Marc Lallemant – 25-11-2013

1. Marché et Innovation Thérapeutique pour l’Enfant: Exemple du programme de Recherche et Développement VIH pédiatrique de DNDi Marc Lallemant – 25-11-2013

2. Despite of PMTCT, a stable number of children in need of therapy

3. 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

4. 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

5. 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)

6. 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)

7. 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

8. 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

9. 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)

10. 6 New Treatments Developed Since 2007 • Easy to Use  Affordable  Field-Adapted  Non-Patented

11. 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

12. 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

13. Formulation Challenges of Lopinavir and Ritonavir LPV RTV

14. 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)

15. The Concept of 4-in-1 Granules

16. The DNDi-Cipla partnership

17. 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

18. 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

19. 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

20. 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

21. 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

22. Registration – Feasibility - Access Implementation studies to: • Assess • Field effectiveness • Safety • Acceptability • Instructions for use • Facilitate in country registration • Facilitate program adoption

23. 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

24. 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