The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: GSK3532795 (formerly ) Study Number: 25891 (Bristol-Myers Squibb [BMS] Study Number: AI46838) Title: A Phase 2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy and Doseresponse of /GSK3532795, Given on a Backbone of Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults Rationale: Existing antiretroviral (ARV) therapies have safety (both short and longer term) and tolerability associated concerns. This study was conducted to evaluate the efficacy of three doses of /GSK3532795 (a novel second generation human immunodeficiency virus [HIV] maturation inhibitor) when given in combination with tenofovir/emtricitabine (). This study was to provide supportive data to select a safe and therapeutic dose of /GSK3532795 for subsequent development. NOTE: ViiV Healthcare (VH) purchased the HIV portfolio from Bristol-Myers Squibb (BMS) in February 216. This included the Maturation Inhibitor GSK3532795 (formerly known as ). Phase: 2b Study Period: 28-Jan-215 to 26-May-216 Study Design: This was a randomized, active-controlled, double-blind clinical trial. Subjects were randomized 1:1:1:1 to one of four different treatment arms. The study consisted of Screening, Baseline visit (Day 1), optional Week 2 intensive pharmacokinetic (PK) Visit, Visits Week 4 Week 96, and a follow-up visit. The study ended early after Week 24 for virologic resistance and gastrointestinal (GI) intolerability. Centres: 58 centres in 12 countries (United States [9 centres], Germany [7 centres], Canada [6 centres], Spain [6 centres], Argentina [5 centres], France [5 centres], Italy [4 centres], Mexico [4 centres], South Africa [4 centres], Chile [3 centres], Poland [3 centres], and United Kingdom [2 centres]). Indication: Human Immunodeficiency Virus Infection Treatment: Subjects were to receive 6 milligrams (mg) once daily (QD)+ 3/2 mg QD; or 12 mg QD+ 3/2 mg QD; or 18 mg QD+ 3/2 mg QD; or efavirenz (EFV) 6 mg QD+ 3/2 mg QD for a duration of 96 weeks. Objectives: To evaluate antiviral efficacy of 3 doses (6, 12 and 18 mg) of /GSK3532795, and EFV, each when given in combination with tenofovir/emtricitabine () by determining the proportion of treatmentnaïve subjects with plasma HIV-1 RNA <4 copies per millilitre (c/ml) at Week 24 Primary Endpoint/Efficacy: The primary endpoint was the proportion of subjects with plasma HIV-1 RNA <4 c/ml at Week 24. Secondary Outcome (Endpoints)/Efficacy: The antiviral efficacy was to be determined by the proportion of subjects with plasma HIV-1 ribonucleic acid (RNA) <4 c/ml at Weeks 48 and 96 using the Food and Drug Administration (FDA) snapshot algorithm The antiviral efficacy was also to be assessed by the proportion of subjects with plasma HIV-1 RNA <2 c/ml at Weeks 24, 48, and 96 using the FDA snapshot algorithm approach with positive response defined as HIV-1 RNA <2 c/ml The emergence of HIV drug resistance among samples selected for drug resistance testing was to be assessed using the most recent version of the International acquired immune deficiency syndrome (AIDS) Society (IAS- USA) list of HIV-1 drug resistance mutations Changes from baseline in log1 HIV-1 RNA and in cluster of differentiation 4 (CD4)+ cell counts and changes in the percentage of CD4+ cells over time were to be assessed using on-treatment laboratory results and prespecified visit windows The frequency of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation (DC) were tabulated directly from the case report forms (CRFs). The summary counted the number of subjects that have at least one event. The occurrence of new AIDS defining events (Centers for Disease Control and Prevention [CDC] Class C events) were to be tabulated from the CRFs. The summary counted the number of subjects that have at least one event. The steady-state plasma PK of /GSK3532795 was to be assessed using the intensive PK data, collected at Week 2 from a subset of subjects 1
Statistical Methods: Analysis Populations: Enrolled subjects: Subject who signed an informed consent form and were assigned a Patient Identification number (PID) Randomized subjects: Enrolled subjects who received a treatment assignment from the interactive voice response system (IVRS) Treated subjects: Randomized subjects who received at least 1 dose of /GSK3532795 or EFV Modified Intent to Treat Analysis Set [mitt]): All randomized subjects who received at least 1 dose of BMS- 955176/GSK3532795 or EFV. Observed analysis set: A collection of subjects that have data within an interval of interest. Evaluable PK population: all treated subjects who have adequate PK profiles Statistical Analysis: In general, categorical variables were tabulated with counts and percents. Continuous variables were summarized with univariate statistics (eg, mean, median, standard error). Longitudinal analyses use pre-defined visit week windows. Unless otherwise specified, windows around planned measurement times are constructed based on the midpoint between planned study visits (ie, half the duration of time between study visits), and data are summarized at each scheduled visit. For the calculation of descriptive statistics of observed data, subjects must have a baseline measurement to be evaluable for longitudinal tabulations of parameter values and changes from baseline. Tabulations of the following endpoints present the number of unique subjects with an event: protocol deviations; interruptions of study therapy; non-study medications; adverse events; and laboratory abnormalities. Thus, multiple occurrences of the same event are counted only once per subject. Efficacy Analyses The efficacy analyses were based on the treated subjects. Primary Efficacy Analysis(es) The primary efficacy endpoint is the proportion of subjects with plasma HIV-1 RNA < 4 c/ml at the Week 24 snapshot. This endpoint is assessed with the FDA snapshot algorithm. The primary analysis was based on a modified ITT (mitt) approach. A sensitivity analysis was conducted using an observed values approach. Response rates were tabulated by treatment arm with exact binomial 95% confidence intervals. Subgroup summaries were provided to examine the impact of baseline viral load and HIV-1 Clade AE (Clade AE versus Other) for both the mitt and the observed values approach. Secondary Efficacy Analysis(es) The secondary endpoints were summarized by treatment arm. Pharmacokinetic Analyses at Week 2 Geometric means and coefficients of variation (CV) were presented for maximum concentration (Cmax), area under the concentration time curve over one dosing interval [AUC(TAU)], the pre-dose plasma concentration (C), and the plasma concentration at the end of one dosing interval (i.e. 24 hours post-dose, Ctau). Medians and ranges were presented for the time of maximum plasma concentration (Tmax). Study Population: Men and non-pregnant women, at least 18 years of age who were antiretroviral treatment-naïve (defined as no current or previous exposure to >1 week of an antiretroviral drug) with plasma HIV-1 RNA 1 c/ml and CD4 T-cell count >2 cells/cubic millimetre (mm 3 ) were included in the study. Subjects with resistance or partial resistance to any study drug; current or historical genotypic and/or phenotypic drug resistance testing showing resistance to EFV, tenofovir (TDF), emtricitabine (FTC), certain thymidine analog mutations (TAMs) and certain protease inhibitor (PI) mutations; positive hepatitis B virus (HBV)/hepatitis C virus (HCV) were excluded from the study. 6 mg+ 12 mg+ 18 mg+ EFV 6 mg+ Number of Subjects: Planned 5 5 5 5 Randomised, N 52 53 52 53 Total Number Subjects Withdrawn, 1 (19.2) 11 (2.8) 1 (19.2) 1 (18.9) N (%) Withdrawn due to Adverse Events 3 (5.7) 5 (9.6) 9 (17.) n (%) Withdrawn due to Lack of Efficacy 3 (5.8) 4 (7.5) 2
n (%) Withdrawn for other reasons n (%) 6 (11.5) 4 (7.5) 5 (9.6) Demographics EFV 6 mg+ 6 mg+ 12 mg+ 18 mg+ N (mitt) 5 52 51 53 Females: Males 8:42 8:44 7:44 7:46 Mean Age, years (SD) White, n (%) 31.8 (8.26) 39 (78.) 34.7 (11.29) 38 (73.1) 35.5 (11.34) 41 (8.4) 32.9 (9.35) 4 (75.5) Primary Efficacy Results: Proportion of Responders (HIV-1 RNA <4 c/ml) at Week 24 Snapshot (mitt) 6 mg+ N=5 12 mg+ 18 mg+ EFV6 mg+ HIV-1 RNA <4 c/ml a, n (%) [95% 38 (76.) [61.8-43 (82.7) [69.7-42 (82.4) [69.1-41 (77.4) confidence interval] 86.9] 91.8] 91.6] [63.8-87.7] HIV-1 RNA >=4 c/ml, n (%) 1 (2.) 7 (13.5) 4 (7.8) 3 (5.7) No Virologic data in window, n (%) 2 (4.) 2 (3.8) 5 (9.8) 9 (17.) a=response was assessed with the snapshot algorithm, which used the last plasma HIV-1 RNA value in the predefined visit window to classify a subject's response status. Secondary Outcome Results: Proportion of Responders (HIV-1 RNA <2 c/ml) at Week 24 Snapshot (mitt) 6 mg+ N=5 12 mg+ 18 mg+ EFV 6 mg+ HIV-1 RNA <2 c/ml a, n (%) 4 ( 8.) 44 (84.6) 43 (84.3) 44 (83.) HIV-1 RNA >= 2 c/ml, n (%) 8 (16.) 6 (11.5) 2 (3.9) No Virologic data in window, n (%) 2 (4.) 2 (3.8) 6 (11.8) 9 (17.) a = Response was assessed with the snapshot algorithm, which used the last plasma HIV-1 RNA value in the predefined visit window to classify a subject's response status. Newly Emergent Genotypic Resistance Profile (mitt) 6 mg+ N=5 12 mg+ 18 mg+ EFV 6 mg+ Underwent resistance testing n (%) 5 (1) 6 (1) 4 (1) 1 (1) Sequenced 5 (1) 5 (83.3) 2 (5) 1 (1) RT Substitution 3 (6) 5 (1) 2 (1) NRTI substitutions 3 (6) 5 (1) 2 (1) K65K/R 1 (5) K7K/E 1 (2) M184 3 (6) 5 (1) 2 (1) I 1 (2) 1 (2) I/V 1 (2) V 2 (4) 3 (6) 2 (1) NNRTI substitutions 1 (2) 1 (2) V16V/I 1 (2) E138E/G 1 (2) Summary Statistics for Change from Baseline Over Time in HIV-1 RNA (log1 c/ml) Mean (SD) EFV 6 mg+ 6 mg+ 12 mg+ 18 mg+ N=5 Pre-treatment (Baseline) 4.336 (.6689) 4.299 (.7289) 4.222 (.682) 4.489 (.7295) 3
absolute value Changes from Baseline: Mean (SD) Mean (SD) Mean (SD) Mean (SD) Week 4: Day 29-2.82 (.587) -2.74 (.5382) -2.143 (.593) -2.315 (.4597) Week 8: Day 57-2.38 (.6995) -2.254 (.796) -2.335 (.641) -2.515 (.642) Week 12: Day 85-2.372 (.8221) -2.343 (.7584) -2.442 (.6373) -2.73 (.6252) Week 16: Day 113-2.53 (.8656) -2.423 (.7964) -2.514 (.6426) -2.876 (.699) Week 24: Day 169-2.56 (.813) -2.548 (.7937) -2.57 (.7279) -2.919 (.7586) Week 32: Day 225-2.517 (.839) -2.66 (.7349) -2.582 (.6551) -2.878 (.7542) Week 4: Day 281-2.913 (.5622) -2.846 (.5992) -2.673 (.5465) -2.829 (.7215) Week 48: Day 337-2.48 (.676) -2.538 (.5144) -2.767 (.678) -2.97 (.598) Summary Statistics for Change from Baseline Over Time in CD4 Cell Count (cells/microliter [µl]) Mean (SD) 6 mg+ N=5 12 mg+ 18 mg+ EFV 6 mg+ Screening (Baseline) absolute 458.2 (232.15) 46.6 (214.5) 441.7 (182.98) 414.4 (162.72) value Changes from Baseline: Mean (SD) Mean (SD) Mean (SD) Mean (SD) Week 4: Day 29 41.6 (148.92) 71.5 (169.22) 52.9 (149.54) 71.1 (145.1) Week 8: Day 57 59.1 (219.64) 8.4 (127.52) 88.4 (177.68) 117.4 (23.74) Week 12: Day 85 11.4 (17.87) 118.6 (179.42) 129.7 (175.73) 142.5 (118.39) Week 16: Day 113 Week 24: Day 169 9.8 (2.76) 94.3 (175.) 98.4 (173.53) 79.7 (199.46) 128. (212.9) 92.5 (144.4) 14.5 (179.7) 134.7 (151.7) Week 32: Day 225 Week 4: Day 281 114.8 (19.12) 176.1 (161.74) 96.2 (167.77) 342.3 (25.51) 97.7 (174.75) 152.8 (219.4) 171.5 (148.97) 199.3 (161.7) Week 48: Day 337 94.6 (15.21) 194.5 (13.27) 28.7 (9.61) 289. (244.9) Safety Results: An on therapy AE was defined as an AE with onset on or after the start date of study medication but not later than one day after the last date of study medication. An on therapy serious adverse event (SAE) was defined as a SAE with onset on or after the start date of study medication and up to 3 days after the last dose of medication. EFV 6 mg+ 6 mg+ 12 mg+ 18 mg+ N=5 Subjects with any AEs, n(%) 41 (82.) 45 (86.5) 45 (88.2) 48 (9.6) Subjects with any AEs leading 1 (2.) 3 (5.8) 4 (7.8) 9 (17.) to discontinuation of study drug, n(%) Most Frequent Adverse Events n (%) n (%) n (%) n (%) On-Therapy Diarrhoea 19 (38.) 19 (36.5) 31 (6.8) 6 (11.3) Abdominal pain Nausea 4 (8.) 3 (6.) 5 (9.6) 4 (7.7) 11 (21.6) 6 (11.8) 7 (13.2) Vomiting 2 (4.) 5 (9.6) 3 (5.9) Abdominal pain upper 3 (6.) 3 (5.8) 4 (7.8) Dyspepsia 5 (9.6) 1 (2.) Pharyngitis Upper respiratory tract infection 5 (1.) 3 (6.) 3 (5.8) 6 (11.5) 2 (3.9) 2 (3.9) 3 (5.7) Influenza 2 (4.) 5 (9.6) 1 (2.) 3 (5.7) 4
Nasopharyngitis 3 (6.) 3 (5.8) 4 (7.8) Sinusitis 3 (6.) 1 (2.) Conjunctivitis Dizziness 3 (6.) 2 (3.8) 2 (3.9) 19 (35.8) Headache 3 (5.8) 4 (7.8) 6 (11.3) Insomnia 1 (2.) 8 (15.7) 2 (3.8) Abnormal dreams 4 (7.7) 1 (2.) 5 (9.4) Fatigue Back pain 3 (6.) 1 (2.) 3 (5.9) 4 (7.8) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] 6 mg+ N=5 12 mg+ 18 mg+ EFV 6 mg+ Subjects with non-fatal SAEs, n (%) [related] 1 (2.) 2 (3.8) [1] 1 (2.) 5 (9.4) [1] Abdominal pain Colitis Ulcerative 1 (2.) [1] Toothache Intervertebral discitis Urinary tract infection 1 (2.) Ventricular extrasystoles Overdose Hepatic enzyme increased [1] Pneumothorax spontaneous Subjects with fatal SAEs, n (%) CDC Class C AIDS Events 6 mg+ N=5 12 mg+ 18 mg+ EFV 6 mg+ Oesophageal Candidiasis Pharmacokinetic Results for /GSK3532795 at Week 2: 6 mg+ 12 mg+ 18 mg+ Cmax (ng/ml) Tmax (h) Median [n] (Min-Max) AUC(TAU) (ng.h/ml) C (ng/ml) Ctau (ng/ml) 1945 [8] (16) 4. [8] (1.58-8.17) 34227 [8] (19) 165 [8] (25) 11 [9] (15) 3162 [6] (29) 4.29 [6] (3.98-5.12) 55252 [6] (33) 181 [6] (33) 1657 [6] (4) 4645 [1] (16) 5.5 [1] (1.-12.) 87128 [1] (21) 2729 [1] (18) 276 [1] (27) Conclusion: Overall, 76% to 82.7% of subjects on /GSK3532795 treatment arms and 77.4% of subjects on EFV treatment arm had HIV-1 RNA < 4 c/ml at Week 24 (mitt snapshot algorithm). Although the efficacy of /GSK3532795 12 and 18 mg arms was similar to the EFV reference arm, a relatively higher and unacceptable rate of GI intolerability and higher rate of NRTI resistance was observed across all three BMS- 955176/GSK3532795 treatment arms. In 6 mg+ group, 41 subjects were reported with AEs with the most frequently reported being diarrhoea and pharyngitis. In 12 mg+ group, 45 subjects were reported with AEs with the most frequently reported being 5
diarrhoea and upper respiratory tract infection. In 18 mg+ group, 45 subjects were reported with AEs with the most frequently reported being diarrhoea and abdominal pain. In EFV 6 mg+ group, 48 subjects were reported with AEs with the most frequently reported being dizziness and nausea. One subject each in 6 mg+ and 18 mg+ groups were reported with non-fatal SAEs; 2 subjects in 12 mg+ group and 5 subjects in EFV 6 mg+ group were reported with non-fatal SAEs. There were no fatal SAEs reported in the study. Based upon the AI468-38/25891 Week 24 primary endpoint analysis, it was determined that BMS- 955176/GSK3532795 was not optimal for Phase 3 development due to GI intolerability and treatment-emergent resistance, and the compound will not be advanced into planned Phase 3 studies. 6