4/6/2015

1

ANTIBACTERIALS:

Recent Releases

&

Pipeline Promises

Idaho Society of Health-Systems Pharmacists

Gerry Barber, RPh, MPH

Department of Pharmacy Services

University of Colorado Hospital April 11, 2015

Disclosures

Commercial Grants:• Cubist C. difficile in solid organ Tx recipients

• Merck ESBL research (ertapenem) among pts with UTI

Speaker bureau: Cubist

4/6/2015

2

Assessment Questions

1. A new ABX attains QIDP status giving it 10 years of

market exclusivity

True False

2. Both dalbavancin & oritavancin have T1/2 > 200 hrs

True False

3. Surotomycin is an orally-active cyclic lipopeptide

in Phase III studies for ABSSSI

True False

Probability of Market Entry,Costs

Adams CP, et. al. Health Affairs 2006; 25:420-428.

4/6/2015

3

New Drug Development

� Enormous Costs to Reach Approval

� $802 million per new entity1

� Others: $500 million + 2

� Vary by therapy (ie, RA vs. GU)

� Vary by regulatory policy

� Continuing Trend: for Chronic Diseases

� 70’s – 80’s: not a single new antibiotic class

� Resistant infxns, iatrogenic issues: new ABX

� 2012: GAIN Act – FDA QIDP designation 3

� Seems to bring ABX to market quicker, but…

� Are they innovative ABX???

1. DiMasi JA, et al. J Health Economics 2003;22:151-185.

2. Adams CP, et al. Health Affairs 2006; 25:420-428.

3. Keener AB. Nature 2014;20690-691.

Ceftolozane/tazobactam (ZerbaxaTM)

Merck

Indications:

� Complicated urinary tract infxns (cUTI),

including pyelonephritis

� Complicated intrabdominal infxns (cIAI), with

metronidazole

� Adult patients, designated susceptible

organisms

4/6/2015

4

Ceftolozane/tazobactam

Pharmacology / MOA:

� Inhibitor of cell wall synthesis

� Ceftolozane: anti-pseudomonal cephalosporin

� Tazobactam:

� Inhibits some beta-lactamases

� Little relevant anti-bacterial activity

Ceftolozane/tazobactam

Injectable, fixed dose combination product:

� Cephalosporin - ceftolozane SO4 1g

� β-lactamase inhibitor - tazobactam Na 0.5g

4/6/2015

5

Ceftolozane/tazobactam (Zerbaxa)

Phase 3, (n=806)

� Outcomes:

� Clinical Response: ZERB+METR non-inferior to Meropenem

� 83% vs. 87.3% ZERB+METR vs. Meropenem, respectively

� Common ADR > 3% : N/V/D, constipation, HA , pyrexia

Comp. IAI CR: Resolution S&S of IAI at TOC visit (24-32 days p 1st dose)

2014 Cubist. Lexington, MA

ZERB 1.5g + METR 500mg vs. Meropenem 1g: ivpb q8h x 4-14d

Ceftolozane/Tazobactam “Take homes”

� C/T 1.5g ivpb q8h (1-hr infusion for compl. IAI, UTI)

� Renal dose adjustments needed

� Anti-pseudomonal β-lactam , selective activity against g(-),

g(+) pathogens, ESBLs, and B. fragilis

� Not active against KPC & metallo beta-lactamases

� Caution in pcn or β-lactam allergy

� Pregnancy Category B

� Nearing end of Phase 3 VAP trials

Agent Dose Daily Cost

Ceftol/Tazo 1.5g q8h $251.00

Pip/Tazo 4.5g q8h $ 23.47

Meropenem 2g q8h $ 60.38

4/6/2015

6

Dalbavancin (DalvanceTM)

ActavisIndication:

� Treatment of ABSSSI caused by designated

susceptible gram + organisms

Pharmacology / MOA:

� 2nd gen. semisynthetic lipoglycopeptide:

- Disrupts cell membrane biosynthesis

- Anchors in lipophilic bacterial membrane, ‘ing

stability

- Bactericidal

- Long T1/2: Dosed ivpb 1g initially, then 0.5g on day 8

Dalbavancin IVPB

1g dose; then 0.5g on day 8

4/6/2015

7

Dalbavancin

Phase 3, Discover 1 & 2 Trials (n=1312)

� Outcomes:� Early CR: Dabavancin non-inferior to comparator

� 79.7% vs. 79.8% pooled analysis, DALB vs. comparator, respectively

� ADR > 2% : Nausea, ~4%; HA, ~ 3.5% both arms

� Serious TEAE: 1 anaphylaxis (dalbavancin)

Discover – 1 Early CR: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects

SIRS criteria pts: 62%

Discover – 2 Early CR: same as aboveSIRS criteria pts: 43%

Boucher H, et al. NEJM. 2014;370:2169-2179.

DALB x 2 doses vs. fd Vanco > 3d, +/- LZD 600mg po q12h x total 10-14 d

Dalbavancin

Jones RN, et al. Diagn Microbiol Infect Dis. 2013:75;304-307

4/6/2015

8

Dalbavancin

STPN isolates US 2002 – 2010 (n=9503)

Jones RN, SENTRY database / Durata, Chicago, IL

Dalbavancin “Take homes”

� Dalbavancin 1g ivpb; day 8: 0.5g ivpb (ABSSSI)

� Renal: CrCl < 30 mL/min = 750mg x 1; 375mg day 8

� HD: no dose change; w/o regard to timing of HD

� Hepatic: mild – mod dysfxn: AUC ~30% (caution)

� Time, conc. dependent cidal activity

� IVPB lipoglycopeptide, g (+) activity

� MRSA, MSSA

� S. pyogenes, agalactiae, anginosus group

� Enterococcus (VSE only). Empirically: Not a good bet

4/6/2015

9

Dalbavancin “Take homes” (cont’d)

� Synergy w/ other ABX: not shown

� DDI, DLs: not reported; Preg Cat C

� Caution: pts w/ hx ADR, intolerance to glycopeptides

� Outpatient treatment of ABSSSIs

� Alternative option to vancomycin for ABSSSIs

� Allergy to vancomycin or alternative agents

� Limited resource patients ?

� Ongoing studies: Single 1.5g dose & CAP

Oritavancin (OrabactivTM)

The Medicines Co.

Indication:

� Treatment of ABSSSI caused by designated susceptible gram + organisms

Pharmacology / MOA:

� 2nd gen. semisynthetic lipoglycopeptide:

- Disrupts cell membrane biosynthesis

- Inhibits polymerization & transpeptidation of cell

wall biosynthesis

- Bactericidal

- Long T1/2 (245 h): Dosed ivpb 1200mg x single dose

4/6/2015

10

Comparative Properties

Dosing IVPB 1g once; 0.5g day 8 1200mg once

Diluent

Rate

D5W 100 - 500 mL

30 minutes

D5W 1000 mL

3 hours

T1/2 ~204 hours ~245 hours

Vd

Protein Binding

~9 L

93%

~87 L

85%

Renal Excretion ~33% ~5% (< 1% feces)

Cost ~ $4,500 ~ $2,400

Property Dalbavancin Oritavancin

Zhanel G 2012 CID 54 (S3): S214-S219.

Belley 2010 AAC 54:5369-5371.

2014 Durata, Chicago, IL

2014 The Medicines Company, Parsippany, NJ

.

Oritavancin

Phase 3, Solo 1 & 2 Trials (n=1963)

� Outcomes:� Early CE: ORIT non-inferior to vancomycin

� 82.3% vs. 78.9% and 80.1% vs. 82.9%, both ORIT vs. Vanc, respectively

� ADR > 2% : N/V/D, HA, dizziness , LFTs, ~ ORIT vs. Vanc

� Tachycardia & infusion site phleb, each > 3% & twice incidence w Vanc

Solo – 1 & 2 Early CE: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects; >20%

decrease in baseline lesion at 48-72h . Also,

investigator-assessed PTE (7-14d p End of Tx)

Corey GR, et al. NEJM. 2014;370:2180-2190

Corey GR, et al. CID. 2015;60:254-262.

ORIT 1200mg ivpb once vs. Vanco 1g or 15mg/kg ivpb q12h x 7-10d

4/6/2015

11

Enterocococcal BSI Isolates: Oritavancin & other g(+) Agent Activity

Arias CA, et al: CID. 2012;54 (Suppl 3);S233-S238.

n = 884 isolates. Subset of SENTRY 2010, US Hospitals

Oritavancin “Take homes”

� Oritavancin 1200mg ivpb over 3 hours once (ABSSSI)

� No renal or hepatic dose adjustments

� Non-dialyzable; no dosing recs for severe renal or hepatic

dysfxn

� Conc. dependent bactericidal activity

� Synergy: oxacillin

� IVPB lipoglycopeptide, g (+) activity

� MRSA, MSSA

� S. pyogenes, agalactiae, dysagalactiae, anginosus group

� Enterococcus faecalis (VSE only)

� In-vitro: seemingly good VSE & VRE activity

4/6/2015

12

Oritavancin “Take homes” (cont’d)

� Contraindication

� Heparin x 48h post- ORIT dose as PTT falsely elevated

� Inhibits CYP450

� AUC of warfarin (~31%)

� Drug-Lab: artificially prolong PT/INR up to 24h

� Pregnancy Category C

� Caution: pts w/ hx ADR, intolerance to glycopeptides

� Elderly (?) small sample subjects > 65 yo

� Tachycardia

� Infusion-related events – slow rate, or interrupt

� Ongoing studies: -------

Tedizolid (SivextroTM)

Trius Merck

Indication:

� Treatment of ABSSSI caused by designated

susceptible gram + organisms

Pharmacology / MOA:

� Oxazolidinone:

- Prodrug tedizolid PO4 tedizolid (active moiety)

- Binds to 50S ribosomal subunit, inhibits protein

synthesis

- Bacteriostatic

4/6/2015

13

Oxazolidinone structures

Rybak JM, et al. Pharmacotherapy. 2014:34;1199.

Comparative Properties

Dosing IV or PO 200mg daily x 6 d 600mg q12h x 10 d

T1/2 9-11 hours 4-5 hours

Bioavailability >90% >90%

Vd

Protein Binding

~80 L

87%

~50 L

31%

ELF / AM to plasma ~40 / 20 fold ~4 / 0.13 fold

Renal Excretion ~18% ~30%

Price ($ IV / PO) $235 / $235 $140 / $260*

Property Tedizolid Linezolid

Bien P, et al. ICAAC 2010.

Prokocimer P, et al. AAC 2011;55:583-592.

Swaney SM, et al. AAC 1998;42:3251-3255.

Conte Jr JE, et al. AAC. 2002;46;1475-1480.

Housman ST, et al. AAC. 2012;56:2627-2634.

* Generic 2015

4/6/2015

14

Comparative Properties

Dosing IV or PO 200mg daily x 6 d 600mg q12h x 10 d

T1/2 9-11 hours 4-5 hours

Bioavailability >90% >90%

Vd

Protein Binding

~80 L

87%

~50 L

31%

ELF / AM to plasma ~40 / 20 fold ~4 / 0.13 fold

Renal Excretion ~18% ~30%

Price ($ IV / PO) $235 / $235 $140 / $260*

Property Tedizolid Linezolid

Bien P, et al. ICAAC 2010.

Prokocimer P, et al. AAC 2011;55:583-592.

Swaney SM, et al. AAC 1998;42:3251-3255.

Conte Jr JE, et al. AAC. 2002;46;1475-1480.

Housman ST, et al. AAC. 2012;56:2627-2634.

* Generic 2015

Tedizolid

Phase 3, Establish 1 & 2 Trials (n=1415)

� Outcomes:� Early CR: TDZ non-inferior to LZD

� 79.5% vs. 79.4% and 85% vs. 83%, both TDZ vs. LZD, respectively

� ADR > 2% : N/V/D, HA, dizziness : same TDZ vs. LZD

� PLT < 112 x 103

/mm3

: TZD 2.3% vs. LZD 4.9%

Establish – 1 Early CR: no increase in baseline lesion at 48-72h; temp < 37.60 C among ITT subjects

Establish – 2 Early CR: >20% decrease in baseline lesion at 48-72h among ITT subjects

Prokocimer P, et al. JAMA. 2013;309:559-569.

Moran GJ, et al. Lancet ID. 2014;14:696-705.

TDZ 200mg q day x 6 d vs. LZD 600mg ivpb/po q12h x 10d

4/6/2015

15

Tedizolid “Take homes”

� Tedizolid 200 mg daily, ivpb/po x 6 d (ABSSSI)

� No renal or hepatic dosing adjustments

� Oxazolidinone, g (+) activity

� MRSA, MSSA

� S. pyogenes, agalactiae, anginosus group

� E. faecalis

� Not a good bet: UTI

� Synergy w/ other ABX: not shown

� Serotonergic DIs, myelosuppression warnings presently

absent… Caution warranted

� Pulm penetration, STPN activity Rx off-label lung infxns

On the horizon…

� Cadazolid

� Surotomycin

� Plazomicin

4/6/2015

16

Cadazolid (ACT 179811)Actelion

� Novel oral-active chimeric quinolonyl-

oxazolidinone

� Potent inhibitor of protein synthesis

� Weakly inhibits DNA replication

� Target: C. difficile infection

� Feb 2014: QIDP status

� Q4 2013: 2 x Phase III studies “IMPACT”

� To accrue ~ 1300 subjects

� CDZ 250mg po BID vs. Vanco 125mg po QID

Cadazolid

� Phase II dose-escalation trials (Sweden)

� 250mg, 500mg, 1g po BID vs. Vanco 125mg po QID

� Clin cure rates, all doses = non-inferiority, similar TEAE

� Sust. clin cure 4 weeks p last dose favor CDZ 250mg (as effective as 1g dosing)

4/6/2015

17

Cadazolid

Test of Resistance Development

Locher HH, et al. AAC. 2014;58:892-900.

Surotomycin (CBT 813315)Merck

Pharmacology / MOA

� Oral cyclic lipopeptide

� Disrupts membrane potential; binds / depolarizes

Mascio CT, et al. AAC. 2012;56:5023-5030.

Daptomycin

4/6/2015

18

SurotomycinActivity Spectrum� C. difficile (n=556), other intestinal anaerobes (n=445), Enterobacteriaceae (n=56)

� Resistance is rare and likely of low clinical significance given high fecal concs.

Citron DM, et al. AAC.2012;56:1613-1615.

Surotomycin

� QIDP status, currently Phase III

� Phase II dose-finding trial, CDAD:

Drug/Dose (PO) Recurrence Global Cure

SUR 125mg BID 17/61 (27.9%) 44/66 (66.7%)

SUR 250mg BID 10/58 (17.2%) 47/67 (70.1%)

VAN 125mg QID 21/59 (35.9%) 37/56 (56.1%)

GC = clinical cure & no recurrence 4 weeks p last dose

Patino H, et al. 51st ICAAC 2011: poster K205a

4/6/2015

19

Plazomicin (ACHN 490)

Achaogen� Semisynthetic aminoglycoside “neoglycoside”

� Q1 2014: Phase III superiority trial for CRE

� Phase II PLZ 15mg/kg qd vs LEVO 750mg IV qd

� cUTI + pyelonephritis: Similar MBE & TOC rates

� In vitro ACBA & PSAE isolates, 16 NYC hospitals

� Better w AGME isolates than permeability/efflux

� Synergy: β-lactams

� BARDA funding $100+ million

� Biowarfare, Y. pestis, F. tularensisRiddle V, et al. 52nd ICAAC 2012.

Landman D, et al. JAC. 2010;doi:10.1093/jac/dkq278

Plazomicin

� Pharmacokinetics (15 mg/kg dosing)

� Linear

� Protein binding ~16%

� Cmin ~ 0.4 (24h, mcg/mL)

� Cmax ~144 (24h, mcg/mL)

� AUC0-24 ~230 (h . mg/L)

� Half-life ~ 3.5 hours

� Renal Elim ~90%

� Urine collection ~805 mg/L (0-4 h)

Cass RT, et al. Antimicrob Agents Chemother. 2011;55:5784-5880.

4/6/2015

20

So, Which are Keepers?

� Consider all PK/PD characteristics & clinical scenario

� Likely broader off-label indications

� Application / receipt of new indications

� Outcomes

� ADRs

� Drug interactions

� User friendliness

� Patent application strategies

Time Will Tell…

ABT-773 / cethromycin

(originally Abbott, Taisho, then

Advanced Life Sciences)

III (moderate – severe

community-acquired

bacterial pneumonia)

Ketolide. Reversibly binds

to the 50S subunit of the

bacterial ribosome, blocking

protein synthesis, preventing

bacterial growth and

reproduction. Binds at 2

sites of bacterial ribosome

compared with current

macrolide agents binding at

1 site. (Note: solithromycin,

a fluoroketolide, binds at 3

sites and has iv and po

formulations).

Potent pneumococcal and

atypical respiratory organism

activity, including macrolide-

resistant strains. Oral

formulation; wide distribution

into pulmonary

compartments including

epithelial lining fluid. Like

solithromycin, additional side

chain structures /

modifications appear to

ameliorate CNS adverse

effects of telithromycin (lacks

telithromycin’s pyridine-

imidazole side chain) and

necessitate additional

bacteria mutations to effect

resistance. Has FDA

orphan-drug-status for

prophylaxis in patients

exposed to inhalational B.

anthracis (anthrax),

tularemia and plague.

Agent Number Study Phase MOA Comments Chemical Name(Company)

4/6/2015

21

ACHN-975 (Achaogen) I (safety, dose-

escalation trial)

Novel, LpxC-

inhibitor. LpxC-1 is

an inhibitor of LpxC,

a deacetylase

enzyme present in

many Gram-negative

bacteria [73].

Subcutaneous

injection in murine

models infected with

MDR-Acinetobacter

baumannii do not

actively kill or stunt

bacterial growth, but

stunt endotoxin

production and the

subsequent ability of

the bacteria to

activate the sepsis

cascade.

Development to

target MDRO-gram-

negatives including

MDR-Pseudomonas

aeruginosa.

Agent Number Study Phase MOA CommentsChemical Name(Company)

BC-3881 (Nabriva Therapeutics) II (Acute Bacterial Skin

and Skin Structure

Infections)

Novel pleuromutilin

antimicrobial; inhibits bacterial

protein synthesis by interaction

with 23S rRNA of the 50S

bacterial ribosome subunit.

Potent in vitro activity against

common Gram-positive skin

organisms including S. aureus

(MSSA and MRSA),

coagulase-negative

Staphylococcus spp.

Streptococcus agalactiae, and

S. pyogenes. Also exhibits in

vitro activity against a broad

spectrum of Gram-positive and

gram-negative community

respiratory pathogens including

S. pneumoniae, including

Moraxella catarrhalis and

Haemophilis influenza as well

as atypical bacteria, Legionella

pneumophila, Chlamydia

pneumoniae, and Mycoplasma

pneumonia

Intravenous formulation dosed

q12h in first human ABSSSI

trial (duration 5 – 14 days).

Previously utilized in veterinary

medicine or topical use in

humans (retapamulin, Altargo®,

Altabax® Glaxo-Smith Kline)

due to toxicity. In ABSSSI

demonstrated comparable

clinical success to vancomycin.

Relatively well-tolerated among

141 subjects, most frequent

AEs were headache, nausea,

and infusion site phlebitis.

Expected to move to Phase III

trials.

Agent Number Study Phase MOA CommentsChemical Name(Company)