Can Pharmacology Help Peter L Anderson Pharm D

#IAS 2017 | @IAS_conference Conflict of Interest • PLA receives research grants and contracts

#IAS 2017 | @IAS_conference Future Pr. EP Pharmacology • Long Acting – CAB, VRC

#IAS 2017 | @IAS_conference Pr. EP Pharmacology goal • Concentration-response & surrogate measures for

#IAS 2017 | @IAS_conference Objectives Conc-effect ingredients i. Pr. Ex trial data STRAND study

#IAS 2017 | @IAS_conference MSM Conc-effect 86% RR (21%-99%) 100% RR (95%CI 86 -100)

#IAS 2017 | @IAS_conference Preliminary Plasma Surrogates LA CAB (mcg/m. L) VRC 01 4

#IAS 2017 | @IAS_conference Genital & rectal distribution (gap) • TAF 2 -10 -fold

#IAS 2017 | @IAS_conference How Pharmacology can help • Long t-1/2, Phase I PK,

#IAS 2017 | @IAS_conference Thank you… • • • Colorado Antiviral pharmacology laboratory LR

#IAS 2017 | @IAS_conference Residual ring vs HIV protection • Residual dapivirine & “dose-response”

#IAS 2017 | @IAS_conference Surrogate for FTC-TDF in MSM ~2500 person years (37 cases):

#IAS 2017 | @IAS_conference Adherence • Shows experimental conditions met • Correlates with trial

#IAS 2017 | @IAS_conference Starting stopping (gap) Half-life minutes 1 day 6 days Onset:

#IAS 2017 | @IAS_conference MSM conc-effect STRAND DOT PK • > 95% RR for

#IAS 2017 | @IAS_conference Pr. EP Pharmacology Human concresponse retrospectively. Rowland Tozer. LLW 2011

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Can Pharmacology Help? Peter L. Anderson, Pharm. D. University of Colorado Anschutz Medical Campus #IAS 2017 | @IAS_Conference

#IAS 2017 | @IAS_conference Conflict of Interest • PLA receives research grants and contracts from Gilead Sciences, paid to his institution.

#IAS 2017 | @IAS_conference Future Pr. EP Pharmacology • Long Acting – CAB, VRC 01 b. NAbs, delivery systems (e. g implantable TAF) • New orals F-TAF • TDF-FTC in control arms

#IAS 2017 | @IAS_conference Pr. EP Pharmacology goal • Concentration-response & surrogate measures for effects – Dose-effect modelling – Starting and Stopping • Fill knowledge gaps

#IAS 2017 | @IAS_conference Objectives Conc-effect ingredients i. Pr. Ex 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- Corneli. JAIDS 2014. Liu PLOS One 2014. Castillo-Mancilla ARHR 2013. Grant Lancet ID 2014. Landovitz. IAS 2017. Cottrell JAC 2017.

#IAS 2017 | @IAS_conference MSM Conc-effect 86% RR (21%-99%) 100% RR (95%CI 86 -100) IPERGAY; 86% (CI 40, 98) efficacy, average of 3. 75 doses week

#IAS 2017 | @IAS_conference Preliminary Plasma Surrogates LA CAB (mcg/m. L) VRC 01 4 X PAIC 90 (664 ng/m. L) derived in HIV infected/pre-clinical 10 mg/kg q 8 weeks 1 mcg/m. L 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

#IAS 2017 | @IAS_conference 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 Hendrix Lancet HIV 2017. Cottrell JAC 2017. Spreen JAIDS 2014. Cottrell. Expert Opin Drug Metab Toxicol. 2015

#IAS 2017 | @IAS_conference 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

#IAS 2017 | @IAS_conference Thank you… • • • Colorado Antiviral pharmacology laboratory LR Bushman J Castillo-Mancilla DV Glidden RM Grant AY Liu Susan Buchbinder JJ Kiser S Ma. Whinney S Seifert

#IAS 2017 | @IAS_conference 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 TUAC 0105 LB.

#IAS 2017 | @IAS_conference Surrogate for FTC-TDF in MSM ~2500 person years (37 cases): IPREX OLE (28 cases); ATN 110/113 (7 cases); Pr. EP-DEMO (2 cases) # of Breakthrough Infections (out of 37) 25 20 15 10 IPERGAY; 86% (CI 40, 98) efficacy, average of 3. 75 doses week 5 0 DBS (TFV-DP fmol/punch): BLQ - 349 350 -699 ≥ 700 Adherence interpretation: No dosing < 2 doses/wk 2 -3 doses/wk ≥ 4 doses/wk 44% (-31, 77) 84% (21, 99) 100% (86, 100) HIV risk reduction (OLE): (95% CI)

#IAS 2017 | @IAS_conference Adherence • Shows experimental conditions met • Correlates with trial efficacy • Brief snapshots in time • Relevance for LA? Fonner AIDS 2016

#IAS 2017 | @IAS_conference Starting stopping (gap) Half-life minutes 1 day 6 days Onset: ASAP Duration: probably depends on if any replication occurred (so onset)… Not clear if vaginal and rectal same… 15 days 44 months Silicano. http: //www. medscape. com/viewarticle/410275_5 ; Tsai J Virol 1998

#IAS 2017 | @IAS_conference MSM conc-effect STRAND DOT PK • > 95% RR for ≥ 4 doses/wk • Dose-effect modeling consistent with IPERGAY results…. 4 -day half life… Liu. PLOS One 2014. Glidden Lancet HIV 2016. Anderson STM 2012. Seifert CID 2015. Grant Lancet ID 2014.

#IAS 2017 | @IAS_conference Pr. EP Pharmacology Human concresponse retrospectively. Rowland Tozer. LLW 2011 Hendrix. Lancet HIV. 2016