Carbavance® TANGO-1 phase III trial results
Transcript of Carbavance® TANGO-1 phase III trial results
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Carbavance (meropenem-vaborbactam) phase III trial results
Agenda
Introduction Clive Meanwell, MD, PhDChief Executive Officer
TANGO I results Jeff Loutit, MB, ChBVice President, Chief Medical OfficerInfectious Disease Innovation Group
CommentaryNext steps
Mike Dudley, PharmDSenior Vice President, Research & Development and Co-LeadInfectious Disease Innovation Group
Investment thesisQ&A
Clive Meanwell
Key strategic objectives for MDCOExecution focus
November 2015 Progress
Deliver on R&D Advancing 4 potential blockbusters
Divest non-core assets Divested 6 in-market products
Raise non-dilutive capital Up to $1.15b via divestitures1
Reduce cash burn Cutting SG&A by $65-80m per year
Optimize capitalstructure
Refinanced/extended maturity for $220m of 2017 convertible notes
1: Includes approximately $438 million in upfront payments and $715 millon in potential future milestone payments
Delivering on R&DAdvancing 4 potential blockbusters
Carbavance®Gram negativeinfections including CRE
PCSK9siLDL lowering
in ASCVD
MDCO-216 arterial plaque regression
ABP-700iv sedation and
anesthesia
Carbavance (meropenem-vaborbactam) phase III trial results
Overview
• Carbavance® (meropenem-vaborbactam) met FDA and EMA pre-specified 1o endpoints for non-inferiority
• Achieved statistical superiority over piperacillin-tazobactam using FDA primary endpoint
• Safety and tolerability comparable to control treatment
• TANGO 1 will be central to regulatory submissions
• Plan to submit NDA to FDA in early 2017
• FDA designated Qualified Infectious Disease Product and granted Fast Track status
• Urgent, growing global threat of deadly gram-negative CRE superbugs
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
TANGO-1 results
Jeff Loutit, MBChBVice President, Chief Medical Officer
Infectious Disease Innovation Group
Carbavance (meropenem-vaborbactam) phase III trial results
Background
• Complicated UTIs are a major cause of hospitalization
• Anatomic or functional abnormalities, or co-morbidities
• Enterobacteriaceae (E. coli, Klebsiella sp.) common causes
• Treated in inpatient setting with cephalosporins, piperacillin-tazobacatam, fluoroquinolones and carbapenems
• Emerging carbapenemases in Enterobacteriaceae pose a major and increasing threat to therapeutic effectiveness
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Rationale
Carbavance: combination designed to treat CRE infections
Meropenem
• Widely used carbapenem
• Standard-of-care for serious G- infections
• High potency and safety
• Broad spectrum coverage
• Resistant to ESBLs
Vaborbactam
• First in a new class of BLIs
• Discovered at MDCO labs
• Potent inhibitory activity optimized against KPC carbapenemase
• Pharmacologically well-matched with meropenem
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Objectives
Double-blind, double dummy active controlled trial to assess:
• Efficacy of Carbavance (meropenem-vaborbactam)
• Safety and tolerability
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Study design
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Screen Treat for up to 10 days Follow-up
cU
TI o
r A
Pre
qu
irin
g ≥
5 d
ays
IV R
x
End Of IV Treat’(≥15 doses)FDA endpoint
Test of cureEMA endpointDay 15-19
Last follow-upDay 22-26
Meropenen-vaborbactam2g-2g q8h iv 3 hDummy (saline)
≥15 doses transition to oral Rx if clinically indicated and criteria met
Piperacillin-tazobactam4g/0.5g q8h iv 30 minDummy (saline)
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Study population
Populations Meropenem-vaborbactam
Piperacillin-tazobactam
Total
N N N
Intention to treat 274 276 550
Modified intention to treat (MITT)/Safety
272 273 545
Microbiologic modified intent to treat (mMITT)
192 182 374
Microbiologic evaluable (ME) 178 169 347
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Efficacy: FDA primary endpoint
FDA Primary EndpointmMITT Population
Meropenem-Vaborbactam
Piperacillin-Tazobactam
Overall Success1 at EOIVT 188/192 (98.4%) 171/182 (94.0%)
Difference (95% CI) 4.5% (0.7%, 9.1%)
Overall success: Clinical outcome of Cure or Improvement and microbiologic outcome of eradication (defined as the baseline bacterial pathogen being reduced to < 104 CFU/ml)EOIVT: End of Intravenous TherapymMITT: Microbiologic modified intent to treat population
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Efficacy: EMA co-primary endpoints
EMA Primary EndpointCo-Primary
Meropenem-Vaborbactam
Piperacillin-Tazobactam
Microbial Eradication at TOC mMITT Population
128/192 (66.7%) 105/182 (57.7%)
Difference (95% CI) 9.0% (-0.9%, 18.7%)
Microbial Eradication at TOCME Population
118/178 (66.3%) 102/169 (60.4%)
Difference (95% CI) 5.9% (-4.2%, 16.0%)
Microbial eradication: defined as the baseline bacterial pathogen being reduced to < 103 CFU/mlTOC-Test of CuremMITT-microbiologic modified intent to treat populationME-microbiologic evaluable population
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Safety: Adverse events
System organ class preferred term
Meropenem-vaborbactam
Piperacillin-tazobactam
Total
N = 272 N = 273 N = 545
n (%) n (%) n (%)
Treatment emergent adverse events (TEAEs)
106 (39.0) 97 (35.5) 203 (37.2)
Drug-related TEAEs 41 (15.1) 35 (12.8) 76 (13.9)
Discontinuation of study drug due to an AE
7 (2.6) 14 (5.1) 21 (3.9)
Serious AE 11 (4.0) 12 (4.4) 23 (4.2)
Death 2 (0.7) 2 (0.7) 4 (0.7)
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Summary
In a double-blind, double dummy active controlled trial versus piperacillin-tazobactam in cUTI, Carbavance:
• Met FDA pre-specified non-inferiority margin and met criteria for superiority for efficacy
• Met EMA pre-specified non-inferiority margin for efficacy
• Demonstrated comparable safety and tolerability
• Results were consistent across clinical and microbiological endpoints, in different study populations and in subgroups
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary
Mike Dudley, PharmDSenior Vice President, Research & Development and Co-Lead
Infectious Disease Innovation Group
Commentary on Carbavance programPlanned NDA/MAA phase III package
TANGO 1 TANGO 2
Patients Complicated UTI and acute pyelonephritis(cUTI/AP)
cUTI/AP, HABP/VABP, cIAI and/or bacteremia known/suspected CRE
Design Randomized 1:1Double blind
Randomized 2:1Open label
Comparator Piperacillin-tazobactam
Best available therapy
Total patients 550 Up to 150
Study sites 60 60
BARDA contract Yes Yes
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programOngoing BARDA support
Progressive partnership and contract
Efficient program - 6 years from discovery to end of TANGO-1
BARDA contract total commitment to date ~$55.8 million (total $91.8 million if all options exercised)
Cost-sharing arrangement includes non-clinical, clinical, manufacturing, and associated regulatory activities
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programCRE a growing and urgent threat
CDC threat category “Urgent”
Extensive IV antibiotic use in hospital1
Rise of resistance2,4
High disease burden and mortality (20-50%)3,4,5
Limited treatment options
1. Arlington Medical Resource (AMR) Audit; Decision Resources Pharmacor; HCUP National Inpatient Sample (NIS) Database2. Sievert et al. Infect Cont Hosp Epidem. 2013; 34(1):1-14; Eurofins-TSN / CDDEP3. Spellberg and Rex. Nat Rev Drug Discov. 2013; Dec; 12(12): 963; EviMed Analysis of Premier Database4. Vital Signs: Carbapenem-Resistant Enterobacteriaceae. MMWR 2013;62:165-70.5. Alexander E et al. ICAAC 2015
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programEvolving resistance demands innovation
Successive generations of beta lactam antibiotics ± BLIs
Most recent challenge of carbapenemases (KPC)
1970sTEM-1
TEM-2
2010KPCs
2015Ceph+ BLI
20171
Carbapenem+ BLI
1980s -ESBLs
1: Estimate
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programEvolving resistance demands innovation
Antibiotic resistance in Klebsiella pneumoniae in the U.S.
0%
5%
10%
15%
20%
1999 2003 2007 2011
% r
esi
sta
nc
e
.
Aminoglycosides
Carbapenems
Cephalosporins
Fluoroquinolones
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programMarket demand for new products strong
Company Product Year Sales
Johnson & Johnson Levaquin® 2008 $1.64B
Pfizer/Wyeth Zosyn® 2008 $1.26B
AstraZeneca Merrem® 2008 $897M
Merck Primaxin® 2007 $763M
Merck Invanz® 2015 $569M
Source: Company SEC filings
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Commentary on Carbavance programNext steps
Complete manufacturing development in 2016
Continue to enroll TANGO-2
Compile NDA for submission in early 2017
QIDP
Fast track review
EMA submission 2017
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Carbavance (meropenem-vaborbactam) phase III trial results
Summary
• Carbavance® met FDA and EMA pre-specified primary endpoints in patients with cUTI
• Statistical superiority over piperacillin-tazobactam using FDA primary endpoint
• Safety and tolerability comparable to control treatment
• TANGO 1 will support regulatory submissions
• Plan to submit NDA to FDA in early 2017
• FDA designated Qualified Infectious Disease Product and granted Fast Track status
• Urgent, growing global threat of deadly gram-negative CRE
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market
Investment thesisPotential for attractive growth in antimicrobial medicine
Platform of antibiotic and beta-lactamase inhibitors targeting serious drug-resistance threats
Proven product discovery, development, regulatory capabilities
Effective partnership with BARDA
Established relationships with leading investigators
Productive interactions with regulators
Commercial set-up in US Orbactiv® and Minocin IV®
Potential partnerships ex-US
Carbavance® (meropenem-vaborbactam) is an investigational agent not approved for commercial use in any market