Antiretroviral Treatment: What's in the Pipeline Joseph P. McGowan, MD, FACP, FIDSA Professor of Medicine Hofstra North Shore-LIJ School of Medicine October 14, 2015 Which describes best how HIV Maturation Inhibitors Work? A. Block of release of budding viral progeny from CD4 cell surface B. Block integration of HIV DNA from forming stable pro-virus C. Inhibits protease cleavage step of viral polypeptide D. Engages virus in endless video game play 44% 29% 25% 2% Block of release of buddi.. Block integration of HIV... Inhibits protease cleavag... Engages virus in endless... 1
Session Objectives -To describe the need for new antiretroviral treatment options - To describe promising investigational agents in existing ARV classes - To review the landscape of emerging novel targets for antiretroviral therapy development Why do we need new ARV therapies? HIV/AIDS remains a global health threat despite current treatment options HIV management requires life-long treatment with combination therapy which must be safe and tolerable ARV options for treatment experienced patients may be limited due to cross class resistance, DDIs, adverse effects, chronic medical conditions, complexity Novel therapies would need to target different steps of the viral life cycle, have unique resistance profiles, be tolerable and have few DDIs. 2
Investigational Agents of Interest NRTIs Tenofovir Alafenamide Festinavir (formerly BMS-986007) NNRTI Doravirine (formerly MK-1439) Rilpivirine (long-acting parenteral nanosuspension) Integrase inhibitor Cabotegravir (oral and long-acting parenteral nanosuspension) Entry inhibitors PRO140 (CCR5 mab) Cenicriviroc (CCR5/CCR2 antagonist) Ibalizumab (CD4 mab) BMS 663068 (pro-drug of gp120 attachment inhibitor) Maturation inhibitors BMS-955176 Drug Delivery: TDF vs. Tenofovir Alafenamide Fumarate (TAF) 3
Studies 104 and 111: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV Therapy Phase 3 (2 trials combined) Treatment-naive HIV RNA >1000 copies/ml egfr >50 ml/min No HBV or HCV coinfection Randomization 1:1 E/C/F/TAF qd (n=866) (Elvitegravir/cobicistat/ emtricitabine/taf) E/C/F/TDF qd (n=867) (Elvitegravir/cobicistat/ emtricitabine/tenofovir DF) Week 0 144 E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide 10 mg; TDF: tenofovir DF 300 mg. Non-inferiority margin: 12% (based on week 48 FDA snapshot analysis of percentage of patients with HIV RNA <50 copies/ml). Baseline characteristics: Median age: 33-35 years. Male: 85%. Black race/ethnicity: 26%. Median HIV RNA: 4.5 log 10 copies/ml. Median CD4 count: 405 cells/µl. Median egfr: 114-117 ml/min. Sax PE, et al. Lancet. 2015;385:2606-2615. 4
Patients (%) Studies 104 and 111: Overall Results With TAF in a Single-Tablet Regimen in Initial HIV Therapy HIV RNA <50 copies/ml TAF was non-inferior to TDF Treatment difference: 2.0% (- 0.7, 4.7) High and similar response rates irrespective of age, sex, baseline HIV RNA level, and baseline CD4 count Gain in CD4 count Significantly greater increase with TAF versus TDF (211 versus 181 cells/µl; P=0.024) Treatment-emergent resistance <1% in both arms HIV RNA <50 Copies/mL (FDA Snapshot Analysis) 92% 90% E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide; TDF: tenofovir DF. Non-inferiority margin: 12%. Sax PE, et al. Lancet. 2015;385:2606-2615. E/C/F/TAF (n=866) E/C/F/TDF (n=867) Studies 104 and 111: Safety E/C/F/TAF (n=866) E/C/F/TDF (n=867) Discontinuations due to adverse events (%) 0.9 1.5 Most common adverse events (%) Diarrhea Nausea Headache Upper respiratory tract infection Grade 3 or 4 laboratory abnormality (%) Creatine kinase elevation LDL elevation Hypercholesterolemia Hematuria AST elevation Serum amylase elevation Neutropenia (<1000 cells/µl) ALT elevation E/C/F: elvitegravir/cobicistat/emtricitabine; TAF: tenofovir alafenamide; TDF: tenofovir DF. Sax PE, et al. Lancet. 2015;385:2606-2615. 17 15 14 11 7 5 2 2 2 2 2 1 19 17 13 13 6 2 1 2 2 3 2 1 5
Mean Change (%) Mean Change (%) Mean Change (ml/min) Studies 104 and 111: Change in egfr (Cockcroft-Gault) With TAF or TDF TAF versus TDF Significantly smaller decreases in egfr (Cockcroft-Gault) (P<0.001) Significantly less proteinuria, albuminuria, and tubular proteinuria (P<0.001) No cases of tubulopathy/fanconi syndrome in either arm Discontinuations due to renal adverse events E/C/F/TAF: 0 (0%) E/C/F/TDF: 4 (0.5%) Mean Change in egfr E/C/F/TAF (n=866) E/C/F/TDF (n=867) -6.6 P<0.001-11.2 E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide; TDF: tenofovir DF. 0 12 24 36 48 Treatment Week Sax PE, et al. Lancet. 2015;385:2606-2615. Studies 104 and 111: Changes in Spine and Hip BMD With TAF or TDF Spine BMD Hip BMD E/C/F/TAF (n=845) E/C/F/TDF (n=850) E/C/F/TAF (n=836) E/C/F/TDF (n=848) -1.30 P<0.001-0.66 P<0.001-2.86-2.95 0 24 48 Treatment Week E/C/F: elvitegravir/cobicistat/emtricitabine. TAF: tenofovir alafenamide; TDF: tenofovir DF. 0 24 48 Treatment Week Sax PE, et al. Lancet. 2015;385:2606-2615. 6
Median Values (mg/dl) Studies 104 and 111: Fasting Lipids at Week 48 189 177 E/C/F/TAF Baseline Week 48 E/C/F/TDF Baseline Week 48 3.7 3.7 115 109 114 108 51 48 Total Cholesterol LDL HDL Triglycerides TC:HDL Ratio P<0.001 P<0.001 P<0.001 P=0.027 P=0.84 E/C/F: elvitegravir/cobicistat/emtricitabine; TAF: tenofovir alafenamide; TDF: tenofovir DF. P values are versus comparator arm. Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF versus 2.9% E/C/F/TDF (P=0.42). Sax PE, et al. Lancet. 2015;385:2606-2615. 13 Tenofovir Alafenamide-Containing Single- Tablet PI Regimen in Treatment-Naïve Patients Once-Daily Regimens Phase 2 study (48 weeks) Treatment-naïve Double-blind HIV RNA >5000 copies/ml CD4 >50 cells/mm 3 egfr >70 ml/min No HBV, HCV Randomization 2:1 Darunavir/Cobicistat/ Emtricitabine/Tenofovir Alafenamide 1 Fixed-Dose Combination Tablet (n=103) Darunavir + Cobicistat + Emtricitabine/Tenofovir DF 4 tablets (n=50) Primary Endpoint Week 24 HIV RNA <50 Copies/mL (FDA Snapshot) Mills A, et al. JAIDS. 2015;69:439-445. 7
Patients (%) Single-Tablet PI Regimen: Baseline Demographics DRV/COBI/FTC/TAF (n=103) DRV + COBI + FTC/TDF (n=50) Males (%) 92 94 Median age (years) 31 36 Race (%) White/ Black/Hispanic 60/35/22 60/34/18 Asymptomatic HIV infection (%) 90 88 Median HIV RNA (log 10 copies/ml) >100K copies/ml (%) Median CD4 (cells/mm 3 ) <200 cells/mm 3 (%) Estimated GFR (ml/min) (Cockcroft-Gault) 4.67 22 368 11 4.58 14 433 20 116 110 TAF: tenofovir alafenamide. Mills A, et al. JAIDS. 2015;69:439-445. Single-Tablet PI Regimen: Virologic and Immunologic Outcomes Viral suppression and failure rate were comparable between both arms No patients developed resistance Both arms were well tolerated Discontinuations due to adverse events low (1% versus 4% in the singleversus multiple- tablet regimen, respectively) 1 case of proximal renal tubulopathy in the multipletablet regimen TAF: tenofovir alafenamide. Mills A, et al. JAIDS. 2015;69:439-445. HIV RNA <50 Copies/mL DRV/COBI/FTC/TAF (n=103) DRV + COBI + FTC/TDF (n=50) Weighted Difference:-6.2% Weighted (95% CI: -19.9, 7.4) Difference:+3.3% (95% CI: -11.4, 18.1) 84% 75% 77% 74% Week 24 Week 48 8
Single-Tablet PI Regimen: Additional Safety and Tolerability Data Select treatment-emergent adverse events (%)* Diarrhea Upper respiratory tract infection Fatigue Nausea Rash Median change at week 48 (mg/dl) Total cholesterol LDL-C HDL Triglycerides Serum creatinine Week 48 change in bone mineral density (%) Spine Hip DRV/COBI/FTC/TAF (n=103) 21 16 14 13 12 40 26 7 29 0.06-1.57-0.84 DRV + COBI + FTC/TDF (n=50) 26 14 18 10 8 5 (P<0.001) 4 (P<0.001) 3 (P=0.009) -5 (P=0.007) 0.09-3.62 (P=0.003) -3.82 (P<0.001) TAF: tenofovir alafenamide. *Grades 1-4, occurring in >10% of patients. Mills A, et al. JAIDS. 2015;69:439-445. Switching From TDF- to TAF-Based Regimens in Virologically Suppressed Pts Randomized, active-controlled, open-label study Primary Endpoint Wk 48 Pts with HIV-1 RNA < 50 copies/ml ( 96 wks) and egfr > 50 ml/min on stable TDF-based regimen for 48 wks (N = 1436) Switch to EVG/COBI/FTC/TAF QD* (n = 959) Continue previous TDF-based regimen (n = 477) Continue through Wk 96 *EVG/COBI/FTC/TAF (150/150/200/10 mg). Previous TDF-based regimens: EVG/COBI/FTC/TDF (n = 459), EFV/TDF/FTC (n = 376), ATV/(COBI or RTV) + TDF/FTC (n = 601). Primary endpoint: proportion of pts with HIV-1 RNA < 50 copies/ml after 48 wks of treatment Mills A, et al. IAS 2015. Abstract TUAB0102. 9
Median % Change in Spine BMD (Q1, Q3) Wk 48 HIV-1 RNA < 50 c/ml (%) Switching From TDF- to TAF-Based Regimens: Virologic Outcomes Primary Endpoint EVG/COBI/FTC/TAF TDF-based regimen P <.001 P =.02 P =.02 P = NS 100 97 93 96 90 97 92 98 97 80 60 40 20 n/n = 0 932/ 959 444/ 477 All Prior Regimens 241/ 251 112/ 125 390/ 402 183/ 199 Prior Prior EFV/TDF/FTC Boosted ATV + TDF/FTC 301/ 306 149/ 153 Prior EVG/COBI/ FTC/TDF Mills A, et al. IAS 2015. Abstract TUAB0102. Reproduced with permission. Switching From TDF- to TAF-based Regimens: Renal and Bone Outcomes 4 3 2 1 0-1 -2-3 EVG/COBI/FTC/TAF TDF-based regimen Baseline Wk 24 Wk 48 1.79-0.28 P <.001 Regimen EVG/COBI/ FTC/TAF (n = 959) TDF-based regimen (n = 477) Renal Events Leading to Discontinuation Acute renal failure Interstitial nephritis Chronic kidney disease Elevated serum creatinine Fanconi syndrome (mild jaundice) Increased creatinine Nephritic colic (nephrolithiasis) Hip BMD was similarly increased for pts treated with TAF regimen (P <.001) Mills A, et al. IAS 2015. Abstract TUAB0102. Reproduced with permission. 10
Pts (%) Switching Pts With HIV/HBV Coinfection to a TAF-Based Regimen International, multicenter, single-arm, open-label phase IIIb trial (N = 72) Pts with virologically suppressed HIV infection on any regimen, chronic HBV coinfection, and egfr > 50 ml/min switched to EVG/COBI/FTC/TAF for 48 Wks HIV-1 RNA < 50 c/ml 100 94 92 80 HBV DNA < 29 IU/mL 100 80 86 92 60 60 Wk 24 Wk 48 40 40 20 20 0 By Wk 48, 2/70 (3%) pts lost HBsAg/gained HBsAb; 2/30 (7%) pts had lost HBeAg; 1/30 (3%) pts gained HBeAb Significant improvement in median Wk 48 FibroTest score with switch (-.04; P =.018) Gallant J, et al. IAS 2015. Abstract WELBPE13. Reproduced with permission. 0 GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment Multicenter, open-label phase III trial Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable egfr CG [30-69 ml/min]) (N = 242) TDF-Based ART (n = 158) Non-TDF Based ART (n = 84) Wk 24 Wk 48 EVG/COBI/FTC/TAF (N = 242) Wk 96 PI NNRTI INSTI CCR5 Antag. TDF ABC Other NRTI ART use,% 44 42 24 3 65 22 7 5 Baseline characteristics: Median age: 58 years. Hypertension/diabetes: 40%/14%. Median CD4: 632 cells/mm 3. Median egfr: 56 ml/min (<60 ml/min: 66%). Dipstick proteinuria grade 1/2/3-4: 23%/10%/0%. Primary Endpoint Week 24 Change From Baseline in egfr No NRTI Gupta S, et al. IAS 2015. Abstract TUAB0103. 11
Actual GFR (ml/min) Change in egfr (ml/min) Study 112: Change in GFR After Switch to E/C/F/TAF in Patients With Renal Impairment Actual GFR at Week 24 (Iohexol Clearance) Mean Change in egfr at Week 48 (Cockcroft-Gault) Baseline Week 24 59 58 63 63 50 49 0.2-0.6-1.8 All Patients Yes No TDF in Previous Regimen Baseline egfr (ml/min): 56 58 53 All Patients Yes No TDF in Previous Regimen Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103.. Study 112: Change in GFR and Other Outcomes After Switch to E/C/F/TAF Actual GFR was unaffected by E/C/F/TAF switch, regardless of previous regimen egfr remained unchanged through week 48 Significant improvements after E/C/F/TAF switch (P<0.05) Spine and hip bone mineral density Urinary tubular proteins and fractional excretion of uric acid Albuminuria and proteinuria Cholesterol fractions in patients not on a TDF-based regimen at time of switch These 48-week data support the renal and bone safety of E/C/F/TAF in HIV patients with renal impairment (egfr 30-69 ml/min) Gupta S, et al. J Int AIDS Soc. 2015;18(suppl 4):35-36. Abstract TUAB0103.. 12
Doravirine (DOR) Investigational NNRTI Pre-clinical Potent at low miligram dose Not a CYP450 inhibitor or inducer Metabolized by CYP3A4 Active in vitro against viral strains with K103N, Y181C, G190A, E101K, E138K or K103N/Y181C Clinical Multiple doses in 40 HIV- men X 10d: no rash/cns events (except HA) PK supportive of once-daily dosing Lai AAC 2014;58:1652-1663 Anderson Antivir Ther 2015;20:397-405 Doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled Study population: HIV+, treatment-naïve (N=18) Schurmann AIDS 2015 (epub 9/13/15) 13
Doravirine: Phase 2b Dose Finding (Part 1) Randomized: TDF/FTC + 4 doses of DOR vs. EFV Results: VL <40 Non-CNS tox 48 wk DOR vs. EFV nausea (8% vs. 2%) fatigue (7% vs. 5%) diarrhea (5% vs. 10%) Morales-Ramirez CROI 2014 #92LB wk 48: 73% 72% 76% 83% 71% Gatell Glasgow 2014 #O434 Doravirine: Phase 2b (Part 2) Randomized: TDF/FTC + DOR 100 mg vs. EFV (N=132) Results (combining parts 1 and 2; N=216): CNS Toxicity (48 wks) overall (DOR 22% vs. EFV 44%; p<0.001) dizziness (DOR 9% vs. EFV 28%) insomnia (DOR 6% vs. EFV 3%) abnormal dreams (DOR 6% vs. EFV 17%) nightmares (DOR 6% vs. EFV 8%) Gatell Glasgow 2014 #O434 Significant interaction with rifampin ( DOR >57%) Judge CROI 2015 #521 14
P007: DOR + TDF/FTC vs EFV + TDF/FTC in ART-Naive Pts Infected With HIV Double-blind, randomized, 2-part study Pts were stratified by HIV-1 RNA or > 100,000 copies/ml Wk 96 ART-naive, HIV-positive pts with HIV-1 RNA 1000 copies/ml and CD4+ cell count 100 cells/mm 3 (N = 216*) Doravirine + TDF/FTC (n = 108) Efavirenz + TDF/FTC* (n = 108) *Combined pts from 2 study parts: Part 1 was a dose-finding study (n = 84) and Part 2 enrolled additional pts with the current dosing schema (n = 132). Doravirine dosed at 100 mg QD. Efavirenz dosed at 600 mg QD. Wk 24 results reported. Gatell JM, et al. IAS 2015. Abstract TUAB0104. P007: Key Results Pts With HIV-1 RNA < 40 c/ml, %* DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) Wk 8 27.8 26.9 Wk 16 63.6 57.5 Wk 24 72.2 73.1 Baseline HIV-1 RNA 100,000 c/ml (n/n) 83.3 (55/66) Baseline HIV-1 RNA 60.5 > 100,000 c/ml (n/n) (23/38) 85.7 (54/63) 65.8 (25/38) Event, % DOR + TDF/FTC (N = 108) EFV + TDF/FTC (N = 108) One or more AE 75.9 84.3 Serious AE 0.9 4.6 Discontinued due to AE 0.9 5.6 Drug-related AE 27.8 55.6 Pts with 1 CNS event 26.9 46.3 *NC = F approach. Observed failure approach. Most virologic failure was due to low-level viremia Virologic failure, HIV-1 RNA 40 copies/ml: DOR, 15.7%; EFV, 10.2% Virologic failure, HIV-1 RNA 200 copies/ml: DOR, 3.7%; EFV, 0.9% Resistance testing was performed in 1 pt in each arm who failed treatment; no NRTI or NNRTI mutations detected Gatell JM, et al. IAS 2015. Abstract TUAB0104. 15
DOR Phase 2: Study 007 Study regimen: TDF/FTC + DOR or EFV 100,000 c/ml >100,000 c/ml n/n 55/66 54/63 61/66 58/63 23/38 25/38 35/38 36/38 Patients with >1 CNS event: 27% (DOR) vs. 46% (EFV) *Excludes: Patients who discontinued due to non-treatment related reasons but with last RNA <40 c/ml, or due to AE, or who lack data in week 24 window. Gatell IAS 2015 #TUAB0104 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion BMS 663068 Ibalizumab gp41 gp120 CCR5 Inhibitors maraviroc enfuvirtide V3 loop CD4 Cell Membrane CCR5/CXCR4 (R5/X4) Adapted from Moore JP, PNAS 2003;100:10598-10602. 16
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BMS- 626529: Resistance, Mechanism, PK gp 160 population sequencing: M426L substitution correlated with resistance (high IC50 and poor VR) no selection of M426L day 1 to 8 Temsavir (BMS-626529 ) binds pre-cd4 bound gp120, restricting conformational change No PK Interactions with ATV or ATV/r No PK Interactions with DRV/r or DRV/r + ETR (ETR alone fostemsavir -BMS-663068) FDA breakthrough designation 7/15 Zhou JAC 2014;69:573 Langley Proteins 2014 (epub) Zhu CROI 2013 #534 Landry CROI 2015 #523 18
Patients (%) BMS-626529 (HIV-1 Attachment Inhibitor Prodrug) in ART Experienced Patients (Interim Results) Ongoing, phase 2b, dose-ranging study in treatment-experienced patients (n=251) BMS-626529 binds to HIV-1 gp120 (prevents initial attachment and cell entry in host CD4) HIV RNA >1000 copies/ml CD4 >50 cells/mm 3 Randomized arms were raltegravir + tenofovir DF and either BMS-626529 400 or 800 mg bid, 600 or 1200 mg qd Atazanavir/r Similar CD4 gains in all arms Well tolerated with no dose-response safety signal baseline susceptibility in 12% of pts due to envelope polymorphisms; screened by baseline IC 50 Patients were pre-screened for baseline resistance.. Lalezari J, et al. 21 st CROI. Boston, 2014. Abstract 86. 80% 400 bid (n=50) Week 24 Interim Results ( FDA Snapshot ) 69% 800 bid (n=49) 77% 600 qd (n=51) BMS-626529 (mg) 72% 1200 qd (n=50) 75% ATV/r qd (n=51) 19
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Ibalizumab: HIV-neutralizing mab directed to domain 2 of human CD4 (5A8, TNX-355) Humanized monoclonal antibody Structure of ibalizumab Fab bound to 2-domain CD4 (2.2Å) Freeman et al, Structure, in press 24
Maximum percent inhibition (MPI) IC 50 ( g/ml) Breadth and potency of ibalizumab (MPI and IC50) against a panel of 118 HIV clones 100 10 80 60 1 40 0.1 20 0 20 40 60 80 100 Viruses 0.01 Ibalizumab Mechanism of Action: HIV-1 entry inhibitor. Ibalizumab, a humanized monoclonal antibody (mab), binds to extracellular domain 2 of the CD4 receptor. Half-life (T½): 3 to 3.5 days on average Currently in Phase III trial for HIVinfected, treatment-experienced adults infected with multi-drug resistant HIV-1. Dose: Loading dose of 2000 mg IV infusion followed by IV ibalizumab 800 mg every 2 weeks 25
Ibalizumab as PrEP? Moving toward proof of principle with the current form: Phase 1 study in healthy volunteers Passive protection against SIV challenge in macaques Making a better ibalizumab: Improve route Improve stability Improve affinity Improve PK Improve breadth Ultimate goal: Decrease dose to <10 mg Decrease frequency to 2 months Decrease cost http://www.vaccineenterprise.org/conference/2011/sites/default/files/s04.02,%20ho.pdf 51 HIV Maturation Inhibitor 26
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AI468002: BMS-955176 + ATV ± RTV for Treating Pts Infected With HIV Randomized, multipart phase IIa trial Max. Median Decline Day 28* in HIV-1 RNA through Day 42 (log 10 c/ml) BMS-955176 40 mg QD + ATV 300 mg QD + RTV 100 mg QD -2.02 (n = 8) HIV, subtype B infected PI- and MI-naive pts with HIV-1 RNA 5000 c/ml and CD4+ cell count 200 cells/mm 3 (N = 28) BMS-955176 40 mg QD + ATV 400 mg QD (n = 8) BMS-955176 80 mg QD + ATV 400 mg QD (n = 8) ATV 300 mg QD + RTV 100 mg QD + TDF 300 mg QD/FTC 200 mg QD (n = 4) *Followed through Day 42. BMS-955176 prevents viral maturation by inhibiting cleavage between p24 and Gag SP1. -1.86-2.23-2.39 No serious AEs or discontinuations for AEs 1 grade 3/4 Tx-related AE in BMS-955176 80 mg + ATV 400 mg arm (transient neutropenia) Hwang C, et al. IAS 2015. Abstract TUAB0106LB. 31
Cabotegravir (CAB) Integrase inhibitor similar to DTG; similar resistance Potent in HIV+ individuals (5, 10, 30, 60 mg oral) Margolis EACS 2013; Spreen HIV Clin Trials 2013;14:192 Nanotechology formulation; SC + IM injections T ½ 21-50 days! Supports monthly or quarterly dosing Safety: ISR (all mild) and nodules with SC dosing Treatment + prevention Spreen JAIDS 2014;67:481 Combination of CAB LAP + RPV-LA Phase 1 pilot study, randomized, repeat doseescalation study with oral lead-in (of CAB) in HIV- individuals (N=47) Monthly and quarterly dosing of CAB LAP IM with co-dosed monthly RPV-LA SC Endpoints: Safety, tolerability, PK Results: generally safe and well-tolerated with grade 1 ISR most common; target drug concentrations achieved Spreen JAIDS 2014;67:487 32
LATTE Study: Cabotegravir + Rilpivirine as 2-Drug Oral Maintenance Therapy Phase 2b study (96 weeks) Treatment-naïve Open-label HIV RNA >1000 copies/ml CD4 >200 cells/mm 3 Stratified by HIV RNA and NRTI Induction (24 weeks) Cabotegravir (10, 30, 60 mg) + 2 NRTIs* Maintenance (72 weeks) 744 (10, 30, 60 mg) + Rilpivirine Efavirenz + 2 NRTIs* Week 0 24 48 96 Primary Endpoint HIV RNA <50 copies/ml (FDA Snapshot ) Patients in the cabotegravir arm with HIV RNA <50 copies/ml at week 20 were switched to a maintenance regimen at week 24. Cabotegravir: novel integrase inhibitor that is a dolutegravir analogue (oral and injectable formulations). *Emtricitabine/tenofovir DF or abacavir/lamivudine. Margolis DA, et al. Lancet Infect Dis. 2015;Jul 17. [Epub ahead of print]. LATTE 1: CAB and RPV Oral Maintenance Virologic Success: HIV-1 RNA <50 c/ml by FDA Snapshot (ITT-E) 80 60 40 20 0 Proportion, % (95% CI) 100 BL 2 4 8 12 16 242628 32 36 40 48 60 72 84 96 CAB 10 mg (n=60) CAB 60 mg (n=61) CAB 30 mg (n=60) EFV 600 mg (n=62) Margolis Lancet ID 2015 (epub 7/17/15) 33
LATTE Study: Cabotegravir + Rilpivirine as 2-Drug Oral Maintenance Therapy Oral cabotegravir + rilpivirine maintained HIV RNA suppression at a similar rate as efavirenz + 2 NRTIs Resistance at virologic failure 1 patient with both integrase and NNRTI resistance (previously reported) 2 patients with NNRTI resistance only Cabotegravir regimen was well tolerated, with a low discontinuation rate due to adverse events (3.9%) Cabotegravir 60-mg dose had more adverse events and discontinuations relative to the 10- and 30-mg arms Cabotegravir 30 mg qd was selected for further clinical development HIV RNA <50 copies/ml (%) Week 96 Results Cabotegravir (n=181) EFV (n=62) 76 63 CD4 gain (cells/mm 3 ) 259 289 Virologic failure (%) 3 10 Discontinuations due to adverse events (%) Key Outcomes Select grade 3/4 laboratory abnormalities (%) CPK ALT Lipase Total bilirubin Total neutrophils Creatinine 3.9 15 10 1.6 6.0 0 2.2 0 15 2 2 0 3 0 Margolis DA, et al. Lancet Infect Dis. 2015;Jul 17. [Epub ahead of print]. Which describes best how HIV Maturation Inhibitors Work? A. Block of release of budding viral progeny from CD4 cell surface B. Block integration of HIV DNA from forming stable pro-virus C. Inhibits protease cleavage step of viral polypeptide D. Engages virus in endless video game play 77% 15% 8% Block of release of buddi.. Block integration of HIV... Inhibits protease cleavag... Engages virus in endless... 0% 34
Which describes best how HIV Maturation Inhibitors Work? Block of release of budding viral progeny from CD4 cell surface 8% 8% Block integration of HIV DNA from forming stable pro-virus 15% 15% Inhibits protease cleavage step of viral polypeptide 77% 77% Engages virus in endless video game play 0% 0% First Slide Second Slide Thank you Joseph P. McGowan, MD jmcgowan@nshs.edu 35