Transcript Drugs for MDR TB

Issues in development for an
MDR TB indication
Leonard Sacks MD
Division of special pathogens and transplant products
FDA
Pros and cons in developing drugs
for MDR TB
• Area of pressing medical need
• Drug effect potentially very
obvious (e.g. in patients with
positive sputum despite years
of MDR therapy)
• Effectively may resemble
monotherapy if other drugs
have failed
• May be faster than
demonstrating efficacy in drug
sensitive patients (Analogous
to EBA)
• Accelerated approval
• MDR TB is not a
homogeneous disease
• Definitions of resistance varyclinically, microbiologically
• Treatment regimens are
complex
• Monotherapy is not a viable
approach
• Reliability of sputum
conversion as a surrogate for
clinical outcome is not clear.
Traditional efficacy studies
ARM A
• Drugs ABCD
• 95% Success
ARM B
• Drugs ABCX
• 96% Success
Just to see a failure, we need many patients per arm
To compare these small differences with confidence we need a
large study
In this non-inferiority model, the effect of drug X may be masked by
the rest of the regimen
MDR study
ARM A
• Optimized
background
• Success 3%
ARM B
• Optimized
background + X
• Success 40%
In this study, only a handful of patients are needed to show
superiority
The drug effect is almost entirely attributable to drug X
Past experience with drugs for
resistant conditions
How have we dealt with resistance
in the past?
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MDRSP
VRE
MRSA
Resistant HIV
Cancer resistant to chemotherapy
MDR S Pneumoniae
• Established efficacy for drug sensitive S.
pneumoniae in randomized controlled
blinded studies.
• Micro evidence of activity in MDRSP
• Independent mechanism of action
• Clinical success in 15 cases of pneumonia
due to MDRSP
MDR S Pneumoniae
Source: product label
Vancomycin resistant enterococcus
Synercid• for Vancomycin resistant E fecium bacteremia
• for complicated skin and skin structure infection
– two comparative trials in complicated skin infections
– no primary efficacy demonstrated in drug-sensitive
enterococcal infection
– Drug was approved based on subpart H using
clearance of bacteremia as a surrogate for clinical
outcome. Data from four non-comparative studies in
1222 patients with VRE bacteremia
Vancomycin resistant enterococcus
Linezolid• Randomized double blind studies for
the following:
– VRE infections,
– pneumonia
– skin infections
Linezolid- dose ranging study for
VRE
Source: product label
Resistant HIV
• Tipranavir
– For combination ARV use
– For highly treatment experienced patients or virus
resistant to multiple protease inhibitors
• Approval based on viral suppression at 24 weeks
Tipranavir clinical studies
Source: Product label
Some points on clinical drug
development for resistant infections
• Generally, initial development for drug
sensitive disease
• Controlled data in resistant infections
• Dose response in resistant infections
• Data in resistant infections with historical
controls
• Tipranavir is the closest model addressing
the issue of combination therapy
Quinolones for MDR TB
Quinolones
• What have we learned about quinolones and
resistant TB?
• In vitro
– MIC
– Mechanism of action
• Animals
• Human (retrospective)
– EBA
– Non-comparative
– Comparative
• Historical
Quinolones
MICs
In vitro and in vivo activities of Moxifloxacin and clinafloxacin against MTB Ji B. Lounis N, Maslo C, Truffot-Pernot C,
Bonnafous P, Grosset J Antimicrob, agents and chemo 1998;42:2066-2069
MICs to 15 drug-sensitive and 5 MDR strains
MICs to 18 drug-sensitive strains
In vitro and in vivo activities of Levofloxacin against MTB Ji B. Lounis N , Truffot-Pernot C, Grosset J Antimicrob, agents and
chemo 1995;39:1341-1344
Quinolones
animal models
Mouse 30 day survival rates after IV infection with H37Rv
(Rx day 1-28)
In vitro and in vivo activities of Moxifloxacin and clinafloxacin against MTB Ji B. Lounis N, Maslo C,
Truffot-Pernot C, Bonnafous P, Grosset J Antimicrob, agents and chemo 1998;42:2066-2069
Quinolones
Human EBA data
5 day EBA
The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis R Gosling, L Ulso, N Sam, E Bongard, E Kanduma, M
Nyindo, R Morris, S Gillespie. Am J Respir Crit Care Med 2003;168:1342-1345
Quinolones
Human data
– Retrospective (historical controls)
– MDR cure rate (1973-1983) 56%
– MDR cure rate (1984-1998) 75%
–
Treatment and outcome analysis of 205 patients with multidrug resistant tuberculosis Chan E, Laurel V.
Strand M. Chan J. Huynh M, Goble M, Iseman M Am J respir Crit Care Med 2004, 169:1003-9
Quinolones
Human data
Survival (TB related) –
quinolones versus no
quinolones
•Retrospective (Not
randomized)
•Confounders- surgery
Thoughts on study design for
drugs to treat MDR TB
Study populations
• Primary MDR
– disease more homogeneous
– Very low rates in US- target high risk areas e.g. Estonia
• Secondary MDR
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Typically extensive cavitation and fibrosis
Surgery often needed
Problem of drug entry into fibrotic lesions
Patients usually well known to clinics
• HIV MDR
– Outbreak setting - probably less appropriate
• Number of drugs to which resistance is documented 2, 3
or 7?
• Extent of disease- cavitation, fibrosis, extent
Entry criteria
• establishing resistance
• documenting persistent positive cultures
despite prior therapy.
Study arms
• The need for not one but two or more new
agents
• Have we reached the point where we can
compare a new MDR drug cocktail with a
quinolone cocktail?
Traditional approach to a
resistance claim
• Establish microbiological efficacy for
resistant organisms
• Identify independent mechanism of action
• Demonstrate similar in vitro MICs for drug
sensitive and MDR strains of the organism
• Establish efficacy in drug sensitive
infection (randomized controlled trials)
• Limited treatment experience in MDR
cases
Beginning of the road model
• Primary resistance to Rifampin and INH usually
determined from baseline culture about 1 month
after starting therapy
• Not always identified as clinical drug failure.
Some respond to initial therapy though response
may be slower (median 2 months)
• preferable to enroll those with positive sputum
culture after 1 month (at initiation of therapy for
resistant infection)
Possible schema for studying 2
rifampin and INH resistance
Smear positive
after 30 days INH and Rifampin resistance determined
smear positive
New drug + second line drug
smear negative
?quinolone + second line drug
When 1 month cultures available those with a negative
culture are excluded from efficacy analysis
End of the road model
• Patients with 6 or 7 drug resistance and
persistent sputum positivity
• In such individuals, a drug with a novel
target, good micro against MDR, MDR
animal models, volunteer safety data,
limited human data on comparative
sputum conversion rates could
conceivably lead to a limited approval.
Possible schema for studying high
grade MDR
Known high grade MDR
3 months treatment failure
Culture positive
Background + New drug
Background + placebo
Alternatives to placebo include
•dose ranging,
•immediate versus delayed dosing,
•historical control data with predetermined minimal efficacy
standard
End of the road
“Reverse EBA”
Placebo
first
Drug
first
%Culture
positive
Days
• Where the drug is very efficacious, small
numbers of patients would be needed to
show efficacy
Conclusions
• There are several precedents for
development of drugs for resistant
infection
• MDR may provide an opportunity to
demonstrate the efficacy of new anti-TB
agents in small numbers of patients
• Several study designs are possible
• MDR studies may be conducted in parallel
with studies in drug sensitive disease