TB THERAPEUTICS RESEARCH
Issues, Challenges, and Opportunities
TCRB/DAIDS/NIAID
October, 2012

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
3

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
WHO, NGOs, etc.
GATB
PHARMAs
Coordinate all
Phase II combination studies
FDA/EMA, etc.
EDCTP – PanACEA
UKMRC

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
6

• 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
8

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
9

Role of Phase IIA EBA Studies
First 14 days of a Classic Mouse Study
Best sterilizer?
mmm

And the winner is…

From McCune R M, Tompsett R, McDermott W
J Exp Med 1956; 104: 763-802.

• Have become “POC” rite of passage
• High EBA
0-2 is unique for INH
• EBA
0-14 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 EBA
0-14 sterilizing activity
, but have potent
• 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

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

• 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
17

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
HRZE failure
2003
T = -2 months
PPtOCZ failure
2005
HZPPtCO failure
HZKLfRb failure
HLf failure
2009 DST R: HPSEREtCKORbMCp , S: Z(?)
T = 0 months
2007 2009
T = 6 months
Sm/C: ++/28 +++/15
CONFIDENTIAL
-/-

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
23

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
24

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
25

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
26

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
27

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?
28

Pediatric TB Research Priorities: Treatment
• Limited data on pharmacokinetics and safety of current and new TB drugs in children:
– 1 st , 2 nd 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

• 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?

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
32

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

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
• 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
*
36

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/O
2
, 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
38

2-Pyrazinecarboxylic acid
39

PZA
40

42

43

PZA
44

MAMS-TB-001
Sites:
Study start:
2 x Cape Town; 2 x Johannesburg; 3 x Tanzania
November 2012; End: Sept. 2013
Sponsor:
Chief Investigator:
University of Munich (Michael Hoelscher)
Martin Boeree
Control (124): 2 months HRZE + 4 months HR
Arm 2 (62): 3 months HRZQ
300mg
Arm 3 (62): 3 months HR
20mg
ZQ
300mg
Arm 4 (62): 3 months HR
20mg
ZM
Arm 5 (62): 3 months HR
35mg
ZE
+ 3 months HR
+ 3 months HR
+ 3 months HR
+ 3 months HR
+ 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
47

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
48

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
49

Combination Drug Development
Pre-clinical
Acute
Efficacy
Relapse
Acute
Efficacy
Relapse
Phase I
Tolerance
PK/DDIs
Dose
Adjustment
Phase IIA
“EBA”
< 14 Days
Quantitative
Cultures
PK/PD
Phase IIB
“SSCC” Phase III
> 8 Weeks
Quant. Cx
OR
Time to Cx –
OR SSCC
PK/PD
Clinical
Endpoints
MDR Trials
1) 8 weeks
Then
2) 24+ weeks
DS TB
Rx
MDR USE
Combination
“Approvals”

Combination REGIMEN Development
Preclinical
Pharm/Tox
Efficacy
Acute
Relapse
Phase I
Tolerance
PK/DDIs
Dose
Adjustment
Phase II A&B
“ EBA/SSCC* ”
DS TB - > 8 Weeks
Quant. Cultures OR
Time to Cx- OR
SSCC
PK/PD
Phase III
Clinical
Endpoints
MDR Trials
1) 8 weeks
Then
2) 24+ weeks
TB TREATMENT
APPROVALS
ACCELERATED
FOR DS USE
FULL
FOR
DS
USE
FOR MDR USE Combination
“ Approvals ”

? Immune-Based
Therapy
Improved Models/
Testing
Drug
Discovery
PZA
Detection/
Quantitation
Fundamental
Biology/Targets
Drug Sequencing/
Staging
52

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 …
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

8.5
Mouse EBA Studies
Figure 2. Mouse EBA on INH essentiality
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
0 2
Control
14 RHZE
2RHZE/ 12RZE
2RHZE/ 12RZME
4 7
Days
11 14
Same arms will be compared in ACTG 5307
58

Global TB Drug Pipeline 1
Discovery
Preclinical Development
Clinical Development
Lead Identification
• Summit PLC compounds
• Benzimidazoles
Lead Optimization
Preclinical
Development
• Nitroimidazoles
• Mycobacterial Gyrase
Inhibitors
• Riminophenazines
• Diarylquinoline
• Translocase-1
Inhibitor
• MGyrX1 inhibitor
• InhA Inhibitor
• GyrB inhibitor
• LeuRS Inhibitor
• BTZ 043
• TBD 354
• CPZEN-45
• SQ641
• SQ609
• DC-159a
• Q201
•
Phase I
AZD 5847
Phase II*
• Bedaquiline (TMC)
Phase III
• SQ 109
• PA 824
• Levofloxacin
• Linezolid
• Sutezolid (PNU)
• HD Rifamycins
• Delamanid (OPC)
• Moxifloxacin
1 Projects 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