VIKING STUDIES. Efficacy and safety of dolutegravir. treatment-experienced subjects

Transcription

1 VIKING STUDIES Efficacy and safety of dolutegravir treatment-experienced subjects (DTG) in UK/DLG/0083/14e(2) Date of preparation: February 2017 Prescribing information is available at the end of this presentation

2 DECLARATION OF INTEREST

3 DTG TRIALS IN TREATMENT-EXPERIENCED ADULT SUBJECTS WITH HIV SAILING 1 INI-naïve N=719 Phase III, randomised, double-blind, active-controlled, parallel group, non-inferiority, multicentre study of: DTG (50 mg QD) + BR RAL (400 mg BID) + BR VIKING 2 (Cohort I) INI-resistant N=27 Phase IIb open-label, single-arm multicentre study (Cohort I) of: DTG 50 mg QD + OBR (not incl. RAL) VIKING 2 (Cohort II) INI-resistant N=24 Phase IIb open-label, single arm multicentre study (Cohort II) of: DTG (50 mg BID) + OBR (not incl. RAL) Subjects required to have 1 fully active ARV for Day 11 optimisation (not required for Cohort I) VIKING-3 3 INI-resistant N=183 Phase III, open-label, single-arm, multicentre study of: DTG (50 mg BID) + OBR (not incl. RAL) VIKING-4 4 INI-resistant N=30 Phase III, open-label, placebo-controlled, multicentre study of: DTG 50 mg BID vs placebo (both plus current failing regimen) At Day 8, all subjects received DTG (50 mg BID) + OBR (containing 1 fully active ARV) BID, twice daily; BR, background regimen; QD, once daily; OBR, optimised background regimen 1. Cahn P, et al. Lancet 2013;382:700 8; 2. Eron JJ, et al. J Infect Dis 2013;207:740 8; 3. Castagna A, et al. J Infect Dis 2014; 210: 740-8; 4. Akil B, et al. Antivir Ther 2015; 20:

4 VIKING-3 Primary objective: antiviral efficacy at Day 8 and Week 24 Primary endpoints Secondary endpoints incl. Change from baseline in HIV-1 RNA with DTG 50 mg BID at Day 8 Proportion of subjects with HIV-1 RNA <50 copies/ml at Week 24 Predictors of response (e.g. baseline INI resistance) Safety and tolerability Castagna A, et al. J Infect Dis 2014; 210:

5 VIKING-3: STUDY DESIGN (N=183) Main eligibility criteria: HIV-1 RNA 500 copies/ml Screening or documented historic evidence of resistance to RAL and/or EVG and resistance to 2 ART classes other than INIs Screening visit ~Day -35 Screening period up to a maximum of 42 days Functional monotherapy phase DTG 50 mg BID and continue failing ART regimen Optimised phase DTG 50 mg BID + OBR with OSS 1 Day 1 Day 8 Week 24 analysis Week 48 analysis OSS, overall susceptibility score, determined by Monogram Biosciences net assessment OBR optimised background regimen Adapted from Castagna A, et al. J Infect Dis 2014; 210: ; Nichols G, et al. IAS PosterTULBPE19

6 BASELINE CHARACTERISTICS Characteristic, n (%)* DTG 50 mg BID (N=183) Male gender 141 (77) African American/African heritage 49 (27) CD4+ cells/mm 3, median (IQR) 140 (40-330) CDC class C, n (%) 102 (56) Hepatitis B and/or hepatitis C positive, n (%) 38 (21) VIKING-3 was conducted in a diverse population of patients with advanced disease Adapted from Castagna A, et al. J Infect Dis 2014; 210:

7 PATIENTS HAD EXTENSIVE PRIOR USE OF MULTIPLE ARVS AND EXTENSIVE ARV RESISTANCE Characteristic DTG 50 mg BID (N=183) Prior ART Duration in years, median (range) 14 ( ) Number of ARVs, median (range) 14 (3 23) DRV/r, n (%) 134 (73) ETR, n (%) 103 (56) ENF, n (%) 89 (49) Resistance, n (%) INI (RAL and/or EVG)* 183 (100) 3 NRTI major mutations 133 (73) 2 NNRTI major mutations 108 (59) 2 PI major mutations 129 (70) *INI resistance = presence of T66A/I/K, E92Q/V, Y143C/H/R, Q148H/K/R, N155H or a RAL FC >1.5 or EVG FC > (73%) at screening, 50 (27%) with historic detection only; historic resistance for eligibility was as follows: 42/50 subjects had primary mutation at positions 92 (n = 2), 143 (n = 4), 155 (n = 19), 148 (n = 15) or multiple primary mutations (n = 2) and the remaining 8/50 had historic phenotypic resistance to RAL. Adapted from Castagna A, et al. J Infect Dis 2014; 210: ; Nichols G, et al. IAS Poster TULBPE19

8 Subjects with HIV-1 RNA <50 copies/ml (%) IN TREATMENT-EXPERIENCED PATIENTS, DTG DEMONSTRATES EFFICACY FOR THE MAJORITY OF INI- RESISTANT PATIENTS AT 48 WEEKS Day 8 efficacy: DTG was associated with significant reductions from baseline in HIV-1 RNA: change from baseline: 1.43 log 10 copies/ml HIV-1 RNA (95% CI: 1.52 to 1.34; p<0.001) /183 (69%) At Week 24, 126/183 (69%) were fully suppressed At Week 48, 116/183 (63%) were fully suppressed (HIV-1 RNA <50 copies/ml) by Snapshot algorithm 116/183 (63%) BL D Week At Week 24,135/183 (74%) achieved HIV-1 RNA <400 copies/ml At Week 48,125/183 (68%) achieved HIV-1 RNA <400 copies/ml Adapted from: Castagna A, et al. J Infect Dis 2014; 210: ; Vavro CL, et al. EUDRW Oral 10

9 Proportion (%) of patients HIV-1 RNA <50 copies/ml EFFICACY RESPONSE RATES AT WEEK 24 AND WEEK 48 WITH INCREASING BASELINE RESISTANCE % 24 week 48 week % 71% 56% 40 25% 29% /114 No Q148H/K/R mutations* 20/31 Q secondary mutation 4/16 Q148 2 secondary mutations No Q148H/K/R mutations* Q secondary mutation Q148 2 secondary mutations *Y143, N155, T66, E92 or historical resistance evidence only Key secondary mutations were G140A/C/S, L741 and E138A/K/T Week 24 & 48 snapshot analysis Adapted from Castagna A et al. J Infect Dis 2014; 210: ; Vavro CL et al. EUDRW Oral 10

10 VIROLOGIC SUCCESS AT WEEK 24 AND WEEK 48 (SNAPSHOT, ITT-E) 1,2 Subjects, n (%)* *Snapshot outcome Defined as HIV-1 RNA <50 copies/ml ITT-E, intent-to-treat exposed Week 24 DTG 50 mg BID (N=183) Week 48 DTG 50 mg BID (N=183) Virologic success 126 (69) 116 (63) Virologic non-response 50 (27) 58 (32) Data in window 50 copies/ml 28 (15) 18 (10) Discontinued for insufficient viral load response 9 (5) 22 (12) Discontinued for other reasons while not <50 copies/ml 3 (2) 4 (2) Change in background ART 10 (5) 14 (8) No virologic data at cut-off 7 (4) 9 (5) Discontinued due to AE or death 5 (3) 5 (3) Discontinued for other reasons 2 (1) 4 (2) Adapted from: Castagna A, et al. J Infect Dis 2014; 210: ; ViiV Healthcare Ltd. Data on File. UK/DLG/0076/14

11 NUMBER OF SUBJECTS (%) WHO MET PROTOCOL- DEFINED VIROLOGIC FAILURE (PDVF) DTG 50 mg BID ITT-E, N=183 Cumulative number of PDVF* PDVF at Week 24 PDVF at Week 48 All PDVF 36 (20%) 41 (22%) Virologic non-response 21 (11%) 21 (11%) Rebound 15 (8%) 20 (11%) *PDVF was defined as any HIV-1 RNA value >400 copies/ml and meeting the following criteria: <0.5 log 10 decrease at Day 8, confirmed decrease of <1 log 10 copies/ml by Week 16, confirmed 400 copies/ml on or after Week 24, confirmed 400 copies/ml after prior confirmed <400 copies/ml or confirmed >1 log 10 copies/ml above a nadir of 400 copies/ml 5 (2%) subjects experienced PDVF between Week 24 and Week 48 Four additional subjects met PDVF post-week 48 at Week 60 (n=2), Week 72 and Week 84. A total of 45 subjects were evaluated for treatment-emergent resistance Adapted from: Vavro CL, et al. EUDRW Oral 10

12 DISTRIBUTION OF BASELINE INI MUTATION CATEGORY ITT-E (N=183) Subjects with PDVF (N=45) INI mutation category Baseline PDVF Q mutations 21 (11%) 13 (29%) Q mutation 32 (17%) 9 (20%) 2 primary mutations 8 (4%)* 2 (4%) ** Y (15%) 4 (9%) N (18%) 4 (9%) T66 1 (<1%) - Primary not detected 60 (33%) 13 (29%)*** *4 patients with Q148 with T66 or Y143 mutations; **2 patients with Q148 with Y143 or T66 mutations ***6 patients with only screening or historic evidence of Q148 mutations but not present at baseline 67% (30/45) who met PDVF had Q148 mutations at baseline or historically Adapted from: Vavro CL, et al. EUDRW Oral 10

13 TREATMENT-EMERGENT INI GENOTYPIC RESISTANCE DETECTED AT PDVF Codon Genotype at PDVF PDVF genotypic population (n=39),* n (%) Any 22 (56) 97 T97T/A, T97A 10 (26) 138 E138A, E138E/K, E138K 9 (23) 148 Q148H, Q148Q/H, Q148Q/R/K 6 (15) 140 G140G/S, G140S 4 (10) 155 N155H 4 (10) 74 L74L/M/V, L74L/M, L74I 3 (8) 92 E92E/Q 2 (5) 157 E157E/Q 1 (3) 147 S147G 1 (3) 143 Y143Y/H 1 (3) *39/45 subjects with paired baseline and PDVF samples 3 subjects with historic Q148H: 2 with Q148H at screening but not baseline; one with Q148R at baseline and Q148Q/R/K at PDVF Emergent mutations were at well-characterised INI resistance-associated positions 18/22 (82%) subjects harboured Q148 pathway virus at baseline or historically Adapted from: Vavro CL, et al. EUDRW Oral 10

14 DTG WAS GENERALLY WELL TOLERATED WHEN PRESCRIBED TWICE-DAILY 24-WEEK DATA AE, n (%) All events (N=183) Drug-related (N=183) Any AE (Grade 2) 106 (55) 27 (15) Diarrhoea 11 (6) 4 (2) Headache 8 (4) 3 (2) Injection site reaction 7 (4) - Pneumonia 7 (4) - Cough 6 (3) - Bronchitis 6 (3) - Nausea 6 (3) 3 (2) Pyrexia 5 (3) - Rash 5 (3) - Arthralgia 5 (3) - Insomnia 5 (3) - Any SAE 31 (17) 2 (1) Syncope* - 1 (<1) Drug eruption, hyperbilirubinaemia, ALT increased - 1 (<1) *Grade 2; Subject on DRV + ETR There were few discontinuations due to safety events (5/183 subjects; 3%) Adapted from: Castagna A, et al. J Infect Dis 2014; 210:

15 SUMMARY OF SAFETY BETWEEN WEEK 24 AND WEEK 48 AE, % No new safety signals since Week 24 analysis AEs between Week 24 and Week 48 Most common, drug-related AEs DTG 50 mg BID (N=183) Nausea 6 Diarrhoea 5 Drug-related SAEs 0 AEs leading to withdrawal and lab abnormalities, from baseline to Week 48 AEs leading to withdrawal 4 Grade 3 or 4 ALT elevations 4 Median changes in serum creatinine noted by Week 4 were stable to Week 48 Adapted from: Vavro CL, et al. EUDRW Oral 10

16 Mean change (SD) from baseline in Cr (μmol/l) SMALL INCREASES IN SERUM CREATININE OCCURRED IN THE FIRST WEEK AND REMAINED STABLE OVER 24 WEEKS Sample size (n) Cr, creatinine; OCT2, organic cation transporter 2; SD, standard deviation Weeks As previously described, 1 a small initial increase in serum creatinine via inhibition of the renal transporter OCT2 was observed by Week 2 2 Serum creatinine levels then remained stable through to Week 24 Adapted from 1. Koteff J, et al. Br J Clin Pharmacol 2013;75: ; 2. Nichols G, et al. HIV Oral 232

17 VIKING-3: CONCLUSIONS In treatment-experienced patients, DTG demonstrated efficacy for the majority of INI-resistant patients at 48 weeks Mean decrease of 1.43 log 10 HIV-1 RNA c/ml at 8 days of functional monotherapy 69% (126/183) at Week 24 and 63% (116/183) at Week 48 achieved HIV-1 RNA <50 c/ml with DTG + OBR Response rates to DTG were significantly reduced with increasing baseline integrase resistance DTG 50 mg BID was generally well tolerated despite advanced disease status Withdrawals due to AEs were infrequent Castagna A, et al. J Infect Dis 2014; 210: ; Vavro CL, et al. EUDRW Oral 10

18 TIVICAY (DOLUTEGRAVIR) LICENSED INDICATION TIVICAY is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age Population Patients without documented or clinically suspected resistance to the integrase class Patients without documented or clinically suspected resistance to the integrase class, when co-administered with some medicines e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin Patients with resistance to the integrase class (documented or clinically suspected) In the presence of documented resistance including Q secondary mutations from G140A/C/S, E138A/K/T, L741, an increased dose may be considered for patients with limited treatment options (less than 2 active agents) due to advanced multi class resistance Adolescents aged 12 and above and weighing at least 40 kg and without documented or suspected resistance to the integrase class Recommended dose 50 mg once daily 50 mg twice daily 50 mg twice daily 100mg twice daily 50 mg once daily TIVICAY Summary of Product Characteristics, January 2017

19 TIVICAY FOR USE SPECIAL WARNINGS AND PRECAUTIONS Integrase class resistance with Q secondary mutations from G140A/C/S, E138A/K/T & L74I Hypersensitivity reactions Immune Reactivation Syndrome Opportunistic infections Drug interactions Osteonecrosis Please consult the Summary of Product Characteristics for full prescribing information TIVICAY Summary of Product Characteristics, January 2017

20 ABBREVIATIONS AE, adverse event ALT, alanine aminotransferase ART, antiretroviral therapy ARV, antiretroviral BID, twice daily BR, background regimen CDC, Centers for Disease Control CI, confidence interval Cr, creatinine DRV/r, darunavir/ritonavir DTG, dolutegravir ENF, enfuvirtide ETR, etravirine EVG, elvitegravir HIV, human immunodeficiency virus INI, integrase inhibitor IQR, interquartile range ITT-E, intent-to-treat-exposed NNRTI, non-nucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor OBR, optimised background regimen OCT2, organic cation transporter 2 OSS, overall susceptibility score PDVF, protocol-defined virologic failure PI, protease inhibitor QD, once daily RAL, raltegravir RNA, ribonucleic acid SD, standard deviation

21 PRESCRIBING INFORMATION TIVICAY (DOLUTEGRAVIR 50MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indication: HIV in >12 years and >40kg as part of combination therapy. Dosing: 50mg once daily with or without food if no proven/ suspected integrase resistance. 50mg twice daily with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John s Wort or rifampicin. Adults with proven/ suspected integrase resistance: 50mg twice daily preferably with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Pregnancy/ lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: 30 tablets EU/1/13/892/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Tivicay is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: January Zinc code: UK/DLG/0055/13(9) Adverse events should be reported. For the UK, reporting forms and information can be found at Adverse events should also be reported to GlaxoSmithKline on Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: , medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on