New and improved LPV/r based formulations for infants and young children Marc Lallemant - IAS July 1 st 2013

MalariaLeishmaniasis Sleeping Sickness (HAT) Chagas Disease Paediatric HIV Helminth infections DNDi: R&D to Respond to the Needs of Patients Suffering from Neglected Diseases…

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

From NVP to LPV/r based first-lines! NVP based ART LPV/r + 2 NRTIs 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 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

Formulation Challenges of Lopinavir and Ritonavir High solubilityLow solubility High permeabilityZDV, FTC Low permeability3TC, ABC RTV, LPV LPV RTV

DNDi Initial Explorations  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) o Nano particles o Nano dispersions Encouraging PK in animals Poor taste; 5 years minimum time line (NCE)

The Concept of 4-in-1 Granules

The DNDi-Cipla partnership

% of patients with C min > 3mg/L WHO 2010 FDA WHO 2010 modified % of patients with C min > 1mg/L WHO 2010 FDA WHO 2010 modified Weight band Dosing accepted by WHO To be included in 2013 guidelines US and European paediatric ARV PK databases merge; Developmental PK modelling; Exposure simulations: New LPV/r dosing harmonizes WHO weight band table for LPV/r and accompanying NRTIs.

New dosage of 4-in-1 FDC included in WHO urgently needed fomulations

4-in-1 Granules Development Timeline LPV/R Assemble 4-in-1 Registration stability LPV/r granules vs. Liquid comparative bioavailability in healthy adult volunteers Clinical batch 4-in-1 Accelerated stability Bioequivalence in healthy adult volunteers (4-in-1) 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 Industrial scale up Cipla pharma DNDi Clinical

Superboosting PK Study in South Africa PK 6 months RIF based TB therapy PI based antiretroviral therapy 6 months RIF based TB therapy PI based antiretroviral therapy PK >= 1 month after RIF discontinuatio n >1 month after RIF initiation >= 1 month after RIF discontinuatio n 3 months after RIF discontinuatio n RIF based TB therapy initiated first Antiretrovira l therapy initiated first PK  Limited data on pharmacokinetics, safety and efficacy of superboosted LPV/r 1:1 in young children  More data is needed to support superboosting in children of various ages and clinical conditions using the new rifampicin doses.

RTV Booster Development Timeline Taste masked granules Registration stability RTV granules vs. Liquid comparative bioavailability in healthy adult volunteers Pivotal Bioequivalence HAV in healthy adult volunteers Superboosting PK, safety, efficacy of newly developed RTV Dossier submission to FDA Industrial scale up 2x2 PK Superboosting PK, safety, efficacy of RTV liquid formulation Cipla pharma DNDi Clinical

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

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

Brooklyn Chest Hospital – Cape Town Thank you 18 Photo: Anne Detjen The DNDi pediatric HIV team Janice Lee Gwenaelle Carn Jean René Kiechel Marc Lallemant DNDi teams 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