Targeted Cancer Therapies Beyond PARP Next Generation DDR - - PowerPoint PPT Presentation

Targeted Cancer Therapies

Beyond PARP – Next Generation DDR Therapeutics

Safe Harbor Statement

Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company’s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances that may cause events or the Company’s actual activities or results to differ significantly from those expressed in any forward-looking statement. In some cases, you can identify forward-looking statements by terminology such as “may”, “will”, “should”, “plan”, “predict”, “expect,” “estimate,” “anticipate,” “intend,” “goal,” “strategy,” “believe,” and similar expressions and variations thereof. Forward-looking statements may include statements regarding the Company’s business strategy, potential growth opportunities, clinical development activities, the timing and results of preclinical research, clinical trials and potential regulatory approval and commercialization of product candidates. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described under the heading “Risk Factors” in documents the Company has filed with the SEC. These forward-looking statements speak only as of the date of this presentation and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Certain information contained in this presentation may be derived from information provided by industry sources. The Company believes such information is accurate and that the sources from which it has been obtained are reliable. However, the Company cannot guarantee the accuracy of, and has not independently verified, such information. Trademarks: The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. 2

ProNAi Therapeutics

A clinical-stage drug development company advancing targeted cancer therapies

NASDAQ: DNAI Headquarters: Vancouver, BC Development: San Francisco, CA IPO: July 2015 Shares (30/9/16): 30.35M outstanding 36.98M fully diluted Cash on hand (30/9/16): $122.7M*

3

• We are an ambitious oncology drug

development company oriented to registration and commercialization.

• We have a world-class management team

with a proven track record in oncology drug development.

• We are building a broad and diverse pipeline
• f promising assets against emerging targets
• n the leading edge of cancer biology.
• Our two product candidates, PNT737 and

PNT141, target the DNA Damage Response (DDR) network, a scientifically validated approach with broad potential across

• ncology.
• Our DDR program expands beyond PARP

inhibitors, to provide for broader clinical and commercial opportunity.

*$7.0M upfront fee to CPF paid subsequent to the end of the quarter

Our Pipeline of ‘Next Generation’ DDR Therapeutics

4

Preclinical Phase 1 Phase 2

Targeting Cell division cycle 7 (Cdc7)

Phase 1 Monotherapy

Adult solid tumors, Currently enrolling

Phase 1 Combination

Adult solid tumors, Currently enrolling Plan to file IND H2 2017

Targeting Checkpoint kinase 1 (Chk1)

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

7

• 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.

Burgeoning Scientific Validation for Targeting DDR

8 Focus Issue: DNA Damage Repair June 2016 June 2016

Industry Validation of DDR’s Potential in Cancer: PARP Inhibitors Lead The Way

9

May 2016

ProNAi’s DDR Program: Expanding Beyond PARP

10

• 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.

Cancer’s Genomic Instability: Over-Reliance on Key Cell Cycle Checkpoints

11

• 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.

ProNAi’s DDR Approach: Targeting an Achilles’ Heel of Cancer

12

• 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.

Our Next Generation DDR Portfolio: PNT737 & PNT141

13

• Highly-selective small molecule inhibitor
• f the serine-threonine kinase

Checkpoint kinase 1 (Chk1).

• Chk1 is a central regulator of the DDR

network and of multiple cell cycle checkpoints.

• Oral bioavailability of PNT737 affords

greater flexibility in dosing strategies compared to IV agents.

• Currently in two Phase 1 clinical trials in

patients with advanced cancer.

• Highly-selective small molecule inhibitor
• f the serine-threonine kinase Cell

division cycle 7 (Cdc7).

• Cdc7 is a key regulator of DNA replication

and the DDR network.

• Broad development scope in solid and

liquid tumors.

• Mono- and combo- therapy development

potential.

• Clinical studies expected to begin by the

end of 2017.

Our DDR Program: Significant Potential in Oncology

14

Chemotherapy

Combinations with DNA damaging chemotherapy

DDR Combinations

Synergy with other DDR targeting agents to maximize DNA damage

Radiotherapy

Sensitize to ionizing radiation

Immuno-Oncology

DDR targeting agents coupled with immune activation

DDR Monotherapy

Exploit replicative stress and genetic instability for synthetic lethality

PNT737 Targeting Chk1

PNT737: Best-In-Class Pedigree

16

Discovered and initially developed by scientists at:

• The Cancer Research UK Cancer

Therapeutics Unit at The Institute

• f Cancer Research (ICR)
• Sareum Holdings

Clinical development currently taking place in facilities funded by:

• Cancer Research UK (CRUK)
• The National Institute for Health

Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden and ICR

• The Experimental Cancer Medicine

Centre Network

Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London

PNT737: Best-In-Class Characteristics

Criterion PNT737 LY2606368 Presentation: Oral i.v. Biochemical IC50: Chk1 1.4 nM ~1 nM Biochemical IC50: Chk2 1850 nM 8 nM Selectivity: Chk1 vs. Chk2 1320x ~10x 17

10 mg/kg in BALB/c mice

• PNT737 is orally bioavailable, potent, and highly

selective for Chk1 over Chk2.

• PNT737 has an excellent PK profile,

and demonstrates robust efficacy in numerous in vivo cancer models as a single agent and in combination.

HT29 Lung

• PNT737 selectivity:

15/124 kinases at 10 µM ERK8 = 100x All other kinases >200x CDK2 = 2750x CDK1 = 6750x

Cmin

PNT737 Targets Chk1 – A Critical DDR Component

18

• 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.

Biology of PNT737 Sensitivity: Exploiting Cancer’s Genetic Alterations

• Synthetic lethality due to Chk1 inhibition has

been linked to four major classes of genetic alterations:

• Oncogenic drivers

(e.g. MYC, KRAS, etc.)

• DNA repair mutations

(e.g. BRCA , FA, etc.)

• Tumor suppressors

(e.g. p53, RAD50, etc.)

• Replicative stress

(e.g. ATR, Chk1, etc.)

• Exogenous drivers of DNA damage, like

chemotherapy, are also demonstrated to enhance PNT737 sensitivity.

• Our clinical approach is to select patients with

defined genetic alterations to create synthetic lethal backgrounds for PNT737 therapy.

19

Genomic Alterations Differ Across Indications: ‘Right Genetics In The Right Patients’

20

• Mutational frequencies (oncogenic drivers; replications stress; DNA repair; tumor

suppressors) differ across indications.

• Certain indications harbor significant genomic instability, and are promising target

indications for therapeutic intervention with PNT737.

• ProNAi’s clinical development strategy - genetically-defined patient selection in

indications predicted to be sensitive to PNT737 inhibition.

Red = most frequently mutated; Green = least frequently mutated Bladder

Squamous NSCLC

Ovarian Cancer

Prostate

Lung Adenocarcinoma

Head & Neck

Pancreatic

Cholangiocarcinoma

Invasive Breast

AML

PNT737: Overall Development Strategy

21

Immuno-Oncology Chemotherapy

• Gemcitabine and Gemcitabine/Cisplatin

combinations exploit known potentiating effects of Chk1i.

• Pre-clinically, Chk1i+Cdc7i combination is

extremely synergistic.

• Chk1i+PARPi might expand/enhance PARPi

sensitivity.

• PD-1/PDL-1 combination marries known

drivers of neoantigen presentation in “double checkpoint” strategy.

Monotherapy

• Exploit synthetic lethality in genetically-

defined populations with predicted high sensitivity to PNT737.

DDR Potential Clinical Opportunities Current Clinical Trials

Two Clinical Trials Initiated at Royal Marsden, UK

• Principal Investigator: Dr.

Udai Banerji, Cancer Research UK Reader in Molecular Cancer Pharmacology at the ICR and Consultant at The Royal Marsden.

• Design: Dose escalation design to establish the recommenced Phase 2 dose for further
• evaluation. Expansion cohorts to evaluate promising patient populations. Possibility to

define additional genetically-selected cohorts.

• Primary outcome measures: Safety and tolerability, drug
• related dose limiting toxicity.

22

A Phase I Trial of ‘PNT737’ in Patients with Advanced Cancer

ClinicalTrials.gov Identifier: NCT02797964

Estimated Enrollment: 40 patients

• Advanced Solid Tumors

A Phase I Trial of ‘PNT737’ in Combination with Gemcitabine Plus Cisplatin or Gemcitabine Alone in Patients with Advanced Cancer

ClinicalTrials.gov Identifier: NCT02797977

Estimated enrollment: 70 patients

• Advanced Solid Tumors
• Non-small Cell Lung Cancer expansion
• Pancreatic Cancer expansion

PNT737: Monotherapy Clinical Development – Exploiting Synthetic Lethality

23

• Inhibition of Chk1 by

PNT737 may be synthetically lethal to cancer cells harboring genetic mutations in genes such as MYC, RAS, ATR, ATM and p53.

• Clinical opportunities

include:

• DLBCL: ~20% MYC
• Prostate: ~20% MYC
• Ovarian: ~40% MYC
• TNBC: ~30% BRCA1/2
• SCCHN: ~10% ATR

PNT737: Combinations with DNA-Damaging Chemotherapies

24

• Inhibition of Chk1 by

PNT737 may be synergistic in combination with chemotherapeutic agents.

• Clinical opportunities

include:

• Gemcitabine/

Cisplatin: >27,500 patients in US/EU; bladder, bile duct, NSCLC, etc.

• Gemcitabine: >50,000

patients in US/EU; pancreatic, bile duct,

• varian, etc.

PNT737: Upcoming Milestones

25

Immuno-Oncology Chemotherapy

• Complete formal CTA transfer

= Q1 2017

• Preliminary ‘Combination’ data

= Y/E 2017

• Medical conference data

= 2018

• Chk1i + Cdc7 preclinical data

= H2 2017

• Chk1i + PARPi preclinical data

= H2 2017

• Chk1i+PDL-1 preclinical data

= H2 2017

Monotherapy

• Complete formal CTA transfer

= Q1 2017

• Preliminary ‘Synthetic Lethality’ data = Y/E 2017
• Medical conference data

= 2018

DDR Potential Clinical Opportunities Current Clinical Trials

PNT737: Broad Long-Term Development Strategy

• Conduct research designed to explore markers of sensitivity to PNT737 that may facilitate

patient selection and to identify additional therapeutic combination strategies.

• Expand development into the US with an IND application filing planned for H2 2017.

26

DDR Combinations Immuno-Oncology Radiotherapy DDR Monotherapy Chemotherapy

PNT141 Targeting Cdc7

PNT141: Selective Small Molecule Targeting Cdc7

28

• PNT141: highly-selective and

potent cell division cycle 7 (Cdc7) inhibitor.

• Cdc7: key regulator of both DNA

replication and DNA damage response.

• Broad development scope in solid

and liquid tumors.

• Mono- and combo- therapy

development potential.

Cdc7: Key Function in the DDR Network

29

• Cdc7 activates DNA

replication during S-phase in response to growth promoting signals (e.g. cyclins, Myc, Ras) and stabilizes stalled replication forks during replication stress.

• Stalled replication

forks activate ATR and Chk1 signaling.

• Potential synergies

may be achieved by combining Cdc7 and Chk1 inhibition.

PNT141: First-In-Class/Best-In-Class Opportunity

• Preclinical data and published literature suggest a variety
• f indications with potential for response to Cdc7

inhibitors:

– Solid tumors: breast, ovarian, pancreatic, melanoma, colorectal, uterine, thyroid, etc. – Hematological malignancies: AML, DLBCL, etc.

• PNT141’s selectivity profile offers possible differentiation

and potential safety and efficacy advantages.

• A biomarker-driven patient selection strategy focusing on

drivers of replication stress, genomic instability and proliferation (e.g. p53, BRCA, MYC, KRAS, etc.) may help facilitate clinical trial execution.

• Clinical studies expected to begin by the end of 2017.

30

Advancing Targeted Cancer Therapies

Proven Leadership in Oncology Development

Nick Glover, PhD President and CEO Barbara Klencke, MD Chief Development Officer Angie You, PhD Chief Business & Strategy Officer and Head of Commercial Sukhi Jagpal, CA, CBV, MBA Chief Financial Officer

32

Keith Anderson, PhD Senior Vice President, Technical Operations Wendy Chapman Senior Vice President, Clinical Operations Diane Gardiner Senior Vice President, Human Resources and Administration Christian Hassig, PhD Senior Vice President, Research Chandra Lovejoy Senior Vice President, Global Regulatory Affairs and Head of Quality Emma McCann Senior Vice President, Program Management Gregg Smith, PhD, MBA Senior Vice President, Preclinical

Our DDR Program Expands Beyond PARP

We have established a promising portfolio of DDR assets:

• PNT737 and PNT141 target the DNA Damage Response network, a promising

approach to treating cancer based on leading-edge discoveries in cancer biology. Both molecules have broad development scope and the potential to be established as leading assets in the DDR field.

• Our DDR program expands beyond the scope of PARP inhibitors by focusing on DNA

double strand breaks, genomic instability and cell cycle checkpoints.

• Our near-term development plans for PNT737 and PNT141 encompass synthetic

lethality strategies as monotherapy, and in combination with DNA-damaging

• chemotherapy. Two Phase 1 clinical trials with PNT737 underway.
• In addition, we plan to explore the potential synergy of combining PNT737 and

PNT141 in a proprietary combination.

• Beyond this initial focus, these assets could be combined with other DDR agents

(e.g. +PARPi), and in combinations with immuno-oncology.

33

Targeted Cancer Therapies

www.pronai.com