ANTIMICROBIAL DRUGS ADVISORY COMMITTEE MEETING BRIEFING BOOK Study Drug

171 Pages·2012·3.2 MB·English

ANTIMICROBIAL DRUGS ADVISORY COMMITTEE MEETING BRIEFING BOOK
Study Drug: Plazomicin
NDA Number: 210303
Sponsor: Achaogen, Inc.
1 Tower Place, Suite 300
South San Francisco, CA 94080
Meeting Date: 2 May 2018

ADVISORY COMMITTEE BRIEFING MATERIALS:
AVAILABLE FOR PUBLIC RELEASE

Achaogen, Inc.—plazomicin
AMDAC Meeting Briefing Book (30 March 2018)
Page 1 of 171
TABLE OF CONTENTS
Page
1.  Executive Summary ..........................................................................................................13 
1.1  Proposed Indications ..............................................................................................13 
1.2  Unmet Medical Need .............................................................................................13 
1.3  Regulatory Pathway ...............................................................................................16 
1.4  Overview of the Plazomicin Development Program .............................................17 
1.4.1  Product Characteristics ...........................................................................18 
1.4.2  Summaries of Microbiology and Clinical Pharmacology ......................19 
1.4.2.1  Microbiology ........................................................................19 
1.4.2.2  Clinical Pharmacology .........................................................23 
1.4.3  Overview of Efficacy in the Complicated Urinary Tract
and Bloodstream Infection Indications ..................................................29 
1.4.3.1  Efficacy in the Phase 3 Complicated Urinary Tract
Infection Study (Study ACHN-490-009) .............................29 
1.4.3.2  Efficacy in Bloodstream Infections ......................................32 
1.4.4  Overview of Safety Experience with Plazomicin ..................................36 
1.4.4.1  Safety in the Pooled Phase 2 and 3 Complicated
Urinary Tract Infection Studies
(Studies ACHN-490-002 and ACHN-490-009) ...................37 
1.4.4.2  Safety in the Phase 3 Study in Patients With Serious
Infections Due to Carbapenem-Resistant
Enterobacteriaceae (Study ACHN-490-007) .......................38 
1.4.4.3  Aminoglycoside Class-Associated Toxicities in
the Phase 2 and 3 Clinical Development Program ...............39 
1.5  Overall Summary and Proposed Role for Plazomicin in the Treatment of
cUTI and BSI in Patients with Limited or No Alternative Treatment Options .....42 
2.  Clinical Development Plan Overview ..............................................................................45 
3.  Regulatory History ............................................................................................................46 
4.  Microbiology ....................................................................................................................48 
4.1  Mechanisms of Action and Resistance ..................................................................48 
4.2  Spectrum of Activity ..............................................................................................50 
4.3  In Vitro Pharmacodynamics ..................................................................................52 
4.4  In Vivo Pharmacodynamics ...................................................................................53 
4.5  Potential for Plazomicin Resistance Development ................................................54 
4.6  Clinical Microbiology ............................................................................................56 
4.7  Pharmacokinetics/Pharmacodynamics Targets
and Probability of Target Attainment Analyses .....................................................57 
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TABLE OF CONTENTS (CONT’D)
Page
5.  Efficacy in Complicated Urinary Tract Infection .............................................................60 
5.1  Efficacy in Phase 3 Complicated Urinary Tract Infection Study
(Study ACHN-490-009).........................................................................................60 
5.1.1  Study Design ..........................................................................................60 
5.1.1.1  Key Eligibility Criteria .........................................................61 
5.1.1.2  Choice of Comparator ..........................................................61 
5.1.1.3  Statistical Analysis ...............................................................62 
5.1.2  Patient Disposition .................................................................................63 
5.1.3  Demographics and Other Baseline Characteristics ................................63 
5.1.3.1  Demographics and Disease Characteristics ..........................63 
5.1.3.2  Baseline Infecting Pathogens and Susceptibility .................65 
5.1.4  Efficacy Results ......................................................................................67 
5.1.4.1  Primary, Secondary, and Key
Additional Efficacy Analyses ...............................................67 
5.1.4.2  Efficacy in Important Subgroups
and Patient Subpopulations ..................................................69 
5.1.4.3  Additional Efficacy Analyses ...............................................72 
5.2  Efficacy in Phase 2 Study (Study ACHN-490-002) ..............................................77 
6.  Efficacy in Bloodstream Infection ....................................................................................79 
6.1  Efficacy in the Phase 3 Study in Patients With Serious Infections Due
to Carbapenem-Resistant Enterobacteriaceae (Study ACHN-490-007) ................79 
6.1.1  Study Design ..........................................................................................79 
6.1.1.1  Key Study Eligibility Criteria and Diagnosis Criteria .........82 
6.1.1.2  Choice of Comparator ..........................................................84 
6.1.1.3  Choice of Adjunctive Therapy .............................................84 
6.1.1.4  Statistical Analysis ...............................................................85 
6.1.2  Patient Disposition .................................................................................85 
6.1.3  Demographics and Other Baseline Characteristics ................................87 
6.1.3.1  Demographics and Disease Characteristics ..........................87 
6.1.3.2  Baseline Infecting Pathogens and Susceptibility .................89 
6.1.4  Efficacy Results for Cohort 1 .................................................................91 
6.1.4.1  Primary Efficacy Analysis ...................................................91 
6.1.4.2  Additional Analyses of the Primary Endpoint: Efficacy
in Important Subgroups and Patient Subpopulations ...........94 
6.1.4.3  Additional Efficacy Results .................................................95 
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TABLE OF CONTENTS (CONT’D)
Page
6.1.4.4  Microbiological Response Results .......................................95 
6.1.4.5  Response by Baseline Infecting Pathogen ...........................97 
6.1.5  Emergent Infections .............................................................................100 
6.1.6  Impact of Non-Study Drug Therapy ....................................................100 
6.1.7  Efficacy Results for Cohort 2 ...............................................................100 
6.2  Efficacy Results in the Enterobacteriaceae Bacteremia Subgroup From
Phase 3 Complicated Urinary Tract Infection Study (Study ACHN-490-009) ...101 
6.2.1  Primary Endpoint Analysis in Enterobacteriaceae Bacteremia
Subgroup ..............................................................................................101 
6.2.2  Clearance of Blood Pathogens .............................................................101 
6.3  Mouse Septicemia Study......................................................................................102 
6.4  Summary of Efficacy in Bloodstream Infections .................................................102 
7.  Safety ..............................................................................................................................104 
7.1  Nonclinical Toxicology .......................................................................................104 
7.2  Clinical Safety ......................................................................................................104 
7.2.1  Safety Evaluations ................................................................................104 
7.2.1.1  Specific Safety Assessments for
Nephrotoxicity and Ototoxicity ..........................................105 
7.2.2  Safety Analyses ....................................................................................106 
7.2.2.1  Subgroups for Safety Analysis ...........................................106 
7.2.3  Safety in the Pooled Phase 2 and 3 cUTI Studies ................................106 
7.2.3.1  Disposition of Patients in the Safety Analysis ...................106 
7.2.3.2  Demographics and Baseline Characteristics ......................107 
7.2.3.3  All Adverse Events .............................................................109 
7.2.3.4  Deaths and Other Serious Adverse Events .........................113 
7.2.3.5  Clinical Laboratory Evaluations .........................................114 
7.2.3.6  Vital Signs and Electrocardiograms ...................................114 
7.2.3.7  Safety in Patients with Renal Impairment ..........................114 
7.2.4  Safety in the Phase 3 Study in Patients With Serious Infection
Due to Carbapenem-Resistant Enterobacteriaceae, Including
Bloodstream Infection ..........................................................................116 
7.2.4.1  Disposition of Patients in the Safety Analysis ...................116 
7.2.4.2  Demographics and Baseline Characteristics ......................117 
7.2.4.3  All Adverse Events .............................................................121 
7.2.4.4  Adverse Events by Severity ...............................................122 
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TABLE OF CONTENTS (CONT’D)
Page
7.2.4.5  Treatment-Emergent Adverse Events Resulting in
Discontinuation of Intravenous Study Drug .......................123 
7.2.4.6  Deaths and Other Serious Adverse Events .........................124 
7.2.4.7  Clinical Laboratory Evaluations .........................................125 
7.2.4.8  Vital Signs and Electrocardiograms ...................................125 
7.2.4.9  Safety in Patients with Renal Impairment ..........................126 
7.2.5  Aminoglycoside Class-Associated Adverse Events
in the Clinical Development Program ..................................................126 
7.2.5.1  Nephrotoxicity ....................................................................126 
7.2.5.2  Ototoxicity ..........................................................................129 
7.2.5.3  Neurotoxicity ......................................................................129 
7.3  Postmarketing Experience ...................................................................................129 
8.  Benefit–Risk Discussion .................................................................................................130 
8.1  Nonclinical Benefits .............................................................................................130 
8.2  Clinical Benefits ...................................................................................................131 
8.3  Limitations and Risks ..........................................................................................132 
9.  Conclusion ......................................................................................................................136 
10.  References .......................................................................................................................137 

LIST OF TABLES
Table 1:  Summary of Pivotal Phase 3 Study Features ...................................................17 
Table 2:  Proposed Dosing Regimens Based on Creatinine Clearance Categories .........26 
Table 3:  Two Types of Therapeutic Drug Management ................................................27 
Table 4:  Performance of AUC-Based Therapeutic Drug Management in
a Simulated Population of BSI Patients as Reflected by
Summary Statistics for AUC0–24h .....................................................................29 
Table 5:  Composite of Microbiological and Clinical Cure at Day 5 (mMITT
and ME-Day 5 Populations) and the Test-of-Cure Visit (mMITT
and ME-TOC Populations) (Study ACHN-490-009) ......................................31 
Table 6:  All-Cause Mortality at Day 28 or Significant Disease Related
Complications—mMITT Population, Cohort 2 BSI Subgroup
(Study ACHN-490-007)...................................................................................35 
Table 7:  Overview of Treatment-Emergent Adverse Events and Deaths—Safety
Population (Pooled Studies ACHN-490-002 and ACHN-490-009) ................37 
Table 8:  Overview of Treatment-Emergent Adverse Events and Deaths—Safety
Population (Study ACHN-490-007) ................................................................38 
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TABLE OF CONTENTS (CONT’D)
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Table 9:  Treatment Emergent Adverse Events Related to Renal Function
and Serum Creatinine Increases 0.5 mg/dL—Safety Population
(Pooled Studies ACHN-490-002 and ACHN-490-009) ..................................40 
Table 10:  Treatment Emergent Adverse Events Related to Renal Function
and Serum Creatinine Increases 0.5 mg/dL—Safety Population
(Study ACHN-490-007)...................................................................................41 
Table 11:  Plazomicin Clinical Development Program—Completed Clinical Studies .....45 
Table 12:  Plazomicin Activity Against Isogenic Escherichia coli Expressing
Individual Aminoglycoside-Modifying Enzymes ............................................50 
Table 13:  Antibacterial Activity of Plazomicin Against 2014
Through 2016 US Surveillance Isolates ..........................................................51 
Table 14:  Plazomicin Efficacy in Animal Models Against
Multidrug Resistant Enterobacteriaceae ..........................................................54 
Table 15:  Emergence of Resistance in Patients from Study 009 .....................................56 
Table 16:  Plazomicin PK/PD Targets Against Enterobacteriaceae .................................58 
Table 17:  Study Disposition—ITT Population (Study ACHN-490-009) ........................63 
Table 18:  Demographics and Baseline Characteristics—
mMITT Population (Study ACHN-490-009) ..................................................64 
Table 19:  Uropathogens Identified From Baseline Urine Cultures—
mMITT Population (Study ACHN-490-009) ..................................................66 
Table 20:  Composite of Microbiological Response and Clinical Response at Day 5
(mMITT and ME-Day 5 Populations) and the Test-of-Cure Visit
(mMITT and ME–TOC Populations) (Study ACHN-490-009) ......................68 
Table 21:  Clinical Response at Day 5 and the End-of-Intravenous-Therapy and
Test-of-Cure Visits—mMITT Population (Study ACHN-490-009) ...............72 
Table 22:  Per-Patient Microbiological Response at Day 5 and the
End-of-Intravenous-Therapy and Test-of-Cure Visits—
mMITT Population (Study ACHN-490-009) ..................................................73 
Table 23:  Per-Pathogen Microbiological Eradication Rates at the Test-of-Cure Visit
by Baseline Uropathogen—mMITT Population (Study ACHN-490-009) ......74 
Table 24:  Patients with Superinfections and/or New Infections—
mMITT Population (Study ACHN-490-009) ..................................................76 
Table 25:  Microbiological Response at the Test-of-Cure Visit—
MITT and ME Populations (Study ACHN-490-002) ......................................78 
Table 26:  Diagnosis Criteria for Bloodstream Infection ..................................................83 
Table 27:  Patient Demographics and Baseline Disease Characteristics—
mMITT Population, BSI Subgroup (Study ACHN-490-007) .........................88 
Table 28:  Baseline Pathogens Based on Study-Qualifying Cultures—
mMITT Population, BSI Subgroup (Study ACHN-490-007) .........................90 
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TABLE OF CONTENTS (CONT’D)
Page
Table 29:  All-Cause Mortality at Day 28 or Significant Disease-Related
Complications—mMITT Population, Cohort 1 BSI and
HABP/VABP Patients (Study ACHN-490-007) .............................................92 
Table 30:  All-Cause Mortality at Day 28 or Significant Disease-Related
Complications—mMITT Population, Cohort 1 BSI Subgroup
(Study ACHN-490-007)...................................................................................93 
Table 31:  All-Cause Mortality at Day 28 or Significant Disease-Related
Complications by Subgroup—mMITT Population, Cohort 1
BSI Subgroup (Study ACHN-490-007) ...........................................................94 
Table 32:  Per-Patient Microbiological Response at EOT and TOC—
mMITT Population, Cohort 1 BSI Subgroup (Study ACHN-490-007) ..........96 
Table 33:  Documented Clearance of CRE Bacteremia—mMITT Population,
Cohort 1 BSI Subgroup (Study ACHN-490-007) ............................................97 
Table 34:  Per-Pathogen Favorable Microbiological Response at Test of Cure
by Baseline Pathogen and Pathogen Category—mMITT
Population, Cohort 1 BSI Subgroup (Study ACHN-490-007) ........................98 
Table 35:  Per-Pathogen Favorable Microbiological Response at Test of Cure by
Plazomicin MIC to Each Baseline Pathogen and Pathogen Category—
mMITT Population, Cohort 1 BSI Subgroup (Study ACHN-490-007) ..........99 
Table 36:  Demographics and Baseline Characteristics—Safety Population
(Pooled Studies ACHN-490-002 and ACHN-490-009) ................................107 
Table 37:  Treatment-Emergent Adverse Events Reported in at Least 2% of Patients
in the Pooled Plazomicin Group—Safety Population (Pooled
Studies ACHN-490-002 and ACHN-490-009) ..............................................110 
Table 38:  Incidence of Severe or Worse Treatment-Emergent Adverse Events by
Preferred Term—Safety Population (Pooled Studies ACHN-490-002
and ACHN-490-009) .....................................................................................110 
Table 39:  Adverse Events Leading to Premature Discontinuation of Intravenous
Study Drug—Safety Population (Pooled Studies ACHN-490-002
and ACHN-490-009) .....................................................................................112 
Table 40:  Incidence of Serious Adverse Events by Preferred Term—Safety
Population (Pooled Studies ACHN-490-002 and ACHN-490-009) ..............113 
Table 41:  Risk Factors for Potential Nephrotoxicity .....................................................115 
Table 42:  Patient Disposition—Intent-to-Treat Population (Study ACHN-490-007) ...116 
Table 43:  Patient Demographics and Baseline Disease Characteristics—
Safety Population (Study ACHN-490-007) ...................................................118 
Table 44:  Treatment-Emergent Adverse Events With at Least 5% Incidence in the
Combined Plazomicin Group—Safety Population (Study ACHN-490-007) ....122 
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TABLE OF CONTENTS (CONT’D)
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Table 45:  Incidence of Grade 3 Treatment-Emergent Adverse Events Occurring
in 2 Patients in Any Cohort 1 or Cohort 2 Treatment Group—Safety
Population (Study ACHN-490-007) ..............................................................123 
Table 46:  Incidence of Serious Adverse Events Occurring in 2 Patients in
Any Cohort 1 or Cohort 2 Treatment Group—Safety Population
(Study ACHN-490-007).................................................................................125 
Table 47:  Patients With Any Serum Creatinine Increase of 0.5 mg/dL or Greater
Above Baseline—Safety Population (Pooled Studies ACHN-490-002
and ACHN-490-009) .....................................................................................127 
Table 48:  Patients With Any Serum Creatinine Increase of 0.5 mg/dL or Greater
Above Baseline—Safety Population (Study ACHN-490-007)......................128 
LIST OF FIGURES
Figure 1:  Kaplan-Meier Curve of Overall Mortality through Day 60—
mMITT Population, BSI Subgroup (Study ACHN-490-007) .........................34 
Figure 2:  Documented Clearance of Blood Pathogens in cUTI Patients with
Concurrent Enterobacteriaceae Bacteremia—mMITT Population
(Study ACHN-490-009)...................................................................................36 
Figure 3:  The Plazomicin Chemical Structure and Common Sites of
Aminoglycoside Modification by Aminoglycoside-Modifying Enzymes .......49 
Figure 4:  MIC Distribution of Plazomicin Against Enterobacteriaceae
Isolates Nonsusceptible to Amikacin, Gentamicin, or
Tobramycin (2014-2016 US Surveillance) ......................................................51 
Figure 5:  MIC Distribution of Plazomicin Against Carbapenem-Resistant
Enterobacteriaceae and ESBL Enterobacteriaceae Isolates .............................52 
Figure 6:  Plazomicin Exhibits Rapid Bactericidal Activity in Time-Kill Studies ..........53 
Figure 7:  Plazomicin Suppresses Resistance Outgrowth in an
In Vitro Chemostat Model ...............................................................................55 
Figure 8:  Probability of Plazomicin Stasis Target Attainment Overlaid on the
MIC Distributions of cUTI/AP Baseline Enterobacteriaceae From
Study 009 and UTI Enterobacteriaceae from 2014-2016 US Surveillance .....59 
Figure 9:  Probability of Plazomicin 1-log10 Kill Target Attainment Overlaid on
the MIC Distributions of BSI Baseline Enterobacteriaceae From
Study 007 and BSI Enterobacteriaceae from 2014-2016 US Surveillance ......59 
Figure 10:  Study Design Schema and Overview of Study
Schedule for Study ACHN-490-009 ................................................................60 
Figure 11:  Composite Cure by Study Day—mMITT
Population (Study ACHN-490-009) ................................................................69 
Figure 12:  Composite Cure at the Test-of-Cure Visit by Subgroup—
mMITT Population (Study ACHN-490-009) ..................................................71 
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TABLE OF CONTENTS (CONT’D)
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Figure 13:  Study Design Schema and Overview of Study
Schedule for Study ACHN-490-007 ................................................................80 
Figure 14:  Disposition Flow Diagram for Study ACHN-490-007 ....................................86 
Figure 15:  Kaplan-Meier Survival Curve of Plazomicin Monotherapy vs Untreated
Control Over 96 Hours in a Mouse Model of Septicemia .............................102

LIST OF APPENDICES
Appendix 1:  Tabular Overview of Completed Clinical Studies .........................................144 
Appendix 2:  Population Pharmacokinetics Analysis Population Demographics ...............150 
Appendix 3:  Therapeutic Drug Management Procedures ...................................................151 
Appendix 4:  Additional Information on Statistical Analyses for
Study ACHN-490-007 ...................................................................................153 
Appendix 5:  Summary of Key Program and Regulatory Milestones for
Plazomicin......................................................................................................155 
Appendix 6:  Animal Models Used in Plazomicin Efficacy Studies ...................................158 
Appendix 7:  Eligibility Criteria for Phase 3 Studies ..........................................................161
Appendix 7.1: Eligibility Criteria for Study ACHN-490-009 ...............................................161 
Appendix 7.2: Eligibility Criteria for Study ACHN-490-007 ...............................................165 

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List of Abbreviations
Abbreviation Definition
16S RMTase 16S ribosomal ribonucleic acid methyltransferase
AAC aminoglycoside acetyltransferase
ACE angiotensin-converting enzyme
ACM all-cause mortality
AE adverse event
AME aminoglycoside-modifying enzyme
ANT aminoglycoside nucleotidyltransferase
AP acute pyelonephritis
APACHE II Acute Physiology and Chronic Health Evaluation II
APH aminoglycoside phosphotransferase
ARDS acute respiratory distress syndrome
ASHA American Speech-Language-Hearing Association
AUC area under the concentration-time curve from time zero to 24hours
0–24h
BL/BLI -lactam/-lactamase inhibitor
BMI body mass index
BSI bloodstream infection
CBA colistin base activity
CFU colony-forming unit
CLcr creatinine clearance
CLSI Clinical and Laboratory Standards Institute
CMS colistimethate sodium
CRE carbapenem-resistant Enterobacteriaceae
CRRT continuous renal replacement therapy
CSR Clinical Study Report
CT computerized tomography
CTCAE Common Terminology Criteria for Adverse Events
cUTI complicated urinary tract infection
DDI drug–drug interaction
ECG electrocardiogram
eCRF electronic case report form
ELF epithelial lining fluid
ENG electronystagmography
EOIV end of intravenous therapy
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