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Marché et Innovation Thérapeutique pour l’Enfant: Exemple du programme de Recherche et Développement VIH pédiatrique de DNDi. Marc Lallemant – 25-11-2013. Despite of PMTCT, a stable number of children in need of therapy. Clinton Foundation 2012-2017 forecast.

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marc lallemant 25 11 2013

Marché et Innovation Thérapeutique pour l’Enfant:

Exemple du programme de Recherche et Développement VIH pédiatrique de DNDi

Marc Lallemant – 25-11-2013

clinton foundation 2012 2017 forecast
Clinton Foundation 2012-2017 forecast

Pediatric patient regimens (1L and 2L) in GA countries

Still increasing use of AZT and ABC

d4T-based regimen share below 30% for the first time in 2012

Note: Forecast scenario assumes continued WHO 2010 guidelines implementation and pro-active switching

paediatric hiv so small a market
PaediatricHIV: So smalla market
  • FDA/EMA incentiveskicking in
  • No incentive for generic R&D
  • High risk of market fragmentation
    • Too many formulations of the same drugs
    • Need for consolidated orders to reach manufacturer batch size
  • Medecine Patent Pool
  • FDA/WHO Registration ≠ Access
    • In country regulatory approval
    • Country program adoption (national guidelines)
    • Affordability
    • Efficient supply chain
general considerations for drug dosage forms appropriate for children
General considerations for drug dosage forms appropriate for children

sufficient bioavailability taking into account children's particularities

  • Reaching efficacy target (may undergo a maturation process; for antiretrovirals is assumed to be the same as adults)
  • Below toxicity target (not necessarily well known)

nontoxic excipients for age group

  • Limit of inactive ingredients per the dosing regimen

palatable or acceptable organoleptic properties

  • Taste/Sweetness preference differ around the world

acceptable dose uniformity

Breitkreutz, J. Boos, Exp. Opin. Drug Deliv. 4: 37-45 (2007)

general considerations for drug dosage forms appropriate for children1
General considerations for drug dosage forms appropriate for children

easy and safe to administer

  • Flexible dosage: dispersible or chewabletablets, sprinkles, granules
  • Minimum dosing frequency

socio-culturally acceptable (stigmatization)

precise and clear product information

appropriate for caregivers / setting

  • Stability in Zone IV climatic conditions (30°C, 65 or 70% RH)
  • No clean water required for dispensing medication
  • Heat stable – no refrigeration required

Breitkreutz, J. Boos, Exp. Opin. Drug Deliv. 4: 37-45 (2007)

pediatric antiretroviral drug development and optimization
PediatricAntiretroviral Drug Development and Optimization
  • New drugs (substitution to improve toxicity or increase efficacy)
  • Reformulation (improve drug bioavailability; stability; acceptability; extended release formulations)
  • Co-formulation (FDCs or co-blister pack)
  • Dose adjustment/reduction (reduce toxicity & pill burden/size)
  • New strategies (eg: induction-maintenance; intensification)
    • EFV based pediatric FDCs?
  • Drug manufacturing process (improve API route synthesis and reduce cost)
  • WHO Treatment 2.0
dndi a need driven innovative r d model for neglected patients
DNDi: A needdriveninnovative R&D model for neglected patients
  • Created in 2003 by MSF
  • Has established in 10 years a very robust pipeline
  • Uses and renforce the capacity of endemic countries
  • Importance given to public information and promotion of public leadership for neglected diseases R&D

Geneva Headquarters

Founding Partners

  • Malaysian MOH
  • Oswaldo Cruz Foundation, Brazil
  • Médecins Sans Frontières
  • Institut Pasteur France
  • TDR (permanent observer)
  • Indian Council for Medical Research (ICMR)
  • Kenya Medical Research Institute (KEMRI)

Japan

USA

India

DRC

Malaysia

Kenya

Brazil

7 worldwide offices

slide9

DNDi: R&D to Respond to the Needs of Patients Suffering from Neglected Diseases…

Malaria

Leishmaniasis

Paediatric HIV

Chagas Disease

Helminth infections

Sleeping Sickness (HAT)

6 new treatments developed since 2007
6 New Treatments Developed Since 2007
  • Easy to Use  Affordable  Field-Adapted  Non-Patented
from nvp to lpv r based first lines
From NVP to LPV/r based first-lines!

LPV/r + 2 NRTIs

NVP based ART

FDCs available

Baby and junior dosing

Scored tablets

Can be crushed/dispersed

Easy dosing

  • Liquid only currently
  • Bitter taste
  • Neurotoxic excipients
    • 42% ethanol
    • 15% propylene glycol
  • Needs cold chain
  • Heavy to carry, hard to hide
  • Difficult dosing
  • Need for RTV super-boosting in TB/HIV co-infection
dndi paediatric hiv program objectives
DNDi Paediatric HIV Program Objectives

Develop two solid first-line LPV/r-based fixed-dose combinations (FDC) with two NRTIs, 3TC plus ABC or AZT.

  • Well taste masked
  • Heat-stable without refrigeration, long shelf life
  • single strength for dosing throughout weight bands

Develop complementary granule of RTV to be added to the 4-in-1 LPV/r based FDCs during HIV and tuberculosis treatment

  • 4:1 1:1 LPV/RTV ratio when on RIF
dndi initial e xplorations
DNDi Initial Explorations
  • Nano particles
  • Nano dispersions
    • Encouraging PK in animals
    • Poor taste; 5 years minimum time line (NCE)

Original LPV and RTV formulations were alcohol based oral solutions and soft gel capsules (Abbott)

Replaced for adults and older children with LPV/r tablets (Abbott)

  • Soluble polymer (copovidone)
  • Tablets cannot be used in young children as crushed they loose up to 50% bioavailability

Alternative options

  • Prodrugs (eg. RTV)
ratios strengths weight bands
Ratios, strengths, weight bands
  • ZDV:glucuronyltransferase+ renal excretion
  • 3TC: 5% transsulfoxide; unchanged renal elimination
  • ABC: alcohol dehydrogenase and glucuronyltransferase
  • LPV: Oxidation by CYP3A enzymes

WHO weight bands dosing is a compromise using existing formulations

Assembling drugs with different metabolic pathways and maturation kinetics

new dosage of 4 in 1 fdc included in who urgently needed fomulations
New dosage of 4-in-1 FDC included in WHO urgentlyneededfomulations

% of patients withCmin > 1mg/L

Population pharmacokinetic modeling of 25 LPV/r or NRTI datasets from Europe and the US and simulation of doses

WHO 2010

FDA

WHO 2010 modified

% of patients with Cmin > 3mg/L

WHO 2010

FDA

WHO 2010 modified

slide19

4-in-1 Development Timeline

2013

2014

2015

Assemble 4-in-1

LPV/r granules vs. Liquid bioavailability study in healthy adult volunteers

Clinical batch 4-in-1

Dogs study

Ciplapharma

Accelerated stability studies

Pivotal BioequivalenceHNV (4-in-1)

DNDi

Clinical

Paediatric phase 2 LPV/r granules vs. liquid cross-over PK

Phase 2/3 paediatric pop PK, safety, efficacy study (4-in-1)

Dossier submission to FDA

Implementation study

superboosting trial open and enrolling
Superboosting trial open and enrolling
  • Limited data on pharmacokinetics, safety and efficacy of superboosted LPV/r 1:1 in young children; More data needed to support superboosting in children of various ages and clinical conditions using the new rifampicin doses.

PK

PK

PK

RIF based TB therapy initiated first

>1 month after RIF initiation

>= 1 month

after RIF discontinuation

6 months RIF based TB therapy

PI based antiretroviral therapy

3 months

after RIF discontinuation

Antiretroviral therapy initiated first

6 months RIF based TB therapy

PI based antiretroviral therapy

>= 1 month

after RIF discontinuation

>1 month after RIF initiation

PK

PK

PK

rtv booster development timeline
RTV Booster Development Timeline

2013

2014

2015

Superboosting PK, safety, efficacy of RTV liquid formulation

Ciplapharma

RTV granules

Dogs study

DNDi

Clinical

Registration stability

RTV granules vs. Liquid comparative bioavailability in HNV

Pivotal Bioequivalence HNV study

Superboosting PK, safety, efficacy study

Dossier submission to FDA

registration feasibility access
Registration – Feasibility - Access

Implementation studies to:

  • Assess
    • Field effectiveness
    • Safety
    • Acceptability
    • Instructions for use
  • Facilitate in country registration
  • Facilitate program adoption
slide23

CHAPAS-2

LPV/r sprinkles

Dual NRTIs dispersible tablets

Registration of LPV/r sprinkles

SYRUPS TODAY

LPV/r +2NRTIs granules

clinical batch

FINAL 4-in-1

2012

2014

2013

brooklyn chest hospital cape town
Brooklyn Chest Hospital – Cape Town

Thank you

The DNDi pediatric HIV team

Janice Lee

GwenaelleCarn

Jean RenéKiechel

Marc Lallemant

DNDiteams in Geneva, New York, Nairobi

Penang, Tokyo, Delhi, Rio de Janeiro

Partners

Cipla ltd, MSF, MRC, International Pediatric HIV networks

UNITAID, AFD, MSF International & Norway

Photo: Anne Detjen