new regimen for treat tb

5/28/2018 New regimen for treat TB

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Director, Market Access, TB Alliance

William Wells

Alignment of new TBdrug regimens and drugsusceptibility testing: a

framework for action

March 25, 2013


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The TB drug development pipeline

Resistance and DST algorithms

Turning theory into diagnostic development

Outline

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3/18

3

No new drugs for TB in more than 40 years

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 con-infection

Drug-druginteractionswith ARVs

Co-

administrationwith ARVs

Latent TBInfection

9 months ofisoniazid

Shorter, more

easily toleratedtherapy

Children

Formulationsnot adequately

dosed

Regimens andformulationswith correct

dose

Current Therapy and Unmet Needs

Current

Therapy

Unm

et

Nee

ds


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5/18

2013+: Bedaquiline (TMC-207; Janssen/Tibotec) and delamanid

(OPC-67683; Otsuka) for MDR-TB Based on Phase II results: adding new drug for 6 months on top of existing

MDR-TB regimen

Phase III trial will take several years

2015: Dispersible first-line (HRZ) FDCs for pediatric use

2015: REMoxTB regimens (moxifloxacin) for drug-sensitive TB

2018+: PaMZ for drug-sensitive TB AND some MDR-TB

??: Universal first line regimen with at least 3 new chemical entities(e.g., bedaquiline, delamanid or PA-824, sutezolid, and others)

Timeline for country availability of new TBdrugs and regimens

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6/18

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Randomized, Double-blind; Non-inferiority

Phase 3 REMox TB Trial Design

1 2 3 4 5 6Treatment Duration (months)

HRHRZE630 participantsStandard Regimen

ContinuationIntensive

Placebos

HRZM HRM

Placebos

630 participants

Moxifloxacin

for

Ethambutol

MRZE MR

Placebos

630 participants

Moxifloxacin

for

Isoniazid

Al l par t ic ipants fo l lowed for 12 months post- t reatment

H = isoniazid; M = moxifloxacin; R = rifampin; Z = pyrazinamide; E = ethambutol

1931 patients enrol led in Ch ina, Ind ia, Kenya, Malaysia, Mexic o, South

A fric a, Tanzania, Thailand , Zamb ia


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Treatment outcome benefits Shorter regimens may increase adherence and yield higher effective cure rates

and less emergence of MDR-TB

Less resistance to drugs in regimen (e.g. isoniazid vs moxifloxacin)

Health Systems benefits Reduced cost in healthcare utilization; patient cohort size reduced by one third

Patient benefits Reduced out of pocket costs (fewer visits)

Less time exposed to side effects

PaMZ: similar benefits + one dose for all, no ARV-rif interaction, and

treats ~25% of MDR-TB

Shorten Treatment from 6 to 4 months

Benefits of REMox Regimen

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Clinical, Regulatoryand Market Accessactivities in brief

Timeline for REMox TB


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What is the background,population-basedresistance to drugs inthe combination?

Based on modeling, what individualdrug susceptibility testing (DST)

with what kind of sensitivity and specificitywill be needed?

What is the likely availability of those DST diagnostics? Developed

In field use

At national & district levels

Current DST is focused on the needs of the current regimenbut

what will be needed for the future?

What countries may need to know about drug resistance

Questions for Adoption

Confidential 9


10/18

Typically diagnosis in LMICs is with smear microscopy and no DST

Current treatment algorithm: many countries

HRZE

Xpert (R)

Rs Rr

Hain sl or cultureHRZE

MDR24

cure fail

Confidential 10


11/18

Undiagnosed R resistance, treated with HRZE: Effectively means treatment with HZE or worse. Weak regimen; high likelihood

of treatment failure and mortality for the individual, and of continuing

transmission of drug-resistant strain to the community

During this ineffective treatment, it is very likely that the individual acquires

further resistance (to H, Z and E)

Failure to implement DST is courting disaster not just for the

individual, but for the TB epidemic as a whole

Consequences of having no DST

Confidential 11


12/18

Especially in low income countries, complicated techniques such asculture are feasible only at a very few, centralized locations

Sample referral systems either do not exist or are slow; many

patients are lost to follow up

Mtb grows slowly. So fast DST is almost certainly molecular DST.

Challenges: mutations may be spread over a whole gene (pncAfor

Z resistance) or more than one gene (fluoroquinolone resistance);

this limits both sensitivity and specificity

Good DST = simple and fast DST

Confidential 12


13/18

Xpert uptake not just for DST ability, but often for TB detection

Many high burden countries have insufficient resources to do DST

on all suspects or patients

If resistance prevalence is low, false positives (and need for

confirmatory testing) would be high

Trade-off: DST increases knowledge of patients clinical status

But DST increases burden on health system and patient

If DST results in greater travel costs, multiple visits and diagnosticdelays, it will reduce patient retention and may result in worse

outcomes.

Its not that simple

Test everybody for everything?

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For M: Upfront DST may not be needed or advisable in sub-Saharan Africa, if they have M

resistance in new cases of ~1%

This may be a closer call in Asia, if they have higher prevalence of M resistance among

new cases.

For Z: Baseline resistance among new cases may be ~3% everywhere (i.e., somewhat higher

than for M). This, plus concern about exposing M to an inadequate regimen, may

increase pressure for upfront Z DST.

How low would Z resistance have to be in new cases (algorithm #2) or non-MDR-TB

cases (algorithm #3) for presumptive PaMZ treatment to be OK?

For both: Fast test = molecular test. Achieving a high PPV with a molecular test may be more

challenging for M and Z than it is currently for R (not all mutations known, or known to

be specific to resistant strains). If PPV is low, either reserve DST for high risk

subpopulation and/or need confirmatory testing of positives .

Conclusions on DST algorithms for PaMZ

Confidential 14


15/18

Specifications: which drugs;

surveillance, screening or stand-alone test;

what sensitivity and specificity required;

What decentralization required.

Market size/demand: What resistance prevalence is the cut-off for adoption; therefore which

countries adopt

Where the diagnostic is placed in algorithmstherefore what percentage of

TB suspects or patients get tested

What diagnostics developers need

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16/18

Prediction Predicting new regimen adoption is hard;

Predicting new DST adoption is hard;

Predicting new regimen + new DST adoption is much harder.

Chicken and egg Diagnostic companies only willing to develop new DST if new regimens are

adopted.

But adoption of new regimens relies on availability of new DST assays

Two-fold challenge in predicting demand

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Enabling science Define which mutations correlate with in vitro resistance andhave clinical impact

Establish a strain bank to use for testing of new assays

Surveillance Establish more baseline values for fluoroquinolone resistance among new patients, and

Z resistance among new and MDR-TB patients Modeling impact

Model trade-offs between speed, accuracy, price, and technical specs of DST assays

Model different DST algorithms (e.g., DST for all, DST for retreatment/failure cases only,

or use of novel regimens without DST). Above what threshold of resistance prevalence

would more widespread DST be advisable?

Assay development Finalize target product profiles, so developers have a clear pathway forwards

Use both existing platforms (e.g., FQr via Xpert) and new platforms

Co-development of drugs and diagnostics is the way forwards!

Pathway for action

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18/18

18

Thanks.to Peter Kim, Marco Schito, and all other

members of the Tuberculosis Diagnostics Research

Forum; and to you for listening.

new regimen for treat tb

Documents

regimens55282018 new

new drugs

existingmdrtb regimen

drugsensitive tb

remox tb5282018 new

zamb ia5282018 new regimen

line regimen

remox tb trial design1