Research and Development in TB–

Do We Have the Right Tools for the

Fight?

Dr Lucica Ditiu, Executive Director, Stop TB Partnership

Eastern Partnership Ministerial Conference on Tuberculosis and Its Multi-Drug Resistance

30-31st March 2015

We Can Eliminate TB in 25 years…1908

International TB Congress

1.3 MILLION

9 MILLION estimated TB cases

5.7 MILLION new cases diagnosed

MDR-TB

480,000 estimated new cases

The

Burden

97,000 MDR-TB cases

diagnosed and on treatment

1.5 MILLION DEATHS

125 107

92 79 68 58 50 43

End TB target Global

10 / 100k / 100k

1990 2000 2010 2020 2030year

Global TB incidence

The

Burden Current Tools Won’t End TB Until….

Projected acceleration of TB incidence decline to target level in

WHO Post-2015 Strategy (10 per 100k)

Optimize current tools, pursue universal health

coverage and social protection

Introduce new vaccine, new prophylaxis

Average -10%/year

-5%/year

Current global trend: -2%/year

Average -17%/year

… Our tools

Past Present

7

Drug Sensitive

TB

4 drugs taken for 6 or more

months

Shorter, simpler therapy

Diagnostic

M(XDR)-TB

Injections and drugs taken for

more than 2 years, poorly

tolerated

More effective,

shorter, safer simpler

regimens

Diagnostic

TB/HIV co-

infection

Drug-drug interactions with ARVs

Co-administration with ARVs

Diagnostic

Latent TB Infection

9 months of isoniazid

Shorter, more easily

tolerated therapy

Diagnostic

Pediatric TB

No adequate dosing

formulations

Adequate dosing

regimens and formulations

Diagnostic

Current Treatment and Unmet Needs C

urr

ent

Ther

apy

U

nm

et

Ne

eds

Rapid, accurate, affordable point of care diagnostic

The Cost of Inaction

Source: US CDC, 2014. http://www.cdc.gov/nchhstp/newsroom/2014/TB-Infographic2014.html Slide: Aeras; Picture Credit: MSF

9

The Right Diagnosis Tool

• Point of care test • Rapid (less than 10 minutes)

and accurate • Requires small-easy to

obtain sample • Detects DR-TB • Can be used by all health

workers • Portable and battery

powered

5-year vision for TB Diagnosis

Triage/case finding –

first point of contact

Further work up & treatment –

dedicated unit

Surveillance, QA, training –

specialized unit

E-Health supported solutions

TB

1. Real-time Surveillance

2. Comprehensive, rapid DST

1. Highly sensitive TB

confirmation with rapid DST for

critical drugs

2. Treatment monitoring

3. TB infection with high risk of

disease progression

1. Triage test • incl. for childhood TB & EDPT

2. Syndromic test (bac vs viral)

Source: FIND

A New TB Vaccine

• A new TB vaccine: – More effective and long lasting childhood vaccine

– Adolescent / booster vaccine

Introduced in only 8 high-burden countries could avert >100M cases of

TB by 2050 (60% vaccine efficacy and coverage).

11 Source: Aeras

12

Treatment in 2020

Success will require novel drug combinations

Current Treatment

6-30 Months, not adapted for

children

New Treatments in Development

2-4 Months,

optimized pediatric doses

Aspirational Goal

7-10 Days,

optimized pediatric doses

Source: TB Alliance

13

What Do We Have?

• Two New TB Drugs in 2013 – Bedaquiline and Delamanid - but only 6 new chemical entities in late stage clinical development and only 2 tested in combination regimen (vs 40 new in clinical development for Hepatitis C)

• New Rapid Test for MDR-TB Diagnostic – Xpert MTB / RIF Test

14

Resource Needs TB R&D

Annual Funding Need TB R&D: $2 Billion

2013 Funding for TB R&D: $676 million

Annual Funding Gap: $1.3 billion

Financing TB R&D: Global Plan to Stop

TB 2006-2015 Funding Targets

$600,000,000

$800,000,000

$400,000,000

$200,000,000

$0

Basic Science New Diagnostics New Drugs Operational

Research New Vaccines

$80,000,000

$71,754,311 $95,172,788

$380,000,000

$255,428,811

$740,000,000

$137,658,205

$420,000,000

Global Plan Annual Targets 2013 Funding

$340,000,000

$67,771,567

16

TB R&D Funding in Europe

Source: 2014 TAG Report on TB Funding Trends

• Among top 10 TB R&D global funders are the U.K. Department for International Development (5th), the EDCTP (7th) and the European Commission (8th) • Within the European Union:

• the U.K.-the biggest TB R&D funder ($37.5 million in 2013) • the Netherlands ($9.75 million) • France ($8.49 million) • Germany ($7.72 million)

• In comparison, US spend $250 million a year on TB R&D and India outspends France, Germany and most European countries on TB R&D

17

The Riga Declaration:

Moving from Words to Action?

“…Recognizing the need to scale up investment in TB research and innovation for new tools and approaches to fight TB and MDR-TB to take into account cost effectiveness” “…To strengthen collaboration in research and development for new tools and embrace innovative and patient centred approaches to TB prevention and care”

18

• An improved pipeline of promising drug compounds and vaccine candidates - think about regimens – not only single compounds

• Research and especially clinical trials are global in nature. European countries need mechanisms to financially and technically participate in TB trials

• The European and Developing Countries Clinical Trials Partnership (EDCTP) mechanism – good – to be further supported

• Outside EDCTP - European Commission should develop dedicated channels for funding TB research within larger programs.

• Significant role for coordination of all partners involved in R&D

• Simpler and accessible system allowing also non profit product developers to take initiative

• Create a 2016-2020 R&D pooled fund for countries to develop diagnosis, testing and trial capacity and allow contributions in global trials for late stage research

…Use the opportunities…

Robert Koch and his colleagues set a goal to End TB

in 25 years when the only tool against TB was a

microscope…

20

Acknowledgements : Thank you to the 3 Stop TB Partnership New Tools

Working Groups,TB Alliance, Aeras, FIND, MSF, TAG

Increased resources for R&D will ultimately help people like Agnese beat TB

Thank You

Back up slides

Global TB dx R&D pipeline (case detection/DST) On pathway to WHO evaluation Late or completed development Early development

MDR-TB (Akkoni)

COBAS TaqMan MTB +DST(Roche)

BNP Middlebrook (NanoLogix)

Rapid colorimetric DST

VereMTB (Veredus Laboratories)

LiPA Pyrazinamide (Nipro)

LATE-PCR Lights on / Lights off (Hain)

TBMDx (Abbott)

Meltpro (Zeesan)

MTB-MDR (CapitalBio)

REBA MTB-XDR (YD Diagnostics)

BD Max (BD)

TREK Sensitive MYCOTB (Trek)

GenoTYPE MTBDRsl (Hain)

LiPA MDR-TB (Nipro)

REBA MTB-Rifa (YD Diagnostics)

Xpert Ultra and XDR (Cepheid)

Alere Q (Alere)

Enigma ML (Enigma Diagnostics)

Q-POC (QuantuMDx)

EOSCAPE (Wave80)

RT-PCR Testing Platform (NWGHF/Quidel)

iCubate 2.0 (iCubate)

TBDx system (KGI)

DiagCORE (STAT-Diagnostica)

LabChip G2-3 (Nanobiosys)

Hydra 1K (InSilixa)

EasyNAT TB (Ustar)

BreathLink (Menssana)

Prototype breathanalyzer (Next Dimensions)

TB Breathalyser (Rapid Biosensor Systems)

Aeonose (The eNose Company)

Breath analysis instrument (Metabolomx)

TBDx (Applied Visual Sciences)

Fluorescent microscopy (ID-FISH Tech.)

Automatic TB Screener (Fluorobot)

Genedrive MTB (Epistem)

Truelab/Truenat MTB (Molbio)

Giant African Pouch Rats (Apopo)

Microimager (BD)

CAD4TB (Delft Imaging Systems)

LAM in sputum (Standard Diagnostics)

Multiplex antibody array (mBio)

Alere Determine TB-LAM in urine (Alere)

-lactamase reporter (Global BioDiagnostics)

Molecular Detection/DST

Molecular Detection/DST

Culture-based technologies

Volatile organic compounds

Automated Microscopy & Imaging

Antigen & Antibody detection

Enzymatic detection/DST

Low

complexity

assays

High

complexity

assays

Moderate

complexity

assays

TB LAMP (Eiken)

DNA - the only solid biomarker for TB diagnosis

High

complexity

assays

Moderate

complexity

assays

WHO-endorsed

Limited commercial

availability Expected completion of development

2015 2016 2017+

Hain GenoType

MTBDRplus

Cepheid Xpert® MTB/RIF

Abbott TBMDx

Hain GenoType MTBDRsl

Zeesan MeltPro® Roche

Cobas

Nipro LiPA PZA &

MDR

YD REBA MTB-XDR REBA MTB-Rifa

Hain LATE PCR Lights on /Lights

off MTB-PZA

CapitalBio MTB-MDR

Illumina

Next-

Generation

Sequencing

iCubate

Eiken TBLAMP™

Veredus Laboratories VereMTB™

NanoBioSys LabChip G2-3

Cepheid Xpert® Ultra Xtend-XDR

Northwestern GHT/Quidel

Enigma ML®

MDR TB

Ustar MTB

Akkoni MDR-TB

Alere™ Q

MolBio Truelab/Truenat

Epistem Genedrive®

KGI TBDx System

STAT-Diagnostica DiagCORE

InSilixa HYDRA

QuantuMDx Q-POC™

Wave80 EOSCAPE

BD BD Max

27 Source: TB Alliance

• Arsenal of drugs developed mostly in 1960s Old

• TB treatment today takes 6-30 months. Long

• Many pills must be taken daily; Drug-resistant treatment includes daily injections Complex

• For both health systems and patients. DR-TB, comprising 2.2% of the case burden in South Africa, consumed 32% of the national TB budget of US $218 million

Expensive

• Long & complex; breeds resistance & default; incompatible with some HIV treatments; MDR-TB treatment often fails and toxic Inadequate

Limitations of Current Treatment

TB Vaccines: A Decade+ of Progress

• 2000: no new TB vaccine candidates

• 2002: 1st clinical trial of TB vaccine candidate

• 2014:

Source: Aeras