Safety, tolerability and early
bactericidal activity in sputum of
PNU-100480 (sutezolid) in patients
with pulmonary tuberculosis
RS Wallis1, AH Diacon2, R Dawson3, A Venter2, SO Friedrich2, D Paige1,
T Zhu1, A Silvia1, J Gobey1, C Ellery1, Y Zhang1, E Kadyszewski1
1Pfizer, USA; 2Stellenbosch University and 3University of Cape Town,
South Africa
PNU-100480 (sutezolid)
• Oxazolidinone antimicrobial
– Sulfur-containing linezolid analog with an active sulfoxide metabolite
– Bind 23S RNA and inhibit microbial protein synthesis
– No cross resistance, neither inhibits nor induces CYP3A4
• Preclinical findings
– Superior bactericidal activity vs. linezolid in mouse and whole blood TB models
regardless of LZD dose or concentration
– Earlier sterilization (1-2 months) when combined with standard TB drugs
• Phase 1 findings
– Doses to 600 mg BID generally safe and reasonably well tolerated to 28d
– No significant safety signals, incl. hematology, biochemistry, QT
• Potentially can address 4 major unmet medical needs in TB
– DR, HIV, DS, suspected DR-LTBI
• The present phase 2a study is its first in TB patients
Study inclusion criteria
• Men and women aged 18-65 years
• Pulmonary tuberculosis
– CXR consistent with pulmonary tuberculosis
– Positive sputum acid-fast smears
– Culture or molecular confirmation of drug-susceptible Mtb
• Either HIV-1 uninfected, or HIV-1 infected with CD4 T cell
counts >350/mm3 and not currently receiving ART
• Reasonably normal renal, hepatic, metabolic function
• Willing to provide written informed consent according to ICH
guidelines
3
Study exclusion criteria
• Significant hemoptysis
• TB treatment within the preceding 6 months
– Or positive test for urinary isoniazid metabolite at the time of
screening
• Treatment with MAO inhibitors, tricyclic antidepressants, or
adrenergic agonists such as pseudoephedrine or
phenylpropanolamine within the preceding 7 days
– Due to potential MAO-B activity
4
Randomization and treatment
• Subjects were recruited at 2 sites in South Africa, and were
randomly assigned in blocks of 7 to:
– PNU-100480 600 mg BID
– PNU-100480 1200 mg QD
– Fixed dose combination tablets consisting of isoniazid, rifampin,
ethambutol, and pyrazinamide (Rifafour© e275)
• Neither subjects nor investigators were blinded to assigned
treatment
• Treatment duration was 14 days
– After which all patients commenced standard TB treatment
– Final safety evaluation was on day 42
5
Subject characteristics
Number of subjects
Age (years, mean±SD)
Sex (male/female)
Race (Black/other)
Weight (kg, mean±SD)
Height (cm, mean±SD)
BMI (kg/m2, mean±SD)
Baseline log CFU/ml (mean±SD)
600 mg BID
25
32.3±9.0
20/5
11/14
54.6±6.5
167.4±8.2
19.6±2.9
6.88±1.11
Treatment arm
1200 mg QD
25
34.1±11.7
20/5
8/17
51.1±6.7
167.0±6.1
18.3±1.8
6.91±1.20
HREZ
9
33.8±11.8
7/3
3/6
51.3±7.5
166.5±11.8
18.4±0.5
7.22±0.71
Safety and tolerability
Subjects evaluable for adverse events
Number of adverse events
Subjects with adverse events
Subjects with serious or severe adverse
events
Subjects discontinued due to adverse
events
Subjects with dose reduced or temporary
discontinuation due to adverse events
600 mg
BID
25
23 (44%)
15 (60%)
1200 mg
QD
25
17 (33%)
12 (48%)
9
12 (23%)
5 (56%)
1
0
0
0
0
0
0
0
0
HREZ
7
Adverse events (all causes)
PNU 600mg BID (n=25) PNU 1200mg QD (n=25)
CARDIAC
GASTROINTESTINAL
GENERAL
INFECTIONS
INVESTIGATIONS
METABOLISM
MUSCULOSKELETAL
NERVOUS SYSTEM
PSYCHIATRIC
RENAL AND URINARY
REPRODUCTIVE
RESPIRATORY
SKIN
TOTAL
Mild
0
2
0
1
0
2
2
2
0
0
0
0
6
15
Mod
0
1
0
1
4
0
0
0
0
0
0
0
2
8
Sev
Mild
Mod
0
1
0
No effect on
0
QTc0 interval0
0 -4.2±141 ms
1
BID:
ALT
increase
0 -3.1±12
0ms
0
QD:
2-3x
0 ULN 0
3
0
0
0
0
1
0
0
2
0
0
1
1
0
0
0
0
0Hemoptysis
0
1
1Day 28 1
0
2
1
1
11
7
Sev
0
0
0
0
0
0
0
0
0
0
0
0
0
0
HREZ (n=9)
Mild
0
2
1
1
0
0
2
0
0
0
1
1
1
10
Mod
0
0
0
0
0
0
0
0
0
1
1
0
0
2
Sev
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Early Bactericidal Activity
log CFU
0
• Both PNU dosing schedules
resulted in significant log CFU
reductions from baseline over
the 14 day period of treatment.
– 600 mg BID: -0.09 log/d,
90% CI -0.06 to -0.11
– 1200 mg QD: -0.07 log/d,
90% CI -0.04 to -0.09
• A trend was apparent toward
superior responses with BID
dosing
-1
-2
1200 QD
600 BID
HREZ
-3
0
2
4
6
8
10 12 14
day
Shading indicates 90% confidence interval by mixed effects model repeated measures analysis
Treatment-emergent ALT increases
300
ALT (U/l)
• 7/50 PNU-treated
250
TB patients (14%)
200
• No apparent pre150
disposing factors
• ALT increased to
100
2-3x ULN, accom50
panied by smaller
0
AST increases
0
7
14
21
• No changes in bilirubin or AP
day
• No cases met Hy’s Law criteria
• All were asymptomatic and resolved quickly
28
35
42
10
Glutathione (GSH)
depletion hypothesis
• Drug-induced liver injury is common in TB (10-20%)
– HRZ all are implicated
• GSH, which ordinarily protects against oxidative injury,
is decreased in TB
– GSH is decreased in TB animal models and in TB patients
– Palanisamy, PLoS ONE 2011, and Venketaraman, Microb Path 2008
– Apparently is consumed to protect host cells from the cellular antimicrobial
host response (peroxides, superoxides, NO)
– Lowest levels are in TB patients with drug-induced liver injury
– Chowdhury, Indian J Gastro 2001
• Liver injury due to HRZ can be prevented by supplementation
with N-acetylcysteine (NAC)
– (Baniasadi, Eur J Gastro Hepatol 2010)
11
Summary
• Treatment with PNU-100480 at doses of 600 mg twice daily or
1200 mg once daily for 14 days resulted in significant
reductions in sputum bacillary burden
– A trend toward superior bactericidal effect was apparent when given
twice daily
• Both dosing schedules were generally safe and relatively well
tolerated
• New TB regimens containing PNU-100480 can potentially
address major unmet medical needs in TB treatment
Contact:
robert.wallis@pfizer.com
Questions?
•
•
•
•
•
LZD
NAC
MPS
Parent – metabolite
Proposed clinical plan
EBA comparison with linezolid
Drug
Dose and
duration*
Linezolid 600 mg BID and QD
days 0-7
mean log/d
Study
(90% CI)
-0.082
Dietze,
(-0.054 to -0.110) AJRCCM 2008
Sutezolid 600 mg BID
days 0-6
-0.146
(current study)
(-0.102 to -0.191)
* Both LZD doses appeared equivalent, and here are combined to
increase precision. LZD data indicate effects over the entire
treatment period (7 days). Sutezolid data were limited to days 0-6 for
comparison, as log CFU data were not collected on day 7. Caution is
warranted when comparing with historical data.
Human Pulmonary Tuberculosis
Extracellular infection
Intracellular infection
• Cavities contain large numbers of
log phase bacilli that can give rise
to resistance
• Inadequate treatment results in
failure
• Eradication is termed bactericidal
activity
• Granulomas contain small
numbers of semi-dormant bacilli
that can give rise to persistence
• Inadequate treatment results in
relapse
• Eradication is termed sterilizing
activity
Plasma concentration/MPS IC50
PNU-100480
Linezolid
5
Fold MPS IC50
Fold MPS IC50
5
4
3
2
1
0
4
3
2
1
0
0
6
12
18
Hours
1200 mg QD
600 mg BID
300 mg BID
100 mg BID
24
0
6
12
18
Hours
600 mg BID
300 mg QD
Wallis, AAC 2011
24
Intracellular bactericidal activity
ex vivo whole blood culture
0.4
LZD
PNU
log/d
0.2
0.0
-0.2
-0.4
-0.6
0
1
2
Concentration ( g/ml)
3
Linezolid, sutezolid & metabolites
PNU-101244
Sutezolid
PNU-101603
Linezolid
Linezolid
Sutezolid
PNU-101603
PNU-101244
MIC
(mg/ml)
0.5
MPS IC50
(mg/ml)
5.5
Plasma conc
vs. parent
-
Critical
activity
0.25
0.5
0.5
15.5
4.4
5
5X
0.1X
Intracellular
Extracellular
-
2-mo culture status
highly related to relapse-free cure
3
A
Location
Treatment
Africa Hong Singa- India modification
Kong pore
relapse rate (log ratio)
2
1
T added
Z added
R added
S added
IP shortened
3x/wk
2x/wk
S removed, IP lengthened
0
-1
-2
E->Z
Wallis, Lancet ID 2010
-3
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
Intensive phase shortened
relapse rate (log ratio)
3
Intermittent treatment
3
B
2
Pyrazinamide added
3
C
2
1
Streptomycin added
3
D
2
1
Rifampin added
3
E
2
1
1
0
0
0
0
0
-1
-1
-1
-1
-1
-2
-2
-2
-2
-2
-3
-3
-3
-3
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
F
2
1
-3
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
-0.2
0.0
0.2
0.4
2-month conversion rate (log ratio)
Sutezolid Clinical Plan
Compound 1
Ph1
EBA*
Compound 2
Ph1
EBA*
Compound 3
Ph1
EBA*
Compound 4
Ph1
2-mo
regimen
selection trial:
PNU-100480 (U)
Bedaquiline (J)
plus one of:
SQ109
PA-824
Clofazimine
Imatinib
Rifabutin/PZA
Confirmatory trial:
Selection of
regimens &
durations
Novel DR regimen
Novel DS regimen (UJRbZ)
vs. SOC
2-mo
status
2-mo
status
3 yrs
Nonrelapsing
cure
Adaptive licensing / Accelerated approval
EBA*
XDR
*or alternative
MDR
Outcomes Registry
DS
NAC Supplementation Prevents
TB Drug-Induced Liver Injury
AST
ALT
300
T Bili
200
2.5
2.0
150
mg/dl
U/l
U/l
200
100
100
50
0
1
2
1.0
0.5
0
0
1.5
0.0
0
Week
1
2
Week
HREZ
HREZ+NAC
0
1
2
Week
12/32
0/28 P =.002
Baniasdai, Eur J Gastro Hepatol 2010
23