Transcript Presentation - Working Group for New TB Drugs

TB Drug Development:
Year-in-Review
Barbara Laughon, PhD
Co-Chair Working Group on New TB Drugs
26 October 2016
Working Group on New TB Drugs
Liverpool, U.K.
2015 Global TB Drug Pipeline 1
Discovery
Lead Optimization
Cyclopeptides
Diarylquinolines
DprE Inhibitors
InhA Inhibitor,
Indazoles
LeuRS Inhibitors, Ureas
Macrolides, Azaindoles
Mycobacterial Gyrase
Inhibitors
Pyrazinamide Analogs
Ruthenium(II)
Complexes
Spectinamides
Translocase-1 Inhibitors
Preclinical Development
Early Stage
Development
GLP
Tox.
Clinical Development
Phase I
TBI-166
PBTZ169*
TBA-354
CPZEN-45*
BTZ043*
Q203*
SQ609*
1599*
SEQ-9*
Phase II
Phase III
Sutezolid (PNU-100480) Bedaquiline with OBR2
for MDR-TB
Linezolid EBA
Delamanid (OPC-67683)
SQ109*
with OBR for MDR-TB
Rifapentine for DS-TB
PretomanidHigh Dose Rifampicin
Moxifloxacinfor DS-TB
Pyrazinamide Regimen
Bedaquiline (TMC207)- BedaquilinePretomanid (PA-824) - Pretomanid-Linezolid
Pyrazinamide Regimen NiX-TB Regimen
Levofloxacin with OBR
for MDR-TB
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline,
benzothiazinone, , imidazopyridine amide, New chemical class*
1 Details
for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing
projects without a lead compound series identified can be viewed at
http://www.newtbdrugs.org/pipeline-discovery.php
2OBR
= Optimized Background Regimen
www.newtbdrugs.org
Updated: December 2015
2015 Global TB Drug Pipeline 1
Discovery
Lead Optimization
Cyclopeptides
Diarylquinolines
DprE Inhibitors
InhA Inhibitor
Indazoles
LeuRS Inhibitors, Ureas
Macrolides, Azaindoles
Mycobacterial Gyrase
Inhibitors
Pyrazinamide Analogs
Ruthenium(II)
Complexes
Spectinamides
Translocase-1 Inhibitors
Preclinical Development
Early Stage
Development
GLP
Tox.
Clinical Development
Phase I
TBI-166
PBTZ169*
TBA-354
CPZEN-45*
BTZ043*
Q203*
SQ609*
1599*
SEQ-9*
Phase II
Phase III
Sutezolid (PNU-100480) Bedaquiline with OBR2
for MDR-TB
Linezolid EBA
Delamanid (OPC-67683)
SQ109*
with OBR for MDR-TB
Rifapentine for DS-TB
PretomanidHigh Dose Rifampicin
Moxifloxacinfor DS-TB
Pyrazinamide Regimen
Bedaquiline (TMC207)- BedaquilinePretomanid (PA-824) Pretomanid-Linezolid
Pyrazinamide Regimen NiX-TB Regimen
Levofloxacin with OBR
for MDR-TB
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline,
benzothiazinone, , imidazopyridine amide, New chemical class*
1 Details
for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing
projects without a lead compound series identified can be viewed at
http://www.newtbdrugs.org/pipeline-discovery.php
2OBR
= Optimized Background Regimen
www.newtbdrugs.org
Updated: December 2015
2016 Milestones in TB Drug Research
Advances in Registration/Phase 3 landscape
 TB Alliance – Pretomanid/Moxifloxacin/PZA Phase 3 STAND
trial suspended. Clinical hold lifted September 2016.
 TB Alliance – Nix TB (Pa BDQ LZD) study continues for XDRTB patients.
 Sanofi/CDC TBTC Study 31/ACTG 5349 – Phase 3 rifapentinecontaining regimes for treatment shortening began
enrollment March 2016.
 BMRC – STREAM study of MDR TB regimens fully enrolled.
Stage 2 began in March 2016 with inclusion of bedaquiline.
 University of Cape Town – NExT TB Open-label RCT for MDR
(BDQ, LZD) began enrollment in early 2016.
2016 Milestones in TB Drug Research
Advances in Phase 2 landscape
 Task Foundation/GSK – Results of the meropenem /faropenem
Phase 2 EBA published.
 Boston University/TBTC 32/NIAID – Levofloxacin for MDR-TB (OptiQ) Phase 2 continues recruiting in Peru and South Africa
 TB Alliance – NC-005 (BDQ, Pa, MFX, PZA for 8 weeks) results
presented at the Liverpool UNION meeting Thursday 17:30.
 NIAID – Phase 2 EBA trial of oxazolidinone AZD 5847 completed,
but development halted by AZ. Results published November 2016.
 TRUNCATE – Adaptive alternative design with Phase 2c
progressing. Two-month trials planned for 2017 (Singapore).
 Novartis – Clofazimine Phase 2/3 trial planned for 2016 suspended
due to new guidelines. Company continuing active discussions
with WHO.
2016 Milestones in TB Drug Research
Advances in Phase 1 landscape
 TB Alliance – Phase 1b trial of TBA-354 encounters
toxicity issues and development discontinued
(3/11/2016).
 Qurient – Phase 1a trial of Q203 imidazopyridine amide
(FDA oversight) completed in the US (February 2016).
Phase 1b began enrollment in August 2016.
2016 Milestones in TB Drug Research
Significant changes in development landscape
 iM4TB Foundation (EPFL) – Formulation development
in progress; spray-dried API under study; expecting to
begin Phase 1 with PBTZ-169 in early 2017 in
Switzerland.
 University of Munich – BTZ-043 completing PK/PD
evaluations. GMP drug to be available in 2017.
 GSK – Announces selection of oxaborole candidate
GSK-070 in April 2016.
 Microbiotix – Lead selection in spectinamides
continues for protein synthesis inhibitors
 Lilly Initiative – Negotiating development agreements
for inhalation delivery approach with CPZEN-45
2016 Milestones in TB Drug Research
Significant changes in discovery landscape
 Sanofi – Continues discovery R&D for macrolides
 Gates TB Drug Accelerator – new members Eli Lilly,
Abbvie, and TB Alliance
 Ongoing screening efforts to identify safer and more
potent oxazolidinones
 SPRINT TB/University of Singapore – Multiple
screening, target identification, candidate
development projects reported at the EMBO
Tuberculosis 2016 meeting in Paris
 GSK – New discovery project focusing on betalactams
2016 Milestones in TB Drug Research
Significant changes on the horizon
 Renewed interest in host-directed therapies – NIAID
and others (ex. imatinib (Gleevec), statins,
eicosanoid synthesis pathway inhibitors)
 Fundamental research – new findings in genetic and
metabolic controls for multiple targets; promiscuous
targets (MmpL3); inhibition of non-replicating cells.
 Repurposed drugs under evaluation – Linezolid,
colistin, carbapenems, efflux inhibitors, thioridazine,
dry powder inhalation administration
Benzothiazinone
BTZ 043
 Advanced preclinical development of
BTZ043 continues by the University of
Munich and others
 Inhibits essential enzyme for cell wall
structure (DprE1)
Benzothiazinone
PBTZ 169
 Inhibits essential enzyme for cell wall
structure (DprE1)
 Clinical results from Phase 1a conducted by
NearMedic in Russia presented at EMBO
Tuberculosis 2016 conference
 Formulation development of PBTZ 169
continues by EPFL and iM4TB; Phase 1 to
start in 2017
 Synergistic with bedaquiline
Imidazopyridines
Q203 (Qurient)
 Targets the cytochrome b subunit (QcrB) of
the cytochrome bc1 complex - an essential
component of the respiratory electron
transport chain. Q203 causes depletion of
intracellular ATP.
 Q203 has been licensed to Infectex, LLC for
the Russia and the CIS
 Qurient began Phase 1b safety studies in
the US in 4Q2016
1,4-Azaindole
TBA 7371 (TB Alliance)
 Targets DprE1
 Bactericidal efficacy in
mice
 Good safety margin in rats
 Human clinical trial to begin in 2017
Griselimycin cyclopeptide
SATB 082 (Sanofi, TB
Alliance)
 Targets DnaN
(sliding clamp of
DNA polymerase)
 Candidate to replace CGM analog
announced at EMBO Tuberculosis 2016
conference in Paris
 Good efficacy in mice; LORA assay
 Improved safety profile. Some human
data from the 1970s.
Caprazamycin
CPZEN-45 (IMC, Lilly
TB Drug Initiative)
 Targets WecA (decaprenyl phosphate
GlcNAc-1-phosphate transferase)
 Natural product from Streptomyces strain
 Efficacy in mice against DS and DR Mtb
 Production and formulation development
progressing
The TB Drug Accelerator
The TBDA is a groundbreaking partnership between eight
pharmaceutical companies, eight research institutions, and a product
development partnership that seeks to develop a new TB drug regimen
through collaboration in early-stage drug discovery research.
With Participation From:
16
Global TB Drug Pipeline
Discovery
Lead Optimization
Preclinical Development
Early Stage
Development
GLP Tox.
Clinical Development
Phase 1
Phase 2
Diarylquinolines
TBI-166
BTZ-043*
DprE Inhibitors
CPZEN-45*
1599*
PBTZ-169* PBTZ-169* Linezolid EBA
TBA-7371*
SATB-082*
GSK-070*
InhA Inhibitor, Ureas
Macrolides, Azaindoles
Mycobacterial Gyrase
Inhibitors
OPC-167832
Pyrazinamide Analogs
Ruthenium(II)Complexes
Spectinamides
Translocase-1 Inhibitors, Clp,
MmpL3, Oxazolidinones,
Pyrimidines DprE1, Aryl
Sulfonamides, PKS13,
Squaramides
1
Q203*
Sutezolid (PNU-100480)
High Dose Rifampicin for
DS-TB
Bedaquiline (TMC207)Pretomanid (PA-824) Pyrazinamide Regimen
Levofloxacin with OBR for
MDR-TB
Phase 3
Rifapentine - Moxifloxacin for
Drug Sensitive TB
Delamanid (OPC-67683) with
OBR for MDR-TB
Pretomanid-MoxifloxacinPyrazinamide Regimen (STAND)
Bedaquiline-PretomanidLinezolid NiX-TB Regimen
Bedaquiline-STREAM MDR-TB
Trial Stage 2 with oral OBR (9 mo)
or OBR with injectables (6 mo)
Bedaquiline-Linezolid with OBR
for MDR-TB (NExT Trial)
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline,
benzothiazinone, , imidazopyridine amide. New chemical class*
1 Details
for projects listed can be found at http://www.newtbdrugs.org/pipeline.php and ongoing
projects without a lead compound series identified can be viewed at
http://www.newtbdrugs.org/pipeline-discovery.php
2OBR
= Optimized Background Regimen
www.newtbdrugs.org
Updated: October 2016
Global TB Drug Pipeline
Preclinical Development
Early Stage
GLP Tox.
Riminophenazine
TBI-166
BTZ-043*
Caprazene nucleoside
CPZEN-45*
PBTZ169*
Spectinamide 1599*
Cyclopeptide SATB082*
Clinical Development
Phase 1
Q203*
Phase 2
Sutezolid (PNU-100480)
Linezolid EBA
TBA-7371*
GSK-070*
1
PBTZ169*
High Dose Rifampicin for
DS-TB
Bedaquiline (TMC207)Pretomanid (PA-824) Pyrazinamide Regimen
Levofloxacin with OBR for
MDR-TB
Phase 3
Rifapentine - Moxifloxacin for
Drug Sensitive TB
Delamanid (OPC-67683) with
OBR for MDR-TB
Pretomanid-MoxifloxacinPyrazinamide Regimen (STAND)
Bedaquiline-PretomanidLinezolid (NiX-TB Regimen)
Bedaquiline-STREAM MDR-TB
Trial Stage 2 with oral OBR (9 mo)
or OBR with injectables (6 mo)
Bedaquiline-Linezolid with OBR
for MDR-TB (NExT Trial)
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole,
diarylquinoline, benzothiazinone , imidazopyridine amide. New chemical class*
1 Details
for projects listed can be found at http://www.newtbdrugs.org/pipeline.php
and ongoing projects without a lead compound series identified can be viewed at
http://www.newtbdrugs.org/pipeline-discovery.php.
2
OBR = Optimized Background Regimen
www.newtbdrugs.org
Updated: October 2016
Global TB Drug Discovery Pipeline 1
Hit-to-Lead
Actinomycete Metabolites (U ILL Chicago, Myongii U)
Novel Hit-to-Lead Programs (Lilly DDi) GATB
Adamantanids (U ILL Chicago)
Whole-Cell Hit-to-Lead (GSK, GATB)
Menaquinone Synthase Inhibitors (CSU)
M. tb Energy Metabolism Inhibitors (UPenn, GATB)
Isoprenoid Biosynthesis Inhibitors (Lilly DDi)
Whole-Cell Hit-to-Lead (GATB, Sanofi)
RNA Polymerase Inhibitors (GATB, Rutgers U)
ClpC/P1P2 (GATB)
POA Prodrugs (GATB, Yonsei)
PEPCK (GATB, Roche, TAMU)
1 Details
Lead Optimization
Diarylquinolines (GATB, U Auckland, Janssen)
InhA Inhibitors (GSK)
DprE Inhibitors Azaindoles (GATB, Calibr)
Ureas (Sanofi, GATB)
Ruthenium(II)phosphine/picolinate Complexes (FAPESP/Brazil)
Spectinamides (St. Jude, U Tenn, CSU, UZ, Microbiotix)
Macrolides (GATB, Sanofi)
DrpE Inhibitors (GATB)
Clp (SPRINT TB / A* Star)
MmpL3 (GATB, TBDA)
Oxazolidinones (GATB, IMM, TBDA)
Pyrimidines DprE1 (GATB, GSK, TBDA)
Aryl Sulfonamides (GATB, GSK, TBDA)
PKS13 (GATB, DDU, TAMU, GSK, TBDA)
Squaramides (GATB, TBDA)
for projects listed can be found at http://www.newtbdrugs.org/pipelinediscovery.php and clinical development projects can be viewed at
http://www.newtbdrugs.org/pipeline.php.
Abbreviations of Developers: A*Star- Agency for Scienct Technology and Research CSUColorado State University; FAPESP-São Paulo Research Foundation; GATB-Global Alliance
for TB Drug Development (TB Alliance); GSK-GlaxoSmithKline; Lilly DDi-Lilly TB Drug
Discovery Initiative; RI-Research Institute; SPRINT TB-Singapore Programme of Research
Investigating New Approaches to Treatment of TB St. Jude-St. Jude Children’s Research
Hospital; TAMU-Texas A&M University; U-University; U ILL-University of Illinois; UPennUniversity of Pennsylvania; U Tenn-University of Tennessee; UZ-University of Zurich
www.newtbdrugs.org
Updated: October 2016