Elaine Abrams and Carlo Giaquinto Acceleration part 1: Prioritization and clinical research of priority formulations Elaine Abrams and Carlo Giaquinto

Disclosure Relations that could be relevant for the meeting Company names Sponsorship or refund funds CG; ViiV healthcare, J&J, Gilead Payment or other financial remuneration CG: AB ViiV. EA: Viiv, Merck Shareholder rights N/A Other relations Reference: https://www.cgr.nl/CGR.nl/media/CGR.nl/Gedragscode/Format-of-disclosure-slide-for-speakers-at-refresher-training-meetings.pdf

Prioritization and optimal research are the critical initial steps for acceleration

Developing ARVs for children requires addressing unavoidable complexities HIV natural history is different Higher mortality and VL in younger children HIV affects neurodevelopment and growth Growth and puberty: dosing the same drug in a changing body and a changing brain Drug metabolism is different from adults and can heavily depend on genetic polymorphisms (i.e. EFV) Selection of drug resistance as a result of PMTCT exposure Key comorbidities that impact drug use, tolerability, and toxicity in SSA (TB, malaria, malnutrition, anemia, etc.) Palatability and ease of administration are critical to support adherence

Access to paediatric drugs takes too long… SRA approval Adults Children DELAY Tenofovir DF 2001 2010 9 years Atazanavir 2003 2014 11 years Darunavir 2006 2011 5 years Raltegravir 2007 2013 6 years Rilpivirine NA ? Elvitegravir 2012 Dolutegravir 2017 (partial) 4 years TAF (FDC) 2016 EACH DRUG IS REGISTRED FOR DIFFERENT AGE GROUPS Carlo I think you can say that when you talk about this Burger and van Rossum. Adapted from Improved labelling of antiretrovirals for paediatric use. Lancet HIV. October 2016. Time from first approval in adults to full approval in children takes on average 5-9 years BUT we don’t want everything…only what has the highest potential for public health impact

Paediatric ARV Drug Optimization List Here we can emphasize the consistensy of the messaging and how drugs have graduated from long term to medium term priorities

PADO3 Implementation considerations DTG single: 10 mg scored dispersible tablets remain the priority meantime 50 mg scored tablet could accelerate generic availability to children >15 kg. DRVr: 120/20 mg tablet remains a priority and incentives are being explored. DTG/ABC/3TC: 5/60/30 mg most likely dosing to be validated by the end of the year once 1093 is completed . F/TAF and DTG/XTC/TAF: urgent review of originator timelines, preliminary feasibility work ton the FDC to be undertaken. RAL: 5 mg (instead of 50 mg) scored dispersible to better reflect its added value for neonates and infants. AZT/NVP: still a priority, but probably less urgently needed than other products. DTG/DRVr: Concerns on the size and feasibility of the FDC (confirmed by CADO3) de-prioritized until further clinical trials support the strategy. PADO3 Implementation considerations The reason for keeping this to say that we dont just come up with the list but also actively reviewed it as we have done last december to develop some implementation considerations and provide some level of internal prioritization within the list in a way that is consistent with the expected evolution of policies....transition to next slides

Enabling alignment with policy development GDG Develops evidence based recommendations accounting for product development PADO Prioritize based on existing WHO Guidelines but also provide a vision for policy change Guidance on product development to Industry Indeed PADO does enable effective alignment between formulation development and expected policy change. We do that by reviewing evidence and providing advice to the WHO GDG as happened this last Dec. Now that the recommendations were revised we will consider them for our new round of prioritization in Dec 2018 IMPLEMENTATION

PAWG enabling role PAWG enabling role Once we are done with the PADO prioritization we hand over to PAWG which plays as a critical technical enabler across prioritization, clinical research, development and regulatory approval Defines standards for research to enable accelerated paediatric ARVs development Advise WHO on clinical and pharmacokinetic issues related to the use of ARVs in children Offers scientific advice to stakeholders involved in the development of paediatric ARVs

Closing the loop on paediatric development plans PAWG Industry SRAs PAWG to provide technical opinion on PIP/PSPs to regulators and promote further focus and alignment between agencies Industry to seek PAWG technical advice to inform submission and implementation of PIP/PSPs that address real need Move up Better paediatric development plans completed and approved more quickly

Optimizing trial design for faster paediatric development plans Just point out the concept Penazzato et al., CID, 2017

Key principles to accelerate research to inform development Getting studies right from the very beginning Enrolling more rapidly (in parallel, not sequentially) and based on weight Include adolescents in adult registrational trials Maximizing the use of PK/PD studies and PK modelling Innovating trial design (ie adaptive designs) Collaboration between networks and investigators You may want to check from the paper if anything you would like to add Penazzato et al., CID, 2017

From a sequential to a parallel approach Registrational trial Dosing Safety Strategic trial Efficacy Simplified dosing TB cotreatment Guidelines introduction Age specific recommendations WHO weight band dosing From a sequential to a parallel approach 2011 Dolutegravir 2021 P1093 DTG dosing and safety 4 weeks to <18 months in 5 cohorts Coated tablets, granules and 5mg dispersible tablets ODYSSEY Enrolment of subjects following first 1093 cohorts PK sub-studies to inform dose simplification TB PK to investigate DTG BD plus Rifampicin Guidelines Update Extrapolated efficacy from adults Safety and PK based on P1093 Simplified dosing based on ODYSSEY Overarching rolling recommendation 2018 This will allow use of DTG in children 3 years earlier with potentially 500 000 more children with access to a more effective regimen Cohort I: Adolescents ≥12 to <18 years of age (Tablet formulation) Cohort IIA: Children ≥6 to <12 years of age (Tablet formulation) Cohort IIB: Children ≥6 to <12 years of age (Granules) Cohort III - DT: Children ≥2 to <6 years of age (Dispersible Tablet) Cohort IV - DT: Children ≥6 months to <2 years (Dispersible Tablet) Cohort V - DT: Infants ≥4 weeks to <6 months (Dispersible Tablet)

Looking forward Prioritization and clinical research remain the first critical steps on making better drugs available for children Solutions to focus and accelerate the research undertaken are being tested and appear promising Open and transparent communication with industry and regulators is of critical importance PADO3 prioritization prompted discussion on TB and Hep and PADO like approaches for Hep and TB are being planned When moving beyond HIV, priorities will need to be identified in collaboration with other global initiatives (e.g. DNDi for AMR etc) “GAP-f as a model for rapid drug development is other “orphan” areas including potentially also Non Communicable Diseases” I removed this point because in these presentation we need to focus on prioritization and research rather than GAPf in general