AZD5847
Oxazolidinone for the treatment of
Tuberculosis
CPTR Workshop, 2012
Arlington, VA
Scott Butler
Infection Innovative Medicines Group
AstraZeneca R&D, Boston
AZD5847: An oxazolidinone to treat tuberculosis
MIC
– 163
TB
isolates
MICdistribution
Distribution - 163
Mtu
Isolates
Product Concept: Antimicrobial to be incorporated into
(84 sensitive, 18 SDR, 36 MDR & 25 XDR)
novel combination therapies to treat
DS and/or MDR/XDR tuberculosis
(including HIV co-infected)
HO
Number of isolates
O
F
O
O
N
N
O
60
N
Sensitive
SDR
MDR
XDR
40
20
O
F
HO
AZD5847
0
0.25
0.5
1
2
4
8
16
MIC (M)
• Originally targeted as once daily IV/oral treatment for staphylococcal infections
• Development was discontinued in 2002 when pharmacokinetics in healthy volunteers
did not support QD IV dosing*
• Now re-positioned for the treatment of tuberculosis by oral administration
• Ready to start Phase 2
*Gravestock MB et al.. Bioorg. Med. Chem. Lett. 2003. 13:4179-86
2
AZD5847 is bactericidal against intracellular TB
•
Bone marrow derived macrophage model: AZD5847and rifampicin are effective
against intracellular TB, whereas isoniazid and linezolid are weakly active
Rifampicin
6
AZD5847
5
Untreated
R16
R4
R1
R0.25
4
p < 0.001
Log10CFU/ml
Log10CFU/ml
5
6
Isoniazid
6
3
p < 0.05
Untreated
H16
H4
H1
H0.25
4
3
0
2
4
6
8
10
0
4
0
2
4
6
Days
8
10
6
6
5
5
Untreated
4
p < 0.001
P16ug/ml
Untreated
L16ug/ml
4
L8ug/ml
L4ug/ml
P4ug/ml
L2ug/ml
P2ug/ml
3
P1ug/ml
L1ug/ml
L0.5ug/ml
P0.5ug/ml
0
2
10
p > 0.05
P8ug/ml
3
8
Linezolid
PNU100480
p < 0.001
Untreated
A16ug/ml
A8ug/ml
A4ug/ml
A2ug/ml
A1ug/ml
A0.5ug/ml
6
Days
Log10CFU/ml
4
3
4
6
Days
3
2
Days
Log10CFU/ml
Log10CFU/ml
5
8
10
0
2
4
6
Days
8
10
AZD5847 retains PKPD index vs. slowly dividing TB
in mouse model
•
AZD5847 and Linezolid are equally effective versus rapidly dividing TB in
mouse lung TB model
•
AZD5847 has higher efficacy versus slowly dividing TB, that is key to
achieving sputum sterilization.
Once daily oral dosing for 4 weeks
4
Lower risk of toxicities related to inhibition of
Mitochondrial Protein Synthesis
•
Inhibition of mammalian MPS (by oxazolidinones) has been associated with
myelotoxicity, lactic acidosis, and neuropathies1,2,3
•
AZD5847 maintains lower exposures relative to in vitro IC50 for MPS at therapeutic
doses doses
AZD5847
5
400 B ID f asted/f ed
400 B ID f ed/f ed
800 B ID f ed/f ed
1600 Q D f ed
1200 B ID f ed/f ed
F o ld MPS IC 50
4
3
2
1
0
0
Rx Dose
1.
2.
3.
4.
5
6
12
18
T im e (h)
Garrabou, G., Soriano, A., et al.. (2007). Antimicrob. Agents Chemother. 51, 962-967.
Nagiec, E. E.; Swaney, S. M.; et al.. (2005) Antimicrob. Agents Chemother. 49, 3896-3902.
McKee, E. E.; Ferguson, M.; et al.. (2006) Antimicrob. Agents Chemother. 50, 2042-2049.
Wallis R. S. et al.. (2011) Antimicrob Agents Chemother. 55(2):567-74.
24
Modelling of Ph1 data for likely attainment of
preclinical PD target
• Accounted for: Inter-subject PK variability and the MIC distribution against
M. tuberculosis
• Monte-Carlo simulation - target attainment in 85% patients
• Modeling predicts efficacy @ 800 mg QD / 400 mg BID
15
10
%patients to achieve PD target
Concentration (G.Mean + SD)
uM
SAD 600 mg Crossover
Fed
Fasted
5
0
0
10
20
30
40
q24
q12
q8
50
Time (h)
Human Dose (mg)
6
AZD5847 Ph1 Clinical safety summary
AZD5847 was generally well tolerated over 14 days in healthy
volunteers at doses predicted to drive efficacy in humans
• n=42 single-dose (SAD) subjects; n=45 multiple-dose (MAD) subjects
• Maximum administered dose 2400mg per day x 14 days
•
Predicted therapeutic dose 400mg BID / 800mg QD
• No SAEs; 3 DAEs: pustular rash, self limited rectal bleed, migraine/scotoma
• Most common AE: Dose-related nausea, reduced by dosing with food
• Decreased WBC counts (5/9 volunteers 2400mg/day) and increased
reticulocyte counts (1600-2400mg/day) were observed
• Transient myalgias noted for 3/9 volunteers @ 2400mg/day (no CPK
elevation)
• No clinically significant ECG findings.
7
AZD5847: Carboxylic acid metabolite
•
Exposure
o Metabolite was identified during analysis of pooled plasma samples from
healthy subjects in the MAD study
o Total AUC approximately 50% of the parent compound (free is <10%)
o Exposure of metabolite in rat and dog did not provide in vivo toxicology
qualification
•
Activity
o Metabolite is equipotent to AZD5847 against TB in vitro and has nearly
identical PK profile
•
Safety
o No structural alerts for genetic toxicity and negative in Ames assay
o Active against mitochondrial protein synthesis, however less potent than the
parent molecule (30 µM IC50 versus 13 µM IC50)
o Secondary pharmacology panel (including hERG and cardiac channels)
o
Some differences from parent, but no risks identified
o No change to risk - benefit ratio.
8
Phase 2a: EBA Study (Sponsored by NIAID)
Short duration (14 days) monotherapy with AZD5847 in patients
with drug sensitive TB
• To be conducted in South Africa (TASK, Andreas Diacon)
• Scheduled start in late October
Inclusions/exclusions;
HAINE test to for sensitivity
to rifampin and isoniazid;
Baseline safety labs
Active pulmonary
tuberculosis
documented by
positive sputum
smear x 2
Treatment: 14 days
Daily quantitative sputum culture for M.tb
Days 0-2 = early bactericidal activity
Days 3-14 = sterilizing activity
1
2
Randomization
Initiate SOC for
DS-pulmonary TB
3
4
5
PK sampling days 1 and 14,
trough levels days 5 and 10
Safety labs on days 7 and 14
Treatment groups (total enrollment ~75: 15 per arm)
1. AZD5847 500mg qd
2. AZD5847 500mg bid
3. AZD5847 1200mg qd
4. AZD5847 800mg bid
5. Rifafour 1 tab PO qd (weight based)
9
Endpoint: Rate of change in sputum colony
forming unit (CFU) counts (bactericidal
activity) during the entire 14 days of study
drug administration (EBA0-14)
Next steps
• Preparation for potential Ph2b
•
90 day chronic toxicology studies in mouse and dog (currently setting up)
•
DDI studies as appropriate for specific design and population
•
Pharmaceutical development
Summary
• Oxazolidinones offer a promising (clinically validated) addition to future
novel combination regimens (MDR/XDR treatment or simplification/reduced
duration)
• AZD5847 has potential to differentiate in the clinic:
•
Active against slowly dividing TB
•
Active against intracellular TB
•
Has reduced potency against human mitochondrial protein synthesis
• AZD5847 is safe and well tolerated at predicted efficacious doses
• Phase 2a trial to start October/November 2012
10