TB THERAPEUTICS RESEARCH

Issues, Challenges, and Opportunities

TCRB/DAIDS/NIAID

October, 2012

TB Clinical Trial Limitations?

• Resources!

•Resources!•Resources!

How do we get it done?

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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

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

Coordinate all Phase II

combinationstudies

NIAID – ACTG, TBRUCDC – TBTC GATB

EDCTP – PanACEAUKMRC

PHARMAs FDA/EMA, etc.

WHO, NGOs,etc.

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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

Site Capacity and Efficiency

• Information sharing among sponsors– CPTR & WGND has initiated

• Actively coordinate efforts for site–Evaluations–Preparation–Training–Participation in planned studies

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Recognizing the relative roles of COMBINATION Developers in

contrast to DRUG Developers

and

Providing new DRUG ACCESS to COMBO DEVELOPERS

as soon as feasible

CRITICAL ASPECT FOR PROGRESS

Study Issues – Phase II Trials

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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

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.

• 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

Role of EBA TRIALS

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

• ResponseInnovative, 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 TrialsSputum 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

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)

Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III

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

T = -2 months T = 0 months T = 6 months

23 year old male enrolled in delayed linezolid arm:

2001 2003 2005 2007 2009

HRZE PPtOCZfailure failure

HZPPtCO HZKLfRb HLffailurefailurefailure

2009 DST R:HPSEREtCKORbMCp, S:Z(?)

Sm/C: ++/28 +++/15 -/-

CONFIDENTIAL

PZA – Critical Drug

• 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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PZA

Summary of PZA Day at CDCThursday, 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 surveillance24

Current Drugs for New Combos

For DS/DR combos• Bedaquiline• Sutezolid and AZD-5847• Nitroimidazoles• Clofazimine• PZA *• Moxi/Levofloxacin* – at optimal dose• SQ 109Possible roles in DS combosShort-course INHRifamycins – high dose RMP/RPT or rifabutin 25

Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III

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Therapeutics Development –Risks and Opportunities

RisksChoices 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

Combination Development and Drug Resistance

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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

Caution with some “New” Drug Classes

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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?

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, solid-scored, 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 HIV-infected 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 InnovationOutside of drug & combo

developmentAnd 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 weeksINH* + Rifamycin + PZA (+ ?FQ)• Sterilizing Phase x 6 weeksPZA + 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 period 33

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 DevelopmentTranslational 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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*APPROVED DRUG

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

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PZAPZA Workshop

September 2012

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POA

POA WORKSHOP

2-Pyrazinecarboxylic acid

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PZA

THANK YOU

TB and Impressionism

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BACK-UPS

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PZA

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PZA

MAMS-TB-001

Control (124): 2 months HRZE + 4 months HR

Arm 2 (62): 3 months HRZQ300mg + 3 months HRArm 3 (62): 3 months HR20mgZQ300mg + 3 months HRArm 4 (62): 3 months HR20mgZM + 3 months HRArm 5 (62): 3 months HR35mgZE + 3 months HR

Sites: 2 x Cape Town; 2 x Johannesburg; 3 x TanzaniaStudy start: November 2012; End: Sept. 2013Sponsor: University of Munich (Michael Hoelscher)Chief Investigator: Martin Boeree

One planned interim review by IDMC that could result in dropping arms

+ 6 months subsequent follow-up for all

GATB – NC-001 EBA Trial with Combinations - Pa 824 + PZA + Moxi

GATB - First Novel Combo SSCC: NC-002In patients with M.tb sensitive to Pa, M, and Z

Pa(100mg)-M-Z 2 months of treatment (plus 2-wk EBA substudy)

Rifafour

Pa(200mg)-M-Z

Pa = PA-824; M = moxifloxacin; Z = pyrazinamide

Pa(200mg)-M-Z (MDR) Z dose = 1500mg

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randomize

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

Acute

RelapseEfficacy

Pre-clinical

TolerancePK/DDIs

Dose Adjustment

Phase I< 14 Days

Quantitative Cultures

PK/PD

> 8 WeeksQuant. Cx

OR Time to Cx –

OR SSCCPK/PD

Phase IIA “EBA”

Phase IIB “SSCC” Phase III

MDR Trials 1) 8 weeks

Then2) 24+ weeks

Combination“Approvals”

Pharm/Tox

EfficacyAcute

Relapse

MDR USE

DS TBRx

Clinical Endpoints

Combination REGIMEN Development

Acute

RelapseEfficacy

Preclinical

Tolerance

PK/DDIs

Dose Adjustment

Phase I

DS TB - > 8 WeeksQuant. Cultures OR

Time to Cx- ORSSCC

PK/PD

Clinical Endpoints

Phase II A&B“EBA/SSCC*” Phase III

MDR Trials 1) 8 weeks

Then2) 24+ weeks

Combination“Approvals”

Pharm/Tox

FOR MDR USE

TB TREATMENTAPPROVALS

ACCELERATEDFOR DS USE

FULL FOR DS USE

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RapidReplicators

Intermittent Replicators

N.R.Persisters

Fundamental Biology/Targets

Drug Discovery

Detection/Quantitation

Drug Sequencing/Staging

? Immune-BasedTherapy

Improved Models/Testing PZA

Clinical Research Planning Coordination

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

New Coordinating Groups - Members USG (NIAID, CDC, and Networks) Gates PDPs (FIND, Aeras, GATB) European Funders (EDCTP, MRC)

And now, we enter into the realm of the UNDEAD

Hell no, we won’t grow!

Maybe come back again in 10 years or so?

zzzzzzzz…

Research in Latent Tuberculosis Infection (LTBI) in the Setting of HIV Co-infection

Tuberculosis Clinical Research Branch/TRP/DAIDS

AIDS Research Advisory CommitteeMarch 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-infectionMechanism: R01 GrantType: NewDuration of awards: 5 yearsNumber of awards anticipated: 3-5First year of cost: $1.5M/$2.0M

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Figure 2. Mouse EBA on INH essentiality

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

Control14 RHZE2RHZE/ 12RZE2RHZE/ 12RZME

0 2 4 7 11 14Days

log 1

0 C

FU/ l

ung

Mouse EBA Studies

Same arms will be compared in ACTG 5307

Global TB Drug Pipeline1

Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III

• Delamanid (OPC)

• Moxifloxacin

• Bedaquiline (TMC)

• SQ 109• PA 824• Levofloxacin• Linezolid• Sutezolid (PNU)• HD Rifamycins

• BTZ 043• TBD 354• CPZEN-45• SQ641• SQ609• DC-159a• Q201

Preclinical DevelopmentDiscovery Clinical Development

• Nitroimidazoles• Mycobacterial

Gyrase Inhibitors• Riminophenazines• Diarylquinoline• Translocase-1

Inhibitor• MGyrX1 inhibitor• InhA Inhibitor• GyrB inhibitor• LeuRS Inhibitor

• Summit PLC compounds

• Benzimidazoles

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

• AZD 5847