FLAMINGO 96-WEEK PRESENTATION DATA Efficacy and safety of dolutegravir (DTG) in treatment-naïve subjects UK/DLG/0083/14j(4) Date of preparation: August 2017 Prescribing information is available at the end of this presentation
FLAMINGO: ONGOING PHASE III TRIAL IN TREATMENT-NAÏVE SUBJECTS WITH HIV Treatment-naive HIV-1 RNA 1000 copies/ml No baseline PI or RT resistance Stratified by baseline HIV-1 RNA (> or 100,000 copies/ml) background NRTIs (ABC/3TC or TDF/FTC)* Open-label randomised phase DTG 50 mg QD + 2 NRTIs* (n=242) DRV/r 800/100 mg QD + 2 NRTIs* (n=242) Extension phase DTG + ART Randomisation Week 48 Week 96 Primary endpoint: Proportion with HIV-1 RNA <50 copies/ml at Week 48 (FDA Snapshot) with non-inferiority margin of -12% *Patients could receive ABC/3TC only after screening negative for the HLA-B*5701 allele. Given as 2 x 400 mg tablets Adapted from Clotet B, et al. Lancet 2014;383:2222-31; Molina JM et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153
DEMOGRAPHICS AND BASELINE CHARACTERISTICS DTG 50 mg QD (n=242) DRV/r 800/100 mg QD (n=242) Age, years Median (range) 34 (18-67) 34 (19-67) Gender, n (%) Male 211 (87%) 201 (83%) Female 31 (13%) 41 (17%) Race, n (%) White 173 (71%) 176 (73%) African American/African heritage 60 (25%) 53 (22%) Other 8 (3%) 13 (5%) Baseline plasma HIV-1 RNA Median (log 10 copies/ml) 4.49 4.48 >100,000 copies/ml, n (%) 61 (25%) 61 (25%) CD4+ T-cell count, cells/mm 3 (median) 390 400 HBV/HCV positive, n (%) 9 (4%)/17 (7%) 4 (2%)/15 (6%) Investigator selected ABC/3TC, n (%) 79 (33%) 80 (33%) Adapted from Clotet B, et al. Lancet 2014;383:2222-31
IN TREATMENT-NAIVE PATIENTS, DTG HAD STATISTICALLY SUPERIOR EFFICACY VS DRV/r UP TO 96 WEEKS Proportion (%) with HIV-1 RNA <50 c/ml 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% DTG: 90% DRV/r: 83% DTG 50 mg QD DRV/r 800 mg/100 mg QD DTG: 80% DRV/r: 68% 0 8 16 24 32 40 48 56 64 72 80 88 96 W48 W96-12% 95% CI for Difference Favours Favours DRV/r DTG 0% 0.9% 7.1% 13.2% 4.7% 12.4% 20.2% 25% More rapid virological response with DTG vs DRV/r: 87% vs 31% respectively, at Week 8 * Adjusted difference (DTG - DRV/r) based on Cochran-Mantel-Haenszel stratified analysis adjusting for baseline HIV-1 RNA and background NRTI therapy Adapted from Molina JM, et al. Lancet HIV 2015; 2(4): e127 36; Molina JM, et al. Presentation at HIV Drug Therapy Glasgow 2014; O153
EFFICACY BY SNAPSHOT: HIV-1 RNA <50 copies/ml 100% Percentage of subjects (%) 80% 60% 40% 20% 90% 83% 80% 68% DTG 50 mg QD (n=242) 12% 6% 7% 8% DRV/r 800 mg/100 mg QD (n=242) 21% 10% 12% 4% 0% Virologic success Virologic non-response No virologic data Adapted from: Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36; Clotet B, et al. Lancet 2014;383:2222-31
DTG WAS EFFECTIVE, REGARDLESS OF BASELINE VIRAL LOAD AND BACKGROUND NRTI, UP TO 96 WEEKS DTG 50 mg QD (n=242) DRV/r 800 mg/100 mg QD (n=242) Baseline HIV-1 RNA Background NRTI Percentage with HIV-1 RNA <50 copies/ml (%) 90 80 70 60 50 40 30 20 10 0 80% 82% 73% 52% n=362 n=122 100,000 copies/ml >100,000 copies/ml 90 80 70 60 50 40 30 20 10 0 82% 79% 75% 64% n=159 n=325 ABC/3TC TDF/FTC Adapted from: Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36
DTG HAD A HIGH BARRIER TO RESISTANCE UP TO 96 WEEKS No treatment-emergent INI, PI or NRTI resistance was observed up to 96 weeks in either DTG or DRV/r arms DTG 50 mg QD (n=242) DRV/r 800/100 mg QD (n=242) Protocol-defined virologic failure, n (%) 2 (<1%) 4 (2%) INI mutations, n 0 N/A NRTI mutations, n 0 0 PI mutations, n N/A 0 The two subjects with PDVF in the DTG group were at Week 24, whereas in the DRV/r group all four subjects were post-week 24 PDVF was defined as two consecutive HIV-1 RNA values >200 copies/ml, on or after Week 24 INI, integrase inhibitor; PI, protease inhibitor; PDVF, protocol-defined virologic failure Adapted from: Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36; Clotet B, et al. Lancet 2014;383:2222-31
DTG WAS GENERALLY WELL TOLERATED WITH FEW DISCONTINUATIONS UP TO 96 WEEKS DTG 50 mg QD (n=242) DRV/r 800 mg/100 mg QD (n=242) Overall, n (%) 222 (92%) 217 (90%) Common AEs ( 15% in either arm) Diarrhoea 44 (18%) 74 (31%) Nausea 40 (17%) 48 (20%) Headache 40 (17%) 26 (11%) AEs leading to withdrawal 7 (3%) a 15 (6%) b Drug-related Grade 3-4 2 (<1%) 4 (2%) Serious any event 36 (15%) 21 (9%) Serious drug-related 3 cd 0 Fatal AEs 1 e 0 a Suicide, acute hepatitis C, nephrolithiasis b Hepatitis C, diarrhoea/nausea, dysgeusia, renal colic, substance abuse c DTG + ABC/3TC, suicide attempt with history of suicidality d Includes a, plus n=2 subjects receiving DTG+TDF/FTC (polyarthritis, tendon rupture) e DTG + TDF/FTC, suicide considered unrelated to study drug Adapted from: Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36
DTG WAS GENERALLY WELL TOLERATED WITH FEW DISCONTINUATIONS UP TO 96 WEEKS DTG 50mg QD (n=242) Week 48 Week 96 DRV/r 800/100mg QD (n=242) Proportion (%) of patients with AEs leading to discontinuation 7 6 5 4 3 2 1 2% 4% 3% 6% 0 Discontinuations due to AEs at 96 weeks were 3% for DTG and 6% for DRV/r Adapted from: Clotet B, et al. Lancet 2014;383:2222-31; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36
AT 96 WEEKS, DTG WAS GENERALLY WELL TOLERATED WITH LOWER RATES OF DIARRHOEA VS DRV/r Proportion (%) of patients with experiencing diarrhoea 35 30 25 20 15 10 5 0 18% 31% Rates of diarrhoea DTG 50mg QD (n=242) DRV/r 800/100mg QD (n=242) At 96 weeks, the most common drug-related adverse events in both the DTG and the DRV/r treatment arms were diarrhoea, nausea, and headache Adapted from: Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36
DTG HAD A FAVOURABLE LDL PROFILE VS DRV/r UP TO 96 WEEKS Mean change from baseline, mmol/l 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0-0.1 LDL: Creatinine: Total cholesterol LDL cholesterol DTG 50 mg QD Triglycerides Mean change from baseline Higher number of Grade 2 or higher fasting LDL lab abnormalities by Week 96 in the DRV/r arm (22%) vs the DTG arm (7%), P<0.001 (pre-specified LOCF analysis) At Week 96, the mean change from baseline in serum creatinine was higher in the DTG arm (15.35 µmol/l) compared to the DRV/r arm (3.93 µmol/l) Adapted from Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153 DRV/r 800 mg/100 mg QD 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 TC/HDL ratio
FLAMINGO: SUMMARY In treatment-naïve patients, DTG had statistically superior efficacy vs DRV/r 90% vs 83% were undetectable at Week 48 (P=0.025) 80% vs 68% remained undetectable at Week 96 (P=0.002) DTG was effective regardless of baseline viral load At 48 weeks, 93% of treatment-naïve patients with HIV-1 RNA >100,000 copies/ml were undetectable At 96 weeks, 82% of treatment-naïve patients with HIV-1 RNA >100,000 copies/ml remained undetectable No treatment-emergent INI, PI or NRTI resistance was seen in either arm up to 96 weeks DTG was generally well tolerated up to 96 weeks Diarrhoea was more common in patients receiving DRV/r (18% vs 31%) Significantly fewer patients receiving DTG had Grade 2 fasting LDL values vs DRV/r (7% vs 22%; P<0.001) at 96 weeks Discontinuations due to AEs at 96 weeks were 3% for DTG and 6% for DRV/r Clotet B, et al. Lancet 2014;383:2222-31 and Supplementary Appendix; Molina JM, et al. Presentation at HIV Drug Therapy Glasgow; Nov 2014; O153; Molina JM, et al. Lancet HIV 2015; 2(4): e127 36
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, adolescents and children above 6 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) Recommended dose 50 mg once daily 50 mg twice daily 50 mg twice daily In the presence of documented resistance including Q148 + 2 secondary mutations from G140A/C/S, E138A/K/T, L74I, 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 Children aged 6-<12 and weighing at least 15 kg and without documented or suspected resistance to the integrase class 100mg twice daily 50 mg once daily Dose according to bodyweight 10mg and 25mg tablets available Tivicay Summary of Product Characteristics, July 2017
ABBREVIATIONS 3TC, lamivudine ABC, abacavir AE, adverse event ART, antiretroviral therapy CI, confidence interval DRV/r, darunavir/ritonavir DTG, dolutegravir FDA, Food and Drug Administration FTC, emtricitabine HBV, hepatitis B virus HCV, hepatitis C virus HDL, high density lipoprotein INI, integrase inhibitor LDL, low density lipoprotein NRTI, nucleoside reverse transcriptase inhibitor PDVF, protocol-defined virologic failure PI, protease inhibitor QD, once daily RNA, ribonucleic acid TC, total cholesterol TDF, tenofovir disoproxil fumarate
PRESCRIBING INFORMATION TIVICAY DOLUTEGRAVIR 10MG, 25MG & 50MG TABLETS SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING Indication: HIV in >6 years and >15kg as part of combination therapy. Dosing: Adults & adolescents >40kg: 50mg once daily with or without food if no proven/ suspected integrase resistance. Children 6 to <12 years: dose according to bodyweight: 15-<20kg: 20mg once daily (2x10mg); 20- <30kg: 25mg once daily; 30-<40kg: 35mg once daily (1 x 25mg + 1 x 10mg); When co-administered with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John s Wort or rifampicin, Tivicay 50mg twice daily in adults/adolescents or the weight-based once daily dose twice daily in paediatric patients. Adults with proven/ suspected integrase resistance: 50mg twice daily preferably with food. Limited data in paediatric patients with proven/suspected integrase resistance. 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 SmPC 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: 498.75 for 30 x 50mg tablets EU/1/13/892/001. 99.75 for 30 x 10mg tablets (EU/1/13/892/003). 249.38 for 30 x 25mg tablets (EU/1/13/892/005). 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. Trade marks are owned by or licensed to the ViiV Healthcare group of companies. Date of approval: July 2017. Zinc code: UK/DLG/0055/13(11) Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441. 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: +353 1 676 4971, medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. POM S1A
PRESCRIBING INFORMATION TRIUMEQ (DOLUTEGRAVIR 50MG/ABACAVIR 600MG/LAMIVUDINE 300MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indication: HIV in over 12 years and > 40kg. Screen for HLA-B*5701 prior to use. Do not use if HLA-B*5701 positive. Dose: one tablet once daily with or without food. Elderly: Limited data in 65+ yrs. Creatinine clearance <50ml/min or moderate/severe hepatic impairment: Not recommended. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Both abacavir and dolutegravir are associated with risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Triumeq without delay if HSR suspected. Never reintroduce any dolutegravir- or abacavir-containing product after suspected HSR. Risks of immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise all modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Not recommended if dolutegravir required b.d. (with etravirine [without boosted PI], efavirenz, nevirapine, rifampicin, boosted tipranavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St John s Wort). Use with cladribine not recommended. Use with Mg/Alcontaining antacids, calcium, multivitamins or iron requires dosage separation. Caution with metformin: monitor renal function and consider metformin dose adjustment. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, myalgia, asthenia, fever, elevations of ALT, AST and CPK, blood dyscrasias, suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: 30 tablets: 798.16 EU/1/14/940/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Trade marks are owned by or licensed to the ViiV Healthcare group of companies. Date of approval: July 2017 Zinc code: UK/TRIM/0037/14(8) Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441. 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: +353 1 676 4971, medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.
PRESCRIBING INFORMATION KIVEXA (ABACAVIR 600MG/LAMIVUDINE 300MG TABLETS) (SEE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING) Indications: HIV in adults, adolescents and children weighing at least 25 kg as part of combination therapy. Screen for HLA-B*5701 prior to use. Dose: one tablet daily with or without food. Elderly: No pharmacokinetic data in 65+ yrs. Renal impairment: Creatinine clearance <50ml/min: not recommended. Hepatic impairment: not recommended in moderate or severe hepatic impairment. Monitor closely in mild hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Warnings/precautions: Risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Kivexa without delay if HSR suspected. Never reintroduce any abacavir-containing product after suspected HSR. Risks of virological failure, immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C coinfection. Inconclusive data on relationship between abacavir and MI; minimise modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Use with cladribine, emtricitabine or high doses of cotrimoxazole not recommended. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Hypersensitivity, GI disturbance, headache, anorexia, insomnia, rash, fever, lethargy, fatigue, malaise, arthralgia, muscle disorders, nasal symptoms, cough, alopecia, blood dyscrasias, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis. Basic NHS costs: 30 tablets: 299.41 EU/1/04/298/002. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Trade marks are owned by or licensed to the ViiV Healthcare group of companies. Date of approval: July 2017 Zinc code: UK/ABC3TC/0008/13(10) Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441. 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: +353 1 676 4971, medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.