R&D Webinar: Product Pipeline Update

Transcription

1 R&D Webinar: Product Pipeline Update Dr. Mark Murray, President & CEO Dr. Mark Kowalski, Chief Medical Officer Dr. Ian MacLachlan, Chief Scientific Officer Ian Mortimer, Executive Vice President Bruce Cousins, Chief Financial Officer October 8, Welcome: FLS There are forward-looking statements contained herein that are not based on historical fact, including without limitation statements containing the words believes, may, plans, will, estimate, continue, anticipates, intends, expects, and similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause the actual results, events or developments to be materially different from any future results, events or developments expressed or implied by such forward-looking statements. Such factors include, among others, Tekmira s stage of development, lack of product revenues, additional capital requirements, risks associated with the completion of clinical trials and obtaining regulatory approval to market Tekmira s products, the ability to protect its intellectual property, and its dependence on collaborative partners. These factors should be considered carefully and readers are cautioned not to place undue reliance on such forwardlooking statements. The Company disclaims any obligation to update any such factors or to publicly announce the result of any revisions to any of the forwardlooking statements contained herein to reflect future results, events or developments. 2 1

2 Introduction/Overview: Pipeline TEKMIRA PROGRAMS RESEARCH DEVELOPMENT PHASE I PHASE II PHASE III APPROVED TKM-PLK1 Oncology TKM-Ebola Ebola Virus Infection TKM-HBV Hepatitis B (HBV) TKM-ALDH2 Alcohol Use Disorder TKM-Marburg Marburg Virus Infection Rare Forms of Hypertriglyceridemia Glycogen Storage Disorder Type IV PARTNER PROGRAMS RESEARCH DEVELOPMENT PHASE I PHASE II PHASE III APPROVED Marqibo Adult Relapsed Leukemia (Spectrum) ALN-TTR2 TTR Amyloidosis (Alnylam) ALN-VSP Liver Cancer (Alnylam) ALN-PCS High Cholesterol (Alnylam) BMS Target Selection Undisclosed Collaborations Pharmaceutical / Biotech / Agricultural Companies 3 Welcome: Agenda Overview TKM-PLK1, RNAi oncology therapeutic TKM-Ebola and TKM-Marburg Programs TKM-HBV, RNAi therapeutic for the treatment of Hepatitis B TKM-ALDH2, RNAi therapeutic for the treatment of alcohol use disorder Tekmira s Rare Disease Research Programs Conclusions Question & Answer Forum 4 2

3 TKM-PLK1: Tekmira s Lead Oncology Therapeutic Targeting an Essential Cell Cycle Kinase PLK1 is a validated oncology target; a key regulator of mitosis. Many tumor types have increased PLK1 levels predicting poor clinical outcome. TKM-PLK1 is selective for PLK1 with no crossreactivity to PLK family members or other kinases. PLK1 Expression and Outcome in Hepatocellular Carcinoma He et al., World J Gastroenterol, 29 PLK Negative (n=24/135; 18%) Gene rank: top 1% P-value: 3.8E-2 Fold-change: % PLK Positive (n=111/135; 82%) P=.3 2.9% Liver (7) HCC (12) 5 TKM-PLK1 Clinical Benefit 6 of 15 (4%) evaluable subjects treated at.6 mg/kg had clinical benefit Subject Dose Tumor Type # Prior Regimens Best Response Duration on Study Colon* 3 SD 6 mo /.6 NET* 1 PR 11 mo NET 1 SD 4 mo ACC* 3 SD 6 mo /.6 ACC* 2 SD 1.75 mo ACC* 2 SD** 4 mo.(ongoing) *Subject had progressive disease prior to study. **Subject showed tumor size reduction of 19.3% after Cycle 2 Three out of the four ACC patients (75%) treated with TKM-PLK1 achieved stable disease. Both of the NET patients (1%) treated with TKM-PLK1 demonstrated clinical benefit. No dose dependent changes in liver function tests were observed. 6 3

4 TKM-PLK1: Clinical Benefit in Both GI-NET Patients 64 year old male GI-NET patient: partial response observed ~2 months post-treatment initiation, and patient continued to have a PR after Cycles 4, 6, 8, and 1 72 year old female GI-NET patient: achieved stable disease showed greater than 5% decline in Chromogranin A levels 7 TKM-PLK1: Development Plans and Next Steps Development Rationale: PLK1 expression levels Efficient LNP delivery to tumor Areas of unmet medical need / lack of current therapies Accelerated regulatory opportunity GI-NET (Gastrointestinal Neuroendocrine Tumors) 55, individuals in the U.S. have GI-NET Poor prognosis for advanced metastatic NETs, with 25% of patients surviving less than one year No approved drugs indicated specifically for GI-NET Ph I/II results by mid-214; pivotal trial by end of 214 ACC (Adrenocortical Carcinoma) Rare cancer that forms in the adrenal gland Poor prognosis and large % of patients not good surgical candidates Lack of effective systemic therapies Ph I/II results by mid-214 HCC (Hepatocellular Carcinoma) One of the most common cancers worldwide, with more than 63, people diagnosed each year Represents major unmet medical need with 19, deaths per year Only 1% five-year survival rate after liver resection Ph I/II initiated 1H:

5 Tekmira s Anti-Viral Therapeutics Program A Decade of Anti-Viral Experience RNA Interference is ideally suited to anti-viral applications: Highly selective, sequence specific mechanism of action. Combinatorial approaches prevent viral resistance. Rapid onset of anti-viral activity. RNAi mechanism, combined with LNP delivery is far more potent than small molecule drugs. 9 Ebola and Marburg Viruses A Rigorous Test of Tekmira s Antiviral Therapeutic Strategy Hemorrhagic Fever Viruses High Mortality No Vaccines or Therapy Available WHO Risk Group 4 Pathogens NIH/NIAID Category A Priority Pathogens CDC Category A Bioterrorism Agents Outbreaks Since 1976 Ebola Marburg 1 Ebola Virus Infection Treatment Percent Survival Ebola TKM-Ebola.5 mg/kg TKM-Ebola.2 mg/kg Control 1% protection against Zaire strain Day Marburg Virus Infection Treatment Percent Survival Control 2 TKM-MARV mg/kg NP-718m.5 mg/kg 2n.5 Control mg/kg NP-718m 1% protection Marburg against Angola strain (1% with 24 h delay; 48 h study is ongoing) Day 1 5

6 Chronic Hepatitis B Virus Infection A High Value Unmet Medical Need Globally, over 35 million people are chronically infected with HBV K Treated 2 4 K Diagnosed US Statistics Million Chronic HBV Geographical Distribution of HBV Genotypes The number of HBV patients in therapy continues to grow. Interferons and nucleoside analogs inhibit replication but do little to reduce HBsAg expression. 11 TKM-HBV An RNAi Therapeutic Inhibiting Hepatitis B sag Expression TKM-HBV is a multi-valent therapeutic targeting multiple sites in the HBV genome avoiding resistance. TKM-HBV developed through bioinformatic analysis of 37,457 sequences derived from 478 distinct HBV genomes. Multiple triggers provides broad coverage across genotypes C, A, B and D. TKM-HBV is designed to inhibit HBsAg expression, leading to seroconversion and functional cure. HBV Genome 12 6

7 The Ultimate Goal for HBV: Seroconversion Transition from Immune Tolerance to Immune Clearance The key to a functional cure is developing anti-bodies to HBV surface antigen. RNAi mediated degradation of HBV mrna reduces both viral replication and HBsAg expression, breaking tolerance and allowing for the development of anti-hbsag antibodies. 13 TKM-HBV: Leveraging Clinically Validated LNP Technology Demonstrating Systemic RNAi for HBV Reducing HBsAg Expression HBV DNA/mL serum (log1) LOQ = 2.9 PBS Control Viremia ~2.5 log HBV LNP Control LNP Morrissey et al. Nat Biotechnology. 25. Serum HBsAg (ng/ml) Surface Antigen PBS Control HBV Control LNP LNP Fold Increase in Potency Lipid Conjugate Improvements in LNP Potency MC Year TKM-HBV is a Third Generation LNP product, leveraging Tekmira s improvements in both formulation and payload technology. Tekmira intends to file an IND for TKM-HBV in 2H:214. Phase I data in chronically infected HBV patients in

8 TKM-ALDH2: Product Concept An RNAi Therapeutic for Alcohol Use Disorder ALDH2 is a key enzyme in alcohol metabolism. TKM-ALDH2 silences the ALDH2 gene, causing aversion to alcohol. The strategy is validated by small molecules (disulfiram) and human genetics. RNAi approach offers advantages: Specificity (disulfiram interacts with ~2 different enzymes) Fewer side effects (vs. disulfiram) Prolonged duration of activity Assured patient compliance Inhibition of ALDH2 Blocks Metabolism of Alcohol Causing Acetaldehyde Accumulation and Alcohol Aversion 15 ADH1B ALDH2 Ethanol Acetaldehyde Acetate TKM-ALDH2 is Potent Inhibitor of ALDH2 Gene Expression Livver ALDH2 mrna (Percent Untreated Control) Untreated ALDH2 mrna Reduced by >9% -93% Control LNP ALDH2-LNP Mr ALDH2 Protein Reduced by >9% Untreated ALDH2 LNP β-actin Protein (Control) Liver ALDH2 Activity (mod/min) ALDH2 Enzyme Activity Reduced by >9% Untreated -93.6% Control LNP ALDH2 LNP TKM-ALDH2 potently silences liver ALDH2. Enzyme inhibition is greater than that achieved with disulfiram doses 1- fold greater than those used in the clinic. A single dose of TKM-ALDH2 can silence ALDH2 for greater than 3 days. 16 8

9 TKM-ALDH2 Causes Alcohol Aversion Preclinical Proof of Concept in a Naïve Rat Behavior Model TKM-ALDH2 treatment reduces ethanol consumption in a naïve rat behavior model, on initial and subsequent exposures. µm Plasma Acetaldehyde Plasma Acetaldehyde Minutes after Ethanol Challenge Day 1 Day 7 Day 4 Day 1 % Change in EtOH Consumption Relative to Untreated Controls Multiple Exposure Alcohol Aversion Test LNP Control TKM-ALDH2-56% (p <.5) Day TKM-ALDH2 induced alcohol aversion increases upon repeat exposure to alcohol. 17 TKM-ALDH2 Opportunity and Next Steps Unique Application of RNAi Technology 4, patients are currently receiving pharmacotherapy for Alcohol Use Disorder (AUD). TKM-ALDH2 will be used in the treatment of a clearly defined patient population: Moderate to Severe AUD. TKM-ALDH2 is designed to promote abstinence the ultimate goal of therapy. Tekmira plans to file an IND for TKM-ALDH2 in 2H:214 Rx.4 M In Treatment 1-2 M Alcohol Dependency 7-8 M Alcohol Use Disorder 18 M US Statistics Phase I data in healthy volunteers including alcohol challenge available

10 Research Programs: Rare Forms of Hypertriglyceridemia (HTG) Unmet medical need in: familial hypertriglyceridemia and familial partial lipodystrophy Aim of therapy: reduce elevated triglycerides prevent recurrent acute pancreatitis Multiple molecular targets addressed by one LNP product achieving >95% reduction in plasma triglycerides. Plasma Triglycerides (mg/dl) Plasma Triglycerides >95% Control HTG Chow Western Diet LDLR-Deficient Mice Fed a High-Fat Western Diet 19 Research Programs: Glycogen Storage Disorder Type IV (GSD4) Andersen s Disease A Rare Childhood Metabolic Disorder Unmet medical need GSD4: caused by mutations in glycogen-branching enzyme autoimmune damage progressing to lethal hepatic cirrhosis no treatment exists, apart from liver transplantation. Aim of therapy: knockdown of glycogen synthase reduce GSD4 associated pathology convert patients to GSD phenotype (managed by controlled diet). 2 1

11 Conclusions: Milestones TKM-PLK1 Results from ongoing Phase I/II clinical trial in GI-NET and ACC patients by mid-214, and if supported by the data, initiate a pivotal trial in GI-NET initiated by the end of 214. Initiate a Phase I/II clinical trial in Hepatocellular Carcinoma in the first half of 214. TKM-Ebola Phase I clinical trial to be initiated in the first quarter of 214 with data available in the second half of 214. TKM-HBV Complete preclinical work and file IND filed in the second half of 214, in order to advance TKM- HBV into chronically infected HBV patients with Phase 1 data available in 215. TKM-ALDH2 Complete preclinical work and file IND in second half of 214, with Phase I data in healthy volunteers, including proof-of-concept with alcohol challenge, available in 215. Next Product Nominate next product candidate for development in 214 from broad preclinical research efforts with focused work in rare and orphan diseases, including glycogen storage diseases and rare forms of hypertriglyceridemia. 21 Question & Answer Forum 22 11

12 For more information, please visit: Investor Relations Department Tekmira Pharmaceuticals Corporation 1-89 Glenlyon Parkway Burnaby, BC V5J 5J8 (64)