What’s New in the Antimicrobial R&D Pipeline

Greg Basarab

7th FIDSSA Conference

November 11, 2017

A Gap in Time for Novel Antibacterial Classes

Sulfa Drugs 1935

-Lactams 1942

Tetracyclines, 1949

Chloramphenicol

Macrolides 1952

Glycopeptides 1958

Streptogramins, 1962-3

Lincomycins,

Quinolones

Aminoglycosides 1947

1920 1940 1960 1980 2000 2020

>35 year gap Oxazolidinones 2000

Cyclic Lipopeptides 2003

Diarylquinolines 2012

For Gram-(-)’s: 53 year

gap & counting

3

Mechanistic Classes of Antibacterial Agents

Protein synthesis inhibitors

Inhibitors of peptidoglycan

biosynthesis

DNA topoisomerase

inhibitorsFolate antagonists

Beta-lactams

– penicillins

– cephalosporins

– penems

– carbapenems

– monobactams

Glycopeptides

– e.g. vancomycin

Aminoglycosides

– e.g. gentamicin

Oxazolidinones

– e.g. linezolid

Chloramphenicol

– e.g. thiamphenicol

Lincosamides

– e.g. clindamycin

Aminocyclitols

– e.g. spectinomycin

Tetracyclines

– e.g. doxycycline

Macrolides

– e.g. erythromycin

Streptogramins

– e.g. quinupristin

Pleuromutilins

– e.g. retapamulin

Quinolones

– e.g. ciprofloxacin

ATPase inhibitors

– e.g. novobiocin

Sulfonamides

Trimethoprim

Iclaprim

RNA replication

inhibitorsRifamycins

– e.g. rifampin

Polymixins

– e.g. colistin

Membrane disruption

Membrane depolarization

Cyclic lipopeptides

– e.g. daptomycin

Free radical generator

Metronidazole

5

1

2

1

5

1

5

4

Clinical -lactamase Inhibitors

NDAAdjunct

toDrug

-Lactamase Class

A B C D

Clavulanic acid

1984

1990

amoxicillin

ticarcillin

co-amoxiclav

co-ticarclav

Sulbactam

1991

1994

ampicillin

ampicillin

Unasyn

sultamicillin(prodrug)

Tazobactam

1993

2014

piperacillin

ceftolozane

Tazosyn

Zerbaxa

Avibactam

2015 ceftazidime Zaficefta (±)

• No coverage against class B, zinc and bis-zinc metallo--lactamases• No coverage against key class D -lactamases

5

-Lactamase Primer

Class TypePeni-cillins

Cephalo-sporins(ESBLs)

Carba-penems

Mono-bactams

Represen-tatives

A(2a-2f)

serine 2bc,2ber,

2e,2f2f 2be,2f

TEM-1,30,50,121

SHV-1,10CTX-M014,15

B(B1a-b, B2, B3)

Zn2+

2 x Zn2+ 3a noIMP-VIM

NDM-1

C(1, 1e)

serine no 1e no no

AmpCACT-1CGY

CMY-37

D(2d,2de,

2df)serine no 2d,2de

Oxa1,10,11,15,23,48

Bush, K. J. Inf. Chemother. 19(4), 2013, 549

6

-lactamase inhibitors

-lactamase with PBPIs

PhaseIndications/

Target Pathogens

Mode of

Administration

Vabormere: vaborbactam (boronate) +

meropenemNDA cUTI, HABP/VABP IV

Relebactam (DABCO) + imipenem +

cilastatin3 HABP/VABP IV

Zidebactam (DABCO) + cefepime 1CRE

(ESBLs & KPCs)IV

Nacubactam (DABCO) + meropenem? 1 CRE IV

AAI-101 (-lactam) + cefepime or

piperacillin1

CRE

(ESBLs & KPCs)IV

VNRX-5133 (boronate) +

unknown antibiotic1 MBL producers IV

ETX2514 + sulbactam

(DABCO)1 Aba IV

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Boronate BLI’s

▪ Vaborbactam + meropenemoptimized against KPC mode-of-resistance

▪ Pathogen specific development path for CRE

▪ NDA approval – Aug. 2017 for cUTI(The Medicines Co.) Enterobacteriaceae infections

VNRX-5133 + unknown (IV) – VenatoRX▪ Pre-clinical metallo--lactamase

inhibitor▪ Structure not disclosed▪ Tetrahedral boronate mimics

hydrolytic high-energy intermediate▪ Phase 1

Hecker et al. J. Med. Chem. 58(9), 2015, 3862Jones, RM et al. AAC, 60(9), 2016, 5454

Brem et al. AAC 61(4), 2017, e02260

208 KPC strains K. pneumoniae MP

VB(8 g/ml)

+MP

MIC50

g/ml

16 <0.06

MIC90 >64 1

K. pneumoniaeSHV-11; VIM-2

Mero-penem

Boronate + meropenem

MIC (g/ml)

>8 0.5

8

Extended spectrum DABCO BLIETX2514 – Class A

Class C Class D

▪ Covalent reactivity increased due to strain

▪ Combination w/ sulbactamagainst A. baumannii

▪ Phase 1 (Entasis Therapeutics from AstraZeneca)

Durant-Reville et al. Nat. Microbiol. 2(9), 2017, 17104

9

-Lactam antibacterials

Inhibitors of penicillin binding proteins (PBPs)

Phase IndicationsMode of

Administration

Cefiderocol –

(siderophore cephalosporin)3 HAP IV

Sulopenem (penem) 3 UTI, cIAI PO & IV

GSK-3342830

(siderophore cephalosporin)1 HPA/VAP IV

LYS-228 (monobactam) 1 CRE IV

AIC-449 (monobactam) + BLI? 1 TBD IV

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Novel cephalosporin and novel penem

Sulopenem (IV) – Pfizer (1988)Sulopenem etzadroxil –(PO pro-drug) Iterum Therapeutics▪ Carbapenem-like spectrum (but

lacking Pseudomonas)▪ Carbapenem-like resistance profile▪ Enterobacteriaceae spectrum for

uUTI, cUTI & cIAI▪ Phase 3 – to begin end of 2017

Cefiderocol (IV) - Shionogi▪ Siderophore Fe2+ chelator for

‘Trojan-horse’ uptake into bacterial periplasm

▪ Pseudomonas activity (elevated MICs)

▪ Enterobacteriaceae spectrum –elevated MICs for KPCs

▪ Phase 3 for HAP/VAP

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2nd Generation Monobactams

LYS-228 (IV) - Novartis▪ Phase 1▪ Enterobacteriaceae spectrum –▪ MIC90’s = 0.25 g/ml (wild-type)

0.5 g/ml (ESBLs/AmpC)4.0 g/ml (carbapenemases)

AIC-449 (IV) - AiCuris▪ Phase 1, structure not disclosed▪ Partner BLI combination

➢ Stable to metallo--lactamases (Class B)➢ Greater stability vs aztreonam to serine -lactamases (Class A, C & D)

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Type-II Topoisomerase Inhibitors

Fluoroquinolines, Quinolines, Spiropyrimidinetriones

Phase IndicationsMode of

Administration

Delafloxacin (FQ) NDA cSSTI; CAP PO &IV

Lascufloxacin (FQ) 3 RTI; CAP PO &IV

Finafloxacin (FQ) 2 aEI PO &IV

Gepotidacin (quinoline) 2 cSSTI; STD PO &IV

Zoliflodacin (SPT) 2 STD PO

Alalevonadifloxacin (FQ) 1 cSSTI PO

TNP-2092 (FQ/Rif hybrid) 1 PJI PO

13

FQ-type + Rifampicin

TNP-2092 (IV) – TenNor Therapeutics▪ Gram-(+) agent for prosthetic

joint infections

Ma, Z. J.. Med. Chem.. 59, 2016, 6645..

14

Novel Bacterial Topoisomerase Inhibitors (NBTIs)

Zoliflodacin (PO)- Entasis (from AstraZeneca)▪ Activity against Gram-(+) and fastidious

Gram-(-)▪ Phase 3 in 2018 targeting uncomplicated

gonorrhea▪ No cross-resistance to FQs and other

antibacterial agents

Gepotidacin (IV & PO) – GSK▪ Activity against Gram-(+) and

fastidious Gram-(-)▪ Phase 2 for gonorrhea and cSSSI▪ No cross-resistance to FQs and

other antibacterial agents

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Topoisomerase Target

GepotidacinBinds to Gyrase/DNA complex

MoxifloxacinBinds to Gyrase/cleaved DNA complex

Dependent on Mg2+

Zoliflodacin• Binds to Gyrase/cleaved DNA complex• Independent of Mg2+

DNA Gyrase – creates negative supercoils in dsDNATopoisomerase IV – decantenates intertwined dsDNA

Basarab, G. Top. Med. Chem..2017.

16

Protein biosynthesis inhibitors

Ribosome inhibitors

Phase IndicationsMode of

Administration

Plazomicin (aminoglycoside) 3 cUTI, HAP/VAP IV

Eravacycline (tetracycline) 3 cIAI, cUTI PO & IV

Omadacycline (tetracycline) 3 CAP, cSSTI PO & IV

Solithromycin (macrolide) 3 CAP PO & IV

Nafithromycin (macrolide) 2 CAP PO

TP-271 (tetracycline) 1 CAP PO & IV

TP-6076 (tetracycline) 1 CRE PO & IV

KBP-7072 (tetracycline) 1 CAP PO & IV

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Translation Inhibitors

Plazomicin (IV)- Achogen▪ Unaffected by aminoglycoside-modifying

enzymes▪ Susceptible to 16S rRNA methylase▪ Phase 3 against cUTI; HAP/VAP

Eravacycline (PO & IV)- Tetraphase▪ Fully synthetic tetracycline▪ Unaffected by Tet(M)-rpp

Tet(X)-metabolizing ▪ Susceptible to Tet(A)-efflux▪ Phase 3 for IAI, UTI

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Membrane Disrupters

Colistins & Defensins

Phase IndicationsMode of

Administration

Murepavidin (POL-7080)Cyclic peptide binds to lpt1

2VAP, RTI

(Pseudomonas only)

IV

Brilacidin 2 SSTI IV

SPR-741 (cyclic peptide potentiator) + unknown

1 TBD IV

19

Gram-positive arena

Others

Phase IndicationsMode of

Administration

Cadezolid (Oxa-FQ hybrid) 3 C. difficile PO

Lefamulin (pleuromutilin) 3 Gram-(+) PO & IV

MRX-I/MRX-4 (oxazolidinone) 2/3 Gram-(+) PO & IV

Afabicin (FabI inhibitor) 2 Gram-(+) PO & IV

Ridinilazole (bis-benzimidazole) 2 C. difficile PO

MGB-BP-3 (minor groove binder) 1 C. difficile PO

MCB3837 (Oxa-FQ hybrid) 1 C. difficile PO

Sutezolid (Oxa) 1 Mtb PO

TBA-7371 (DprE1 inhibitor) 1 Mtb PO

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Parting thoughtsWHO: pipeline is insufficient to meet needs over the next decade

• Novel mode-of-action drugs in the pipeline: 4 – all Ph 1; none for Gram-(-)’s

• Novel mode-of-inhibition drugs in the pipeline: 4 - none for serious Gram-(-)’s

• Novel chemical scaffolds in the pipeline: 7

J. Rex, ASM_ESCMID, 2017, Boston

21

More parting thoughts

Timing is right to push forward

• The medical community has prioritized new and expanded infectious disease

control measures

• New medicines

• Rapid diagnostics

• Access to care

• Improved medical practices

• Issues of antibiotic resistance are high on the political agenda (not just the

medical community agenda)

• High profile public/private/philanthropic partnerships & initiatives have recently

been created or been directed at AMR/DRI

• CARB-X

• GARD-P

• Ross Foundation

• Longitudeprize.org

• Wellcome-Trust

• IMI

• GAMRIF

• NIAID

Title

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About H3D

• Founded in 2010 as a University of Cape Town (UCT) accredited research centre

• Current staff of 55 scientists and support including Post Doctoral Fellows (August 2017)

• Drug discovery platform located at three sites across two campuses

Dept of Chemistry

Dept of Pharmacology

IDM

Department of Chemistry

Department of MedicineIDM

H3D is the first and only fully integrated drug discovery unit in Africa and we target neglected infectious diseases that are relevant to African populations

Capabilities

In Vitro ADME

In Vivo PK

Assay DevelopmentDMPK

Medicinal Chemistry

CADD

Ch

em

istry

MicrobiologyTB & Gram-(-)

Biology

Malaria Biology

Cytotoxicity cross-screening