Transcript Dr. Saukkonen

The Threat of MDR TB:
Impetus for TB Drug Development
Jussi Saukkonen, MD
Boston University School of Medicine
October 31, 2006
Case: 30 year old Sudanese male
•
•
•
•
•
2002: Immigrated to US
Low back pain x 3 years
MRI “-” 2003
TST - , 2002. HIV- , 2004
2 m fevers, 1 m night sweats
– T 101.5-103 deg C
• L-S tenderness, hyporeflexic R Achilles
• Blood, sputum, urine cultures negative
2/17/06 MRI: T2
• Vertebral
destruction at
multiple levels
– esp T11, L2, S2
– Extension into
pre-sacral &
epidural spaces,
mass effect
– No spinal cord
compression
CT scan chest
CT-guided FNA
• Right sacral and pre-sacral
spaces sampled
• Bacterial cultures, cytology -.
ISONIAZID, RIFAMPIN,
PYRAZINAMIDE, ETHAMBUTOL
Readmission: sudden increase back pain
Sacral FNA culture: + MTB
• ISONIAZID
• RIFAMPIN
• PYRAZINAMIDE
• ETHAMBUTOL
• STREPTOMYCIN
Operating room
• Findings:
– T11-L2 destruction with large
adjacent phlegmon
• Procedures:
– Debridement and L2 corpectomy
– L1-3 anterior spinal fusion
– T9-L4, post spinal fusion, pedical
screw stabilization
– Allo and autograft
– Harms cage placed
Treatment
• PAS
• Cycloserine
• Levoquin
• Ethionamide
• Capreomycin
Case illustrates MDR problems
• Failure of primary therapy
– Increased morbidity (& mortality)
• Disability
• Increased cost to health care
system
• Failure of conventional diagnostics
• Toxic, multiple drugs
• Prolonged course
MDR BURDEN: 2/3 of cases in 3 Countries
MDR TB cases
700,000
Estimates of Global incidence: 458,000
prevalence*: 1,300,000 ?
600,000
*
458,000
Blower SM et al. Nat Med 2004;10:1111-6
500,000
400,000
310,000
161,000
300,000
115,000
200,000
34,000
100,000
0
Total
China + India +
Russian Federation
China
India
Russian Federation
MDR TB Burden Among
Previously Treated Cases by Regions
MDR TB cases
% MDR TB
150,000
No. MDR cases
% MDR TB
135,000
50%
45%
120,000
40%
105,000
35%
90,000
30%
75,000
25%
60,000
20%
45,000
15%
30,000
10%
15,000
5%
0%
Western Pacific
Region
South-east Asia
Africa high HIV
incidence
Africa low HIV
incidence
Eastern
Mediterranean
Region
Latin America
Eastern Europe
Central Europe
Established
Market
Economies
0
Primary Anti-TB Drug Resistance
United States, 1993–2004
% Resistant
10
5
0
1993
1995
1997
1999
2001
2003 2004
Isoniazid
MDR TB
MDR= resistance to at least INH and RIF
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.
All case counts and rates for 1993–2003 have been revised based on updates
received by CDC as of April 1, 2005.
Primary MDR TB in U.S.-born vs.
Foreign-born Persons, United States,
1993–2004
% Resistant
3
2
1
0
1993
1995
1997
1999
U.S.-born
2001
Foreign-born
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.
All case counts and rates for 1993–2003 have been revised based on updates
received by CDC as of April 1, 2005.
2003
2004
Tugela Ferry,KZN
•HIV/TB co-infected
•responding to ARV
•but not to TB Rx
•53 cases XDR-TB in
1 year
•largest single site
cluster
Extensively drug resistant (XDR) TB
• Resistance to:
– Isoniazid and rifampin
– A fluoroquinolone
– An injectable second line agent
• capreomycin, kanamicin, and
amikacin
XDR, South Africa
• High mortality, esp in HIV
– 64% more likely to die during
treatment than MDR patients.
• Strains (Tugela)
– Beijing W
– KZN
• Similar to Beijing
• susceptible -->XDR
• XDR in all RSA provinces
• Lesotho, Botswana,
Mozambique
Extensively drug resistant (XDR)
TB: WHO SNTBRLN Survey
• Worldwide isolates
– 20% were MDR
– 2% were XDR
• Population based data (% XDR/MDR)
– USA: 4% of MDR cases
– Latvia: 15% of MDR cases
– South Korea: 19% of MDR
Additional MDR TB Burden: CONTACTS
• Decision to treat:
– Susceptibility to & probability of
infection
• Regimens (potential toxicity):
– ZE x 6--12 mo
– ZFQ x 6--12 mo
• Levofloxacin, ofloxacin
– 2 drugs to which the infecting
organism is likely susceptible
• Follow at least 2 yr
MDR & XDR TB Imperatives
• Robust TB Control Program
– Prevent transmission
– Treat and monitor
– Address lifestyle & co-morbidities e.g
ARV
• Adequate access to treatment regimens
• New drugs of little value without strong
& effective TB programs
TB Drug Development:
Up and Coming Stars
TB drug development:
long-term objectives.
• Shorten and simplify treatment
• 6m -->4m-->2m
• Stop generating “MDR” TB
• Replace the first line.
– Reduce time frame needed.
• Simultaneously treat TB & AIDS
• Improved treatment of LTBI
GATB
TB drugs need improvement in:
•
•
•
•
Pharmacokinetics
CYP450 interactions (H & R)
Sterilizing activities (> R)
Individual agents efficacy
throughout treatment (H or E?)
• Avoid potentially antagonistic
interactions
GATB
Sequential Drug Replacement:
Unsatisfactory
E
A
ABCD
F
Y
BCDE
6 years
ABCD
G
C
CDEF
6 years
H
D
DEFG
6 years
24 years
EFGH
6 years
EFGH
Alternatively, replace combinations
Tools are decades old…
Global TB Drug Portfolio
September 2005
Discovery
Preclinical
Clinical Testing
Carboxylates
TB Alliance, Wellesley College
Nitrofuranylamides
NIAID, University of Tennessee
Diamine SQ-109
Sequella Inc.
Diarylquinoline TMC207
Johnson & Johnson
Cell Wall Inhibitors
Colorado State University, NIAID
Nitroimidazole Analogs
Dipiperidines (SQ-609)
Sequella Inc.
Gatifloxacin
NIAID, Novartis Institute for Tropical Diseases,
TB Alliance
OFLOTUB Consortium, Lupin, NIAID TBRU,
Tuberculosis Research Centre, WHO TDR
Dihydrolipoamide Acyltransferase
Inhibitors
Cornell University, NIAID
Novel Antibiotic Class
GlaxoSmithKline, TB Alliance
Non-Fluorinated Quinolone
TaiGen
Moxifloxacin
InhA Inhibitors
GlaxoSmithKline, TB Alliance
Picolinamide Imidazoles
NIAID, TAACF)
Synthase Inhibitor FAS20013
FASgen Inc.
Nitroimidazole PA-824
Chiron Corporation, TB Alliance
Isocitrate Lyase Inhibitors (ICL)
GlaxoSmithKline, TB Alliance
Pleuromutilins
GlaxoSmithKline, TB Alliance
Translocase I Inhibitors
Sequella Inc., Sankyo
Nitroimidazo-oxazole OPC-67683
Otsuka
Macrolides
TB Alliance, University of Illinois at Chicago
Quinolones
Nitroimidazo-oxazole Back-up
Otsukai
Pyrrole LL-3858
Lupin Limited
Methyltransferase Inhibitors
Anacor Pharmaceuticals
Screening and Target Identification
AstraZeneca
Natural Products Exploration
BIOTEC, California State University, ITR, NIAID,
TAACF, University of Auckland
KRICT/ Yonsei University, NIAID,
TAACF, TB Alliance
Thiolactomycin Analogs
NIAID, NIH
Bayer Pharmaceuticals, CDC TBTC, Johns
Hopkins University, NIAID TBRU, TB Alliance
M. Spigelman, GATB
Strategy for developing individual drugs or
combinations
• Phase I: EBA
– Proof of concept, small sample size
– PK, Tolerability/safety.
• Phase II: sterilization potential; endpoints:
– SSCC
– Time to culture conversion
– 2-month culture conversion
• Phase III: test few optimal regimens
– Larger sample size needed.
TB Drugs in Clinical Testing
• Diarylquinoline
TMC207 “J”
• Johnson & Johnson/TIbotec
• Nitroimidazole
PA-824
• GATB
• Gatifloxacin
• OFLOTUB
Consortium/WHO/EU
• Moxifloxacin
• CDC TBTC, Bayer, J.Hopkins
U., TBRU
• OPC67683
• Otsuka
• Pyrrole LL-3858
• Lupin Limited
• SQ109
• Sequella
• Rifapentine
• Sanofi Aventis
• Oxazolidinones
• Linezolid in use
Diarylquinoline TMC207 (aka “J”)
Johnson & Johnson/Tibotec
• Blocks proton pump of ATP
synthase in MTB
• Low MIC
• Good tissue penetration
• Sterilization > than rifampicin
In 3 drug combinations, “J” sterilizes in 2 m
N Lounis et al, IUATLD 2005
Diarylquinoline
TMC207:
Trials
TMC
• PK studies
– Single and 14-day multiple ascending dose
– Well absorbed after a single oral dose
– t1/2 =24 hours
– No severe adverse effects were observed.
• Drug interaction studies with HRZ &
ketoconazole.
• EBA trial in South Africa completed.
• Phase IIb trial started in 2006.
TB Luminaries
Stephenson
Brontes
Leigh
Munster
Nitroimidazopyran PA-824
(GATB): mouse studies
•
•
•
•
Inhibits protein/cell wall lipid synthesis
Sterilization = rifampin or INH
Active against actively & slowly-growing MTB
Continuation phase:
– Activity better than either Moxi or INH
– close to INH+RIF
• MDR:Effective in vitro against clinical isolates
from South Korea, India, and U.S. sites
Antimicrobial Agents and Chemotherapy, Vol. 49, June 2005 2
Nature, Vol 405, 2000.
Continuation phase:
PA824 alone similar to INH+RIF
12
Initiation of treatment
10
2RHZ/4RH
2RHZ/4H
8
2RHZ/4PA
6
2RHZ/4M
Log
10
CFU count
control
3.72
4
4.03
M
H
Pa
RH
2
0
-20
0
56
112
168
CFU counts in the lungs of mice treated with PA-824
(PA) during continuation phase
Courtesy: Dr. J. Grosset
Days
PA-824 (GATB) Phase I studies
•
•
•
•
Single doses up to 1500mg
No significant AE’s or labs
QT WNL
Substantial bioavailability and
exposure
• Half-life > 12 hours
Goethe
Paganini
Moliere
Voltaire
Mona Lisa
OPC-67683 (Otsuka)
• Novel class of TB drugs
• Inhibits mycobacterial cell wall
mycolic acid synthesis
• MIC log lower than H or R
• Highly active against mono and
resistant strains in vitro
• In mice, sterilization at 4m with
ORZ
M. Matsumoto, Otsuka Pharmaceuticals
Pyrroles: Sudoterb (Lupin)
• Plant alkaloid analogue
• Bactericidal activity in vitro similar to
isoniazid
– synergistic with rifampicin
• In vivo studies HRZL sterilized in 3 m
• Including resistant strains
• RZL cure in 3 m (ICAAC 2004)
• Entering Phase I EBA studies
SQ109 (Sequella)
• Favorable pharmacology
– Longer t1/2 than EMB
– Rapid tissue distribution (Lung and Spleen)
• Potent MIC - between INH and RIF
• Bactericidal
• Active in MDR, EMB-R isolates
• Acquired resistance rate lower than INH
• Synergy with other TB drugs
– Lowers the effective RIF dose
• Role: ?replace EMB in intensive phase
?replace INH in continuation
Mandela
Gauguin
Kafka
Tigger
Dostoevski
Fluoroquinolones
• No cross-resistance with other TB drugs
• Commonly used for MDR TB
• Few RCTs
• Anti-TB activity
– HIGHEST: Gatifloxacin, Moxifloxacin,
Sparfloxacin
– NEXT: Levofloxacin
– LOWER: Ciprofloxacin , Ofloxacin
OFLOTUB Consortium Phase 2 Trial
Durban, RSA
1. Phase 2 comparison of ofloxacin,
gatifloxacin and moxifloxacin
• in place of E in control HRZE
2. SSCC (serial sputum colony count)
• at 0,2, and 7 days, then weekly to 56
days of therapy
OFLOTUB Consortium:
Phase 2 Trial
1. Survival analyses of time to conversion
• Cox model hazard ratio “significant” only for Moxi
• (HR=1.47, p=0.06)
2. Bi-exponential model fits best
• two populations of bacteria present
3. Modeling: only Moxi can speed conversion
• with a 17.3% decrease
• Consistent with a gain of 1 months in duration
NB: Results preliminary, issues re liquid vs solid media.
OFLOTUB: Gatifloxacin
Phase III Trial
• Gatifloxacin in place of E in HRZE
intensive phase
• 4 month treatment vs. standard 6 m
• Conducted in Africa
QuickTime™ and a
Photo - JPEG decompressor
are needed to see this picture.
Moxifloxacin
•Potent in vitro MIC90 0.25 ug/ml
•Bactericidal & sterilizing activity in vivo
•T 1/2 12h
•Safe in post-marketing studies
Decrease in MTB CFU with
moxifloxacin
(Am J Respir Crit Care Med 2004; 164:421-6)
Courtesy of J. Grosset
10
Log CFU in entire lung
9
8
7
6
Untreated
2RHZ+4RH
2RHZM+4RHM
2RMZ+4RM
RHZ
RHZM
RMZ
5
4
3
2
2.5 logs
1
0
0
1
2
3
4
Duration of treatment (mos.)
5
6
No relapses among mice treated with RMZ-based
regimens of different durations at 4 months vs.
relapse with RHZ standard regimen
Proportion of mice relapsing by
regimen and duration of therapy
3 Months 4 Months 5 Months
11/12
5/12
1/16
Regimen
2RHZ +
3 RH
2RMZ +
2/12*
0/12*
0/13
3RM
1RMZ +
4/12**
0/12*
0/12
4RM
5RMZ
4/12**
0/12*
0/12
*p<0.01 vs. standard regimen, **p<0.05 vs.
standard regimen
Nuermburger et al / Grosset lab
Moxifloxacin for tuberculosis
• EBA studies
– Moshi, Tanzania (completed)
– Berlin, Germany
– NIH/TBRU: Vitoria Brazil, San Francisco
• Phase II studies: impact on 2 month
culture conversion and safety/efficacy
– JHU/Brazil (FDA Orphan Drug Office)
– CDC TBTC: N. America, Brazil, Uganda,
South Africa, Spain
Kampala
22 Study 27 sites
worldwide
CDC Administrative,
Statistical, and Data
Management Center
2 TBTC sites did not
participate in Study 27
Durban
TBTC Study 27:
2-month culture conversion
Factor
Daily (5/7)
Thrice-weekly Sub-total
Moxifloxacin 48/68 (71%)
51/71 (72%)
99/139 (71%)
Ethambutol
52/68 (76%)
46/70 (66%)
98/138 (71%)
Sub-total
100/136 (74%) 97/141 (69%)
P=0.39
P=0.97
Study 28
• Smear +, Randomized 2 arms
• MRZE
• HRZE
• Exclusion of patients with INH resistance
• Exclusion of patients with FQR resistance
• Primary endpoint
• proportion of patients culture negative
at 2 m
• Proportion who d/c assigned study
medication in 2m
Rifapentine
• MIC 0.02 ug/ml
– 2-3 times lower than for
RMP
• t 1/2 13-14 h
• Approved for continuation
phase treatment of TB
Plasma Concentration ( g/mL)
Plasma Rifapentine and Rifampin
Concentration-Time Profiles
12.00
10.00
RPT
RIF
8.00
6.00
4.00
2.00
0.00
0
12
24
36
48
60
72
Time (h)
Courtesy of J. Grosset
Relapse Rates after Standard Treatment and Twiceweekly Rifapentine with Isoniazid or Moxifloxicin
Regimen*
Standard Daily Regimen
2 wks RHZ (5/7) + 6 wks RHZ (5/7) +
2 mo. RH (5/7)
Twice-weekly P-containing Regimens
2 wks RHZ (5/7) + 6 wks P15HZ (2/7) +
2 mo. P15H (2/7)
2 wks RMZ (5/7) + 6 wks P15MZ (2/7) +
2 mo. P15M (2/7)
%culture + at Relapse at
4 mo.
3 mo.
1/5
8/12
0/5
0/12
0/5
0/12
*Mice were aerosol infected with M. tuberculosis H37Rv. The day after
infection mice harbored 3.77 log10 CFU per lung. Treatment started when the
lung CFU count was 7.06 log10. Mice were sacrificed after 4 months of
treatment and 3 months after completing 4 months of treatment.
Courtesy of J. Grosset
Rifapentine
• Increased dosing has potential
to shorten treatment to 4m
• Candidate for TBTC future
Study 29
–Perhaps with Moxifloxacin
Linezolid
• 1st oxazolidinone for clinical use
–Resistant Gram-positive organisms
• Inhibits protein synthesis at
ribosomal level
• Usually dosed BID IV or po
–equivalent bioavailabilty
Linezolid anti-tuberculous
activity
•
•
•
•
MIC90 0.5-2 mg/L.
t1/2 4-5 hours
Potential synergy with FQ
Excellent mutation prevention
concentraton (MPC)90 of 1.2 mg/L
– Rodriguez Diaz JC, Ruiz M, Lopez M et al. Int J Antimicrob Agents
2003; 21: 354ﾐ6
I n vitro a ctiviti es of l inezo lid against 117 cl inica l
isolates of M. tub er culosis a
MI C ( µg/ ml)
M. tuberc ulosis is olates
(no. of is olat es)
Ran ge
Susce pti ble to fi rst-lin e
0.25 -1
dru gs (7 3)
Re s ista nt to fi rst-line dru gs 0.12 5-1
(44 )
Re s ista nt to on e fi rst-line
0.12 5-1
dru g (25 )
Re s ista nt to mul ti ple fir st0.25 -1
li ne d rugs (19 )
All (11 7)
0.12 5-1
Geo me t ric
50% 90%
mean
0.5
0.5
0.52 4
0.5
1
0.47 7
0.5
1
0.52 9
0.5
0.5
0.41 7
0.5
1
0.50 6
T he MI C of s t rain H3 7R v (A TC C 27 294 ) wa s 0.2 5
µg/ ml .
a
Antimicrobial Agents and Chemotherapy, January 2003, p. 416-417, Vol. 47, No. 1
Linezolid Clinical Experiences
• 3 series: Spain, NL, Korea
– Total 23 MDR patients, at least 18 cures
• Cx neg within 10 d to 2 m
• Linezolid 300-600mg q d or BID dosing
– in combination with multiple agents
– 6 weeks to 24 m
• Toxicity in aggregate:
– 50% peripheral &/or optic neuropathy
– 25% Transfusion-req anemia
Other agents utilized…further
study?
• Not as active as H or R
• Other second line agents
• Thiacetazone
–Bacteriostatic
–Cutaneous toxicity
• Clofazimine
–GI problems
• Amoxicillin/clavulanate
Identify and test optimal
combinations
• Most active combination
–Phase 1 and 2 endpoints
–Aim for 4 month regimen
–Safest most tolerable
• Phase 3
• Objective: 2 month regimen.
Current Estimate of Future
Deliverables
< 2005
2005
2006
2007
2008
2009
2010
Drugs
2012
2013
2014
First New TB Vaccine
in 75 years
Vaccines
Diagnostics
2011
Referral Lab Peripheral Lab
Point of Care
Single New
Drug
New Multi-Drug
Regimen
Peter Small, Bill and Melinda Gates Found