Can Pharmacology Help? Peter L. Anderson, Pharm.D. University of Colorado Anschutz Medical Campus

Conflict of Interest PLA receives research grants and contracts from Gilead Sciences, paid to his institution.

Future PrEP Pharmacology Long Acting CAB, VRC01 bNAbs, delivery systems (e.g implantable TAF) New orals F-TAF TDF-FTC in control arms I will focus on long acting using CAB and VRC01 as examples. Same principles apply for implantables.

PrEP Pharmacology goal Concentration-response & surrogate measures for effects Dose-effect modelling Starting and Stopping Fill knowledge gaps

Conc-effect ingredients Objectives Conc-effect ingredients iPrEx trial data STRAND study data LA, F/TAF Long T-1/2 (hair/TFV-DP); gradients; proximity to HIV exposure Phase I DOT to define conc/adherence/dosing (include tissue) Phase III regression model for conc-effect √ √ Corneli. JAIDS 2014. Liu PLOS One 2014. Castillo-Mancilla ARHR 2013. Grant Lancet ID 2014. Landovitz. IAS 2017. Cottrell JAC 2017.

MSM Conc-effect 86% RR 100% RR (95%CI 86-100) (21%-99%) IPERGAY; 86% (CI 40,98) efficacy, average of 3.75 doses week

Preliminary Plasma Surrogates LA CAB VRC01 10mg/kg q 8weeks CAB (mcg/mL) VRC01 (mcg/mL) Long half life Captures past dosing overlapping with HIV exposure. The only way we are going to. get real surrogates is retrospectively 4 X PAIC90 (664ng/mL) derived in HIV infected/pre-clinical 1 mcg/mL derived in vitro/pre clinical Also need concentration – resistance thresholds, which may be different… Spreen, HIV Clin Trials. 2013; Landovitz. HPTN 2016. Andrews Science 2014. Markowitz. Lancet HIV 2017; Huang, MAbs. 2017

Genital & rectal distribution (gap) TAF 2-10-fold lower vs TDF (as TFV-DP) Cannot use TDF surrogates for TAF CAB low 10-20% Inform importance of systemic vs tissue conc TAF – TFV is 2-10 fold lower in female genital and rectal vs TDF Conc in blood for TAF or TDF in a pod may not work the same oral because oral will deliver some to the rectum Hendrix Lancet HIV 2017. Cottrell JAC 2017. Spreen JAIDS 2014. Cottrell. Expert Opin Drug Metab Toxicol. 2015

How Pharmacology can help Long t-1/2, Phase I PK, Phase III conc-effect CAB – LA conc-effect & conc-resistance Starting-stopping How long to cover tail Known surrogates for TDF-FTC control condition Roadmap for F-TAF (but TDF surrogates do not extrapolate to F-TAF) Rectal/genital drug distribution may help interpret outcomes Long half life Captures past dosing overlapping with HIV exposure.

Thank you… Colorado Antiviral pharmacology laboratory LR Bushman J Castillo-Mancilla DV Glidden RM Grant AY Liu Susan Buchbinder JJ Kiser S MaWhinney S Seifert

Residual ring vs HIV protection Residual dapivirine & “dose-response” for HIV risk reduction. MTN 025 monitoring residual ring. Average drug release per day (mg/day) E Brown, (IAS AIDS 2016). Abstract TUAC0105LB.

Surrogate for FTC-TDF in MSM ~2500 person years (37 cases): IPREX OLE (28 cases); ATN110/113 (7 cases); PrEP-DEMO (2 cases) Infections (out of 37) # of Breakthrough IPERGAY; 86% (CI 40,98) efficacy, average of 3.75 doses week HIV risk reduction (OLE): (95% CI) 44% (-31,77) 84% (21,99) 100% (86, 100) Adherence interpretation: No dosing < 2 doses/wk 2-3 doses/wk ≥4 doses/wk DBS (TFV-DP fmol/punch): BLQ BLQ - 349 350-699 ≥700

Adherence Shows experimental conditions met Correlates with trial efficacy Brief snapshots in time Relevance for LA? Fonner AIDS 2016

Starting stopping (gap) Half-life Onset: ASAP minutes Duration: probably depends on if any replication occurred (so onset)… Not clear if vaginal and rectal same… 1 day 6 days 15 days 15 days 5 half-lives 44 months Silicano. http://www.medscape.com/viewarticle/410275_5 ; Tsai J Virol 1998

MSM conc-effect > 95% RR for ≥ 4 doses/wk STRAND DOT PK > 95% RR for ≥ 4 doses/wk Dose-effect modeling consistent with IPERGAY results…. Need three things. Long half life moiety Phase I to inform dose-adherence relationship Concentration-effect data from trials. Need a fair number of infections with drug concentrations. Captures past dosing overlapping with HIV exposure. 4-day half life… Liu. PLOS One 2014. Glidden Lancet HIV 2016. Anderson STM 2012. Seifert CID 2015. Grant Lancet ID 2014.

PrEP Pharmacology Human conc-response retrospectively. Use HIV-infection dose-response. No surrogate of efficacy similar to HIV-RNA for treatment. Dose finding not practical. Drug concentration surrogates identified retrospectively from clinical studies. Rowland and Tozer. LLW 2011 Hendrix. Lancet HIV. 2016