Overview of new antibiotics in developmentProfessor David Livermore, Professor of Medical Microbiology, University of East Anglia

DAVID M LIVERMORE

New antibacterials in development

University of East Anglia

DisclosuresConsult / advisory – Accelerate, Achaogen, Adenium, Allecra,

Antabio, BioVersys, Centauri, Janssen/J&J, McKinsey, Medicines Co., Meiji, Melinta, Merck, Nordic, Pfizer, Roche, Shionogi, TAZ, Tetraphase, VenatoRx, Wockhardt, Zambon

Lectures – Astellas, bioMerieux, Beckman-Coulter, Correvio, Cepheid, Nordic, Merck/MSD, Pfizer, Wockhardt

Sponsored research – Meiji, Melinta, Merck, Paratek, Roche, Shionogi, Tetraphase, Wockhardt

Shareholdings – Dechra, GSK, Merck, Perkin Elmer, Pfizer amounting to <10% of portfolio value

Licensed since 2015

Drug Class Unique selling point

Ceftazidime/avibactam Ceph-BLI, iv Covers bacteria with KPC, OXA-48

Ceftolozane/tazobactam Ceph-BLI, iv Antipseudomonal activity

Meropenem/vaborbactam Carb-BLI, iv Covers bacteria with KPC

Plazomicin Aminoglycoside iv Evades modifying enzymes

Eravacycline Tetracycline iv Avoids efflux/ribosomal protection; eravacycline MICs lower than tigecyclineOmadacycline Tetracycline iv/po

DalbavancinLipoglycopeptides iv v. long T1/2; 1-2 dose Rx for ABSSSI

Oritavancin

Delafloxacin Quinolone iv/po Active vs. cipro-R S. aureus

Areas of development

• Agents vs. carbapenemase-producers

• Alternatives to i.v. carbapenems against ESBL producers

• Anti-gram-positive agents

• Anti-gonococcals

• Anti-Pseudomonas only

Diazabicyclooctanes… avibactam & beyond

Nacubactam

Relebactam

Zidebactam

WCK4234

DBOs … avibactam & beyondEnterobacteria with P. aeruginosa A. baumannii

KPC OXA-48 MBLs MBL OXA-23Ceftazidime-avibactam

Aztreonam/avibactam

Imipenem-relebactam

Meropenem-nacubactam

Cefepime-zidebactam

Meropenem-WCK4234

Active Variable Resistant Direct activity or ‘enhancer’ effect

Wright et al., CMI 2017;23:704; Papp-Wallace et al. J Med Chem 2018; 61: 4067

0

5

10

15

20

25

≤0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 ≥128MIC (mg/L)

AZT+AVI Aztreonam

Livermore et al. AAC 2011;55:390

Aztreonam-avibactamAztreonam is stable to MBLs….

17 NDM, 13 IMP, 5 VIM

MICs of nacubactam alone for Enterobacteria with MBLs

0

20

40

60

80

100

120

<=1.0 2 4 8 16 32 >32

Cou

nt

MIC (mg/L)

Providencia Morganella

Klebsiella Escherichia

Enterobacter Citrobacter

Mushtaq et al. JAC 2018 epub

Meropenem-nacubactam vs. NDM (158) & VIM (58) Enterobacteriaceae

0

10

20

30

40

50

60

70

80

90

100

NoDBO

Nac 1 Nac 2 Nac 4 Avi 4 NoDBO

Nac 1 Nac 2 Nac 4 Avi 4

% S

usce

ptib

le

DBO and concentration, mg/L

Additionallysusceptible

Susceptible toDBO alone

S to meropenem 4 mg/L S to meropenem 8mg/L

Mushtaq et al. JAC 2018 epub

OXA-type & meropenem-WCK 4234 vs. A. baumannii

0.25

0.5 1 2 4 8 16 32 64 128 >128

OXA-23 6 3 1

+WCK 1 2 6 1

OXA-24/40 2 3 3 2

+WCK 3 1 2 2 2

OXA-51+++ 4 1 4 1

+WCK 1 1 4 3 1

OXA-58 2 3 5+WCK 1 1 1 6 1

Mushtaq et al. JAC 2017; 72: 1688

Imipenem + relebactam vs. P. aeruginosa BSAC 2014-6

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

0.06 0.125 0.25 0.5 1 2 4 8 16 32 128 >256

Isol

ates

(%)

MIC (mg/L)

IMI IMI-REL

Boronate b-lactamase inhibitorsVaborbactam

Combined with meropenem: 2+2g infusion, over 3h

Overcomes KPC only

VNRX-5133

In phase I with cefepime

Broad spectrum, except IMP & Acinetobacter OXA

Cefepime & cefepime/VNRX-5133 vs. KPC +ve Enterobacteriaceae

0

2

4

6

8

10

12

14

16

<=0.

015

0.03

0.06

0.12

50.

25 0.5 1 2 4 8 16 32 64 12

8>1

28

Cou

nt

Cefepime MIC (mg/L)

Cefepime alone

+ VNRX, 4 mg/L

Mushtaq et al. ECCMID 2018, Poster 1537

Cefepime & cefepime/VNRX-5133 vs. OXA-48 Enterobacteriaceae

0

2

4

6

8

10

12

14

16

<=0.

015

0.03

0.06

0.12

50.

25 0.5 1 2 4 8 16 32 64 12

8>1

28

Cou

nt

Cefepime MIC (mg/L)

Cefepime alone

+ VNRX, 4 mg/L

Mushtaq et al. ECCMID 2018, Poster 1537

Cefepime & cefepime/VNRX-5133 vs. OXA-48 Enterobacteriaceae

0

5

10

15

20

25

30

<=0.0

150.

030.

060.

125

0.25 0.

5 1 2 4 8 16 32 64 128

>128

Cou

nt

Cefepime MIC (mg/L)

NDM (40)VIM (40)IMP (13)

Light colours, with VNRX-5133, 4 mg/L

Mushtaq et al. ECCMID 2018, Poster 1537

Shionogi cefiderocol, catechol cephalosporin

Kohira et al., AAC 2016; 60: 729Ito et al., AAC 2015; 60: 7396

Cefiderocol MICs for CPE… on some very iffy plates

0

10

20

30

40

50

60

≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 ≥128

Coun

t

MIC (mg/L)

GES, IMI, SME

OXA-48 like

KPC

IMP

VIM

NDM

Mushtaq et al. ECCMID 2017, Poster 1315

Cefiderocol Phase II, cUTI

Cefiderocol(303)

Imipenem/cilastatin

(149)

Dose for 7-14 days 2g q8h 1g q8h

Composite cure 7 days after end of therapy 73% 55%

Portsmouth et al. LID 2018; 18; 1319p 0.0004

BOS-228 (LYS228)…. a more stable monobactam

Blais et al. 2018 AAC; 62: e01200

New and coming vs. ESBL producers

i.v. oral

Cefepime / tazobactam (Wockhardt)

Sulopenem(Itreum)

Cefepime / AAI101(Allecra)

Tebipenem(Spero)

Ceftibuten/clavulanate(Achaogen)

Licensed Phase III Phase II Phase I

Cefepime-tazobactam 4 mg/L vs. Enterobacteriaceae

0

20

40

60

80

100

120

<0.03 0.0

60.1

20.2

5 0.5 1 2 4 8 16 32 64 128>1

28MIC mg/L

VIMNDMOXA-48KPCK. oxytoca K1ESBLAmpCPenicillinaseControls

Livermore et al JAC 2018; 73: 126

Cefepime is easy to protect…

Cefepime-tazobactam 4 mg/L vs. Enterobacteriaceae

0

20

40

60

80

100

120

<0.03 0.0

60.1

20.2

5 0.5 1 2 4 8 16 32 64 128>1

28MIC mg/L

VIMNDMOXA-48KPCK. oxytoca K1ESBLAmpCPenicillinaseControls

Livermore et al JAC 2018; 73: 126

Cefepime is easy to protect…

Cefepime/tazobactam in Phase III @ 2+2 q8h, 90 min infusion

Cefepime/AAI101 in Phase III @ 2+0.5 q8h, 2h infusion

Activity of tebipenem against ESBL/pAmpC producers, n = 38

0

5

10

15

20

25

30

35

40

<=0.0

15 0.03

0.06

0.12

0.25 0.5 1 2 4 8 16 32 >3

2

No

isol

ates

MIC (mg/L)

ErtapenemImipenemTebipenem

Mendes ASM Microbe 2018 Sunday 560

Iclaprim (MotifBio)

2006-8 Arpida trial @ 0.8 mg/kg iv q12h in ABSSSI vs.linezolid…rejected by FDA & EMA in 2008/9

Now completed Phase III with MotifBio at 80 mg q12h in ABSSSI

Ø Early response 80.9% vs. vancomycin 81.0%

Ø Clinical cure 84.2% vs. vancomycin 87.0%

MIC90 for MRSA >8 mg/L; some cross-resistance to trimethoprim

http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/2010/07/WC500095022.pdf; http://ir.motifbio.com; https://idsa.confex.com/idsa/2016/webprogram/Paper56742.html

Trimethoprim

Iclaprim

Lefamulin (Nabriva)

• iv / oral Pleuromutilin

• Earlier pleuromutilins coccidiostats, or topical (retapamulin, GSK)

• Under FDA review for CAP

Ø Non-inferior to moxifloxacin in Phase III trial

• Covers…S. pneumoniae, H. influenzae, M. catarrhalis, atypicals

• Also active in vitro vs. S. aureus, streptococci & gonococci

Veve, Wagner. Pharmacotherapy 2018; 38: 935

Gepotidacin GSK 2140944

Ross et al. JCM 2014;52:2629Taylor et al. CID 2018; 67: 504.http:://www.clinicaltrials.gov;

Novel inhibitor of topoisomerase II & IV

Inhibits G +ves, fastidious G-ves….. maybe E. coli

Phase II trials for gonorrhoea, SSTI, & pK for uUTI

69 gonorrhoea patients, 66 cures, 2 selections of resistance

Zoliflodacin, oral DNA gyrase inhibitor vs. N. gonorrhoeae

Ø Discovered by AstraZeneca, spun

out to Entasis (AZD/ETX-0914)

Ø Targets DNA topoisomerase II & IV

Ø No X –resistance to quinolones

Ø Active vs. M. genitalium including

macrolide/quinolone-R strains

Ø 99% cure in genital gonorrhoea;

76% in pharyngeal….Jacobsson et al. AAC 2014; 58: 5585

Gouveia et al. JAC 2018; 73: 1291

Sena et al., Microbe 2016; Poster

1308

Murepadavin (POL7080)

• Peptide mimetic : active only vs. P. aeruginosa

• Inhibits LptD - LPS transport to outer membrane

• MIC50/90 0.5/1 mg/L

• MICmax 4 mg/L

• In Phase III for HAP/VAP

Sader et al. AAC 2018, in pressAndolina et al ACS Chem Biol 2018; 13: 666

• Rumours of the death of antibiotic development much exaggerated…

Ø But hard to see how many agents will make a return

• Microbiologists will have fun explaining which cefepime combination to use

Ø … with AAI101, tazobactam, VNRX-5133, zidebactam?

Summary