NIAID TB Clinical Research Agenda Current and Future OCTOBER, 2011 - - PowerPoint PPT Presentation

OCTOBER, 2011

NIAID TB Clinical Research Agenda Current and Future

Clinical Research Funding

2

NIH/ NIAID funds are not significantly expanding

What do we need and how to get it done?

3

Enhance/ adapt existing clinical research

resources for TB

Coordination and Collaborations Develop research strategies/ agendas and

trials designs for more efficient therapeutics development

4

Fundamental Non-Clinical Clinical Ph I Ph IIA Ph IIB Ph III-IV DM ID Resources DAIDSResources

Clinical Trials Networks * Tuberculosis Research Unit Ph I Units Preclinical Services, IND-enabling

* Solicited and Unsolicited Grants - R34/ U01/ BAA

NIAID TB  DM ID NIAID HIV  DAIDS NIAID Clinical Team (TB and TB/ HIV ) NIAID Clinical Team (TB and TB/ HIV )

“ omics” Support Programs Systems Biology, Biomarker Programs

Vaccine & Treatment Evaluation Units

Animal M odels (Candidate Selection) Research Reagents

* Clinical Diagnostics Research Consortium

* TB specific HIV-TB Basic/ Pre-clinical Grants

6

DAIDS Cooperative Agreements

 AIDS Clinical Trials Group (ACTG)  International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  HIV Vaccine Trials Networks (HVTN)

DMID Contracts

 Vaccine and Treatment Evaluation Units (VTEU)  Phase I Clinical Trials Units  Tuberculosis Research Unit (TBRU)*  Tuberculosis Clinical Diagnostics Research Consortium (CDRC)*

Both Divisions  Support for Unsolicited Clinical Research Projects

* TB specific

NIAID Clinical Trials/Research Infrastructure NIAID Clinical Trials/Research Infrastructure

AIDSClinical Trials Group

 International cooperative network established in 1987

 34 domestic and 18 international ACTUs  71 Clinical Research Sites

 Alliance of academic, industry, and government investigators

plus community representatives

 Statistics and Data M anagement Center

 Harvard School of Public Health

Funding

 NIAID and other collaborating institutes  Current year CORE funding, $25 million

 ~$13 million site support grants

Tuberculosis Transformative Science Group

Formed in June, 2011 Chair, Dr. Richard Chaisson

 Johns Hopkins

Vice Chair, Dr. Diane Havlir

 San Francisco General Hospital/ UCSF

International Vice Chair, Dr. Gavin Churchyard

 University of Witwatersrand

UNAIDS 2001

ACTG Clinical Research Sites

K-RITH

HHMI: $70 M plus

• 2008-2018
• Building
• Recruitment 5-7 PIs
• No Clinical Space
• 1/3 of space uncommitted
• No running costs for PIs

BSL-3 Lab BSL-2 Labs (3 PIs per floor) Offices & Meeting Rooms

Leadership and Sites for HIV/AIDS Therapeutic Clinical Trials - Renewals

FY 13 DAIDS FOA Objective:

To establish the Leadership of 1 to 2 HIV International Clinical Trial Networks to carry out the NIAID therapeutic research agenda in the following areas:

 Treatment and chemoprevention of tuberculosis  Treatment and chemoprevention of infectious hepatitis  Cure and/or functional cure for AIDS  Non-infectious co-morbidities and novel interventions for

HIV-infected individuals

FY14 DAIDS FOA Objective:

To establish clinical trials units/sites for performance of studies to carry out the NIAID therapeutic research agenda

11/ 2/ 2011

11

Ver. 1.1

Consortium for TB Biomarkers

(CTBB – aka “Frozen Trial Initiative”)

12

GATB, ACTG, TBTC collaborative project for standardized sample biobanking

 Funded by FDA grant, ACTG supplement (ACTG 5302), and ?

NIAID R24 grant

 Form joint governance body to coordinate, develop

policies/ procedures, oversee operations, etc.

 Develop umbrella protocol to specify type, timing, processing,

shipping of samples, etc. from selected treatment trials

 Contract with repository vendors to establish biobank(s), QA  Constitute advisory group to review sample use proposals

Other trial sponsors are welcome to join

Coordination of Phase II Combo Trials

Coordinate Phase II Combination Work

NIAID – ACTG, TBRU CDC – TBTC GATB EDCTP – PANACEA UKM RC

PHARM As FDA/ EM A, etc. WHO, NGOs, etc.

Forum to Coordinate Phase II/ III Clinical Trials- Initial M eeting 10/ 23/ 11

Phase II combination development plan coordination

 Which combinations would be done by whom/ when  Efficiently/ promptly sharing new study results  Necessary pre-clinical and clinical data to allow study of

specific combos

 Coordination of discussions with Pharmaceutical sponsors

Establishment of an ongoing Phase II/ III Planning Forum

 Drafting a proposal for how groups will work to coordinate  Proposal for support of future activities (conference calls

and meetings)

 Quarterly discussions with 1-2 meetings/ year

Forum to Coordinate Phase II/ III Clinical Trials Other Possible Objectives

Discuss key characteristics to establish new combinations as high priority candidates Consider standardization of study designs, site procedures, labs, endpoint definitions, etc. to improve study comparisons or combining data Discuss potential trial collaborations, necessary standardizations, mutually acceptable study monitoring and QA strategies, etc.

Participants Focus

CPTR Initiative

BM GF—in association with the TB Alliance and C-Path—will work to accelerate the development of new TB drug regimens CPTR Tools Consortium

“Regulatory Science”

1 2 3 CPTR Drug Coalition

“Drug Development”

CPTR Infrastructure

“Key Success Factors”  Data standards/ integration  Qualified biomarkers  Disease progression models  New clinical trial designs  Drug combination testing

and development

 Clinical trial capacity  Regulatory harmonization  Funding  Pharma companies  TB Alliance  TB experts  Regulators  Patient representatives  Others?  Pharma companies  TB Alliance  TB experts  Others  Pharma companies  TB Alliance  Regulators  Patient representatives  Reagan-Udall Foundation  NIH  CDC  BM GF  Other funders

Planning for M DR Trials with New Drugs

17

 Site surveys

 Initial – Completed in ACTG and TBTC

 Initial Observational studies to better define local drug susceptibility patterns and feasibility issues  EARLY coordination of planning/ drug choices  Trials

 Change emphasis to new combos, not single drug additions to OBT

Include M DR/ XDR into new combo trials as soon as possible

 Rapid PZA DST will be essential for next generation of M DR trials  Careful monitoring for new resistance

Recently Completed Studies

18

 ACTG 5221 STRIDE: Timing of ART for HIV-1

infection and tuberculosis

 Camelia (ANRS1295/ NIAID-DAIDSCIPRA KH001)

Early versus late start of antiretroviral therapy in adults with AIDSand tuberculosis

Both appear in yesterdays NEJ

M  ACTG 5267 PK interaction of TM C 207 + EFV

19

STUDY NUM BER BRIEF DESCRIPTION Biomarkers A5302 Evaluation of TB biomarkers of treatment response in upcoming ACTG (A5289/ A5290) and TBTC (Study 31) clinical trials Diagnostics A5253 Sensitivity and specificity of TB diagnostics A5255 FASTER: Rapid TB DST study A5295 Evaluation of Xpert M TG/ RIF Assay DM ID 07- 0061 Interferon-Gamma Release Assays in TB-HIV co-infected children

Summary of NIAID Studies for TB - 1

20

STUDY NUM BER BRIEF DESCRIPTION HIV/ TB A5274 REM EM BER: Empiric TB treatment + ART to reduce early mortality following ART initiation A5284 RIF + GS-9350 (Cobicistat) PK interaction A5290 Comparison of LPV/ r-based ARV ± RAL with RBT and double dose LPV/ r with RIF-based TB RX LTBI A5259 Rifapentine-INH x 3 mos vs SOC for LTBI (TBTC Study 26) A5279 Ultra-short (1 month) daily course of RPT/ INH for LTBI DM ID 07- 0083 Phase I Study of Whether Preclearance of LTBI with INH Enhances Specific Immune Responses to M TB following Subsequent BCG Revaccination in Healthy, HIV-uninfected, PPD+ Adults

Summary of NIAID Studies for TB – 2

21

STUDY NUM BER BRIEF DESCRIPTION M DR A5300 TM C-207 for preventive therapy for M DR/ XDR contacts A5312 The Early Bactericidal Activity of High-Dose Isoniazid among Adult Patients with inhA-related INH-Resistant Tuberculosis Harvard CFAR Inhaled Colistin to Decrease XDR TB Infectivity - Nardell Optimizing Standard Treatment Regimen A5307 Essentiality of INH After Two Doses: Randomized 14-day EBA Comparison

• f Standard RHZE with Only 2d INH + RZE or Substituting M oxifloxacin for

INH (RM ZE) During Days 3 and 14 A5311 Phase I Clinical Trial of the Pharmacokinetics of High-dose Daily Rifapentine, Given as a Single Dose or in Divided Doses to Healthy Volunteers

Summary of NIAID Studies for TB – 3

22

STUDY NUM BER BRIEF DESCRIPTION Optimizing Standard Treatment Regimen – continued DM ID 11- 0050 Double Blind randomized dose ranging trial of high dose rifampin (10-15- 20 mg/ day) for safety and improving treatment outcomes Pediatrics P1073 Study of IRISin children  5 years of age P1078 Safety and Efficacy of Antepartum vs. Postpartum INH Preventive Therapy in HIV-infected Women and Infants IM PAACT CS TM C-207 with OBT for treatment of M DR TB in children Other TBRU EBA Feasibility Study with Standard EHRZ Chemotherapy in Kampala/ M ulago

Summary of NIAID Studies for TB – 4

23

STUDY NUM BER BRIEF DESCRIPTION New Drug Development A5267 PK interaction study of TM C-207 and EFV A5306 Safety, tolerability, and PKI study of PA-824 together with Efavirenz or Ritonavir-Boosted Lopinavir or Rifampin DM ID 11- 0006 M ultiple Dose Extended EBA of Oxazolidinone AZD5847 DM ID 10- 0043 PK interactions of single-dose TM C-207 with steady-state rifabutin or rifampin New Combo Development A5289 TM C-207 substitution of standard drugs for TB treatment A5304/ REM ox Two M oxifloxacin containing treatment shortening regimens compared with the standard regimen

Summary of NIAID Studies for TB – 5

24

Fundamental Biology Drug Discovery Detection/ Quantitation Drug Sequencing/ Staging Immune-Based Therapy Improved M odels/ Testing PZA

Optimal Sequencing/ Staging of Drugs

25

Based on changes in the spectrum of subpopulations and possible antagonistic (and synergistic) interactions

 Progress beyond current intensive and maintenance phases  INH for only a few days  Other drugs most active against replicators early- ?how long  Extend PZA for a longer time in new regimens  Possibly delay use of PZA and new drugs active against NPRs

for some period and use until end of treatment

 Explore optimal sequencing/ timing of new and older

drugs in appropriate models

Inhaled Agents/ Nanoformulations

Drug Comment Supplier

Pyrazinoic Acid Clofazimine Immunomodulators/ Vax? Capreomycin Systemic absorption NOT PZA (a pro-drug) Near-Great Synergizer M END ?

Efficiency in Combination Development - Focus on Phase II

Problem - Serial trials/ amendments are much too

inefficient- Delays caused by protocol development (esp. in group setting) and approvals at all levels

Responses  Innovative, inclusive, new adaptive designs  Early anticipation and resolution for concerns with

new combinations - interactions ad safety  Improved, real-time quantitative response markers  Coordination of planning/ prompt sharing of data

Efficiency in Combination Development - Focus on Phase II

Desirable Features of Adaptive trials

 M ulti-arm and may be multi-step (Phase II A  B)  Frequent ISM C interim reviews (IRs) – drop arms early if less active than control – but trial continues  Add new arms as per study criteria  Seamless transitions, step (A  B)  Flexibility of entry into Phase A step or Phase B step, depending on how much is known  M ay include arms for both DSand DR infections

Efficiency in Combination Development - Focus on Phase II

Desirable Potential Features of Adaptive trials

 Alternate randomization to increase effectiveness of IRs and minimize exposure to less effective regimens  M ay include arms to compare individual drugs in combinations and also factorial randomizations  Evaluation of new “ real-time” quantitative response measurements (imaging, molecular) to eventually

 Greatly improve timeliness of IRs/ decisions  M erge Phase IIA and IIB for new combinations  Better evaluation of activity against NRPs

Caution with some New Drug Classes

30

Safety and efficacy concerns

 Very long half-lives and high tissue concentrations – and trial follow-up durations (Not intensive!)  Some are “CADs” – phospholipidosis  Q-T interval prolongation  M ore toxic metabolites

For combinations –

 Additive effects/ interactions among drugs  Some need to be addressed well before Phase II

TB Therapeutic Clinical Research Priorities

31

 TB/ HIV Therapy – Co-treatment regimens; TB IRIS  Chemoprevention of TB  Improved diagnostics and DST  Pathogenesis and translational research  Prognostic biomarkers for disease progression, treatment response/ relapse  New drugs and combinations for DSand DR TB:

 Efficient Phase I and II evaluations  Phase III  Strategies to minimize resistance  Novel delivery systems and formulations

“… we have much catching up to do, and the TB research effort will require a sustained and long-term commitment from government, academia, industry and philanthropy.”

• -- Anthony S. Fauci, MD

November 20, 2009

Clinical Research Partnerships Clinical Research Partnerships

32

33

THANK YOU