Transcript New TB Diagnostics and Drugs: Potential and Pitfalls

New TB Diagnostics and Drugs:
Potential and Pitfalls
Richard E. Chaisson, MD
Center for AIDS Research and
Center for TB Research
Johns Hopkins University
Federal Funding for Tuberculosis Research and
Control, 1962 - 1990
BR Bloom and CJL Murray, Science 1992;257:1055-64
Cole et al., Nature 1998;393:537-44
TAG 2011 TB Research Report
The Need for New Diagnostics:
“Mind the Gap” in TB case detection
8.8
TB cases (millions)
7.6
Estimated incidence
5.8
Cases detected and notified
3.7
1990
2000
2010
4
Methods for Diagnosing TB Among HIV+
Patients in Rio de Janeiro Clinics, 2005-2010
Diagnostic Method
Smear + only
Culture +
Chest X-ray only
Clinical Diagnosis only
Total
Number
208
49
473
76
853
Percent
24%
6%
55%
9%
100%
TB Diagnostics: Potential
•
•
•
•
•
•
•
New culture platforms
Nucleic acid amplification
Antigen detection
Cytokine expression (e.g., IGRAs)
RNA transcriptional signatures
Volatile compound detection
Novel imaging techniques
Availability of culture and drug susceptibility
testing in TB/HIV high-burden countries
Country
Culture
Drug Susceptibility Testing
N of Labs
N per 5 million
Target = 1
N of Labs
N per 10 million
Target = 1
South Africa
15
1.5
10
2.1
Nigeria
2
0.1
1
0.1
Ethiopia
1
0.1
1
0.1
DR Congo
1
0.1
1
0.2
Kenya
5
0.7
1
0.3
Tanzania
3
0.4
1
0.2
Uganda
3
0.5
2
0.6
Zimbabwe
1
0.4
1
0.7
Mozambique
1
0.2
1
0.5
Cambodia
3
1.0
1
0.7
WHO Global TB Report, 2009
The Rapid March of Diagnostic Technology
• LED Microscopy*
• Line probe assays
for MDR
• Urine LAM
dipstick**
• GeneXpert TB/RIF*
*BSL-3 not required
** Point of care test
Cepheid GeneXpert MTB/RIF Test
Boehme CC et al. N Engl J Med 2010;363:1005-1015
GeneXpert MTB/RIF Performance Characteristics
No. Sputums Tested
3 Sputum Samples
Sensitivity, all
Smear-positive
Smear-negative
1 Sputum Sample
Sensitivity, all
Smear-positive
Smear-negative
Sensitivity
Specificity 98.1 – 99.2%
Sensitivity for RIF-resistance 99.1%
Boehme CC et al. N Engl J Med 2010;363:1005-1015
97.4%
99.8%
90.2%
92.2%
98.2%
72.5%
• Sensitivity HIV+
 93.9%
• Sensitivity HIV 98.4%
Performance of Xpert MTB/RIF vs. other
diagnostic modalities
Boehme et., Lancet 2011
http://www.who.int/tb/laboratory/GeneXpertrolloutJune2012.jpg
Rollout of GeneXpert
MTB/RIF in South Africa
7% of MTB positives RIF-resistant; Yield of AFB smear ~6%
http://www.nhls.ac.za/assets/files/GeneXpert_Update_April%2012%20WS.pdf
Installation of Xpert MTB/RIF machine at DTR Hospital, India
Tibetan Government-in-Exile Department of Health
Sensitivity of Urine LAM ELISA,
by CD4 Count in HIV/TB Patients
100
Lawn et al
90
AIDS 2009;23:1875
80
Shah et al
% Sensitivity
70
JCM 2010;48:2972
60
Gounder et al
50
JAIDS 2011;58:219.
40
30
20
10
0
< 50
50 - 100
> 100
CD4
> 200
Performance of urine lipoarabinomannan (LAM)
antigen vs. sputum AFB smear in hospitalized South
African patients with suspected TB
All confirmed
TB patients
Smear
POS
NEG
Total
N (%)
Smear POS
N (%)
LAM POS
N (%)
Either POS
N (%)
193 (100%)
82 (42%)
114 (59%)
144 (75%)
82 (42%)
111 (58%)
52 (63%)
62 (56%)
Positive Blood
Culture
43 (22%)
13(30%)
35 (81%)
36 (84%)
Positive
Sputum Cx
161 (83%)
73(45%)
94 (58%)
120 (75%)
Shah et al., JAIDS 2009, 52:145-51.
Sensitivity of Urine LAM vs. Urine Xpert for
TB in HIV+ Patients
Lawn, et al. JAIDS 2012:60:289-94
New TB Diagnostics: Pitfalls
•
•
•
•
•
•
Operational implementation
Laboratory/human resource requirements
Diagnostic and treatment logjams
Costs
Scalability
Impact
Patient with TB symptoms
presents to clinic
Physician suspects TB?
Physician orders diagnostic
test?
No
No
Diagnostic test performed
properly?
No
Test result positive?
Test sensitivity
No
Results made available to
clinician and patient?
Patient returns and is offered
treatment?
Cascade of Opportunities
for Poor Outcomes with
TB Diagnostic Tests
Diagnosis Delayed.
Patient returns to clinic?
No
No
Patient suffers from
untreated TB
No
Patient initiates and
completes treatment?
TB morbidity averted, after
diagnostic delay
Adapted from: Dowdy et al., PLoS Medicine
2011:8(7): e1001063
What to do with Xpert Negatives?
A Comparison of Xpert Culture vs. Repeat Xpert
Parameter
Current
Algorithm
X/C
Alternative
Algorithm
X/X
Difference
X/X – X/C
TB cases diagnosed
(% suspects)
TB cases treated
(% cases diagnosed)
447,999
(17.4%)
363,318
(81%)
433,401
(16.8%)
364,443
(84%)
-3%
(-3%)
+0.3%
(+0.4%)
Cost per second test
Cost per suspect
Cost per case
diagnosed
Annual cost of TB
diagnostic program
$13
$59
$342
$25
$53
$315
+92%
-1%
-8%
Rosen et al., CROI 2012
$153 million $136 million
-11%
X=GeneXpert, C=culture
Cost-effectiveness of Urine LAM Antigen in
Hospitalized HIV+ Patients in South Africa
Life Expectancy after TB Cure: 5 yrs
1
1
0.95
0.95
LAM Preferred
0.9
0.85
No LAM Preferred
0.8
LAM Specificity
LAM Specificity
Life Expectancy after TB Cure: 1.5 yrs
LAM Preferred
0.9
0.85
0.8
No LAM
Preferred
0.75
0.75
0.7
0.7
0
0.05
0.1
0.15
0.2
TB Prevalence Among Suspects
Sun et al., AIDS 2012, TUAE01
0
0.05
0.1
0.15
0.2
TB Prevalence Among Suspects
Impact of Hain Genotype MDR in South Africa
MDR TB Diagnoses Doubled with Hain
1
3
2
Sputum
collection
Lab receipt
of sputum
Time Period
DST started
DST results
reported
Median time, days (IQR)
Before
After
p-value
1
Sputum collection to lab
receipt of sample
1 (0-1)
0 (0-1)
<0.001
2
Lab receipt to DST testing
27 (21-34)
19 (12-31)
<0.001
Smear +
Smear 3
DST testing
Sputum collection to DST
Total
results available
26 (21-43)
29 (22-43)
9 (2-14)
13 (9-16)
29 (22-42)
0 (0-1)
<0.001
0.497
<0.001
52 (41-77)
26 (11-52)
0.008
22
Hanrahan et al., CROI 2012
Impact of Hain Genotype MDR in South Africa
Time to MDR treatment before and after Hain
From initial patient sputum sample to date of appropriate MDR therapy
After
Median 62d (32-86)
Before
Median 78d (52-93)
Log-rank test: p=0.046
Hanrahan et al., CROI 2012
Impact of Hain Genotype MDR in South Africa
Time to MDR treatment before and after Hain
From initial patient sputum sample to date of appropriate MDR therapy
After
Median 62d (32-86)
After
Before
Median 78d (52-93)
Log-rank test: p=0.046
Hanrahan et al., CROI 2012
Before (Undetected
MDR simulated)
Rationale for New Drugs for
Tuberculosis
• 500,000 cases annually of MDR TB
– 1 in 10 TB patients in China has MDR
• 15% of TB is HIV-related
– Drug-drug interactions problematic
• 15% of TB is in children
– Formulations inadequate, dosages poorly understood
• 5-20% of TB patients experience adverse effects
– Safer agents needed
• 6-month regimen is miraculous, but not
miraculous enough
– Faster cures are essential
PRECLINICAL DEVELOPMENT
TBA-354
Nitroimidazoles
TB Alliance, U Auckland, U Illinois
CPZEN-45
Caprazene nucleoside
MCRF, Lily TBDDI, NIAID, IDRI
Quinolone DC – 159a
Fluoroquinolone Antibiotics
JATA, Daiichi-Sankyo
Pharmaceutical
SQ609
Dipiperidines
Sequella
SQ641
Capuramycins
Sequella
BTZ043
Benzothiazinones
New Medicines For Tuberculosis
(NIM4TB)
Q201 – Novel anti – TB agent
Imidazopyridine
Quro Science, Inc.
PHASE I
AZD587
Oxazolidinone
Astrazeneca
PHASE II
PHASE III
PA – 824
Nitroimidazoloxazine
TB Alliance
Gatifloxacin
Fluoroquinolone
WHO/TDR
PNU – 100480 (Sutezolid)
Oxazolidinone
Pfizer
Moxifloxacin
Fluoroquinolone
TB Alliance
TMC207 (Bedaquiline)for
MDR- TB
Diarylquinoline
Tibotec BVBA
OPC-67683 (Delamanid)
Nitrodihydroimidazooxazole
Otsuka Pharmaceutical
SQ109
Ethylenediamines
Sequella, NIH
TMC207 (Bedaquiline)for
DS – TB
Diarylquinoline
TB Alliance, Janssen
Rifapentine (TBTC study
29)
Rifamycin
CDC, Sanofi-aventis
http://www.newtbdrugs.org/pipeline.php
The Path to New TB Drugs
Step 1
Identify active
compounds in vitro
Step 2
Step 3
Preclinical Tox, chemistry Evaluate agents/regimens
formulation, etc.
in animal models predictive
of outcomes in humans
Step 5
Phase 3 Clinical Trials for
clinical endpoints
Step 4
Phase 1/2 Trials with
surrogate endpoints
e.g., PK, DDI, EBA, 8wk conversion, TTP
Paradigm Change in TB Drug Development
Global Alliance for TB Drug Development
Timeline for Development of Moxifloxacin
for Shortening TB Treatment
1998
2000
2002
2004
2006
2008
Activity of
Moxi shown
in Mice
JHU/Brazil trial
OfloTub trial
Study 26
Study 28
ReMox TB
OfloTub II
2010
2012
2014
Bedaquiline (TMC207) and Delamanid
Placebo-Controlled Trials with OBR in MDR-TB
9%
48%
Diacon et al., NEJM 2009;360:2397-405
Gler et al., NEJM 2012;366:2151-60
Early Bactericidal Activity of PNU
100480 (Sutezolid)
log CFU
0
-1
-2
1200 QD
600 BID
HREZ
-3
0
2
4
6
8
day
Wallis et al., AIDS 2012
10 12 14
• 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
• Shading indicates 90%
confidence interval by mixed
effects model repeated
measures analysis
The Context:
Approach to TB Drug/Regimen Development
Discovery and Development Process
Phase II  Phase III
Single Compound
Preclinical Development
 Phase I  EBA
Compound 1
Compound 2
Regimen A
Compound 3
Regimen B
Drug
Candidate
Pool
Compound 4
Compound 5
Regimen C
Regimen Identification in Mice
Identification of New Drug
Candidates
Tackling TB Through Technology
Selection of Potential New
Regimens
Log lung CFU count
A novel regimen (PaMZ) is more active
than RHZ in mice
9
8
7
6
5
4
3
2
1
0
Untreated
RHZ
PaMZ
Relapse rate after 4
months
RHZ 10/20 (50%)
PaMZ 0/20 (0%)
*
0
4
*p<0.01 vs. RHZ and RMZ
8
Weeks
12
16
Nuermberger et al, AAC (2008); 52:1522
Extended EBA of the novel PaMZ combo
The NC-001 study
Diacon et al, Lancet, July 23, 2012
Pitfalls in Developing New Drugs for TB
• Toxicity, e.g., Q-Tc prolongation
• Drug-drug interactions
– Especially antiretrovirals
• Lack of robust surrogate endpoints
• Need for large Phase 3 trials
– Low incidence of primary endpoints (relapse)
• Lack of back-ups
• Lack of ambition
Bedaquiline (CYP3A substrate) with EFV (CYP3A inducer)
Bedaquiline
M2 metabolite
Bedaquiline alone
Bedaquiline with EFV
ACTG 5267 Dooley et al. JAIDS, 2012
Lack of drug-drug interactions of
Delamanid and selected antiretrovirals
Paccaly et al., AIDS 2012
Surrogate endpoints in TB clinical trials
EBA
TTP
2-mo conversion
Hafner et al. AJRCCM 1996; Hesseling et al. IJTLD 2010; Conde et al. Lancet 2009; Wallis, Lancet ID 2010
Treatment Priority #1 – Fund the Pipeline
• Development of more new TB
drugs
• Identification of optimal
regimens for
–
–
–
–
Susceptible TB (shortening)
MDR and XDR
HIV+
Children
• Development of methods to
evaluate combinations
• Identification of relevant
biomarkers
Change the Paradigm:
No more second rate, second line drugs
• Develop potent regimens that can treat all
forms of TB
– MDR/XDR
– HIV on ART
– Children
• A menu of options for different patient
populations
– Alternatives for specific clinical needs
The Future?
2016 DHHS/WHO Guidelines for Treatment of
Tuberculosis in Adults, Adolescents and Children
Antituberculosis Drugs
Approved Agents
DNA-dependent RNA Polymerase Inhibitors –
DRPIs
Rifampin, Rifapentine,
Rifabutin
Topoisomerase/Gyrase Inhibitors – TGIs
Moxifloxacin, Levofloxacin
ATP Synthase Inhibitors – ASIs
Bedaquiline, ?clofazimine
Protein synthesis Inhibitors – PIs
Sutezolid, amikacin and others
Nitric Oxide Producers/Electron Transport
Supressors – NOPETS
PA-824, Delamanid
Mycolic Acid Synthesis Inhibitors – MASIs
INH, Ethionamide
Drugs with Uncertain Mechanisms of
Bacteriolysis – DUMBs
Pyrazinamide, SQ109
DHHS/WHO – available online at www.curingtb.notyet; ©2012, JHU Center for TB Research
2016 DHHS/WHO Guidelines for Treatment of
Tuberculosis in Adults, Adolescents and Children
Preferred regimens for patients with active and latent
tuberculosis
Preferred regimens –all patients
DRPI + ASI + TGI + NOPET for 2 months
Genotypic DRPI resistance
ASI + TGI + NOPET + PI for 3 months
Genotypic DRPI + TGI resistance
ASI + NOPET + PI + DUMB for 3 months
Multiple resistance
Use TB Phenosense to customize regimen
Latent TB Infection –DRPI
susceptible
Rifapentine for 1 month
Latent TB – DRPI resistant
Bedaquiline for 3 months
DHHS/WHO – available online at www.curingtb.notyet; ©2012, JHU Center for TB Research
Very Brief (and rushed) Conclusions
• After a long gap, science is being applied to TB
• Enormous progress has been made with TB
diagnostics
– Major challenges with cost and implementation
• There is great potential for new TB drugs, but
considerable challenges remain
– Evaluating regimens is a key priority
• The pipeline is underpopulated, and substantial
investment and commitment are needed
Getting to Zero
Let’s ADD another
zero to the level of
funding for TB drugs,
diagnostics, vaccines
and elimination!
 $6,300,000
Acknowledgements
Susan Dorman
Eric Nuermberger
Colleen Hanrahan
Andreas Diacon
David Dowdy
Dan Everitt
Anne Paccaly
Kerry Dierberg
Robert Wallis
Funders:
NIAID
NICHD
NHLBI
CDC
Bill and Melinda Gates
Foundation
STOP TB Partnership