TB THERAPEUTICS RESEARCH Issues, Challenges, and Opportunities TCRB/DAIDS/NIAID October, 2012
Feb 24, 2016
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