Developing Novel Antibacterials to Treat Multi-drug Resistant Gram-negative Bacterial Infections 13 th Needham Healthcare Conference April 8, 2014
Forward Looking Statements Forward-Looking Statements This presentation contains forward-looking statements. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, prospective products, potential market size and market share, availability of funding, clinical trial results, product approvals and regulatory pathways, research and development costs, timing and likelihood of success, plans and objectives of management for future operations, and future results of current and anticipated products, are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forwardlooking statements. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to our business in general, see our Prospectus filed with the Securities and Exchange Commission on March 12, 2014 and our future periodic reports on Form 10-K or Form 10-Q. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. This presentation concerns drugs that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration (FDA). It is currently limited by Federal law to investigational use, and no representation is made as to its safety or effectiveness for the purposes for which it is being investigated. 1
Achaogen Investment Highlights Developing antibacterial medicines that target growing unmet medical needs Multi-drug resistant, gram-negative bacterial infections with high mortality Plazomicin lead product with strong commercial opportunity High unmet medical need - CRE infections have high mortality rate Growing demand CRE infections increasing due to growing drug resistance Value-based pricing supported by targeted reductions in high mortality rate and cost of care for affected patients Favorable sales model target infectious disease specialists in hospitals Status Phase 3 trial initiated in Q1 2014 Exciting pre-clinical programs targeting Pseudomonas aeruginosa bacterial infections Substantial non-dilutive funding including $104MM BARDA contract Proven leadership team with a track record of drug discovery, global approvals and launches 2
Multi-Drug Resistant, Gram-Negative Bacteria - Serious Global Health Threat Antibiotic-Resistant Infections Lead to 23,000 Deaths a Year, C.D.C. Finds Last-line antibiotics losing ability to kill superbugs in EU 3
Gram-negative Bacterial Infections - High Unmet Need, Few Effective Antibiotics Gram-positive Gram-negative Key pathogens: S. aureus, S. pneumoniae, C. difficile 43% 57% Key pathogens: Enterobacteriaceae, P. aeruginosa, A. baumannii Easier for antibiotics to penetrate bacterial cell Global Bacterial ICU Infections (2007)* Difficult for antibiotics to penetrate bacterial cell Bacterial cell surface Limited unmet need: Many effective antibiotics High unmet need: Few effective antibiotics *Vincent et al. JAMA, 2009, 302(21): 2323-29. Frequency that either a gram-negative or a gram-positive bacterial organism was grown from a set of 4947 ICU isolates, including co-isolates. 4
Shifting Regulatory & Economic Paradigm - New Opportunities Old Limited differentiation, approvals based on non-inferiority Typically high volume, low price business model Uncertain and difficult regulatory environment New Superiority endpoint provides significant product differentiation Significant pricing power in patient populations with resistant infections New regulatory and policy environment 5
Our Research and Development Pipeline Preclinical Phase 1 Phase 2 Phase 3 Milestones Target: Carbapenem-Resistant Enterobacteriaceae (CRE) 2014 - Q1: Phase 3 trial initiated Plazomicin Target: Pseudomonas Aeruginosa 2015 - H2: Phase 3 Interim Analysis #1 2015 - Q4: Supportive Efficacy Trial Top-line Data 2016 - H2: Phase 3 Interim Analysis #2 2017 - H1: Phase 3 Top-line Data LpxC Inhibitors Antibacterial Antibody 2015: At least one IND Target: Gram-negative bacteria Discovery Engine 6
Proven Leadership Team Kenneth Hillan, M.B., Ch.B Chief Executive Officer and Chief Medical Officer Derek Bertocci Chief Financial Officer Darcy Mootz Sr. Director, Corp. Development Extensive background in drug discovery & development and product commercialization Becki Filice Sr. VP, Development Operations and Portfolio Management Christine Murray VP, Regulatory Affairs 7
Carbapenem Resistant Enterobacteriaceae (CRE) & Multi-Drug Resistance Overview 8
Carbapenem Resistant Enterobacteriaceae (CRE) An urgent threat to public health RESISTANCE: CRE are resistant to nearly all of the antibiotics we have SPREAD OF RESISTANCE: CRE easily transfer their antibiotic resistance to other bacteria PREVALENT AND GROWING: CRE prevalence has increased dramatically over the last 10 years DEATH: CRE kill up to 1 in 2 patients who develop bloodstream infections IMPACT: Significant impact to both individual patients and hospital systems CDC Vital Signs, March 2013, http://www.cdc.gov/vitalsigns/hai/cre/ 9
Evolution of Multi-Drug Resistance CRE bacteria are often resistant to multiple classes of antibiotics Enterobacteriaceae* Profiles Evolution of Resistance Antibiotic Class Generally Susceptible MDR CRE Aminoglycosides Fluoroquinolones Cephalosporins Carbapenems Inactive vs. high % strains Active vs. high % strains * Key species within Enterobacteriaceae family include Klebsiella pneumoniae, E. coli, Enterobacter spp. 10
Multi-Drug Resistance in CRE - Associated with Significant Mortality Survival by Antibiotic Susceptibility K. pneumoniae Bloodstream Infections Mortality By Treatment Regimen K. pneumoniae Bloodstream Infections** 1.0 0.8 Susceptible Cephalosporin-resistant, carbapenem susceptible Carbapenem-resistant Regimen All-Cause Mortality Cumulative Survival 0.6 0.4 0.2 0.0 * p = 0.006 0 50 100 150 200 250 300 Colistin*** 46% Tigecycline*** 47% Aminoglycoside*** 38% Combination Therapy 37% Total Length of Stay (days) * From log-rank test for comparison of survival distribution in patients with carbapenem resistant versus ESBL/susceptible K. pneumoniae ** Carbapenemase-producing Klebsiella pneumoniae *** Agents active in vitro Ben-David, et al. Clin. Microbiol. Infect 2012; 18: 54 60 Daikos et al. Expert Rev. Anti. Infect. Ther. 2012, 10:1393-1404 11
Plazomicin: A Next Generation Aminoglycoside AMEs (aminoglycoside modifying enzymes) co-travel with other resistance mechanisms, including carbapenemases AMEs ) AMEs AMEs Plazomicin is engineered to overcome clinically relevant AMEs that inactivate existing aminoglycosides AMEs AMEs Plazomicin retains potent activity vs. multi-drug resistant strains, including carbapenem and aminoglycoside-resistant strains 12
Plazomicin Pre-clinical and clinical data 13
Plazomicin Has Superior Potency Against CRE In vitro Activity vs. Clinical Isolates of CRE Compound Class N MIC 50 (µg/ml) MIC 90 (µg/ml) Plazomicin Aminoglycoside 807 0.5 2 Gentamicin Aminoglycoside 807 4 128 Amikacin Aminoglycoside 806 32 64 Ciprofloxacin Fluoroquinolone 767 8 8 Ceftazidime Cephalosporin 510 64 >128 Piperacillin/tazobactam Penicillin/Betalactamase inhibitor 731 >128 >128 Tigecycline Glycycline 723 1 2 Colistin/polymyxin B Polymyxin 692 1 4 Susceptible Non-Susceptible MIC 50 and MIC 90 (minimum inhibitory concentration in μg/ml) reflect the lowest concentrations at which the drug inhibits growth of 50% and 90% of the bacteria, respectively. N=number of strains within the overall set of 807 bacterial strains tested vs. the given antibiotic. CLSI 2012 susceptibility criteria were used except for tigecycline and colistin, for which EUCAST 2013 criteria were used because CLSI criteria were not available. Isolates selected had an MIC 2 µg/ml for any type 2 carbapenem, a value defined as non-susceptible for this class according to CLSI. Data includes clinical isolates from three studies: 1) J Chemother. 2012 Aug;24(4):191-4, 2) J Antimicrob Chemother. 2011 Jan;66(1):48-53, 3) J Antimicrob Chemother. 2010 Oct;65(10):2123-7 14
Plazomicin Has Superior Activity Against CRE in Mouse Infection Model 4 Human Equivalent Dose Plazomicin Logarithmic Change in CFU /g Infected Tissue 3 2 1 0-1 -2 Colistin Prodrug Tigecycline Initial Infection Load (Stasis) -3 0 1 2 3 4 Multiple of Human Dose, by Total Plasma Exposure (AUC) CFU = Bacterial Colony Forming Unit Each data series represents a CRE clinical isolate tested in model (n=9) Superior activity of plazomicin against CRE in mouse model supports hypothesis that plazomicin may have superior activity in patients 15
Plazomicin Phase 1 Clinical Trials Four studies involving 143 subjects dosed with plazomicin Good tolerability and safety in single doses up to 20 mg/kg and multiple doses up to 15 mg/kg once daily for 5 days Linear, dose-proportional pharmacokinetics Cleared by kidney, dose adjustment needed for patients with moderate to severe renal impairment Penetration into lung tissue similar to other aminoglycosides 16
Demonstrated Efficacy in Phase II cuti trial Similar efficacy to active comparator levofloxacin and an acceptable safety profile Trial Design Protocol: Multi-national, randomized, double-blind study in complicated urinary tract infection and acute pyelonephritis (cuti/ap) Study Drugs: Plazomicin (10 or 15 mg/kg) vs. levofloxacin (750 mg) N = 145 patients By-Patient Microbiological Response Plazomicin 10 mg/kg Plazomicin 15 mg/kg Microbiologically Evaluable (ME) Levofloxacin 750 mg Primary Outcome* N 7 35 21 Eradication, n (%) 6 (86%) 31 (89%) 17 (81%) Modified Intent-to-Treat (MITT)** N 12 51 29 Eradication, n (%) 6 (50%) 31 (61%) 17 (59%) Safety Similar adverse event rates across plazomicin and levofloxacin arms. No drug-related SAEs in the plazomicin arm. Class-related adverse events included: Nephrotoxicity: Minor changes in serum creatinine in 5.2% of evaluable plazomicin patients versus 4.5% in the levofloxacin arm Ototoxicity: mild, permanent tinnitus & mild, transient vertigo (N=1 each) * Microbiological Eradication **Eradication rates in MITT population reflect lack of test-of-cure cultures for some patients 17
Plazomicin Phase 3 study design, rationale and timeline 18
Phase 3 Study Design Pathogen-specific, randomized, open-label, active comparator controlled Presumed or Documented CRE Infection (Bloodstream Infection or Pneumonia) Plazomicin-based regimen 1:1 (n = ~360) Colistin-based regimen Primary Endpoint 28 day all-cause mortality Secondary Endpoints Safety Assessments Pharmacoeconomic Assessments Both regimens will include addition of either meropenem or tigecycline Plazomicin dose may be adjusted by therapeutic drug monitoring (TDM) via a proprietary in vitro assay Presumed infections: based on identification of a carbapenemase-producing Enterobacteriaceae (CRE) 19
Analysis Supports Hypothesis that Plazomicin Can Improve Mortality in Patients with CRE BSI Targeting conservative 12% reduction in mortality vs. observed rate of 21% Meta-analysis of Mortality in Patients with Carbapenemase-Producing Enterobacteriaceae (CRE) Bloodstream Infections All Patients (N=309) Carbapenem MIC 4µg/mL (N=224) Patients segregated by carbapenem MIC Carbapenem MIC < 4µg/mL (N=85) Mortality 35% 14% Potential Impact of an Effective Antibiotic Therapy on Mortality Absolute Difference in Mortality 95% CI 21% [11 30%] Clin Microbiol Infec 2013 Feb;19(2):E72-9, Expert Rev. Anti Infect. Ther. 10(12), 1393 1404 (2012), Daikos unpublished Meta-analysis with Mantel-Haenszel weights 20
Plazomicin Phase 3 Development Program Streamlined program to address unmet medical need 2014 2015 2016 2017 2018 Phase 3 CRE Study Commercial Launch Prep Phase 3 Start Interim Analysis Interim Analysis NDA U.S. Launch Supportive Efficacy Study Safety Study Phase 3 Study: Single registrational, pathogen-focused, superiority study (n=~360) Supportive Efficacy Study: Non-randomized, open-label efficacy and safety study (n=~50) Safety Study: Non-randomized, open-label study to complete safety database (n=~70) 21
Plazomicin Commercial opportunity 22
Attractive Commercial Opportunity for Plazomicin High Unmet Medical Need (CRE) Up to 50% mortality in bloodstream infections Current therapies inadequate Resistance growing on a global basis Strong Market Share Potential Mortality benefit over comparator Potent activity vs. broad spectrum of CRE isolates Favorable physician response Use in definitive and empiric setting Value-Based Pricing Favorable Business Model Superior efficacy Ability to curb spread of costly infections Narrow patient population limits budget impact to any given hospital Pharmacoeconomic cost savings anticipated (e.g., reduction in ICU days) Concentrated market in resistance hotspots facilitates targeted sales approach Development costs limited as Phase 3 program partially funded by award from BARDA Favorable healthcare system developments (e.g., Pew Trusts Forum) 23
Two Key Plazomicin Addressable Patient Segments US and EU-5 Estimated Inpatient Cases in 2013: Bloodstream Infections and Pneumonia Definitive Treatment: Confirmed CRE 4.7 M Total Inpatients 25 % Enterobacteriaceae 2.5 % X X = carbapenemresistance ~30K* CRE cases * Total of ~110K CRE cases when urinary tract and intra-abdominal infections included Empiric Treatment: Risk of CRE 4.7 M Total Inpatients 80% empiric treatment 23 % X X = Infectious Disease (ID) consult ~850K Empiric, ID consult cases Proxy for the number of more complicated cases and/or serious infections A subset of these patients will be deemed to be at risk for CRE (expected to rise over time) Decision Resources, Arlington Medical Resources, primary literature, CDC & ECDC, TEST Surveillance Database, and company internal analysis 24
Carbapenem Resistance in US is Rising Rapidly Rise in outpatient setting particularly concerning Carbapenem Resistance in K. pneumoniae (United States) (%) Braykov et al, Infect Control and Hospital Epi, 2013; 34(3) 25
Key Takeaways from 2013 Pew Trusts Pricing Workshop Panelists from FDA, Pharma, and Payers Panelists generally agreed that the narrow market established by the limited population pathway sets the stage for premium pricing for antibiotics, possibly $15,000 per course Payers may desire patient outcome data to support the use and to justify the cost of limited population antibiotics Select quotes: It has to be a superiority [trial] and some active comparator that makes sense in this scenario in order for anybody, including CMS, to pay for that prize Saira Jan, Director of Clinical Pharmacy Management, Horizon Blue Cross Blue Shield of NJ No one is opposed, I do not think, to having a high priced drug so long as it is sensibly priced it is easy in my mind, I guess, to justify $15,000 Eric Cannon, Chief of Pharmacy at SelectHealth (pharmacy benefit management) I think that it is entirely logical that if you are willing to spend $15,000 for an antineoplastic that would prolong your life 15 months, that you would spend $15,000 for an anti-infective that would give you back 60 years of life John Rex, VP and Head of Infection Development, Global Medicines, AstraZeneca Pew Charitable Trusts Report: A New Pathway for Antibiotic Innovation, http://www.pewhealth.org/uploadedfiles/phg/content_level_pages/issue_briefs/antibioticsreport.pdf Meeting transcript:: http://www.pewhealth.org/uploadedfiles/phg/content_level_pages/other_resource/antibiotics-transcript.pdf 26
Discovery Engine Two lead preclinical programs targeting Pseudomonas aeruginosa 27
Pseudomonas aeruginosa: A Highly Drug Resistant and Deadly Pathogen Key target of Achaogen s research efforts P. aeruginosa Non-susceptibility to carbapenems P. aeruginosa is one of the most common causes of health-care associated infections Infections associated with high morbidity and mortality rates High rates of antibiotic drug resistance Need for new antibiotics targeting Pseudomonas ranked by infectious disease physicians as a top unmet need European Centre for Disease Prevention and Control (ECDC, 2012) CDC, ECDC, Decision Resources, Cystic Fibrosis Foundation 28
LpxC Inhibitors: Novel Mechanism of Action with Significant Potential New class of bactericidal antibiotics - LpxC is an essential enzyme required for outer membrane synthesis in gramnegative bacteria - Potent activity vs. P. aeruginosa - No pre-existing resistance One candidate, ACHN-975, advanced into clinical trials in 2012 Multiple dose study halted due to local tolerability reaction Back-up program has generated additional candidates currently undergoing preclinical assessment In vitro Activity vs. Clinical Isolates of P. aeruginosa Compound MIC 50 (µg/ml) MIC 90 (µg/ml) ACHN-975 0.25 1 Tobramycin 1 >32 Ciprofloxacin 0.5 >4 Ceftazidime 8 >32 Imipenem 2 >16 Colistin 1 4 Susceptible Non-Susceptible 29
Anti-Pseudomonal Therapeutic Antibody Target candidate profile: Monotherapy treatment for serious P. aeruginosa infections Hypothesis-driven approach focused on functionally important targets on the bacterial cell surface (targets not being disclosed at this time) Potential benefits: - Direct bacterial killing - Favorable safety profile typically associated with monoclonal antibodies - Antibody PK profile with a half-life that could support a single-dose cure 30
Achaogen Investment Highlights 31
Achaogen Investment Highlights Developing antibacterial medicines that target growing unmet medical needs Multi-drug resistant, gram-negative bacterial infections with high mortality Plazomicin lead product with strong commercial opportunity High unmet medical need - CRE infections have high mortality rate Growing demand CRE infections increasing due to growing drug resistance Value-based pricing supported by targeted reductions in high mortality rate and cost of care for affected patients Favorable sales model target infectious disease specialists in hospitals Status Phase 3 trial initiated in Q1 2014 Exciting pre-clinical programs targeting Pseudomonas aeruginosa bacterial infections Substantial non-dilutive funding including $104MM BARDA contract Proven leadership team with a track record of drug discovery, global approvals and launches 32