Long Acting Injectables for HIV-PrEP Factors Affecting Dose Selection June 14 to 16, 2017 Mark Milad Milad Pharmaceutical Consulting, LLC Consultant to the Bill and Melinda Gates Foundation
Outline Challenges in global health Dose selection for prevention studies Impact of variability on dose selection Engineering drug forgiveness Tools to simulate long term effectiveness 2
Bill and Melinda Gates Foundation 3
Mismatch and Need for Simplification HIV Prevalence Available Physicians Source: http://www.worldmapper.org/ 4
New Challenges with Products for Population in Sub-Saharan Africa Old Challenges (ICHE5) Genetic Polymorphism of Drug Metabolism and Disease Genetic Disease Demographics Race, Sex, Height, Weight, Age Liver, Kidney, Cardiovascular Disease Smoking, Alcohol Use Food Habits Regulatory Practice Drug Compliance Education, Therapeutic Approach New Challenges Significant Barriers to Adherence Access to Medical Care Travel Distance and Method of Travel Supply Chain Inconsistent Cost Stigma and Need for Privacy Lack of Agency Sex Workers Conceal Medication Use Laws Criminalizing People Who Expose Others to HIV Education Material Differences Western Reference Points Differ from Those in Africa (i.e. Few Stop Lights in Villages) Fewer Health Care Workers (Physician and Nurses) For Long Acting Injectable Skin Thickness 5
Development of HIV PrEP is at a Very Early Stage Compared to Contraceptives Contracept Worldwide 85 M unintended pregnancies (2012) Semi-Permanent or Permanent Sterilization male or female IUDs Implant Taken Every 1-3 months OC Pill Vaginal Ring Taken Daily OC Pill As Needed Diaphragm Condoms male and female Spermicide Non Pharmacologic HIV PrEP Worldwide 2.1 M newly infected with HIV (2015) In-Progress Long acting Injectables Implant Vaginal Ring Taken Daily FTC/TDF As Needed Condoms male and female 6
Concept Target Product Profiles Contraceptives Longer- Acting 6 to 12 months Forgiveness designed into new product 1 month for 6mo-contraceptive Product Consistent and reliable return to fertility Self-Injection Sub-cutaneous (SC) preferred to Intramuscular (IM) Lower side effects HIV PrEP Long-acting Desired duration 6 to 12 mo Preference for SC dosing Injection volume of 2mL or less Lower dose (i.e. 300 mg or less) Gaps in TPP Timer with indicator Quantify result of missed dose Multiple injection location 7
Dose Selection for Prevention Studies Contraception and HIV PrEP have dichotomous and permanent outcomes Require very high rates of efficacy Based on target blood concentrations at trough Near all subjects to remain above a target concentration In a one-dose-fits-all environment, vast majority of subjects will be overdosed Increased variability therefore increases total dose Target Mean 8
PK/PD Simulator for Depo Medroxy-Progesterone Acetate Long Acting Injectable Pharmacokinetic Input Simulated PK Output Pharmacodynamic Input Simulated Endpoint Output (i.e. Ovulation) 9
Concentration % Return to Ovulation Simulation of Increased PK Variability Showing Earlier Return to Ovulation for 5 th Percentile of Women CV in PK Conc 40% 70% Time for 5 th Percentile Return to Ovulation 4.7 mo 4 mo Target % Suppressed Threshold Value Time, Months Time, Months 10
Contraceptive Efficacy Gap Between Perfect and Typical Use Derived from B Hatcher 2014 Typical use: how well the method works when real people in real life use it. Perfect use: how well the method works when it's used in a clinical trial. 11
Drug Forgiveness Forgiveness is defined as the difference between the medication s post-dose duration of beneficial action and the prescribed dosing interval. Relates to the number of doses that can be skipped without causing detectable disease relapse. Definition pertains to daily administration not to long acting where dosed every 3 or 6 months for protection. Feature of the drug or dosage form. Challenge: To engineer product with drug forgiveness. Dartois V 2011 12
Engineering Drug Forgiveness Few of the Variables Choice of API Injection Site Formulation Release Rate Dose Selection Measure Forgiveness PK Outcomes 13
HPTN 084: A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women Women (18 to 45 years old) at risk for acquiring HIV N = 3,200 women in Sub-Saharan Africa Treatment Run In Injection Phase (1yr) Follow UP A Daily oral CAB CAB LA 600 mg Q8 Week, extra dose at Week 4 Open-label daily TDF/FTC B Daily TDF/FTC Daily TDF/FTC Open-label daily TDF/FTC 14
Measure of Forgiveness Based on PK Predicted % of Female Subjects Achieving Trough Concentrations > 4xPA-IC90 Targets Following Delays in CAB LA Dosing Time of Delay Injection Injection 2 (week 4) Injection 3 (week 12) Injection 4 (week 20) 0 (Right On Time) +1 Week +2 Week +3 Week +4 Week 80.4 79.4 75.7 71.5 65.4 92.1 90.0 86.8 83.7 79.1 94.9 92.6 89.6 86.4 83.1 HPTN 084 Protocol V1.0 2 March 2017 https://www.hptn.org/research/studies/hptn084 Provided by Susan Ford, Kelong Han GlaxoSmithKline and Parul Patel, Viiv 15
HIV PrEP Simulator for LA CAB Population PK Parameters Input Subject Adherence Demographics Dose and Transmission Rate (without drug) Exposure Regimen (e.g. 1600 mg LD, 800 mg Q12w PK Model based on data presented in 2014 (Data from Ford et al. 2014, http://www.natap.org/2014/icaac/icaac_32.htm) Model/Simulator built in Microsoft Excel by Bill Poland, Centara Inc Target Trough Plasma Conc (e.g. 4 PA IC90 Frequency Output Individual and Population Conc Time Profiles Probability of Transmission Over Time 16
Simulator for LA CAB Example Individual Subject Profile Population: 1:1 ratio sex Dose: LD 1600 mg, 800 mg Q12W (old regimen) Adherence: SD 2.38 Weeks Poor adherence CAB conc drop below threshold potential exposure/transmission 17
Simulator for LA CAB Example Population Profile Population: 1:1 ratio sex, BMI is median value Dose: LD 1600 mg, 800 mg Q12W (old regimen) Adherence: SD = 2.38 Weeks 95% Mean 50% 5% Although individuals subject concentrations drop below threshold, the population 5th percentile may not drop below threshold 18
Impact of Poor Adherence on Portion of Subjects Infected (example simulator for LA CAB) If 25 % of doses are late by 1 yr 5 yr 10 yr 20 yr 40 yr 0 days (on time) 0.4% 2% 3% 4% 6% 10 days 0.6% 3% 4% 6% 8% 35 days 2% 7% 11% 15% 19% Input: Sex 1:1, Dose: LD 1600 mg, 800 mg Q12W (old regimen), Transmission rate: 0.04/exposure, 2 exposures per week, no early dosing (<tau). Example model based simulation with assumptions, dose, regimen and PK parameters bases on older data. 19
Summary Respond to challenges of dose selection for prevention drugs Consider impact of new sources of variability with long acting injectables in global health Engineer drugs with forgiveness Modeling and simulation to help dose selection and put adherence and forgiveness in context 20
Contributors Bill Poland, Certara Inc, Simulations Susan Ford, GSK insight into HPTN-084 Parul Patel, Viiv insight into HPTN-084 21