TRIUMEQ * (DTG/ABC/3TC): BIOEQUIVALENCE DATA

Transcription

1 TRIUMEQ * (DTG/ABC/3TC): BIOEQUIVALENCE DATA *In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3tc 300 mg were used. Bioequivalence has been demonstrated. DTG, dolutegravir; ABC, abacavir; 3TC, lamivudine UK/TRIM/0048/14(2) Date of preparation: March2017 Prescribing information is available at the end of this presentation

2 DECLARATION OF INTEREST

3 INTRODUCTION: TRIUMEQ AND DTG + ABC/3TC BIOEQUIVALENCE In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3tc 300 mg were used Bioequivalence was demonstrated between the TRIUMEQ as a single-pill and the separate co-administered tablet formulations of DTG + ABC/3TC TRIUMEQ Summary of Product Characteristics, January 2017; Weller S et al. JAIDS 2014;66:393-8

4 Heavily Treatment- Experienced Continuing ART INIs BOOSTED Pls ATRIPLA KEY STUDIES SINGLE Treatment-naïve patients TRIUMEQ QD vs Atripla QD (N=833) SUPERIOR EFFICACY vs Atripla at weeks 48 (primary endpoint), 96 and 144 FLAMINGO Treatment-naïve patients DTG + 2 NRTIs QD vs DRV/r + 2 NRTIs QD (N=484) SUPERIOR EFFICACY vs darunavir/r at weeks 48 (primary endpoint) and 96 ARIA Treatment-naïve women TRIUMEQ QD vs ATV/r + TDF/FTC QD (N=495) SUPERIOR EFFICACY vs atazanavir/r at week 48 (primary endpoint) SPRING-2 Treatment-naïve patients DTG + 2 NRTIs QD vs RAL + 2 NRTIs BID (N=822) NON-INFERIOR EFFICACY vs raltegravir at weeks 48 (primary endpoint) and 96 SAILING Treatment-experienced, INI-naïve patients DTG QD + BR* vs RAL BID + BR* (N=719) SUPERIOR EFFICACY vs raltegravir at week 48 (primary endpoint) STRIIVING Treatment-experienced, stable-switch patients TRIUMEQ QD vs continuing ARV regimen (N=551) NON-INFERIOR EFFICACY up to weeks 24 (primary endpoint) and 48 VIKING-3 Heavily treatment experienced patients with RAL and/or EVG resistant HIV-1 DTG 50mg BD + OBR** (N=183)-single-arm study SUSTAINED EFFICACY up to weeks 24 (primary endpoint) and 48 DTG 50mg + ABC 600mg/3TC 300mg were used. Bioequivalence has been demonstrated.13 * BR - background regimen ** OBR - optimised background regimen 1. Clotet B et al. Lancet. 2014;383(9936): Orrell C et al. Presented at 21st International AIDS Conference, 18th-22nd July, 2016; Durban, South Africa. Abstract THAB0205LB. 3. Walmsley S et al. N Engl J Med. 2013;369(19): Walmsley S et al. J Acquir Immune Defic Syndr. 2015;70: Molina J-M et al. Lancet HIV.2015;2(4):e127-e136. January Raffi F et al. Lancet Infect Dis. 2013;13: Raffi F et al. Lancet. 2013; 381: Cahn P et al. Lancet. 2013; 382: Trottier B et al. Presented at 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, 17th-21st September, 2015; San Diego, CA. LB Lake JE et al. Presented at 21st International AIDS Conference, 18th-22nd July, 2016; Durban, South Africa. Abstract THAB Castagna A et al. J Infect Dis. 2014; 210:

5 BIOEQUIVALENCE

6 TRIUMEQ (DTG/ABC/3TC) SINGLE PILL REGIMEN BIOEQUIVALENCE: INTRODUCTION FDCs have greatly simplified the treatment of patients with HIV DTG is a booster-free INI approved for treatment of HIV-1 infection in combination with other antiretroviral agents ABC and 3TC are NRTIs available as a single pill (Kivexa ) The combination of DTG, ABC and 3TC as a single pill would have several potential advantages over other FDCs, including fewer drug interactions, once daily dosing, no need for boosting and no time-of-day or food restrictions DTG, ABC and 3TC as a single pill is suitable for HLA-B*5701-negative patients TRIUMEQ Summary of Product Characteristics, January 2017; Kivexa Summary of Product Characteristics, October 2016; Ramjan R et al. Trop Med Int Health 2014;19:501-13; Weller S et al. JAIDS 2014;66:393-8

7 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: OBJECTIVES Primary objective Evaluate single-dose bioequivalence in the fasted state between the TRIUMEQ (DTG/ABC/3TC; 50/600/300 mg) single-pill and DTG 50 mg given with separate ABC/3TC (600/300 mg) to healthy volunteers (Part A) Secondary objectives Evaluate the effect of food on the bioavailability of single-dose TRIUMEQ (Part B) Assess the safety and tolerability of single-dose administration of DTG, ABC and 3TC in healthy volunteers either fasted or with food Weller S et al. JAIDS 2014;66:393-8

8 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: STUDY DESIGN Pharmacokinetic study of TRIUMEQ vs component exposures and TRIUMEQ food effect Single-dose, open-label, randomised, two-period crossover study Part A: Bioequivalence 48-hour serial PK sampling 48-hour serial PK sampling Randomisation (N=65) Single-dose TRIUMEQ FDC (fasted) Single-dose DTG + ABC/3TC (fasted) Washout ( 7 days) Washout ( 7 days) Single-dose DTG + ABC/3TC (fasted) Single-dose TRIUMEQ FDC (fasted) 7 and 14 day follow up 7 and 14 day follow up Part B: Food effect 48-hour serial PK sampling Washout ( 7 days) 12 patients from Part A Single-dose TRIUMEQ FDC + high-fat meal Adapted from Weller S et al. JAIDS 2014;66:393-8

9 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: STUDY DESIGN Serial blood samples were collected up to 48 hours after each treatment for determination of AUC and C max for each of DTG, ABC and 3TC Plasma parameters such as AUC and C max are used to determine the pharmacokinetics (PK) of a drug Adapted from Weller S et al. JAIDS 2014;66:393-8 Point estimates and their associated 90% confidence intervals (CIs) were constructed for the differences, test treatment (A) reference treatment (B), for bioequivalence assessment

10 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: STUDY PROCEDURE There was a 7-day washout period between the second dose in part A and the dose in part B Adapted from Weller S et al. JAIDS 2014;66:393-8

11 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: STUDY POPULATION 65 subjects randomised to either Group 1 or Group 2 Group 1 received a single dose of Triumeq FDC followed by DTG + ABC/3TC Group 2 received DTG + ABC/3TC followed by a single dose of TRIUMEQ FDC 62 subjects completed the study

12 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: PATIENT DEMOGRAPHICS Part A Part B Demographics TRIUMEQ fasted (n=65) DTG + ABC/3TC fasted (n=65) TRIUMEQ fed (n=12) Age, mean (SD), years 29.3 (9.59) 29.3 (9.55) 33.8 (11.06) Sex, n (%) Female 22 (34%) 22 (34%) 4 (33%) Male 43 (66%) 43 (66%) 8 (67%) BMI, mean (SD), kg/m (3.72) (3.71) (3.09) Height, mean (SD), cm (10.01) (9.97) (11.64) Weight, mean (SD), kg (13.72) (13.48) (14.75) Race, n (%) African American/African heritage 25 (38%) 25 (38%) 5 (42%) White White/Caucasian/European heritage 34 (52%) 34 (52%) 7 (58%) BMI, body mass index; SD, standard deviation Adapted from Weller S et al. JAIDS 2014;66:393-8

13 Concentration (µg/ml) Concentration (µg/ml) Concentration (µg/ml) TRIUMEQ SINGLE PILL REGIMEN IS BIOEQUIVALENT TO DTG + ABC/3TC (1) Mean plasma concentration time plots (linear) TRIUMEQ FDC fasted (n=65) DTG + ABC/3TC fasted (n=65) 2.5 Mean plasma DTG concentration-time Mean plasma ABC concentration-time 2.5 Mean plasma 3TC concentration-time Planned relative time (h) Planned relative time (h) Planned relative time (h) Adapted from: ViiV Healthcare. Data on File: UK/DLG/0094/14; July 2016

14 TRIUMEQ SINGLE PILL REGIMEN IS BIOEQUIVALENT TO DTG + ABC/3TC (2) Geometric mean ratios and 90% confidence intervals for TRIUMEQ single pill vs DTG + ABC/3TC co-administration (n=65) Zone of bioequivalence ( ) Dolutegravir AUC 0- C max Abacavir Lamivudine AUC 0- C max AUC 0- C max Bioequivalence was shown for all 3 TRIUMEQ components in the single-pill formulation vs separate administration of DTG and ABC/3TC AUC, area under the curve; C max, maximum observed plasma concentration Adapted from: Weller S et al. JAIDS 2014;66:393-8

15 TRIUMEQ SINGLE PILL REGIMEN IS BIOEQUIVALENT TO DTG + ABC/3TC (3) 90% confidence intervals for the geometric mean ratios of key exposure parameters between the FDC and the separate tablets fell within the standard range for all 3 components, confirming bioequivalence Study part A: summary and statistical comparison of selected PK parameters for BE assessment FDC fasted GLS mean (n=62) DTG + ABC/3TC fasted GLS mean (n=62) Ratio of GLS mean (90% CI) DTG PK parameters AUC 0, µg h/ml [0.889, 1.00] AUC 0 t, µg h/ml [0.888, 1.00] C max, µg/ml [0.906, 1.02] ABC PK parameters AUC 0, µg h/ml [0.939, 0.980] AUC 0 t, µg h/ml [0.939, 0.980] C max, µg/ml [0.867, 0.977] 3TC PK parameters AUC 0, µg h/ml [0.940, 1.01] AUC 0 t, µg h/ml [0.928, 0.994] C max, µg/ml [0.885, 0.968] CI, confidence interval; GLS, geometric least squares; PK, pharmacokinetic Adapted from: Weller S et al. JAIDS 2014;66:393-8

16 CHANGES IN DTG, ABC AND 3TC EXPOSURE AND C max WITH FOOD Study part B: statistical comparison of selected PK parameters for food effect assessment DTG PK parameters Ratio of GLS mean [90% CI] TRIUMEQ fed vs TRIUMEQ fasted AUC [1.36, 1.62] AUC 0 t 1.47 [1.35, 1.60] C max 1.37 [1.26, 1.48] ABC PK parameters AUC [0.899, 0.953] AUC 0 t [0.898, 0.952] C max [0.662, 0.905] 3TC PK parameters AUC [0.971, 1.12] AUC 0 t 1.05 [0.963, 1.14] C max [0.879, 1.05] Adapted from: Weller S et al. JAIDS 2014;66:393-8

17 TRIUMEQ AND FOOD DTG plasma exposures with a high-fat meal Approximately 48% higher for AUC and 37% higher for C max than in the fasted condition Indicate that TRIUMEQ can be taken with or without food ABC and 3TC plasma exposures with a high-fat meal Generally similar to fasted exposures C max for ABC was 23% lower with food Consistent with prior results for ABC/3TC, which may be taken with or without food Weller S et al. JAIDS 2014;66:393-8; TRIUMEQ Summary of Product Characteristics, January 2017

18 Adapted from Weller S et al. JAIDS 2014;66:393-8 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: SUMMARY OF DRUG-RELATED AEs Study Part A Only (no events for Part B) Preferred term TRIUMEQ fasted (n=65) DTG + ABC/3TC fasted (n=65) Patients with any drug-related AE, n (%) 12 (18%) 18 (28%) Nausea 10 (15%) 18 (28%) Headache 2 (3%) 4 (6%) Abdominal pain 0 1 (2%) Vomiting 1 (2%) 0 Dizziness 1 (2%) 0 Feeling hot 0 1 (2%)

19 TRIUMEQ SINGLE PILL REGIMEN BIOEQUIVALENCE: CONCLUSIONS Bioequivalence was demonstrated between TRIUMEQ as a single pill and the separate co-administered tablet formulations of DTG + ABC/3TC TRIUMEQ may be taken with or without food Tolerability results (single-dose, healthy volunteers) Part A: numerically fewer drug-related AEs with TRIUMEQ compared with separate DTG + ABC/3TC (18% vs 28%, respectively) Part B: no adverse events were reported Weller S et al. JAIDS 2014;66:393-8; TRIUMEQ Summary of Product Characteristics. January 2017

20 TRIUMEQ INDICATION TRIUMEQ is indicated for the treatment of HIV-infected adults and adolescents who: are above 12 years of age, and weigh at least 40 kg TRIUMEQ is not recommended for use in patients with: HLA-B*5701 allele a creatinine clearance below 50 ml/min, or moderate or severe hepatic impairment TRIUMEQ is contraindicated: in patients with hypersensitivity to dolutegravir, abacavir, lamivudine or to any of the tablet excipients for use with dofetilide* co-administration *Dofetilide is not licensed in the UK or Ireland TRIUMEQ Summary of Product Characteristics, January 2017

21 HLA / HYPERSENSITIVITY CONSIDERATIONS Hypersensitivity reactions have been observed more commonly with abacavir, some of which have been life-threatening, and in rare cases fatal, when not managed appropriately. The risk for abacavir HSR to occur is high for patients who test positive for the HLA B*5701 allele. However, abacavir HSRs have been reported at a low frequency in patients who do not carry this allele. Before initiating treatment with TRIUMEQ, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin TRIUMEQ should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir HSR on a previous abacavir-containing regimen TRIUMEQ Summary of Product Characteristics, January 2017

22 TRIUMEQ : SPECIAL WARNINGS AND PRECAUTIONS FOR USE Liver disease Patients with chronic hepatitis B or C Immune Reactivation Syndrome Mitochondrial dysfunction Myocardial infarction Weight and metabolic parameters Osteonecrosis Opportunistic infections Drug resistance Drug interactions TRIUMEQ Summary of Product Characteristics, January 2017

23 ABBREVIATIONS 3TC, lamivudine ABC, abacavir AE, adverse event AUC, area under the curve BE, bioequivalence BID, twice daily BMI, body mass index CI, confidence interval CL/F, Apparent total clearance of the drug from plasma after oral administration C max, maximum observed plasma concentration CNS, central nervous system DRV, darunavir DRV/r, darunavir/ritonavir DTG, dolutegravir EFV, efavirenz EVG, elvitegravir FDC, fixed-dose combination FTC, emtricitabine GLS, geometric least squares HIV, human immunodeficiency virus INI, integrase inhibitor NRTI, nucleoside reverse transcriptase inhibitor PK, pharmacokinetic QD, once daily RAL, raltegravir SD, standard deviation TDF, tenofovir disoproxil fumarate

24 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/Al-containing 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: 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 Triumeq is a registered trademark of the ViiV Healthcare Group of Companies. Date of approval: January 2017 Zinc code: UK/TRIM/0037/14(7) 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

25 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

26 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 co-infection. 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 co-trimoxazole 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: 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 Kivexa is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: October 2016 Zinc code: UK/ABC3TC/0008/13(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 S1A