hope in the pipeline: new drugs

8/14/2019 Hope in the Pipeline: New Drugs

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Daniel Everitt, MD

Putting science to work forbetter, faster TB cures

Realizing Hope:New TB Cures inDevelopment

IUATLD October 31, 2013


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TB Alliance is a not-for-profit organization dedicated to the discoveryand development of better, faster tuberculosis drugs that are

available to those who need them.


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3Overview: TB Alliance

TB Alliance Vision

Shorter, simpler, HIV-compatible TB regimens that areadoptable, available, and affordable

Current Treatment

6-30

Months

New Treatments inDevelopment

2-4

Months

Our Vision

7-10

Days


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[Enter Presentation Title in Insert > Header & Footer]

Adoptable into treatment policies and drug registries

Available

in public and private sectors

Affordable cost effective for patients, countries, and donors

Our commitment to patients, providers, and programsensures our efforts benefit TB patients around the world.TB Alliance products will be:

AAA Mandate: Our Access Strategy


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No new TB drugs developed in nearly 50 yearsOld

TB treatment today takes 6-30 monthsLong

Many pills must be taken daily; Drug-resistant treatmentincludes daily injectionsComplex

Drug-resistant TB treatment can cost > $10,000Expensive

Long duration makes adherence difficult, breedsresistance; MDR-TB treatment often failsInadequate

Treatments interact with commonly used ARVs, makingtreatment of co-infected patients challengingHIV-Incompatible

Current TB therapy


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6TB Alliance Overview

TB Alliance programs seek to help all TB patient populations

DrugSensitive TB

4 drugs takenfor 6 or more

months

Shorter,

simplertherapy

M(XDR)-TB

Injections anddrugs taken for

more than 2years, poorly

tolerated

More effective,shorter, safer

simplerregimens

TB/HIV co-infection

Drug-druginteractionswith ARVs

Co-

administrationwith ARVs

Latent TBInfection

9 months ofisoniazid

Shorter, more

easily toleratedtherapy

Pediatric TB

No adequatedosing

formulations

Adequatedosing

regimens andformulations

Current Therapy and Unmet Needs

C u r r e n t

T h e r a p y

U n m

e t

N e e

d s


7/307Overview: TB Alliance

Example of a typical MDR-TB regimen

6 drugs, including 1 injection, for 6-9 months aim to directly observe 6 days/week

4 drugs given in the 18-month continuationphase (or longer)

If HIV+, the patient may need to take 3additional ARVs

Less than 10% of MDR-TB patients receiveproper care; of those, 1 in 3 still wont becured

Complex, toxic, and expensiveIneffective MDR-TB Treatment


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50 years with no new TB drugs until

First wave of TB drugs have obtained or arenearing regulatory approval

Bedaquiline

Delamanid

Important first step: Drugs show potentialto improve individual treatment, but moreneeds to be done to broaden those who

can access and benefit from treatment Promising pipeline with many key

advancements coming to fruition in 2014

Promising first stepsEvolving Landscape


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2013 Q3Discovery

LEADIDENTIFICATION

LEADOPTIMIZATION

PHASE 1

Late Development

PHASE 3PHASE 2APRECLINICAL

DEVELOPMENTPHASE 2B

Moxifloxacin/Isoniazid/ Rifampin/Pyrazinamide

Bayer, MRC, UCL

Moxifloxacin/Rifampin/Pyrazinamide/Ethambutol

Bayer, MRC, UCL

REMox-TBATP SynthesisInhibitorsCalibr

Energy MetabolismInhibitors

AZ/University ofPenn

Whole-Cell Hit-to-Lead Program

AZ

Whole-Cell Hit-to-Lead ProgramSanofi

Whole-Cell Hit-to-Lead ProgramNITD

Whole-Cell Hit-to-

Lead ProgramGSK

RNA PolymeraseInhibitorsRutgers University

MycobacterialGyrase InhibitorsGSK

PyrazinamideAnalogsYonsei University

Diarylquinolines Janssen/Universityof Auckland/UIC

IndazolesGSK

DprE InhibitorsCalibr

CyclopeptidesSanofi

MacrolidesSanofi

Novel StructuralSeriesNITD

UreasSanofi

TBA-354

Preclinical TBRegimenDevelopment

JHU

TBI-166IMM

PA-824/Moxifloxacin/Pyrazinamide(PaMZ)

NC-002

Bedaquiline/Clofazimine/Pyrazinamide

PA-824/Bedaquiline/Clofazimine/Pyrazinamide

PA-824/Bedaquiline/Clofazimine

PA-824/Bedaquiline/Pyrazinamide

NC-003

AstraZeneca (AZ)Bayer Healthcare AG (Bayer)Beijing Tuberculosis and Thoracic TumorResearch InstituteCalibrGlaxoSmithKline (GSK)Institute of Materia Medica (IMM)Janssen (Johnson & Johnson)Johns Hopkins University (JHU)

Medical Research Council (MRC)Novartis Institute for Tropical Diseases (NITD)

New York Medical CollegeRutgers UniversitySanofiStellenbosch UniversityUniversity College London (UCL)University of AucklandUniversity of Illinois at Chicago (UIC)University of Pennsylvania School ofMedicine

Yonsei University

TB Alliance R&D Partners:

Early DevelopmentPHASE 4

OptimizedPediatric

Formulations

Isoniazid/ Rifampin/Pyrazinamide/Ethambutol


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REMox TB trial Successful results would enable registration of 4-month moxifloxacin-containing regimen for drug-sensitive TB; firsttreatment shortening in nearly 50 years

NC-002 trial (PaMZ) Results of first trial to treat TB and some MDR-TB patients with in less time. Successful results would lead to Phase3 registration trial of PaMZ regimen

NC-003 trial Testing of addition combination regimens; potential tofurther shorten treatment and expand the impact of bedaquiline.

Results of 3 landmark trials are expected in 2014Strong Momentum in TB Drug Research


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Trial has been completed results are expected in 2014

Evaluating if a 4-month moxifloxacin-basedregimen can perform as well as the current6-month standard of care in drug-sensitiveTB patients

Potential to be the first new drug to treatdrug-sensitive TB in nearly 50 years

shorten treatment by 33% higher cure rates & less emergence of MDR-TB reduce cost and burden to healthcare systems

and patients Conducted at 48 sites in 9 countries, built

tremendous clinical, community capacity

Results expected in 2014REMox TB: A Global Phase 3 Trial


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Testing pipeline of TB drugs together can reduce time needed todevelop novel regimens from decades to years

Innovative Paradigm: Drugs to Regimens


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Shorter, simpler, and safer treatment withbetter adherence

Ability to treat both drug-sensitive anddrug-resistant disease with same regimen

Dramatically cheaper MDR-TB treatment,making global scale-up feasible

Compatible with HIV/AIDS medications

Reduced burden to health care systems Improved outcomes & patient experiences

Benefits of new drug combinationsWhy Novel Regimens?


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A Brief Primer on

TB Drug RegimenDevelopmentTrials



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Classic Phases of Drug Development

(Data based on: Brown, D.; Superti-Furga, G . Drug Discovery Today 2003, 8 , 1067-1077)

Discovery Preclinical Clinical

50 31 19 12 7 4 2ONE

approveddrug

5 Years 1.5 Years 6 Years

N u m

b e r o

f P r o

j e c t s

Global TB Drug Pipeline(10) (7) (7) (2) (6) (2)

Development of a multi-drug regimen could take decades


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The Community of Kibera, Kenya TB is a Disease of Poverty

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51 year old Kenyan man with a cough, weight loss,confusion; wife died 3 years earlier with tuberculosis

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Trial Medication Card

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Tuberculosis (Acid Fast Bacillus AFB) from aSputum Smear Under the Microscope

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TB Colony Forming Units CFUs Now Countable from a Diluted Sputum Specimen

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Overview: TB Alliance 22

A two week trial revealed the regimen: kills 99% of TB bacteria in 2 weeks compares favorably to the standard of care validates paradigm of novel regimen development

PaMZ is now being studied in an 8-week trial. Thisis the first trial to treat drug-sensitive and somedrug-resistant patients with the same regimen.

PA-824+Moxifloxacin +Pyrazinimide

(PaMZ)

NC-001 and NC-002 trialsNovel Regimens in Development

Benefits could include:


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Pa-M-Z killed moreTB bacteria in thefirst 2 weeks thanany other regimen

or combo tested Adds support to

body of evidencethat Pa-M-Z may be

more effective thanexisting treatments

The Regimen Pa-M-Z in NC-001


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Overview: TB Alliance 24

NC-003 is a multiple-arm study testingadditional new TB regimens with thepotential to even further shorten treatmentfor TB and MDR-TB

2-week EBA trial Trial includes multiple combinations consisting ofbedaquiline, PA-824, pyrazinamide, andclofazamine

Potential to expand the number of people thatcan benefit from bedaquiline

NC-003:Trial testing new

regimens

Next generation regimens in the clinicNC-003 trial


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Pediatric TB


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NO safe, appropriately-dosed formulationsof first-line TB drugs for children

Adult treatments are cut or crushed toachieve desired dose

Unpalatable for small taste buds

Difficult to dose correctly and consistently,encourages development of drug-resistant TB

Results in improper or incomplete treatment,threatens child survival

No existing dosing recommendations forbabies under 5kg

Gap of 7 years or more projected betweenlaunch of adult treatments and availabilityof child formulations

Todays Treatment Situation

Credit: Desmond Tutu TB Centre, Department ofPaediatrics and Child Health, Stellenbosch University

Overview: TB Alliance


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Understand and quantify theglobal TB pediatric burden

Collaborate with manufacturersto develop correctly dosed, and

formulated, affordable, quality-assured pediatric TB medicines

Partner with regulators,countries, and donors to clarify

pathways to speed access Use knowledge to shorten the

long gap between the launch ofadult and pediatric products

Requires multi-faceted approachSpeeding treatments to end pediatric TB

MarketUnderstanding

Clinical and

RegulatoryUnderstanding

EngagingManufacturers

Policy andUptake byCountries

EngagingCountries and

Donors

InformationExchange

Overview: TB Alliance


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Q1 2014:Global TBmarketestimated

Q1 2016:PmRN endorsespaediatric TBregulatorypathway

Q1 2016:WHO PQapproval

2016: Finalproductsavailable inthe market

2013:ProjectLaunch

Q1 2015:GlobalStakeholdersMeeting

Q2 2015:

Dosageguidelines forchildren >5kgsubmitted toWHO PQ

Q4 2013:MOU signed withfirst manufacturer

Timeline for FDC of First-Line Pediatric Treatment:

Q1 2014:Webportallaunched



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Engaging communities in TB research: concepts, value, & practice Thursday, 31 October 2013, 09:00 - 17:00, Room 252B

Inclusion of children in national TB prevalence surveys Thursday, 31 October 2013, 13:30 - 17:00 Room 251

FIND/TB Alliance: Alignment of DST and drug regimens Thursday, 31 November 2013 13:00-17:00 Room: Hall Havane, level 3 MDR-TB in children and adolescent TB issues

Friday, 01 November 2013, 14:30 - 16:30 Room Amphithtre Bleu

Recent progress in TB clinical trials Saturday, 02 November 2013, 08:00 - 10:00 Room Amphithtre Bleu

UNITAID/TB Alliance: Catalyzing the pediatric TB drug market Saturday, 02 November 2013, 14:30 - 16:30Room 243

Updates on clinical research, community engagement, and pediatricsTB Alliance Symposia at IUATLD 44


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Thank you!

hope in the pipeline: new drugs

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