Transcript PRESENTATION - FINAL - Critical Path to TB Drug Regimens

TB THERAPEUTICS RESEARCH
Issues, Challenges, and Opportunities
TCRB/DAIDS/NIAID
October, 2012
TB Clinical Trial Limitations?
How do we get it done?
Four Principles
• Enhance/adapt existing global clinical research
capacity and resources for TB
• Coordination and Collaborations
– Other sponsors (US/EU and pharmaceuticals)
– International research agencies
• Develop highly efficient clinical research
strategies and trial designs
• FOSTER INNOVATION
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Forum to Coordinate Phase II/III Clinical
Trials Planning - Initiated 9/11
Phase II combination study planning coordination
• Efficiently/promptly sharing new study results
• Discuss the specific combinations to be studied by
each group and when
• Anticipate barriers – plan timely studies to obtain
necessary pre-clinical and clinical data
– DDIs
– Antagonism
– Additive toxicities
– **Additive Q-T interval prolongation**
Therapeutics - Phase II/III Planning
Coordination Forum
NIAID – ACTG, TBRU
CDC – TBTC
PHARMAs
WHO, NGOs,
etc.
Coordinate all
Phase II
combination
studies
EDCTP – PanACEA
UKMRC
GATB
FDA/EMA, etc.
Coordination and Collaborations
Standardization/harmonization
needed for efficient CT collaboration
•Data elements, standards, endpoint criteria, AE grading
–CDISC/HL7 TB Data Standards Project (2008)
•Lab procedures for diagnostics/endpoints, DST, QA, P+P
•Stored sample collection specifications and procedures
•Drug quality policies for drugs not provided by study
•Planning strategies, agendas, key trials
•Site surveys, qualifications/standards, training, monitoring
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Site Capacity and Efficiency
• Information sharing among sponsors
– CPTR & WGND has initiated
• Actively coordinate efforts for site
–Evaluations
–Preparation
–Training
–Participation in planned studies
CRITICAL ASPECT FOR PROGRESS
Recognizing the relative roles of
COMBINATION Developers in
contrast to DRUG Developers
and
Providing new DRUG ACCESS to
COMBO DEVELOPERS
as soon as feasible
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Study Issues – Phase II Trials
IIA - up to 14 days – EBA / “Extended EBA”
• Change in CFU/day in sputum
IIB - 8-12 week combo studies
• Culture conversion at 8 weeks - proportions
• Time to culture conversion – survival analysis
• *Serial quantitative colony counts – decline
over time in CFU …. or TTP
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Role of Phase IIA EBA Studies
First 14 days of a Classic Mouse Study
mmm
Best sterilizer?
And the winner is…

From McCune R M, Tompsett R, McDermott W
J Exp Med 1956; 104: 763-802.
Role of EBA TRIALS
• Have become “POC” rite of passage
• High EBA0-2 is unique for INH
• EBA0-14 may not correlate with sterilizing
• High or especially low
• Dose ranging by EBA may be useless or
hazardous for some drugs
Combos – 2-Wk EBA vs. 8-Wk Phase IIB
EBA TRIALS FOR COMBINATION REGIMENS
• Not required for activity – not sufficiently
predictive of sterilizing activity
• Safety aspect - Careful monitoring of 2 week
safety data for each participant is essential
with any initial trial of new combos
EBA and Oxazoldinones
• Oxazolidinones have LOW EBA0-14, but have potent
sterilizing activity
• Evaluating dose response by EBA is probably not
detectable without a relatively huge N
• Choosing dose by EBA may be impossible,
meaningless, or WRONG
• Dose “establishment” may need to be performed
in Phase IIB  for example compare:
– J + Z + Oxa Dose 1
J + Z + Oxa Dose 2
Phase IIB Combo Trials
Many possible combinations to study
• Issue
How to evaluate efficiently?
– Serial trials/amendments are too inefficient
– Delays caused by protocol development (esp. in group
setting) and approvals at all levels
• Response
Innovative, inclusive, new adaptive designs
Efficiency in Combination Development –
Phase II B
Features of Adaptive trials
• Make changes allowed by protocol as guided by study
data without amendment
• Periodic ISMC interim reviews – drop arms early if less
active than control
• Add new arms as per study criteria
- Issue
• Short trial length (usually 8 weeks)
• Not enough new combinations yet to take optimal
advantage of the “MAMS”-type design, esp. for MDR
Phase IIB Trials
• Combination(s) vs. standard of care therapy
–Issue
No accepted MDR standard Rx
• Sputum culture-based primary endpoint
– Issue
Use of “SSCC” by CFU on solid media to week eight
has advantages, but is arduous/expensive
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Use of TTP for 8 Weeks
Phase IIB Combo Trials
Sputum culture-based 8week primary endpoint
• Issues
– 3 weeks or more to obtain culture data
 CANNOT perform efficient, seamless Phase (IIa IIb - III) adaptive transitions
– Does not assess killing of non-replicating
persisters (NPRs)
 CANNOT adequately predict cure/relapse
(Holy Grail biomarker)
Phase II Combination Trials
Lead Identification
Lead Optimization
Preclinical
Development
Phase I
Phase II*
Phase III
What is needed?
Rapid early treatment response markers to change
paradigm from culture AND include killing of NRPs
HOW?
– Resuscitation promoting factors
– Molecular-based (mRNS/rRNA, phages)
– Imaging (PET-CT, PET-MRI)
Mathematical modeling: MBL assay-determined bacterial
decline for 111 patients using data from day 0 to day 56.
Ribosomal RNA assay
Honeyborne I et al.
J. Clin. Microbiol. 2011;
49:3905-3911
23 year old male enrolled in delayed linezolid arm:
2001
2003
HRZE
PPtOCZ
failure
failure
2005
2007
HZPPtCO
HZKLfRb
failure
failure
2009
HLf
failure
2009 DST R:HPSEREtCKORbMCp, S:Z(?)
T = -2 months
Sm/C:
++/28
T = 0 months
+++/15
CONFIDENTIAL
T = 6 months
-/-
PZA – Critical Drug
PZA
• Best sterilizer and synergizer
- Issue
• Lack of reliable or rapid DST
Rapid, accurate, affordable DST is critical to
design best regimens for trials and for care
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Summary of PZA Day at CDC
Thursday, December 15, 2011, CDC, Atlanta
• CDC/DTBE’s Lab Branch will work to improve reliability
of culture-based/phenotypic PZA DST
• NIAID to help establish/coordinate sequencing of
isolate collections among many partners
•  comprehensive/global database for correlations
• Develop clinical trial service laboratories to provide
rapid turn-around pncA sequencing in Africa by 2013
• Foster development of more practical DST method
• Use as a model for DST development for new drugs
and to establish ongoing surveillance
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Current Drugs for New Combos
Lead Identification
Lead Optimization
Preclinical
Development
Phase I
Phase II*
Phase III
For DS/DR combos
• Bedaquiline
• Sutezolid and AZD-5847
• Nitroimidazoles
• Clofazimine
• PZA *
• Moxi/Levofloxacin* – at optimal dose
• SQ 109
Possible roles in DS combos
Short-course INH
Rifamycins – high dose RMP/RPT or rifabutin
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Therapeutics Development –
Risks and Opportunities
Risks
Choices of drugs/doses will be made based on the best
available, but not perfect evidence
•Mouse model data (combo choices; INH truly antagonistic?)
•EBA studies (optimal dosing for EBA vs. sterilization)
Opportunities
•Correlate outcomes of Phase III/IV CTs with conclusions
made from animal (mouse) model and EBA-type studies
•Accept/improve these tools or find better tools
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Combination Development
and Drug Resistance
Prevention of resistance
• Drugs vary in potential for resistance
development AND protection of partner drugs
• These potentials have NOT been systematically evaluated
in preclinical studies (usual mouse model)
• Need routine evaluation of new combinations
– Hollow fiber system (as well as for activity)
– Highly selectively in the nude mouse model
• Identify need to add “protection drug” to new combos or not
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Caution with some “New” Drug Classes
Safety and efficacy concerns
• Very long half-lives and high tissue concentrations
• Consider more extended (not intensive) trial follow-up
for safety and efficacy vs. experience with current drugs
For combinations
• Additive toxic effects and with long half-lives
– Potentially additive Q-T interval prolongation
(Bedaquiline + clofazimine)
Difficult to study – when will peak effect occur
and how long will increase
last?
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Pediatric TB Research Priorities: Treatment
• Limited data on pharmacokinetics and safety of current and
new TB drugs in children:
– 1st, 2nd line, MDR drugs
• Better pediatric TB drug formulations needed, especially for
administration to young infants – (rather than liquid, solidscored, crushable, dissolvable, films, inhalation, subcutaneous
delayed release nanoparticles?)
• Shorter and more optimal TB treatment regimens for drug
sensitive/resistant TB (HIV-, HIV+ children)
• Need studies of TB-antiretroviral drug interactions in HIVinfected children
• Optimal management CNS disease and TB drug penetration
into CNS
Critical Questions
• How many new drugs will actually be fully
approved after Phase III?
– “have not reached a critical mass”
• What impact will they make on duration?
• Will resistance develop to the new drugs
sooner rather than later?
Fostering Innovation
Outside of drug & combo
development
And addressing translational gaps
Not Classic Drug/Combo Development:
Translational Gap Area
1) Deliver/maintain HIGH concentrations of
active drugs at right place & time
• Efflux pump inhibitors
• Alternative delivery routes (inhalation)
• Optimal sequencing/staging/duration of individual
drugs in combos
• Targeting tissues/cells/compartments/bacilli
– New pro-drugs (e.g., POA)/formulations
– Multiple payload and
targeting NANOTECHNOLOGY
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Bactericidal and Sterilizing
Dosing Phases
• Bactericidal Phase x 2 weeks
INH* + Rifamycin + PZA (+ ?FQ)
• Sterilizing Phase x 6 weeks
PZA + Bedaquiline #
+ clofazimine #
+ oxazolidinone or nitroimidazole
Explore optimal timing/sequencing/staging of
combinations in appropriate in appropriate models NOW
*INH for few days? - ACTG 5307 will address
# Bedaquline+clofaz – prolonged tissue levels after end of dosing period33
Nanoformulation Engineering
• Several layer nanomaterial coating
for multiple payloads – hydrophilic/phobic
– Anti-TB drugs – in combinations
– Immunomodulators or antigens
– Drug efflux pump inhibitors, inhibit Ca and K efflux from lysozyme
• Embedded surface molecules to
– Activate immune cells
– Decrease or increase adherence to or uptake by specific cell
types (liver vs. lung) - targeted entry
– Tissue/cell targeting allows delivery of agents not
absorbed orally OR systemically toxic at usual doses
• Sustained release of payload contents (less drugx2)
Beyond Drug/Combo Development
Translational Gap Area
2) Host-directed Therapies (HST)
• Therapeutic vaccines
• Small molecule host -directed therapies
RE-PURPOSING, not new molecules
Adjunctive small molecule
host -directed therapies
Cytokine Zoo - inhibitors
• TNF-α, IL-6 – Thalidomide derivatives*, telmisartan*,
PDE inhibitors*, several in trials
• TGF-β - Pirfenidone*
• Leukotrienes – Curcumine (turmeric), zileuton*
Host cell (macrophage) vulnerability/defenses
• Imatimib* (TyrK inhibitor)
Host tissue protection
*
• MMP-1 inhibition
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Rationale for Specific, Small Molecule
Adjunctive Immunomodulators in TB Rx
• Improving TB-induced immune defects
Particularly for macrophages
– May be particularly useful with immunodeficiency
–
• Decreasing tissue pathology/sanctuaries
(less inflammation, necrosis, caseation, granulomas…
Better blood flow/O2, more permeable local environment, fewer inhibitory molecules…)
Improved bug clearance occurs in models
– Improved immune cell function
– Improved immune cell access
– Improved anti-TB drug delivery to bacilli
PZA Workshop
September 2012
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WORKSHOP
2-Pyrazinecarboxylic acid
39
THANK YOU
PZA
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TB and Impressionism
BACK-UPS
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43
PZA
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MAMS-TB-001
Sites:
2 x Cape Town; 2 x Johannesburg; 3 x Tanzania
Study start:
November 2012; End: Sept. 2013
Sponsor:
University of Munich (Michael Hoelscher)
Chief Investigator:
Martin Boeree
Control (124): 2 months HRZE
+ 4 months HR
Arm 2 (62):
Arm 3 (62):
Arm 4 (62):
Arm 5 (62):
+ 3 months HR
+ 3 months HR
+ 3 months HR
+ 3 months HR
3 months HRZQ300mg
3 months HR20mgZQ300mg
3 months HR20mgZM
3 months HR35mgZE
+ 6 months subsequent follow-up for all
One planned interim review by IDMC that could result in dropping arms
GATB – NC-001 EBA Trial with
Combinations - Pa 824 + PZA + Moxi
GATB - First Novel Combo SSCC: NC-002
In patients with M.tb sensitive to Pa, M, and Z
Pa(200mg)-M-Z
randomize
Pa(100mg)-M-Z
2 months of treatment (plus 2-wk EBA substudy)
Rifafour
Pa(200mg)-M-Z (MDR)
Z dose = 1500mg
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide
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GATB Trials
NC-003 Study drugs/combos -14-day EBA trial:
• PZA
• Clofazimine
• J + Pa 824 + PZA
• J + Pa 824 + Clofazimine
• J + PZA + Clofazimine
• J + Pa 824 + PZA + Clofazimine
- Sept. 2012 initiation
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GATB Trials
NC-004 Study drugs/combos -14-day EBA trial:
• To be determined – combinations to include
bedaquiline, nitroimidizoles, oxazolidinones….
• ? Levofloxacin doses, it not done by Opti-Q?
• Initiation - Late this year
New nitroimidazole (TBA 354) to replace PA 824
• Phase I – Late Fall 2012
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Combination Drug Development
Pre-clinical
Acute
Efficacy
Pharm/Tox
Relapse
Efficacy
Acute
Relapse
Phase I
Tolerance
PK/DDIs
Dose
Adjustment
Phase IIA
“EBA”
Phase IIB
“SSCC”
Phase III
< 14 Days
Quantitative
Cultures
> 8 Weeks
Quant. Cx
OR
Time to Cx –
Clinical
Endpoints
PK/PD
OR SSCC
PK/PD
MDR Trials
1) 8 weeks
Then
2) 24+
weeks
MDR USE
DS TB
Rx
Combination
“Approvals”
Combination REGIMEN Development
Preclinical
Pharm/Tox
Efficacy
Acute
Relapse
Phase I
Tolerance
PK/DDIs
Dose
Adjustment
Phase II A&B
“EBA/SSCC*”
Phase III
DS TB - > 8 Weeks
Quant. Cultures OR
Time to Cx- OR
SSCC
PK/PD
MDR Trials
1) 8 weeks
Then
2) 24+
weeks
Clinical
Endpoints
TB TREATMENT
APPROVALS
ACCELERATED
FOR DS USE
FOR MDR USE
FULL
FOR
DS
USE
Combination
“Approvals”
Drug
Discovery
? Immune-Based
Therapy
Improved Models/
Testing
PZA
Detection/
Quantitation
Drug Sequencing/
Staging
Fundamental
Biology/Targets
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Clinical Research Planning Coordination
New Coordinating Groups Members
 USG (NIAID, CDC, and Networks)
 Gates PDPs (FIND, Aeras, GATB)
 European Funders (EDCTP, MRC)
Forum for TB Diagnostics
Research
TB Vaccine Collaborative
Committee
TB Therapeutics Phase II
Research Coordination Forum
Existing Partnerships
 Critical Path to TB Regimens
 Gates Foundation
 US Federal TB Task Force
 FDA/EMA
 Stop TB Partnership WGs
 Pharmaceutical Companies
 Community-based, e.g. TAG
And now, we enter into the realm of the
UNDEAD
zzzzzzzz…
Hell no, we won’t grow!
Maybe come back
again in 10 years
or so?
Research in Latent Tuberculosis Infection
(LTBI) in the Setting of HIV Co-infection
Tuberculosis Clinical Research Branch/TRP/DAIDS
AIDS Research Advisory Committee
March 14 , 2012
LTBI initiative
Objective: Define host (genetic and immunologic),
microbiologic (immune evasive and metabolic adaptive)
mechanisms and interactions involved with development,
maintenance, and activation of LTBI in the context of HIV
co-infection
Mechanism: R01 Grant
Type: New
Duration of awards: 5 years
Number of awards anticipated: 3-5
First year of cost: $1.5M/$2.0M
Mouse EBA Studies
Figure 2. Mouse EBA on INH essentiality
8.5
8.0
log10 CFU/ lung
7.5
7.0
6.5
6.0
5.5
Control
14 RHZE
2RHZE/ 12RZE
2RHZE/ 12RZME
5.0
4.5
4.0
0
2
4
7
11
14
Days
Same arms will be compared in ACTG 5307
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Global TB Drug Pipeline1
Discovery
Lead Identification
•Summit PLC
compounds
•Benzimidazoles
1 Projects
Preclinical Development
Lead Optimization
•Nitroimidazoles
•Mycobacterial Gyrase
Inhibitors
•Riminophenazines
•Diarylquinoline
•Translocase-1
Inhibitor
•MGyrX1 inhibitor
•InhA Inhibitor
•GyrB inhibitor
•LeuRS Inhibitor
Preclinical
Development
•BTZ 043
•TBD 354
•CPZEN-45
•SQ641
•SQ609
•DC-159a
•Q201
Clinical Development
Phase I
•AZD 5847
Phase II*
Phase III
•Bedaquiline (TMC)
•SQ 109
•Delamanid (OPC)
•PA 824
•Levofloxacin •Moxifloxacin
•Linezolid
•Sutezolid (PNU)
•HD Rifamycins
that have not identified a lead compound series are considered to be in the screening phase
of development and are not included. As of publication, there are 11 screening projects in progress as
described on http://www.newtbdrugs.org/pipeline.php.
*Initiation of drug combination studies