Targeted Cancer Therapies Beyond PARP – Next Generation DDR Therapeutics
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ProNAi Therapeutics A clinical ‐ stage drug • We are an ambitious oncology drug development company oriented to development company registration and commercialization. advancing targeted cancer • We have a world ‐ class management team therapies with a proven track record in oncology drug development. • We are building a broad and diverse pipeline NASDAQ: DNAI of promising assets against emerging targets on the leading edge of cancer biology. Headquarters: Vancouver, BC Development: San Francisco, CA • Our two product candidates, PNT737 and PNT141, target the DNA Damage Response IPO: July 2015 (DDR) network, a scientifically validated approach with broad potential across Shares (30/9/16): 30.35M outstanding oncology. 36.98M fully diluted • Our DDR program expands beyond PARP Cash on hand (30/9/16): $122.7M* inhibitors, to provide for broader clinical and commercial opportunity. *$7.0M upfront fee to CPF paid subsequent to the end of the quarter 3
Our Pipeline of ‘Next Generation’ DDR Therapeutics Preclinical Preclinical Phase 1 Phase 1 Phase 2 Phase 2 Targeting Checkpoint kinase 1 (Chk1) Phase 1 Monotherapy Adult solid tumors, Currently enrolling Phase 1 Combination Adult solid tumors, Currently enrolling Targeting Cell division cycle 7 (Cdc7) Plan to file IND H2 2017 4
Beyond PARP: Our DNA Damage Response (DDR) Program
Our DNA is Under Constant Attack • Our DNA is continuously subject to damage through a variety of endogenous and exogenous mechanisms. 6
The DDR Network Detects & Repairs Damaged DNA • The DDR network is a system of cellular pathways that monitor and repair DNA damage to maintain genomic integrity throughout the cell cycle. • The DDR comprises cell cycle checkpoints, which temporarily inhibit cellular replication to repair damaged DNA. 7
Burgeoning Scientific Validation for Targeting DDR Focus Issue: DNA Damage Repair June 2016 June 2016 8
Industry Validation of DDR’s Potential in Cancer: PARP Inhibitors Lead The Way May 2016 9
Clinical Proof of Concept for Drugging the DDR: Key Data Summary PARP inhibitor: • 14/16 (88%) response rate in metastatic prostate in a retrospective olaparib analysis of biomarker positive patients with DDR mutations. Wee1 inhibitor: • 2 PRs in SCLC; both patients had mutations in TP53 and RB1, one also had AZD1775 BRCA1 mutation. • 2 PRs in monotherapy: 1 PR head ‐ and ‐ neck had BRCA mutation, 1 PR in ovarian had BRCA mutation. • 27% PR rate in combo with carboplatin in p53 mutated ovarian cancer refractory/resistant to carboplatin + paclitaxel. ATR inhibitor: • 4 PRs (17%), 12 SDs (52%) in combination with cisplatin in platinum VX740 resistant or refractory ovarian cancer with no patient selection/enrichment. CHK1/2 inhibitor: • 5/13 PRs (38%) response rate in high grade serious ovarian cancer, non LY2606368 BRCA mutated. CHK1/2 inhibitor: • Durable 3+ year CR in combinations with irinotecan in invasive small cell AZD7762 cancer of the ureter having RAD50 and p53 mutations. CHK1 inhibitor: • 1 CR (ongoing >9 months) in sarcoma with lung metastases; 1 PR (lasted GDC ‐ 0575 >1 year) in p53 mutated leiomyosarcoma with extensive metastases; both in combination with low dose gemcitabine. 10
ProNAi’s DDR Program: Expanding Beyond PARP • PARP inhibitors are intended to prevent the repair of DNA single strand breaks. • Our DDR program expands beyond the scope of PARP inhibitors. • We focus on impeding the repair of DNA double strand breaks, the most deleterious form of DNA damage, as well as by striking at targets that control DNA replication and cell cycle progression. 11
Cancer’s Genomic Instability: Over ‐ Reliance on Key Cell Cycle Checkpoints • Replication stress induced by oncogenic drivers (e.g. MYC and RAS) combined with loss of function in tumor suppressors (e.g. p53 and ATM) results in persistent DNA damage and genomic instability. • Cancer cells tolerate genomic instability and elevated DNA damage via an over ‐ reliance on checkpoints such as Chk1 and Cdc7. 12
ProNAi’s DDR Approach: Targeting an Achilles’ Heel of Cancer • Synthetic lethality may be achieved in these genetically mutated cancer cells by inhibiting Chk1 and Cdc7, remaining components of the DDR network that are now essential to replication. • Many standard chemotherapeutic agents also induce DNA damage and may be synergistic with Chk1 and Cdc7 inhibitors. 13
Our Next Generation DDR Portfolio: PNT737 & PNT141 • Highly ‐ selective small molecule inhibitor • Highly ‐ selective small molecule inhibitor of the serine ‐ threonine kinase of the serine ‐ threonine kinase Cell Checkpoint kinase 1 (Chk1). division cycle 7 (Cdc7). • Chk1 is a central regulator of the DDR • Cdc7 is a key regulator of DNA replication network and of multiple cell cycle and the DDR network. checkpoints. • Broad development scope in solid and • Oral bioavailability of PNT737 affords liquid tumors. greater flexibility in dosing strategies • Mono ‐ and combo ‐ therapy development compared to IV agents. potential. • Currently in two Phase 1 clinical trials in • Clinical studies expected to begin by the patients with advanced cancer. end of 2017. 14
Our DDR Program: Significant Potential in Oncology Chemotherapy Combinations with DNA damaging chemotherapy DDR Monotherapy DDR Combinations Exploit replicative Synergy with other stress and genetic DDR targeting agents instability for to maximize DNA synthetic lethality damage Radiotherapy Immuno ‐ Oncology Sensitize to ionizing radiation DDR targeting agents coupled with immune activation 15
PNT737 Targeting Chk1
PNT737: Best ‐ In ‐ Class Pedigree Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London Discovered and initially developed by Clinical development currently taking scientists at: place in facilities funded by: • The Cancer Research UK Cancer • Cancer Research UK (CRUK) Therapeutics Unit at The Institute • The National Institute for Health of Cancer Research (ICR) Research (NIHR) Biomedical Research • Sareum Holdings Centre (BRC) at The Royal Marsden and ICR • The Experimental Cancer Medicine Centre Network 17
PNT737: Best ‐ In ‐ Class Characteristics Criterion PNT737 LY2606368 Presentation: Oral i.v. Biochemical IC 50 : Chk1 1.4 nM ~1 nM Biochemical IC 50 : Chk2 1850 nM 8 nM 10 mg/kg in BALB/c mice Selectivity: Chk1 vs. Chk2 1320x ~10x • PNT737 is orally bioavailable, potent, and highly HT29 CRC selective for Chk1 over Chk2. • PNT737 selectivity: 15/124 kinases at 10 µM ERK8 = 100x All other kinases >200x CDK2 = 2750x • PNT737 has an excellent PK profile, CDK1 = 6750x and demonstrates robust efficacy in numerous in vivo cancer models as a single agent and in combination. Cmin 18
PNT737 Targets Chk1 – A Critical DDR Component • DNA damage can be resolved by several complementary mechanisms that are activated by DNA damage sensing factors. • Homologous recombination repair (HRR) is an error ‐ free repair process employed in response to double strand breaks and collapsed replication forks. • One of Chk1’s functions is as a critical component of the HRR machinery. 19
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