Turning the Tide on Cancer
January 2021
Forward-Looking Statements
Certain statements in this presentation are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as "anticipate," "believe," "forecast," "estimated" and "intend" or other similar terms or expressions that concern our expectations, strategy, plans or intentions. These forward-looking statements are based on our current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, our need for additional financing; our ability to continue as a going concern; clinical trials involve a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results; our clinical trials may be suspended or discontinued due to unexpected side effects or other safety risks that could preclude approval of our product candidates; risks related to business interruptions, including the outbreak of COVID-19 coronavirus, which could seriously harm our financial condition and increase our costs and expenses; uncertainties of government or third party payer reimbursement; dependence on key personnel; limited experience in marketing and sales; substantial competition; uncertainties of patent protection and litigation; dependence upon third parties; our ability to develop tests, kits and systems and the success of those products; regulatory, financial and business risks related to our international expansion and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. There are no guarantees that any of our technology or products will be utilized or prove to be commercially successful. Additionally, there are no guarantees that future clinical trials will be completed or successful or that any precision medicine therapeutics will receive regulatory approval for any indication or prove to be commercially successful. Investors should read the risk factors set forth in our Form 10-K for the year ended December 31, 2019, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and we do not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances.
Investment Highlights
3rd Generation, 1st-in-class,
Oral PLK1 Inhibitor
Onvansertib overcomes the shortcomings of prior PLK inhibitors:
- Highly selective for PLK1
- Orally administered
- 24-hourhalf-life
- Flexible dose and schedule
Specifically targets a known mechanism of cell division that is required for tumor cell viability
Preliminary clinical data demonstrate the safety, tolerability and efficacy of onvansertib in combination with SOC across multiple indications
Strong Lead Program in KRAS-mutated mCRC
Supported by compelling preliminary clinical data from a Phase 1b/2 trial showing a ten-foldimprovement in ORR compared to SOC
Preclinical data support:
- MOA of synthetic lethality between KRAS mutant mCRC and PLK1 inhibition
- Synergy with irinotecan and 5-FU
First Indication: 2nd line treatment in patients who have failed 1st line treatment with FOLFOX with/without bevacizumab
FDA Fast Track Designation
Integrated Biomarker
Strategy
Circulating Tumor DNA: changes in KRAS mutational burden in blood are predictive of subsequent tumor shrinkage (mCRC)
Circulating Tumor Cells: changes are predictive of overcoming anti- androgen resistance (mCRPC)
Circulating Tumor DNA: changes are predictive of decreases in leukemic bone marrow cells (AML)
Diversified Pipeline Across
Numerous Cancers
Clinical data from ongoing trials support the use of onvansertib in combination regimens across numerous aggressive cancers:
- mCRC Phase 1b/2 trial
- mCRPC Phase 2 trial
- AML Phase 2 trial
Potential expansion opportunities:
- Chronic myelomonocytic leukemia
- Pancreatic cancer
- Triple negative breast cancer
- Lung cancer
- Ovarian cancer
PLK: Polo-like Kinase; SOC: Standard-of-care; ORR: Overall response rate; MOA: Mechanism of action; mCRC: metastatic colorectal cancer;
mCRPC: metastatic castration resistant prostate cancer; AML: Acute myeloid leukemia
2020 Corporation Presentation I 3
Experienced Management Team With Drug Development and Biomarker Technology Expertise
Mark Erlander, PhD | Vicki Kelemen | |||||
Chief Executive Officer | Chief Operating Officer | |||||
Brigitte Lindsay
Vice President of Finance
2020 Corporation Presentation I 4
Onvansertib
3rd generation, 1st in class, oral and highly selective PLK1 inhibitor addressing unmet needs across a broad range of cancer indications
PLK1 is a Proven Therapeutic Target that is Overexpressed in Most Cancers
- PLK1 is a serine/threonine kinase and master regulator of cell-cycle progression
- PLK1 controls G2/mitosis (G2/M) checkpoint
- Inhibition of PLK1 causes mitotic arrest and subsequent cell death
- Emerging data demonstrate that PLK1 is also a key regulator of cellular functions beyond mitosis that are essential for tumor growth:
- Biosynthesis of DNA
- DNA Damage Response
1Zitouni et al., Nat Rev Mol Cell Biol. 2014 Jul;15(7):433-52; PLK1: Polo-like kinase 1
Inhibition of PLK1 causes mitotic arrest
and subsequent cell death1
2020 Corporation Presentation I 6
PLK1-Specific ATP Competitive Inhibitor1
Biochemical Profile |
Profile Characteristics
Co-crystal of Onvansertib with PLK1
Enzyme | IC50 (μM) |
PLK1 | 0.002 |
PLK2 | >10 |
PLK3 | >10 |
CK2 | 0.4 |
FLT3 | 0.4 |
CDK1/CycB | 3.8 |
42 additional kinases in house | >10 |
>190 additional kinases in the | >10 |
Millipore panel | |
Small Molecule
Formulation
Plasma Protein Binding
Metabolic
Overview
Pharmacokinetics3
MW 648.60 Daltons
5mg and 20mg oral gelcaps
95% at 10μM and 91% at 50μM
Moderate intrinsic clearance (9.3 mL/min/kg)1
2 metabolites identified in metabolic profiling in low quantities (parent drug accounted for 93% of total drug-related material)1
No Cytochrome P450 inhibition at therapeutic concentrations2
Systemic exposure of drug increased with dose, as shown by an increase in Cmax and AUC0-24
Tmax is approximatively 3h Half-life is approximately 24h
Substituted by His in
PLK2 and PLK3
•
Onvansertib •
•
1Valsasina Mol Cancer Ther 2012
A selective, ATP competitive PLK1 inhibitor
Selectivity is driven by polar interaction with the side chain of Glu140 of PLK1 Interaction is hampered in both PLK2 and PLK3 where Glu140 is replaced by histidine
2020 Corporation Presentation I 7
Onvansertib has Optimal Drug Properties and Synergistically Combines with Standard-of-Care Therapies
Optimal Drug Properties
Synergistic in Combination with Standard-of-
Care Chemo and Targeted Therapies
Demonstrated
Safety and
Tolerability
Predictive
Biomarker
Oral
Administration
High Selectivity
For PLK1
Onvansertib
24-hourHalf-life
Synergistic in
Combination
Flexible Dosing
and Scheduling
Ideal
Pharmacokinetics
Taxol®
(paclitaxel)
Venclexta® (venetoclax)
Camptosar®
(irinotecan)
5-FU
Beleodaq®
(belinostat)
Zytiga®
(abiraterone)
Onvansertib
Velcade®
(bortezomib)
Avastin®
(bevacizumab)
Cytarabine
Doxorubicin
Cisplatin
Gemzar®
(gemcitabine)
2020 Corporation Presentation I 8
Second-Line Treatment of KRAS-Mutated mCRC
Phase 1b/2 open-label trial of onvansertib + FOLFIRI/bevacizumab
Trial Sites: USC Norris Comprehensive Cancer Center; Mayo Clinics (Arizona, Rochester, Jacksonville), Kansas University Medical Center, CARTI Cancer Center
Principal Investigator: Dr. Heinz-Josef Lenz
New Second-Line Therapies are Needed to Improve Response and Increase Progression-Free Survival
50% of patients with mCRC | Prognosis is poor with a five- | Other drugs currently in development |
have a KRAS mutation | year survival rate of 10% | do not address the most prevalent |
KRAS mutations in mCRC |
4%
Response
to SOC
5.5
Months
PFS
Significant limitations to standard-of-care (SOC)
Historically, second-linestandard-of-care treatment in KRAS-mutated mCRC has had an overall response rate of 4% and progression-free survival (PFS) of 5.5 months1
1Kubicka et al, Annals of Oncology 2013; 2342-2349; mCRC: Metastatic colorectal cancer
2020 Corporation Presentation I 10
KRAS is a Pivotal Diagnostic Biomarker in the CRC Treatment Paradigm
- KRAS-mutatedpatients do not benefit from anti-EGFR agents:
- No increase in OS, PFS and ORR was observed in KRAS mutant patients treated with EGFR inhibitors vs control arm1,2
- The use of anti-EGFRs is therefore limited to KRAS wild-type patients
- Mutations in KRAS represent also the most frequent mechanism of resistance to anti-EGFRs (i.e. cetuximab)
KRAS Mutant | KRAS Wild-type | Treatment Paradigm | |
mCRC | |||
KRAS | KRAS | ||
Mutant | Wild Type | ||
Chemotherapy ± | Chemotherapy + | ||
bevacizumab | EGFR inhibitor |
1Karapetis et al., NEJM 2008;359:1757-1765;2Amado et al., JCO 2008, 26:1626-1634
2020 Corporation Presentation I 11
Second-line Treatment: Real World Utilization in the US
Flatiron Health Data
255
Cancer clinics representing
1.7 million active cancer patients
14,315
Colorectal cancer patients
7,034
Colorectal cancer patients who
receive second line therapy
Source: Hess, L. International Journal of Colorectal Disease; 2019. Data is limited to limited to second-line regimens used in >1% of the cohort. FOLFOX:
fluoropyrimidine, leucovorin, oxaliplatin. FOLFIRI: fluoropyrimidine, leucovorin, irinotecan, FOLFOXIRI: fluoropyrimidine, leucovorin, irinotecan, oxaliplatin
Denotes combination with bevacizumab
Denotes combination with other antiangiogenics
2020 Corporation Presentation I 12
New Second-line mCRC Treatment is an Unmet Need
Outcomes for patients in the 2nd line setting is poor
- Efficacy of FOLFIRI: 4% ORR and 2.5 months PFS1
- Addition of bevacizumab to FOLFIRI improves outcomes2
- However, while KRAS WT patients benefit from the addition of bevacizumab, there was no statistically significant improvement in OS for KRAS-mutant patients3
KRAS | Treatment | ORR | PFS | HR and significance | OS | HR and significance of |
(months) | of PFS | (months) | OS | |||
FOLFIRI | 5% | 4.5 | HR=0.61 | 11.1 | HR=0.61 | |
KRAS WT | (95 % CI 0.49-077) | (95 % CI 0.53-0.90) | ||||
FOLFIRI + Bev | 7% | 6.4 | 15.4 | |||
P <0.0001 | P=0.0052 | |||||
KRAS | FOLFIRI | 3% | 4.1 | HR=0.70 | 10 | HR=0.92 |
(95 % CI 0.56-0.89) | (95 % CI 0.71-1.18) | |||||
MUTANT | FOLFIRI + Bev | 4% | 5.5 | 10.4 | ||
P = 0.0027 | P=0.4969 | |||||
1Tournigand et al., JCO 2004;22(2):229-3; 2Bennouna et al., Lancet Oncol. 2013; 14(1):29-37; 3Kubicka, S, Annals of Oncology 2013, 24:2342-2349; CI: | 2020 Corporation Presentation I 13 |
confidence interval, HR: hazard ration, ORR: objective response rate, PFS: progression-free survival, OS: overall survival, WT: wild-type, MUT: mutant |
Magnitude of Response with Other Antiangiogenic Therapy
The anti-angiogenic agents aflibercept and ramucirumab have been approved in combination with chemotherapy in 2nd line treatment, although they are used to a much lesser extent than bevacizumab
Trial | Agent/ARM | Patients | ORR | 95% CI of ORR (%) |
VELOUR Sub-group1 (received | FOLFIRI + | 643 (325 FOLFIRI | 11.8% | 6.7 - 16.9 |
first line therapy and | ||||
aflibercept | +aflibercept) | |||
bevacizumab) | ||||
RAISE2 | FOLFIRI + | 1361 | 13.4%* | 10.7 - 16.6 |
ramucirumab | ||||
* 20% of patients were Asian, which has higher response rate |
1Van Cutsem et al., Target Oncology 2016, 11:383-4002Tabernero et al., Lancet Oncology 2015;16:499-508
2020 Corporation Presentation I 14
Synthetic Lethality: Cells with KRAS Mutations are Hypersensitive to Inhibition of PLK1
The output of the RAS-mutated pathway activates PLK1, which is inhibited by onvansertib
Onvansertib Addresses KRAS Mutation | Cell Viability in Onvansertib-Treated KRAS Mutant | |
Subtypes in mCRC | and Wild Type Isogenic CRC Cells |
2% | 1% | |||
6% | 6% | |||
8% | 39% | |||
18%
22%
G12D G12V G13D G12C G12S G12A Q61H G12R
PLK1: Polo-like Kinase 1; mCRC: Metastatic colorectal cancer
2020 Corporation Presentation I 15
PLK1 and RAS Cooperative Relationship
RAS activates PLK1 through a MEK/ERK-independent mechanism
The downstream target of KRAS, pCRAF, localizes to the mitotic spindle poles at mitosis where it interacts with PLK1 and promotes PLK1 activation, leading to mitosis and tumor progression1
Data suggest that KRAS-activated cells are dependent on PLK1 for their proliferation and survival and inhibition of PLK1 by onvansertib could inhibit tumor growth
1Mielgo et al., Nat. Med. 2011; 17(12):1641-5
RAS
RAF
P
P
MEK
P
ERK
Onvansertib
P
CRAF PLK1
PLK1 Activity
Mitotic Progression
Proliferation/Survival
2020 Corporation Presentation I 16
Synergy: Onvansertib in Combination with SOC Irinotecan and 5-FU
Onvansertib works synergistically in combination with standard-of-care FOLFIRI (irinotecan and 5-FU)
HCT-116 (with G13D KRAS mutation)
Synergy in Combination with Irinotecan | Synergy in Combination with 5-FU | ||
2020 Corporation Presentation I 17
PLK1 Regulates DNA Damage Response1,2
DNA Damaging | G2/M Arrest | |
Agents | ||
DNA Damage
Response
(DDR) arrests cells at G2/M checkpoint
• Irinotecan
• 5-FU
1van Vugt & Yaffe, Cell Cycle 2010 9:2097-2101;2van Vugt et al., 2010, PLoS 8:1-19
Mitosis
- Checkpoint adaptation
- PLK1 inhibits DDR, induces mitotic entry for tumor cells & cell division
Cell Death
- Keeps tumor cells in G2/M arrest leading to apoptosis
- For cells that escape, mitosis is blocked, also leading to apoptosis
2020 Corporation Presentation I 18
Phase 1b/2 Open Label Trial of Onvansertib + FOLFIRI/bevacizumab
Trial Design
1 CYCLE = 28 Days | |||||||||||
Treatment Course = 14 Days | Treatment Course = 14 Days | ||||||||||
1 | 2 | 3 | 4 | 5 | 6 - 14 | 1 | 2 | 3 | 4 | 5 | 6 - 14 |
Onvansertib | Onvansertib | ||||||||||
FOLFIRI + bevacizumab | FOLFIRI + bevacizumab | ||||||||||
Efficacy Endpoints
- Overall response in patients who receive ≥1 cycle (2 courses) of treatment
- Progression-freesurvival (PFS)
- Decreases in KRAS mutation burden and response to treatment
What is Clinical Trial Success
- ≥5 of 26 (~20%) patients achieve clinical response confirmed by radiographic scan
- Achieve median progression-free survival of ≥ 6 months
2020 Corporation Presentation I 19
Phase 1b Enrollment and Patient Baseline Characteristics
Dose Escalation Patient Cohorts
(as of 06-Jan-2021)
Number of | Dose Level 0 | Dose Level +1 | Dose level +2 |
Onvansertib | Onvansertib | Onvansertib | |
patients (N) | |||
12 mg/m2 | 15 mg/m2 | 18 mg/m2 | |
Completing 1st | |||
6 | 6 | 6 | |
cycle | |||
Currently on | 0 | 3 | 2 |
Treatment | |||
- Phase 1b: 3+3 dose escalation design to assess the safety of the combination and identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of onvansertib
Total patients N=18 | Median [range] or n (%) |
Age (years) | 59 [37-83] |
Sex | |
Male | 8 (44%) |
Female | 10 (56%) |
ECOG | |
0 | 8 (44%) |
1 | 10 (56%) |
Primary tumor site | |
Colon | 9 (50%) |
Rectum | 7 (39%) |
Unknown | 2 (11%) |
Liver metastasis | |
None | 7 (39%) |
Liver and other | 8 (44%) |
Liver only | 2 (17%) |
Number of metastatic organs | |
1 | 7 (39%) |
≥2 | 11 (61%) |
Prior Bevacizumab treatment | |
Yes | 13 (72%) |
No | 5 (28%) |
2020 Corporation Presentation I 20
Phase 1b Safety Assessment
Most Common Treatment-Emergent AEs
Adverse Events (AEs) | Grade | Grade | Grade | Grade | All | • | 5 patients had G4 adverse events: | |
1 | 2 | 3 | 4 | Grades | - | 1 patient had a G4 neutropenic fever at dose level 12 mg/m2 | ||
Fatigue | 4 | 7 | 1 | 0 | 12 | |||
- | 1 patient had a G4 neutropenia at dose level 15 mg/m2 | |||||||
Nausea | 8 | 3 | 1 | 0 | 12 | |||
- | 3 patients had a G4 neutropenia dose level 18 mg/m2 | |||||||
Neutropenia | 1 | 2 | 4 | 4 | 11 | |||
Diarrhoea | 7 | 2 | 0 | 0 | 9 | • The onvansertib RP2D was confirmed at 15 mg/m2 | ||
Alopecia | 6 | 1 | 0 | 0 | 7 | |||
Abdominal pain | 1 | 4 | 1 | 0 | 6 | • | The combination regimen was well tolerated: | |
Anaemia | 4 | 1 | 0 | 0 | 5 | |||
WBC decrease | 2 | 3 | 0 | 0 | 5 | |||
- | Of all AEs only 8% (17/202) were G3/G4 | |||||||
Vomiting | 3 | 1 | 1 | 0 | 5 | |||
- | The only G3/G4 AE reported in ≥2 patients were | |||||||
Stomatitis | 4 | 1 | 0 | 0 | 5 | |||
neutropenia (n=8); which was managed by dose delay, | ||||||||
Thrombocytopenia | 2 | 2 | 0 | 0 | 4 | |||
growth factor and/or discontinuation of the 5-FU bolus; | ||||||||
Mucosal inflammation | 1 | 2 | 0 | 0 | 3 | |||
no patients went off trial due to neutropenia | ||||||||
Dyspepsia | 3 | 0 | 0 | 0 | 3 | |||
ALT increased | 2 | 1 | 0 | 0 | 3 | • | No major or unexpected toxicities were attributed to | |
Abdominal distension | 3 | 0 | 0 | 0 | 3 | |||
onvansertib | ||||||||
Back pain | 3 | 0 | 0 | 0 | 3 | |||
Epistaxis | 3 | 0 | 0 | 0 | 3 |
n=number of patients (total N=18); WBC=white blood cells; ALT= alanine aminotransferase
2020 Corporation Presentation I 21
Phase 1b Preliminary Efficacy
18 mg/m2 15 mg/m2 12 mg/m2
Treatment Response and Duration | Changes in Tumor Size From Baseline |
(as of 06-Jan-2021) | 100 | 01-003 | |||||||||||||||||||||||||
→ Treatment ongoing | |||||||||||||||||||||||||||
weeks | 02-004 | ||||||||||||||||||||||||||
8weeks | weeks weeks | weeks | weeks weeks weeks | 80 | |||||||||||||||||||||||
40 | |||||||||||||||||||||||||||
01-007 | 16 | 24 | 32 | 48 | 56 | 64 | Reason for discontinuation | change% in target fromlesionsbaseline | PD | 02-005 | |||||||||||||||||
60 | |||||||||||||||||||||||||||
02-008 | Stable Disease (SD) | 01-011 | |||||||||||||||||||||||||
01-006 | Curative surgery | 01-006 | |||||||||||||||||||||||||
01-003 | ⊗ | Patient/MD decision | 40 | ||||||||||||||||||||||||
02-004 | Treatment-unrelated AE | 20 | 01-007 | ||||||||||||||||||||||||
02-005 | ⊗ | 02-008 | |||||||||||||||||||||||||
01-010 | Radiographic assessment | 0 | SD | ||||||||||||||||||||||||
⊗ | 01-010 | ||||||||||||||||||||||||||
01-011 | |||||||||||||||||||||||||||
→ | Partial Response (PR) | -20 | |||||||||||||||||||||||||
01-019 | |||||||||||||||||||||||||||
02-012 | → | Progressive Disease (PD) | -40 | PR | 02-012 | ||||||||||||||||||||||
-60 | |||||||||||||||||||||||||||
01-013 | → | Onvansertib dose adjustments | 01-013 | ||||||||||||||||||||||||
02-016 | 01-014 | ||||||||||||||||||||||||||
01-014 | Baseline | weeks | weeks | weeks | weeks | weeks | weeks | weeks | weeks | ||||||||||||||||||
Dose level -1 | 02-016 | ||||||||||||||||||||||||||
02-015 | Dose level +1 | ||||||||||||||||||||||||||
0 | 28 | 56 | 84 | 112 | 140 168 196 224 | 252 280 308 336 | 364 392 420 | 448 476 | 8 | 16 | 24 | 32 | 40 | 48 | 56 | 64 | |||||||||||
Received bevacizumab in 1st line | |||||||||||||||||||||||||||
Days of treatment | |||||||||||||||||||||||||||
- 18 patients were treated in Phase 1b (6 patients at each dose level); 2 patients discontinued during cycle 1; 2 patients have completed cycle 1 but have not had their first 8-week scan
- 12 of 14 (86%) patients evaluable for efficacy* achieved a clinical benefit (SD + PR)
- 5 (36%) patients have achieved a partial response (PR)
- 4 patients had a confirmed PR; 1 patient went on to have curative surgery
- 1 patient with non-confirmed PR went off study following PR due to treatment-unrelated AE
- Time to achieving a PR ranges from 2 to 6 months in patients on treatment
*completed at least 1 cycle of treatment and had radiographic scan or progressed within 8 weeks while on treatment
2020 Corporation Presentation I 22
KRAS Mutant Allelic Frequency (MAF) Biomarker Analyses
% KRAS MAF Decrease Following 1 Treatment Cycle
KRAS MAF Over Time
PR | SD | PD | ||||||||||
MAF at baseline | 0 | |||||||||||
% change in KRAS Cycle 2 Day 1 from | -50 | |||||||||||
75% decrease | ||||||||||||
-100 | ||||||||||||
-004-010-005-007-013 | -016-019-012-011-006 | -008-015 | ||||||||||
02 | 01 02 | 01 | 01 | 02 01 | 02 | 01 | 01 | 02 | 02 |
50 | |
(%) | 40 |
MAF | 30 |
KRAS | 20 |
10 | |
0 |
C1D1C1D7C2D1C3D1C4D1C5D1C6D1C7D1C8D1C9D1
Visit
02-004 KRAS G13D | |||
02-005 KRAS G12V | PR | ||
01-010 KRAS G12A | |||
01-007 KRAS G12D | |||
01-013 KRAS A146T | |||
01-006 KRAS G12V | |||
01-011 KRAS G12D | |||
02-012 KRAS G12V | SD | ||
02-016 KRAS G12D | |||
01-019 KRAS G12D | |||
02-008 KRAS G12C | PD | ||
02-015 KRAS G12D | |||
- KRAS MAF was measured by digital droplet PCR (ddPCR) at baseline (Cycle 1 Day 1, pre-dose) and on-treatment (Day 1 of Cycles 2 to 9)
- 12 of 14 patients had a KRAS mutation detected by ddPCR at baseline (all had a KRAS mutation detected by NGS)
- Clinical responses were observed across different KRAS mutations, including the 3 most common in CRC (G12D, G12V, G13D)
- The greatest decreases in KRAS MAF after 1 cycle of treatment were observed in patients achieving a PR (all patients had >75% decrease) and SD (4 of the 5 patients had reductions >75%), the 2 patients who progressed showed a more modest decrease in KRAS MAF (-55% and -26%)
PR: partial response, SD: stable disease, PD: progressive disease; CXD1: Cycle X Day 1
2020 Corporation Presentation I 23
Conclusions
- Safety Assessment:
- The combination of onvansertib and FOLFIRI/Bev is well-tolerated
- Onvansertib RP2D was established at 15 mg/m2
- Preliminary Efficacy:
- 12 of 14 (86%) patients evaluable for efficacy achieved a clinical benefit (SD + PR)
- 5 (36%) patients achieved a partial response (PR), including 4 confirmed PRs; 1 patient proceeded to curative surgery
- KRAS Mutant Allelic Frequency (MAF) Biomarker:
- Clinical responses were observed across different KRAS variants, including the 3 most common in CRC
- Patients achieving a PR or SD showed the greatest decreases in plasma mutant KRAS after one cycle of therapy
- Phase 2:
- Further assess the safety and efficacy of onvansertib at the RP2D in combination with FOLFIRI + bevacizumab
- Evaluate the value of KRAS liquid biopsy to predict treatment response
2020 Corporation Presentation I 24
KRAS-Mutated mCRC Expanded Access Program (EAP)
- Program initiated in June 2020 and first patients were enrolled in July / August
- Treatment regimen: onvansertib 15 mg/m2 + FOLFIRI/bevacizumab
- Eligibility criteria includes:
- Patients not eligible for clinical trial (including patients who have received multiple lines of treatment)
- Patients who have previously been treated with FOLFIRI (with or without bevacizumab)
- Findings from first 9 patients enrolled in July / August 2020:
- 6 of 9 (66%) patients have shown tumor shrinkage and remain on treatment to-date with durable response lasting ~6 months (all 9 patients received prior FOLFIRI-based regimen)
- Of the 6 patients showing tumor shrinkage, 5 different KRAS mutations were represented (G12A, G12C, G12V, G13D, A146T)
- Changes in KRAS mutant allelic frequency (MAF) in patients after the first cycle of treatment are predictive of subsequent tumor shrinkage (as seen in the clinical trial)
- No serious adverse effects (SAEs) have been reported to-date
2020 Corporation Presentation I 25
Catalysts and Milestones: KRAS-Mutated mCRC
Positive Phase 1b/2 results may provide an opportunity for a Phase 2b registrational trial
May 2020: Fast Track | September 2020: ESMO | January 2021: ASCO-GI | Q1 2021: FDA meeting to |
discuss regulatory path | |||
Designation | presentation | presentation | |
(anticipated) | |||
mCRC: Metastatic colorectal cancer
2020 Corporation Presentation I 26
Metastatic Castration-Resistant Prostate Cancer
Phase 2 open-label trial of onvansertib + abiraterone
Trial Sites: Beth Israel Deaconess, Dana Farber, Mass General Hospital
Principal Investigator: Dr. David Einstein
New Therapeutic Options are Needed to Overcome Resistance to SOC Androgen Receptor Signaling Inhibitors (ARSi)
Resistance develops to treatment with standard | ARSi's offer a median overall survival | No effective treatment options are |
of care ARSi's within 9-15 months1 | (mOS) benefit of only ~4 months1 | available for the up to 40% of mCRPC |
patients with an AR-V7 mutation2 |
9-15
Months until
ARSi resistance
~4
Month mOS
benefit
Limited options for patients once resistant to abiraterone
New treatment options are needed to extend the duration of response to ARSi's and increase overall survival
1Antonarakis, Emmannel - Current Understanding of Resistance to Abiraterone and Enzalutamide in Advanced Prostate Cancer; Clinical Advances in Hematology & Oncology - May 2016 - Volume 14, Issue 5; 2Armstrong et al., 2019, JCO 37: 1120-1129; SOC: Standard-of-care; mCRPC: Metastatic castration resistant prostate cancer
2020 Corporation Presentation I 28
Onvansertib Extends the Response to Androgen Receptor
Signaling Inhibitors
Onvansertib works synergistically in combination with abiraterone (Zytiga®) and significantly increases mitotic arrest
Onvansertib + Abiraterone (Zytiga®) Demonstrate
Synergy in mCRPC model (C4-2)1
Onvansertib + Abiraterone (Zytiga®) Significantly
Increase Mitotic Arrest1
1Patterson & Yaffe, 2019, MIT; mCRPC: Metastatic castration resistant prostate cancer
2020 Corporation Presentation I 29
Phase 2 Open Label Trial in of Onvansertib + Abiraterone
Disease Control Assessed by PSA Stabilization
Trial Design:
Dosing Schedule | Duration | Efficacy Endpoint | |||
Cohort A (n = 24) | |||||
Onvansertib 24mg/m2 | Days 1-5(21-day cycle) + Zytiga® (Abiraterone) | 4 Cycles = 12 Weeks | Disease Control | ||
Cohort Closed | (PSA Stabilization or Decline) | ||||
Cohort B (n = 32) | Onvansertib 18mg/m2 | Days 1-5(14-day cycle) + Zytiga® (Abiraterone) | 6 Cycles = 12 Weeks | Disease Control | |
(PSA Stabilization or Decline) | |||||
Cohort C (n = 32) | Onvansertib 12mg/m2 | Days 1-14(21-day cycle) + Zytiga® (Abiraterone) | 4 Cycles = 12 Weeks | Disease Control | |
(PSA Stabilization or Decline) | |||||
Eligibility Criteria
Initial resistance to Zytiga; 2 consecutive rises in PSA levels
Efficacy Endpoint:
Internationally Recognized Prostate Cancer Working Group
- Primary: disease control evaluated as PSA decline or stabilization (PSA rise <25% over baseline)
What is Clinical Trial Success
- ~30% patients achieve primary efficacy endpoint of disease control at 12 weeks (PSA stabilization or decrease); confirmed by radiographic scan
- Achieve median radiographic PFS of ≥6 months
Note: radiographic assessment by RECIST v1.1 [CR = disappearance of all target lesions, PR = ≥30% decrease, PD = ≥20% increase, SD = does not
meet criteria for PR nor PD]; mCRPC: Metastatic castration resistant prostate cancer; PSA: Prostate specific antigen; PFS: Progression-free survival
2020 Corporation Presentation I 30
Patient Baseline Characteristics and Enrollment Status
Patient Baseline Characteristics
Total patients N=39 | Median [range] or n (%) | |
Age in Years | 72 [54-87] | |
Nonwhite Ethnicity | 5 | (13%) |
ECOG | ||
0 | 34 (87%) | |
1 | 5 | (13%) |
Years Since Diagnosis | 5 | [1-18] |
Grade Groups 4 and 5 | 24 (62%) | |
De Novo Metastatic Disease | 13 (33%) | |
Presence of Bone Metastasis | 33 | (85%) |
Presence of Visceral Metastasis | 13 | (33%) |
Baseline PSA, ng/mL | 12.5 [0.6-224] | |
AR-V7+ at Baseline* | 9 | (23%) |
Baseline CTC Count per mL of blood** | 2.2 [0-87] |
ECOG: Eastern Cooperative Oncology Group, AR-V7: androgen receptor variant
7, CTC: circulating tumor cells
*AR-V7 status was evaluated using the EPIC and Johns Hopkins University testing platforms **CTC count was performed by EPIC
Enrollment as of October 16th, 2020
Number of patients (N) | Arm A | Arm B | Arm C |
Treated | 24 | 11 | 4 |
Currently on Treatment | 1 | 1 | 4 |
Completing 12-weeks | 14 | 8 | 3 |
Discontinued before 12 weeks | 10 | 2 | 0 |
Progressive Disease (PD) | 3 | 1 | 0 |
Adverse Event | 5 | 1 | 0 |
Withdrew Consent | 2 | 0 | 0 |
Patients evaluable for efficacy | 17 | 9 | 3 |
(completed 12 weeks + PD) | |||
2020 Corporation Presentation I 31
Phase 2 Data Demonstrate the Safety and Efficacy of Onvansertib in mCRPC
Safety Assessment
Adverse events | Grade 1 | Grade 2 | Grade 3 | Grade 4 | All grades |
Total Patients N=39 | |||||
Anemia | 10 | 5 | 1 | 16 | |
Thrombocytopenia | 11 | 1 | 1 | 13 | |
Fatigue | 10 | 2 | 12 | ||
Neutropenia | 1 | 1 | 7 | 3 | 12 |
Hypophosphatemia | 3 | 3 | 4 | 10 | |
WBC decrease | 2 | 2 | 3 | 2 | 9 |
Back pain | 2 | 3 | 5 | ||
Hypokalemia | 3 | 1 | 1 | 5 | |
Constipation | 4 | 0 | 4 | ||
Nausea | 3 | 1 | 4 | ||
- Most frequent Grade 3 and 4 adverse events (AEs) were expected, on-target, hematological associated with onvansertib mechanism of action
- Hematological AEs were reversible and effectively managed by dose delay, dose reduction and/or growth factor support
2020 Corporation Presentation I 32
Phase 2 Data Demonstrate the Efficacy of Onvansertib and and Durability of Response Including Patients with AR Alterations
Efficacy Evaluation at 12-Weeks
Total Patients Evaluable N=29 | Arm A | Arm B | Arm C |
Evaluable for efficacy* | 17 | 10 | 4 |
Treatment Response and Duration for Patients
Completing 12 Weeks of Treatment
Completed 12-week treatment | 14 | 8 | 4 |
Progressed within 12 weeks | 3 | 2 | 0 |
Disease control** | 5 (29%) | 3 (30%) | 3 (75%) |
Radiographic stable disease | 9 (53%) | 5 (50%) | 4 (100%) |
Durable response (>7 months) | 4 (23%) | 4 (40%) | NA |
- Completed 12 weeks of treatment or progressed within 12 weeks
- Defined as PSA stabilization or decline (PSA rise <25% over baseline)
Arm B (5+9) Arm C (14+7)
Arm A (5+16)
03-043
01-044
02-045
02-046
01-025
01-026
03-030
01-024
02-041
01-033
03-039
02-042
01-014
03-017
03-037
01-021
02-036
03-013
02-003
03-004
02-007
03-023
03-009
01-019
03-028
02-020
months | months months1 | year | ||
year | ||||
. | ||||
3 | 6 | 9 | 5 | |
1 |
→
→
→
→
0 | 100 | 200 | 300 | 400 | 500 | 600 |
Days of treatment |
PSA endpoint
Partial response
Stable disease Radiographic Progressive disease assessment
Physcian decision | Reason for | |
Patient decision | discontinuation | |
Adverse event* | other than PD |
- Ongoing
Transitioned to Arm B
AR-V7+
AR T878A AR alterations AR Amplification
202020CorporationPresesentationI I3333
Phase 2 Data Demonstrate the Efficacy of Onvansertib and Durability of Response Including Patients with AR Alterations
Treatment Response and Duration for Patients
Completing 12 Weeks of Treatment
Efficacy in patients with AR alterations:
- 8 of the patients evaluable for efficacy had at least 1 AR alterations: AR-V7+ (n=6), AR T878A mutation (n=2) and/or AR amplification (n=3)
- 3 (37%) patients achieved disease control
- 4 (50%) patients had radiographic stable disease
- 3 patients had durable responses (range 7-9 months)
*AR-V7 status was evaluated using the EPIC and Johns Hopkins University testing platforms. Genomic profiling of circulating tumor DNA was performed using Gardant360® test
Arm B (5+9) Arm C (14+7)
Arm A (5+16)
03-043
01-044
02-045
01-025
01-026
03-030
01-024
02-041
01-033
03-039
02-042
01-014
03-017
03-037
01-021
02-036
03-013
02-003
03-004
02-007
03-023
03-009
01-019
03-028
02-020
months | months | months year | . | ||
year | |||||
6 | 5 | ||||
3 | 9 | 1 | 1 |
→
→
→
0 | 100 | 200 | 300 | 400 | 500 | 600 |
Days of treatment |
PSA endpoint | ||
Partial response | Radiographic | |
Stable disease | ||
assessment | ||
Progressive disease | ||
Physcian decision | Reason for | |
Patient decision | discontinuation | |
Adverse event* | other than PD |
- Ongoing
Transitioned to Arm B
AR-V7+
AR T878A AR alterations AR Amplification
2020 Corporation Presentation I 34
Onvansertib-Induced Circulating Tumor Cell Decrease is Associated with Progression-Free Survival
Circulating tumor cell (CTC) count, reported as favorable or unfavorable (<5 versus ≥5 CTC/7.5mL of blood, respectively) is a
prognostic factor for survival in CRPC - conversion from unfavorable to favorable is associated with improved survival
Percent Change in CTC: 12-Weeks vs Baseline in Patients with Unfavorable CTC Level at Baseline
At baseline, 27 (73%) of 37 patients had unfavorable CTC count; 10 were analyzed following 12 weeks of treatment:
-
5 (50%) patients had an ≥80% CTC decrease, including 2
AR-V7+ patients (01-024 and 01-025) - 4 (40%) patients converted from unfavorable to favorable CTC level, including 3 patients with no detectable CTC
- Median time on treatment was 9.2 months for patients with CTC decrease (n=5) vs 4.9 months for patients with CTC increase (n=5)
CRPC: Castration resistant prostate cancer
2020 Corporation Presentation I 35
Identifying an Onvansertib-Abiraterone Response Gene Signature
Onvansertib/Abiraterone
• Synergy study | Abiraterone induces expression of | Identification of an |
• RNA-sequencing | mitotic genes in prostate cancer | Abi/Onv synergy gene signature |
cells synergistic for Onv+Abi | ||
Identified 4 molecular subtypes: | Abi/Onv synergy gene signature is | |
• Luminal A | enriched in the Basal subtype, a subtype | |
Transcriptome analysis of 32,000 | • Luminal Proliferating | representing ~30% of CRPC patients and |
• Basal | associated with lower response to | |
prostate cancer specimens | • Basal Immune | androgen deprivation therapy (ADT) |
Currently analyzing archived | Transcriptome analysis with | |
tissue from patients enrolled | Correlate clinical response with | |
in the trial | Decipher Biosciences | Basal molecular subtype |
2020 Corporation Presentation I 36
Catalysts and Milestones: mCRPC
Positive Phase 2 results may provide an opportunity for a Phase 2b registrational trial
October 2020: Prostate | February 2021: ASCO- | April 2021: AACR | Q3 2021: FDA meeting to |
Cancer Foundation (PCF) | GU presentation (planned) | presentation (planned) | discuss regulatory |
pathway (anticipated) | |||
2020 Corporation Presentation I 37
New Clinical Programs Planned
Chronic Myelomonocytic Leukemia (CMML) Pancreatic Ductal Adenocarcinoma (PDAC)
Phase 2 Study to Evaluate the Safety and Efficacy of Onvansertib in RAS- Pathway Mutant CMML
Study Rationale
- Proliferative CMML is enriched for activating RAS pathway mutations such as NRAS, KRAS, CBL, PTPN11 and NF1, all of which have been associated with adverse outcomes
- RAS pathway mutations drive proliferative CMML via a novel RAS-KMT2A-PLK1 axis, which can be therapeutically targeted with PLK1 inhibitors
- In-vitroand in-vivo experiments with onvansertib as a single agent have shown a dose-dependent inhibition of CMML cell growth, with improved cell differentiation
Activating RAS Pathway Can Be Therapeutically
Targeted with PLK1 Inhibitors
PLK
1
2020 Corporation Presentation I 39
Phase 2 Two-Arm Randomized Trial of Onvansertib +/- Decitabine in RAS-Pathway Mutated CMML
Determine the safety and efficacy of onvansertib, a novel oral PLK1 inhibitor in RAS-pathway mutant chronic myelomonocytic leukemia
Trial Design:
Dosing Schedule | Duration | Efficacy Endpoint | ||
Two Arms: | ||||
Onvansertib 15 mg/m2 | Days 1-14 | 3 cycles monotherapy (option to add | Interim analysis of first 18 patients after | |
Arm A (n=32) Treatment Naïve | decitabine at cycle 4 if lack of efficacy | |||
(21-day cycle) | 3 cycles to evaluate objective response | |||
Arm B (n=32) Relapsed/Refractory | with single agent) | |||
Eligibility Criteria:
- Newly diagnosed or relapsed/refractory to prior therapy
- RAS pathway mutant: NRAS, KRAS, PTPN11, CBL and NF1 with frequency allele of ≥5%
Efficacy Endpoint:
- Rate of complete remission (CR)
What is Clinical Trial Success
- Achieve ≥25% CR rate in treatment naïve cohort
- Achieve ≥12.5% CR rate in the relapsed and refractory cohort
402 2020CorporationPresesentationI I40
Phase 2 Study of Onvansertib in Combination with 5-FU and Nal-IRI for Second Line Treatment of KRAS-Mutated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)
Study Rationale
- KRAS is the most common oncogene mutated in pancreatic adenocarcinoma, which is present in ~95% of tumors
- Mutant KRAS is essential for PDAC growth, where the constitutive activated RAS proteins contribute to tumorigenesis, treatment resistance and metastases
- No effective RAS inhibitors have been approved for the treatment of KRAS-mutated pancreatic cancer
Metastatic Pancreatic Cancer Patients
Have Poor Outcomes
• Significant need for new effective second line treatment option
2020 Corporation Presentation I 41
Phase 2 Open Label Trial of Onvansertib + 5-FU and Nanoliposomal Irinotecan in KRAS-Mutated PDAC
Trial Design (~40 patients):
1 CYCLE = 14 Days
Treatment Course (Days)
1 | 2 | 3 | 4 | 5 | 6 - 14 |
Onvansertib 15 mg/m2
5-FU + Nanoliposomal Irinotecan (nal-IRI)
Eligibility Criteria
- Prior abraxane/gemcitabine and no prior irinotecan or Nal-IRI
Efficacy Endpoints
- Best overall response (complete response [CR] or partial response [PR]) and disease control rate (CR, PR or stable disease [SD])
- Progression-freesurvival (PFS) rate at 6 months
- Overall survival (OS)
- Reduction in KRAS allelic burden in liquid biopsies
What is Clinical Trial Success
- Achieve ≥26% overall response rate (ORR) - 9 out of 35 patients
- Achieve ≥36% progression free survival rate at 6 months - 13 out of 36 patients
2020 Corporation Presentation I 42
Corporate
Strong Patent Portfolio
Core Technology: 3 Issued Patents to 2030 in US, Europe and Asia, with anticipated extension to 2035
Compound (onvansertib): US 8614220
Salt forms of onvansertib: US 8648078
Combinations with anti-neoplastic compounds: US 8927530
PLK: Polo-like kinase; PSA: Prostate specific antigen
Evergreening: Combination Therapy
Exclusive license from MIT for 2 US issued patents with broad method claims for combination of PLK inhibitor + anti- androgen compounds to treat any cancer
US 9566280; US 10155006; Expiration 2035
Evergreening: Biomarkers
Method for assessing PLK1 target phosphorylation status for identifying patients to be treated with PLK1 inhibitors
PCT US1948044, Expiration 2039
Method for treating patient with a PLK inhibitor when there is a PSA rise
Provisional, Expiration 2040
2020 Corporation Presentation I 44
Cardiff Oncology At-A-Glance
Clinical-stage biotech company, developing onvansertib, an oral, highly-selectivePolo-like Kinase 1 (PLK1) inhibitor, to treat cancers with the greatest medical need for
new effective therapies
Exchange | Nasdaq: CRDF |
Cash & Cash Equivalents (as of 10/31/20) | $131.8M |
Q1 - Q3, 2020 Average Quarterly Cash Burn | $3.8M |
Headquarters | San Diego, CA |
2020 Corporation Presentation I 45
Investment Highlights
3rd Generation, 1st-in-class,
Oral PLK1 Inhibitor
Onvansertib overcomes the shortcomings of prior PLK inhibitors:
- Highly selective for PLK1
- Orally administered
- 24-hourhalf-life
- Flexible dose and schedule
Specifically targets a known mechanism of cell division that is required for tumor cell viability
Preliminary clinical data demonstrate the safety, tolerability and efficacy of onvansertib in combination with SOC across multiple indications
Strong Lead Program in KRAS-mutated mCRC
Supported by compelling preliminary clinical data from a Phase 1b/2 trial showing a ten-foldimprovement in ORR compared to SOC
Preclinical data support:
- MOA of synthetic lethality between KRAS mutant mCRC and PLK1 inhibition
- Synergy with irinotecan and 5-FU
First Indication: 2nd line treatment in patients who have failed 1st line treatment with FOLFOX with/without bevacizumab
FDA Fast Track Designation
Integrated Biomarker
Strategy
Circulating Tumor DNA: changes in KRAS mutational burden in blood are predictive of subsequent tumor shrinkage (mCRC)
Circulating Tumor Cells: changes are predictive of overcoming anti- androgen resistance (mCRPC)
Circulating Tumor DNA: changes are predictive of decreases in leukemic bone marrow cells (AML)
Diversified Pipeline Across
Numerous Cancers
Clinical data from ongoing trials support the use of onvansertib in combination regimens across numerous aggressive cancers:
- mCRC Phase 1b/2 trial
- mCRPC Phase 2 trial
- AML Phase 2 trial
Potential expansion opportunities:
- Chronic myelomonocytic leukemia
- Pancreatic cancer
- Triple negative breast cancer
- Lung cancer
- Ovarian cancer
PLK: Polo-like Kinase; SOC: Standard-of-care; ORR: Overall response rate; MOA: Mechanism of action; mCRC: metastatic colorectal cancer;
mCRPC: metastatic castration resistant prostate cancer; AML: Acute myeloid leukemia
2020 Corporation Presentation I 46
Thank You
for more information contact: ir@cardiffoncology.com
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Cardiff Oncology Inc. published this content on 15 January 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 15 January 2021 16:47:05 UTC