missing formulations for paediatric hiv treatment and the dakar call for action improving access to...
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Missing formulations for paediatric HIV treatment and the Dakar Call for Action
Improving Access to Optimized Treatment for Children Living with HIV
Melbourne, 22 July 2014
Marc Lallemant & Janice LeeDNDi
Malaria Leishmaniasis
Sleeping Sickness (HAT) Chagas Disease Filaria
Drugs for Neglected Diseases Initiative10 years Patient focused Research &
Development
Easy to Use Affordable Field-Adapted Non-Patented
Six New Treatments Developed and Distributed
WHO guidelines: from 2010 to 2013
• CHER trial => Diagnose early and start ARV immediately• P1066 trial => In younger children LPV/r is more potent than NVP
WHO 2010 guidelines
WHO 2010 guidelines
Malaria Leishmaniasis
Sleeping Sickness (HAT) Chagas Disease
Paediatric HIV
Filaria
In 2010, DNDi called upon by partners to work on developing child friendly
LPV/r based formulations
Suboptimal Nevirapine (NVP) vs. impossible lopinavir (LPV/r)
NVP/2NRTIs LPV/r + 2NRTIs
FDCs availableBaby/junior dosingScored tabletsCrushed/dispersedEasy dosing
Liquid onlyHorrible tasteNeurotoxic excipients
• 42% ethanol• 15% propylene glycol
Needs cold chainHeavy to carry and hideDifficult dosingRTV super-boosting for TB/HIV
But NVP inferior efficacyHigh viral loadResistant viruses
AZT or ABC
LPV/r3TC
RTV
Modular format allows flexibility to replace drug in the combination
To be added during HIV/TB therapy
4-in-1 granules in Fixed-Dose Combinations
DNDi-Cipla Target ProductThe Right Dose, The Right Taste
4 products in 1: granules (FDC)
Simply open and use with water, milk, food
No taste
No cold chain
Suitable for infants (< 2 mos-3 yrs)
TB-treatment manageable
Affordable
4-in-1 initial questionsR&D questions
– Are the four molecules compatible?– What amount of each drug needed per unit dose
to cover all weight bands?– How to taste mask without losing bioavailability?– How likely is the new formulation bioequivalent to
originator products?– What paediatric clinical data will be necessary for
registration?
IP and Market shaping questions– How to deal with IP issues, for research and for
market? – What needs to be done to assist in country
registration?– How to facilitate adoption in national guidelines
and procurement by national treatment programs
WHO Generic
tool
PK modelling
for validation
Formulation
development
Clinical data
SRA Approval
2013 2014 2015
SYRUPS TODAY
CHAPAS-2LPV/r
sprinkles
Registration of LPV/r sprinkles
Dual NRTIs dispersible
tablets
LPV/r +2NRTIs granules clinical batch FINAL 4-in-1
Many other formulations are needed to facilitate field implementation of the WHO guidelines
Pediatric Antiretroviral Drug Optimization group was task to identify within pipeline, medium- and long-term priorities for the development of the paediatric drugs and formulations
WHO 2013 Guidelines & Pediatric Antiretroviral Drug Optimization (PADO) conference
1st line 2nd line 3rd line ?< 3 Yrs ABC or AZT/3TC/LPV/r (P)
ABC or AZT/3TC/NVP (A)
No change or AZT or ABC /3TC/NVP
AZT or TDF or ABC/3TC/LPV/r Regimens
based onRAL and/or ETV and/or
DRV/r
> 3 Yrs < 10 Yrs
ABC/3TC/EFV (P)ABC or TDF/3TC+NVP (A)
TDF/3TC/EFV (A)AZT/3TC/NVP or +EFV (A)
AZT/3TC/LPV/rAZT/3TC/LPV/rAZT/3TC/LPV/r
ABC or TDF/3TC/LPV/r
> 10 Yrs TDF/3TC/EFV (P)AZT/3TC/NVP or +EFV (A)
TDF/3TC/NVP (A)
AZT/3TC/LPV/rABC or TDF/3TC/LPV/r
AZT/3TC/LPV/r
Critical factors for the development of paediatric ARV formulations
• Differential maturation of absorption and metabolic pathways during the first years of life
• Drug toxicity and tolerability of lifelong treatments• Need for drug optimization to give priority to simplicity to
enable task shifting and integration of services while ensuring– efficacy, – tolerability, – robustness, – cost– effectiveness, – no overlapping resistance in treatment sequencing and– convenience for both children and caregivers
Prioritized paediatric formulationsPADO/WHO missing
formulationsMedium and long-term priorities for children• ABC/3TC/EFV • (AZT or ABC)/3TC/LPV/r • DRV/r • RTV pellets • RAL/3TC /(AZT or ABC)
New drugs to be given priority • DTG based FDCs• TAF based FDCs• PI/COBI
Other missing formulations in WHO Treatment guidelines
• TDF/3TC/EFV• TDF/3TC• ATV/r
Dakar PADO-Industry Roundtable
There has been a very significant improvement in paediatric ARV formulations over the past decade
• generic companies have developed many solid paediatric Fixed Dose Combinations
• Originator companies now develop solid formulations for young children e.g. RAL, RTV, ATV, DTG, EVG, ETV
• Originator companies are increasingly willing to share licenses for paediatric formulations
Dakar PADO-Industry Roundtable
But development of the needed formulation will not happen by itselfEach formulation poses unique challenges:
• Intellectual property• Pharmacokinetics: absorption &
metabolism• Pharmaceutical and clinical
development: taste, stability• Regulatory requirement• Industrial scale-up and Access
PADO / Industry Joint Call to Action• Donors: continue to support R&D, treatment, and care of
this specific neglected population, from neonates to adolescents with HIV.
• All paediatric HIV stakeholders: prioritize and streamline paediatric development plans
• Industry: collaborate with each other, and explore ways to share patents, which will enable the development of FDCs with drugs from different companies.
PADO / Industry Joint Call to Action• National regulatory bodies: fast-track and accelerate
approvals by engaging in harmonized regulatory mechanisms at regional level
• Researchers, industry, governments, and civil society: collaborate in accelerating the progress in bringing new drugs and formulations to children infected with HIV
• Decision makers (Ministries of Health, financing institutions, and development partners): optimize paediatric ARVs aligned with WHO recommendations and thereby limit market fragmentation
PHTI: A coalition to deliver the needed formulations
Optimized first-line
regimen for children
DNDi/CiplaDevelop and
validate infant-friendly
formulation of ABC (or AZT)/3TC/
LPV/r
Medicines Patent Pool
Address patent-related issues
through voluntary licenses with ViiV
and, in discussions,
AbbVie
WHO PrequalificationInform developers of expected needs
for review; prioritize review
as product becomes available
CHAI and Paediatric ARV Procurement
Working Group Market shaping and preparation
UNITAID (co)funding
PHTI Strategy Group
)
Product Specific Team
Eg. ABC/3TC/EFV
Experts Originator &
Generic pharmaceutical
companies
Stakeholders
PHTI: A focused and light structure to help accelerate Development, Production and Procurement
WHO Paediatric Antiretroviral Working Group & PADO
Product Specific Team
Eg. DRV/r
Experts Originator &
Generic pharmaceutical
companies
Product Specific Team
……
Experts Originator &
Generic pharmaceutical
companies
Product Specific Team
……
Experts Originator &
Generic pharmaceutical
companies
Product Specific Team
……
Experts Originator &
Generic pharmaceutical
companies
Thank you very much
for your attention
PHTI: An integrated approach
Product Specific Team• Composition: experts,
pharmaceutical companies, PHTI coordinator if required, chair person
• Identify work needed to fill gap of formulation development
• Develop work plans, timelines, budget
• Perform the work from formulation to access
Stakeholders
WHO, PADO
Reporting / feedback twice a year
Strategic and administrative support
Reporting and feedback quarterly
Alignment with WHO/PADO priorities