1. Optimizing the Paediatric ARV Pipeline Nandita Sugandhi Clinton Health Access Initiative &IATT CSWG ICASA 2015, Harare Zimbabwe November 30, 2015

2. Overview of the Paediatric Pipeline Does “optimization” = “harmonization” Prioritizing the paediatric ARV pipeline? Where are we with new future drugs and dosage forms What can we do now to optimize paediatric treatment

3. Wouldn’t it be simpler if we could harmonize paediatric ART with adult treatment? When formulations are different, benefits of harmonization are potentially limited Development of scored dispersible adults tablets would be great but not yet a reality

4. 94 adult patients All ages & weight bands One pill, once-a-day 6 paediatric patients Multiple drugs formulations and regimens Multiple ages and weight bands Pediatric ARV pipeline is small but complex.

5. PADO priorities ( P aediatric A RV D rug O ptimization) New formulations of existing drugs that already have registration for children or in advanced paediatric development Identifying priority regimens for optimal sequencing which include newer compounds for which paediatric development has not been completed

6. ABC/3TC/EFV STR for preferred paediatric 1 st line for children >3 years Final TPP: Dispersible, scored tablet, 150/75/150 Following recent confirmation of ALE dosage, generic manufacturers have started development

7. “4 in 1”= 2 NRTI’s + LPV/r LPV/r oral pellets tentatively approved by USFDA in 2015 but 4 in 1 still in development LIVING study- Field implementation using LPV/r pellets before availability of better-adapted 4-in-1 LPV/r based FDCs, in order to :  provide better treatments to infants today and promote in-country registration & adoption  provide supportive clinical data on the feasibility, effectiveness, safety, and PK of the new products in routine treatment settings The patients will switch to 4-in-1 LPV/r/AZT/3TC (40/10/30/15mg) or LPV/r/ABC/3TC (40/10/30/15mg) granules (heat stable) as soon as the products become available. A protocol amendment will be done at that time

8. Darunavir with Ritonavir boosting (DRV/r) Lifelong treatment requires consideration for treatment after failure on LPV/r DRV/r can be sequenced after both LPV/r and ATV/r failure Currently no paediatric co-formulation of DRV + RTV available Priority for development – Dosage form 120mg/20mg capsules for twice-daily dosing – Granules may also be feasible – Other potential technologies (freeze drying)

9. Raltegravir (RAL) Twice daily integrase inhibitor We have dosing and approval down to 4 weeks We have pediatric formulations (chewable tab) for >10kg but powder for suspension for <10kg Low genetic barrier as compare to DTG Currently limited availability Limited interest for adults Weight band (kg)RAL Dose using chewable tablet 3 to <625mg BID* 6 to <1050mg BID* 10 to < 1475mg BID (consistent with USPI) 14 to < 20100mg BID (consistent with USPI) 20 to < 25150mg BID (consistent with USPI) * Chewable tablets currently only approved for children ≥2 yrs and ≥10kg

10. Dolutegravir (DTG) Low dose/kg is good for infants and children High genetic barrier ideal for poorly adherent children and adolescents OD and good toxicity profile Currently approved in > 12 years P1093 dose-finding study is ongoing for children and young infants No paediatric FDC yet but planned for coformulation with abacavir and lamivudine

11. Tenofovir Alafenamide (TAF) Current alignment with adults on the NRTI backbone is only down to adolescents >35 kg due to concerns around TDF bone toxicity TAF has potential for reduced toxicity and wider use than TDF Currently investigated only in 6 years and older TAF full PIP has only been planned in co- formulationlack of single strength approval is a barrier to development of alternative promising formulations such as DTG/TAF/XTC

12. IATT Optimal and Limited-Use ARV Formularies The IATT Paediatric Optimal Formulary and Limited use lists support programs to select from a list of existing optimal paediatric ARV formulations Focusing on optimal products helps create a sustainable supply of paediatric ARV’s and provides incentives for suppliers to invest in new drugs The Formulary is meant to be revised regularly. The next revision is planned for 2016 Q1 2016

13. LPV/r oral pellet policy briefs LPV/r oral pellets tentatively approved by USFDA in 2015 LPV/r oral pellets are heat-stable and dosing has been established down to 3kg Field evaluation is ongoing to determine if very young infants are able to able the pellets LPV/r oral pellets may provide a better alternative to deliver the preferred 1 st line ART regimen for infants and young children <3 years. Guidance now available on administration of LPV/r oral pellets and supply planning for the introduction of LPV/r oral pellets

14. Conclusion The “optimal” paediatric dosage form doesn’t exist yet DTG/TAF/XTC is the promising regimen that would likely allow for full harmonization of 1st line regimens across age groups Paediatric Pipeline drugs and dosage forms need to be prioritized for development – ABC/3TC/EFV 150mg/75mg/150mg – 4 in 1 – DRV/r 120mg/20mg – Integrase Inhibitors – TAF Current optimization opportunities exist that pave the way for new paediatric ARV’s in the pipeline

15. Thank you! Acknowledgements: Martina Penazzato Elaine Abrams Marianne Gauval Marc Lallemant