v Dr Anton Pozniak Chelsea and Westminster Hospital, London Injectable ARVs a S.W.O.T Analysis

Transcription

1 18 th Annual Resistance and Antiviral Therapy Meeting v Dr Anton Pozniak Chelsea and Westminster Hospital, London Thursday 18 September 2014, Royal College of Physicians, London Injectable ARVs a S.W.O.T Analysis Anton Pozniak Consultant Physician Director of HIV Services Chelsea and Westminster Hospital London UK 1

2 Injectable ARVs Strengths- Timing interval Weaknesses Adverse event predictors Resistance Opportunities PREP Threat Two/three drugs formulations Access Cure Some Memories of Injectables 4 2

3 They worked -T20 Efficacy 100 TORO 100 RESIST 100 POWER Patients (%) % 55% Patients (%) % 54% Patients (%) % 67% <400 copies/ml LPV/r FUZEON + LPV/r <400 copies/ml TPV/r FUZEON + TPV/r <50 copies/ml TMC114/r FUZEON + TMC114/r Haubrich et al. IDSA Abstract 785. But BD dosing Pharmacokinetics of T-20 support subcutaneous administration 10 TRI-003, 100 mg BID, Day 14 T20-205, 50 mg BID, Day 28 TRI-003, 50 mg BID, Day Time (hours) 3

4 And..Enfuvirtide Resistance Can Emerge Quickly D1 Ref D10 D30 FC = 0.5 FC = 8 FC = 400 ENF IC 50 Distribution at Baseline in TORO 1, ENF IC 50 Distribution at Failure in TORO 1, Maroldo L, et al. CROI Abstract 717. D1, D10, D30, treatment days 1, 10, and 30 for a single patient. And this relative to my other HIV/AIDS drugs, injections have not limited or altered my ability to... T20 Percentage of patients who agree (somewhat or strongly) Travel Privacy of health Personal appearance Perform daily activities Be intimate w/partner Perform work Social relationships Family life Vigorous activities Prepare meals Moderate activities 53% 61% 63% 63% 75% 77% 86% 88% 89% 95% 95% 4

5 The Need for Injectables HAART recommended for HIV treatment Continuous need for optimization of current treatment Preventative HIV vaccine development is challenging PrEP has been introduced and clinical trials are underway Development of novel agents includes long-acting (LA) ARV formulations Injectable ARVs Strengths- Timing interval Weaknesses Adverse event predictors Resistance Opportunities PREP Threat Two/three drugs formulations Access Cure 5

6 GSK744 and TMC278 Nanosuspensions Drug nanocrystal suspended in liquid = nanosuspension Nanomilled to increase surface area and drug dissolution rate Allows ~100% drug loading vs. matrix approaches for lower inj. volumes GSK mg/mL Component GSK A (d50 ~200 nm) Mannitol Surfactant System Water for Injection Function Active Tonicity agent Wetting/Stabilizer Solvent TMC mg/mL R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9 Component TMC278 (d50 ~200 nm) Glucose Surfactant System Water for Injection Function Active Tonicity agent Wetting/Stabilizer Solvent 12 6

7 Cabotegravir GSK (744) HIV-1 integrase inhibitor, dolutegravir analogue Oral drug (t ½ = 40 hours) Long-acting SC or IM injection (apparent t ½ 40 days) Good virologic response at 5 and 30 mg/day as oral 10- day monotherapy Spreen et al. HIV Clin Trials. 2013;14: Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. GSK744 LAP q 4 Week or q 12 Week Regimens Achieve Plasma Concentrations >4 x PA-IC90 in Healthy Adults Mean GSK744 plasma concentration-time profiles m g I M L D, m g S C q 4 w x 3 Plasma GSK (µg/ml) m g I M L D, m g I M q 4 w x m g I M L D, m g I M q 4 w x m g I M q u a rt e rl y x 2 4 * P A - I C 9 0 ( µ g / m L ) T im e ( w e e k s ) GSK744 5mg/day po Ctau = 0.6 ug/ml = q 28 day injection = q 84 day injection 7

8 Trying to achieve the right concentration over time TMC278-C158: Plasma Exposure Following Repeated Dosing (1200, 600, 600 mg) TMC278 LA 1200mg TMC278 LA 600mg TMC278 LA 600mg Target 1 = mean C trough Mean TMC278 (ng/ml) Hour Day Target 2 = upper limit of the lowest quartile of exposures (derived from 25 mg dose of OD oral TMC278 in Phase III trials) PK of TMC278 1st IM injection (Day 1) (Mean ± SD) 2 nd IM injection (Day 29)* (Mean ±SD) 3 rd IM injection (Day 57) (Mean ±SD) C max (ng/ml) ± ± ± AUC 29days (ng.h/ml) ± ± ± Verloes et al, NBC *one outlier excluded from analysis; OD = once daily Injectable ARVs Strengths- Timing interval Weaknesses Adverse event predictors Resistance Opportunities PREP Threat Two/three drugs formulations Access Cure 8

9 Systemic Safety Results: GSK744 Oral and LAP was Generally Safe and Well-tolerated Alone and With TMC278 LA Co-administration in Healthy volunteers All adverse events were mild or moderate No drug-related SAEs or clinically significant trends in laboratory abnormalities, ECGs or vital signs Non-Injection Site Adverse Event (AE) (reported >1 subject) GSK744 (ORAL) GSK744 +/- TMC278 (IM) GSK744 (SC) (N=47) (N=40) (N=10) Mild Mod. Mild Mod. Mild Mod. Subject with Any Drug-related AE, n (%) 7(15) 1(2) 5(13) 3(8) 1(10) 0 Headache 4(9) 1(2) 1(3) 1(3) 1(10) 0 Abdominal pain 1(2) 0 1(3) 0 1(10) 0 Injection Site Safety Results: Local Injection Site Reactions (ISRs) Are Common but Generally Well-tolerated and Self-limited GSK744 (IM) GSK744 (SC) TMC278 (IM) 18 No. subjects w/ injections N=40 N=10 N=19 Max no. inj. per subject/actual total per group 5 / / 30 3 / 57 No. subjects reporting any ISR on study 32 (80%) 10 (100%) 18 (95%) ISR Events, n (% of total events) mild mod Any Pain Erythema Nodule 116 (81) 76 (53) 28 (19) 28 (19) 11 (8) 0 6 (4) 0 ISR: n (%) or mean (range) Duration (days) mild mod (98) 5 (1-32) 9 (1-31) 31 (5-71) 25 (19) 2 (2) 1 (1) 28 (21) 0 23 (17) 0 Duration (days) mild mod (87) 7 (3-14) 11 (1-33) 59 (5-140) 31 (69) 6 (13) 6 (13) 2 (4) 0 3 (7) 0 Duration (days) -- 5 (1-10) 5 (5-5) 48 (24-65) 9

10 744 and Rilpivirine As Two Drug Oral Maintenance Therapy: LATTE Study Design Phase IIb, randomized, multicenter, partially blind, dose-ranging study NRTI subjects with a W20 HIV-1 RNA <50 c/ml simplified to RPV at W24 Oral Induction Phase Oral Maintenance Phase HIV ART-naive HIV-1 RNA 1000 c/ml CD4 200 cells/mm 3 1:1:1:1 Randomization Stratified by VL and NRTI mg + 2 NRTIs* mg + 2 NRTIs mg + 2 NRTIs mg + RPV 25 mg mg + RPV 25 mg mg + RPV 25 mg EFV 600 mg + 2 NRTIs D1 *ABC/3TC or TDF/FTC Week Primary endpoint: % HIV-1 RNA <50 c/ml at 48 weeks (FDA Snapshot ) Intent-to-treat exposed (ITT-E) received at least one dose of Investigational Product (IP) Intent-to-treat maintenance exposed (ITT-ME) received at least one maintenance dose 100 Primary Endpoint Virologic Success: HIV-1 RNA <50 c/ml by FDA Snapshot (ITT-E) 744 overall response W24 87% 744 overall response W48 82% Induction Phase Maintenance Phase 80 Proportion, % BL EFV response W24 74% Week EFV response W48 71% Median (IQR) change from baseline CD4+ cell count (cells/mm 3 ) Week overall +219 (141,343) EFV +227 (134,369) mg (N=60) mg (N=60) Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. 10

11 Adverse Events Neuropsychiatric AEs more commonly seen with EFV Headache was more commonly seen with 744 (22%) than EFV (11%) Predominantly Grade 1 and 2; no withdrawals due to headache mg n= mg n= mg n=61 EFV 600 mg n=62 Grade 2-4 drug-related events (total) 5 (8) 8 (13) 13 (21) 12 (19) (>3% any arm) Insomnia 1 (2) 2 (3) 0 4 (6) Nausea 0 2 (3) 3 (5) 1 (2) Fatigue 0 2 (3) 1 (2) 1 (2) Headache 1 (2) 1 (2) 3 (5) 0 Rash (2)* 5 (8) Grade 2-4 drug-related events (W24+) 1 (2) 2 (4) 3 (5) 2 (4) Serious adverse events (all) 6 (10) 2 (3) 3 (5) 3 (5) AEs leading to withdrawal 1(2) 1 (2) 4 (7) 8 (13) Events with >1 subject Dizziness (3) ALT increased (3) ** 0 *Grade 2; concomitant acute syphilis All Grade 2 One drug-related SAE: suicide attempt (EFV) **Two subjects with steatohepatitis developed asymptomatic Grade 4 ALT elevations, with normal bilirubin levels, at Week 4 and Week 8, which resolved off IP. Protocol-Defined Virologic Failure 744 total EFV n=181 n=62 Subjects with PDVF during Induction 3* (2%) 3 (5%) *1 subject per 744 dose No NRTI, NNRTI or INI treatment-emergent mutations 744 total n=160 EFV n=47 Subjects with PDVF during Maintenance 2** (1%) 1 (2%) IN genotypic results at BL and time of PDVF 1 1 INI-r mutations 1 0 PR/RT genotypic results at BL and time of 2 1 PDVF NRTI-r mutations NNRTI-r mutations ** mg treatment emergent INI (Q148R) and NNRTI (E138Q) at W48; 744 FC = 3; RPV FC = and RPV concentrations <50% of expected; extreme calorie restricted diet W40-W48 ** mg PDVF at W36; no treatment-emergent mutations PDVF: <1.0 log 10 c/ml decrease in plasma HIV-1 RNA by Week 4 OR confirmed HIV-1 RNA 200 c/ml at or after Week 16 or after prior suppression to <200 c/ml Margolis et al. CROI 2014; Boston, MA. Abstract 91LB

12 Possible Weakness of approach No Efficacy data Injectable ARVs Strengths- Timing interval Weaknesses Adverse event predictors Resistance Opportunities PREP Threat Two/three drugs formulations Access Cure 12

13 PREP 13

14 SSAT040 A pharmacokinetic evaluation of the exposure and distribution of TMC278LA for use as pre-exposure prophylaxis, in plasma and genital tract / rectal compartments, following a single intramuscular dose at different doses in HIV negative healthy volunteers. HIV negative volunteers (60 female, 6 male) Aged years Low behavioural risk for infection Female: > 50% of enrolled; self-identified African or African-Caribbean ancestry Administered 300 (n = 20), 600 (n = 20), 1200 (n = 20) mg RPV-LA (G001 formulation) intramuscularly (gluteus maximus) Sampling: - plasma PK - cervicovaginal fluid (CVF; females) & rectal fluid (RF; males) PK - tissue biopsies: vaginal (VT; females) & rectal (RT; males) PK - cervicovaginal lavage (CVL; females) PK & PD Day 0 0 (4 h) 0 (8h) Plasma PK Genital/rectal fluid PK Tissue Biopsy (vaginal/rectal)pk CVL for PK and PD 14

15 PLASMA 300, 600 & 1200 mg doses: Dose proportionality: geometric mean (90% CI) RPV (ng/ml) PK parameter F 300 mg F 600 mg F 1200 mg C max ng/ml 33.7 ( ) 81.9 ( ) ( ) T max day 7.9 ( ) 6.0 ( ) 6.2 ( ) t½ day 42.6 ( ) 39.1 ( ) 38.2 ( ) C 28 ng/ml 19.3 ( ) 44.2 ( ) 82.9 ( ) C 56 ng/ml 9.1 ( ) 22.6 ( ) 45.3 ( ) C 84 ng/ml 6.4 ( ) 16.2 ( ) 30.2 ( ) AUC 84 ng.day/ml ( ) 2934 ( ) ( ) TARGET? Time (days) CVF 300, 600 & 1200 mg doses: Dose proportionality: geometric mean (90% CI) RPV (ng/ml) PK parameter F 300 mg F 600 mg F 1200 mg C max ng/ml 67.4 ( ) 99.3 ( ) ( ) T max day 5.3 ( ) 7.2 ( ) 8.5 ( ) t½ day 33.6 ( ) 31.1 ( ) 43.7 ( ) C 28 ng/ml 24.8 ( ) 39.4 ( ) 84.8 ( ) C 56 ng/ml 12.4 ( ) 18.3 ( ) 35.9 ( ) C 84 ng/ml 11.7 ( ) 14.9 ( ) 35.9 ( ) AUC 84 ng.day/ml ( ) ( ) ( ) TARGET? Time (days) 15

16 SSAT040: PD data CVL samples collected by aspiration of 10 ml normal saline (after cervical lavage) at baseline, 28 and 56 days post-dose N = 10 on 300mg and N = 10 on 1200mg Antiviral activity determined against HIV-1BaL challenge of TZM-bl cells PK/PD correlation established using all data points from both doses Thanks to Betsy Harold and Pedro Mesquita, Albert Einstein College of Medicine. SSAT040: PD data HIV-1 inhibition (%) HIV-1 inhibition (%) Thanks to Betsy Harold and Pedro Mesquita, Albert Einstein College of Medicine. 16

17 Injectable ARVs Strengths- Timing interval Weaknesses Adverse event predictors Resistance Opportunities PREP Threat Two/three drugs formulations Access Cure 17

18 Injectable ARVs Will it only work if Need to have 2/3 ARVs in 1 injection? Volume, IM or IV and cost of goods May cost more than pills Perceived as only for poor adherers Treatment: challenges Adverse effects need for oral lead in period Efficacy: would it be a maintenance strategy following oral doses when high VL Long-term low level exposure at the end of therapy - need for oral drug intake to cover PK tail Potential risk for induction of viral resistance Non-immediately-reversible selective pressure in case of resistance Lack of patient acceptability data Safety in pregnancy 18

19 Thanks to Marta Boffito Akil Jackson SSAT 19