1. 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 Lee DNDi mlallemant@dndi.org

2. MalariaLeishmaniasis Sleeping Sickness (HAT) Chagas Disease Filaria Drugs for Neglected Diseases Initiative 10 years Patient focused Research & Development

3.  Easy to Use  Affordable  Field-Adapted  Non-Patented Six New Treatments Developed and Distributed

4. 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

5. MalariaLeishmaniasis 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

6. Suboptimal Nevirapine (NVP) vs. impossible lopinavir (LPV/r) NVP/2NRTIs LPV/r + 2NRTIs FDCs available Baby/junior dosing Scored tablets Crushed/dispersed Easy dosing Liquid only Horrible taste Neurotoxic excipients 42% ethanol 15% propylene glycol Needs cold chain Heavy to carry and hide Difficult dosing RTV super-boosting for TB/HIV But NVP inferior efficacy High viral load Resistant viruses

7. 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 Product The 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

8. 4-in-1 initial questions R&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

9. SYRUPS TODAY CHAPAS-2 LPV/r sprinkles Registration of LPV/r sprinkles Dual NRTIs dispersible tablets LPV/r +2NRTIs granules clinical batch FINAL 4-in-1

10. 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 1 st line2 nd line 3 rd 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 on RAL 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/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/r ABC or TDF/3TC/LPV/r AZT/3TC/LPV/r 

11. 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

12. Prioritized paediatric formulations PADO/WHO missing formulations Medium 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

13. 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

14. Dakar PADO-Industry Roundtable But development of the needed formulation will not happen by itself Each formulation poses unique challenges: Intellectual property Pharmacokinetics: absorption & metabolism Pharmaceutical and clinical development: taste, stability Regulatory requirement Industrial scale-up and Access

15. 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.

16. 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

17. PHTI: A coalition to deliver the needed formulations Optimized first-line regimen for children DNDi/Cipla Develop 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 Prequalification Inform 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

18. PHTI Strategy Group ) Product Specific Team Eg. ABC/3TC/EFV Experts Originator & Generic pharmaceutical companies 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 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 Product Specific Team …… Experts Originator & Generic pharmaceutical companies Product Specific Team …… Experts Originator & Generic pharmaceutical companies Product Specific Team …… Experts Originator & Generic pharmaceutical companies

19. Thank you very much for your attention

20. 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