COLON CANCER)
CONTROLS UHN REFERENCE* RVU-293
MILESTONES FOR HPK1 INHIBITOR +anti-mPD1 5 mg/kg 75 mg/kg BID, 21 days 100 mg/kg BID, 21 days
D1, D4, D8, D11
COMBINATION WITH
+anti-mPD1 5 mg/kg +anti-mPD1 5 mg/kg
TGI = 24.4% TGI = 60.9%
2021 LEAD OPTIMIZATION
ANTI-mPD-1
TGI = 69.8%
H2 2022 PRECLINICAL DEVELOPMENT
2023 INITIATION OF IND-ENABLING STUDIES
2023+ IND FILING
*currently Treadwell Therapeutics, in phase I clinical trials
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
VALUE
INFLECTION 2021: demonstrated synthetic lethality
POINTS
Chan 2019
24Small molecules for MTAPdel cancers
MTAP deletion PROGRAM IN RYVU RYVU HAS IDENTIFIED UNIQUE INHIBITORS WITH CLEAR DIFFERENTIATION
AND STRATEGY VS CLINICAL COMPETITORS
MAT2A – the only pharmacologically
KEY RATIONALE
1
validated synthetic lethal target in context Several patentable chemical series,
of MTAP deletion confirmed biomarker inhibition
Dual approach, differentiated inhibitor
MoA of MAT2A and a confidential target #2
2
Best-in-class potential Full in vitro pharmacology cascade in
NOVELTY
Strong differentiation place, crystallography and in vivo
pharmacology up and running
MTAP deletions, up to 15% of all cancers, one
TOP TUMOR of the largest genetically defined population:
INDICATIONS pancreatic, lung, DLBCL, bladder, esophageal (by %: RYVU MAT2AS LHIT V - 2cmpd
5 3 0 8 -exhibits
01 synthetic lethal phenotype: 3
3 D s o ft a g a r a s s a y , 1 0 d a y s
differential activity in isogenic pair in HCT116 (3D)
mesothelioma, GBM) MAT2A: Strong selectivity vs putative
120
HCT116 W T TOX TARGET identified by Ryvu (to
MTAP and p16 status 100
H C T116 KO 14 possibly avoid Agios clinical DLT)
BIOMARKERS
SAM (plasma), SDMA (tissue) levels
% G ro w th
80
W T + 1 0 M M TA
60
Target #2 currently at hit ID and
confirmation stage
Target druggable with small molecules 40
DEVELOPABILITY
Selective MAT2A Ryvu inhibitors identified
20
VALUE 0
INFLECTION HIT ID and hit expansion -3 -2 -1 0 1 2
POINTS L o g ( C o n c . [ M ] )
HCT116 WT HCT116 KO14 WT + 10 M MTA
IC50 0.24 2.5 0.81
Span 2.4 95 83
25Broad 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 • Ph. II complete
(MEN1703) AML interim data
PIM / FLT3
AML / • Initial Ph. Ib data • Ph. II initiation
RVU120 MDS • Final Ph. Ib data • Interim data
CDK8 • Ph. Initiation • Ph. I Interim data
Solid tumors
• Ph. II initiation
• IND-enabling studies • Ph. I dose escalation
STING Solid tumors
• Lead
HPK1 Solid tumors • Non-GLP tox
optimization
• Lead optimization
WRN Solid tumors • Hit-to-lead
• IND-enabling
• Lead optimization
MTAP Solid tumors • Hit-to-lead
• IND-enabling
2021 2022+
2 Clinical stage assets 3+ Clinical stage assets
2 Human PoCs 3+ Human PoCs
7+ Early pipeline programs 10+ Early pipeline programs
26Ryvu R&D Center for Innovative Drugs
Move completed in July 2020
2017 August 2018 April 2020 June 2020 July 2020
Preparations for the investment; All labs and offices
Initiation Completion of major Obtained occupation permits,
obtaining a grant from the fully operational
of construction works construction works first laboratories launched
Ministry of Development
Usable area > 86,000 sq. ft Investment budget > $20m
of the Center
Value of the grant
from the Polish Ministry ~$9m
# workplaces ~300 associates
of Development
• Investment initiated in 2017 – before the corporate split from Selvita CRO
• Provides Ryvu with adequate and consolidated research infrastructure
• Has enabled the spin-out of Selvita (CRO) and value creation of >$100m for Ryvu
shareholders
• Ryvu has secured funds for investment from joint pre-split cash balance
* Exchange rate used – average NBP for 2019 – 1 USD = 3.8395 PLN
27Financial results & employment
$ million 2019 2020
# of employees
Revenues 8.9 9.6 Cash position
March 12, 2021
Partnering 1.0 4.0
$40M
Grants 7.8 5.5
Costs 20.7 18.7
EBIT -11.8 -9.2 Financing secured until
> 160 employees
EBITDA -9.7 -6.0 Q1 2023
CAPEX -9.8 -9.5
> 80 PhDs
28Covid-19 impact on Ryvu Therapeutics
Clinical trials:
• Industry risk: Clinical trials in locations impacted by Covid-19 such as the US has been by Covid-19 pandemic in multiple ways
(slow or suspended enrollment, difficulties in patient monitoring, delayed DRCs, etc.)
• Clinical studies provide patients suffering from life threatening disorders such as AML and hrMDS with potential new therapeutic options – risk/benefit management policies
are mainly dependent on individual site decisions
• Expected negative impact on enrollment – data availability in H1 2021 vs. Q4 2020 originally planned
Research operations:
• Poland has been one of the countries least impacted by Covid-19 in Europe in the first wave of Covid-19
• Second wave with much more serious impact started in Europe in the fall and Poland has been severely impacted
• Ryvu introduced the first risk Covid-19 management steps during the first wave and kept vigilance ever since
• Ryvu labs have been operating at ~90% capacity, now using extra space in the new research center to maximize social distancing
• 50% of non-lab associates work remotely
• Weekly rapid test of Ryvu employees to minimize risk of internal spread
• Outsourcing – limited capacity at some CROs. Key providers less impacted. Risk-management with Asia and European Asian CROs.
• More difficult and slower access to some research materials.
Other industry specific risks:
• Slowed-down business development (pharma demand)
• Market volatility and more difficult access to capital
29Ryvu investment highlights and near term milestones
Developing small molecule therapies which address high value emerging
targets and pathways in oncology
SEL24(MEN1703)
Phase 2 PoC data (2021)
Diverse pipeline targeting kinases, synthetic lethality and immuno-oncology
RVU120
First-in-class selective CDK8 inhibitor (RVU120) with potential across Phase 1 interim data (H1 2021)
multiple indications
Validation from strategic collaborations including partnership with Menarini New programs expected
on SEL24(MEN1703)
to enter the clinic in 2022
NEAR TERM MILESTONES:
Extensive early stage pipeline delivering near term clinical candidates
Additional near-term PC/
late discovery targets
Robust internal drug discovery engine and partnership options for early-stage candidates
Partnering deals
Limited cash burn thanks to non-dilutive grants and cost-efficient discovery
platform, significant resources located in Poland
in the early pipeline
30Contact data
Ryvu Therapeutics S.A.
www.ryvu.com
ryvu@ryvu.com
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