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GSK2336805

Phase 2

Hepatitis C, Chronic | Small molecule | Infectious Disease |GSK plc|Last Updated: Dec 11, 2017

Success Probability
Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
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Market & Valuation
rNPV $3.2B
Market Size $9.4B
Revenue Basis $1.6B
Competitors 6
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Trial Design
RandomizedDouble-BlindACTIVE_CONTROLLEDBiomarker
Total Trials2
Total Enrollment302
FDA Designations
No designations recorded
Clinical Trials (2)
NCT IDTitlePhaseStatusEnrollmentVelocityDesignStartCompletionLast UpdatedSitesCountries
NCT01648140Dose Ranging of GSK2336805 in Combination TherapyPHASE2 COMPLETED 286Aug 1, 2012Jul 16, 2014Jun 2, 201734 United States, Belgium +4
NCT01439373Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 With Peginterferon and Ribavirin in Chronic Hepatitis C SubjectsPHASE2 COMPLETED 16Jul 7, 2011Dec 5, 2011Dec 11, 201710 United States, Puerto Rico
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Study Endpoints
Primary Endpoints
Number of Participants Achieving eRVR
Week 4 and Week 12

eRVR is defined as plasma HCV ribonucleic acid (RNA) \<lower limit of quantification (LLOQ) and target not detected at Weeks 4 and 12. Participants who discontinued prior to Week 12 assessments or had missing HCV RNA values at Weeks 4 and 12 were treated as non-responders.

Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) up to Week 12
From the start of study treatment up to Week 12

An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, or disease(new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points up to Week 12
Baseline (Week 0) up to 12-week treatment period

Blood pressure measurements were taken to observe vital signs and included SBP and DBP at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and Post-treatment (PT) Follow Up (FU) Weeks 4, 12 and 24. Change from Baseline in SBP and DBP is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Heart Rate at the Indicated Time Points up to Week 12
Baseline (Week 0) and Day 2, Weeks 1, 2, 4, 6, 8, and 12

Vital sign monitoring included heart rate, measured at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4, 12 and 24. Change from Baseline in heart rate is summarized for each post-Baseline assessment upto Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the basophils, eosinophils, lymphocytes, total neutrophils, platelet count and white blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of red blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the red blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of hemoglobin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hemoglobin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Hematocrit at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of hematocrit at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hematocrit values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of mean corpuscle volume at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the mean corpuscle volume values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Albumin at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of albumin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the albumin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of ALP, ALT, AST, CK and GGT at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4 Change from Baseline in the ALP, ALT, AST, CK and GGT values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Direct Bilirubin, Total Bilirubin and Creatinine at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of direct bilirubin, total bilirubin and creatinine at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the direct bilirubin, total bilirubin and creatinine values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Chloride, Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus and Urea/Blood Urea Nitrogen (BUN) at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of Chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Creatinine Clearance at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Blood samples were collected for the measurement of Creatinine Clearance at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. It is estimated by Cockcroft-Gault Equation. Change from Baseline in the Creatinine Clearance values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Number of Participants With Shift From Baseline in Urinalysis Data up to Week 12
Baseline (Week 0), Weeks 2 and 12

Urine samples were collected for urinalysis at Baseline, Weeks 2, 12, 18, 24, 48 and PT FU Weeks 4. Number of participants with shift from Baseline in urinalysis to normal (NL), abnormal (ANL) and missing (MIS) data up to Week 12 are summarized. Urine bilirubin (UBIL), urine glucose (UGLU), urine ketones (UKET), urine leukocyte esterase test (ULET) for detecting WBC, urine nitrite (UNIT), urine occult blood (UOB) were performed with dipstick method. Urine microscopy (UM) is performed to detect bacteria (BAC), red blood cells (RBC) and white blood cells (WBC). Other urinalysis parameter included urine pH (UpH) and urine specific gravity (USG). Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in Electrocardiographic (ECG) Heart Rate Values at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1 and 12

The ECG parameter heart rate was measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Mean Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval and QT Interval Corrected Bazett's Formula (QTcB), QT Interval Corrected Using Fridericia's Formula (QTcF) Values at the Indicated Time Points up to Week 12
Baseline (Week 0) and Weeks 1 and 12

The ECG parameters including PR interval, QRS duration, uncorrected QT interval, QTcB, QTcF were measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG parameters are summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis
Day 28

RVR was defined as the proportion of participants below the assay lower limit of detection (LOD) \<18 International units per milliliter (IU/mL) for Hepatitis C virus (HCV) ribonucleic acid (RNA) after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure . Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants.

Number of Participant Achieving RVR at Day 28, (Primary and Supportive Analyses)
Day 28

RVR was defined as the proportion of participants LOD \<18 IU/mL for HCV RNA after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure. Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants. The primary and supportive analysis differs from the nominal analysis as supportive analysis is assessed at Day 28 ± 2 (2 days visit window) whereas, the nominal analysis was assessed at Day 28.

Probability of Participants With HCV Genotype 1 Achieving RVR At Day 28, Nominal Analysis
Day 28

The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed by nominal analysis was reported.

Probability of Participants With HCV Genotype 1 Achieving RVR at Day 28, Primary and Supportive Analyses
Day 28

The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed was reported.

Number of Participants With HCV Genotype 1 With Virologic Response
Day 7, 14 and 21

Serum for determination of HCV genotype was collected at the screening visit. Genotype was determined by the VERSANT HCV genotype 2.0 Assay (LiPA). Number of participants with HCV genotype 1 were reported.

Change From Baseline in HCV Viral Load During 24 Hour (h) Following a Single Dose of GSK2336805 on the Log 10 Scale
Day 1 (Baseline [Pre-dose], 1, 2, 4, 6, and 8 and 24 h)

Blood samples for determination of HCV RNA levels were collected at immediately prior to and 1, 2, 4, 6, and 8 and 24 h after the first dose in Part 1 (Day 1). Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. Change from Baseline was computed as value at post Baseline specified time point minus Baseline value. Virus RNA levels reported as \<43 are undetectable levels. If the result for HCV RNA (IU/ML) was \<43, then change from Baseline was calculated using 42, and the change from Baseline on the log scale was calculated using log (42).

Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE) During Treatment Period
Up to Day 28

AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Change From Baseline in QTcF Interval at Day 2 and 28
Baseline (Day 1, Pre-dose ), Day 2 and Day 28

Single 12-lead electrocardiogram (ECG) was obtained. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. QTc Interval was calculated using Frederica correction formula: QTcF = QT / (RR)\^1/3. Change from Baseline was calculated by subtracting the Baseline assessment value from post Baseline visit value. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. The change from Baseline in QTc Interval at Day 2 and 28 were reported.

Secondary Endpoints
Number of Participants With Any AEs and Any SAEs After Week 12
From Week 12 up to PT Week 24 FU
Number of Participants Achieving Very Rapid Virologic Response (vRVR), Rapid Virologic Response (RVR), Complete Early Virologic Response (cEVR), Sustained Virologic Response 12 and 24 (SVR12 and SVR24) With Response Guided Treatment (RGT)
From the start of the treatment up to PT FU Week 24
Mean GSK2336805 Plasma Concentrations on Day 1, Day 2, Week 4, and Week 12
Day 1, Day 2, Week 4, and Week 12
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Study Design & Arms
AllocationRANDOMIZED
MaskingDOUBLE
ModelPARALLEL
PurposeTREATMENT
Treatment Arms
ArmTypeDescription
T40EXPERIMENTALHepatitis C virus (HCV) genotype 1 GSK2336805 40 mg, pegylated interferon alpha-2a, and ribavirin arm
T60EXPERIMENTALHepatitis C virus (HCV) genotype 1 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm
PRTACTIVE_COMPARATORHepatitis C virus (HCV) genotype 1 Telaprevir, pegylated interferon alpha-2a, and ribavirin arm
G4EXPERIMENTALHepatitis C virus (HCV) genotype 4 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm
GSK2336805EXPERIMENTALStudy Part 1
PlaceboPLACEBO_COMPARATORStudy Part 1
GSK2336805 + pegylated interferon alfa-2a + ribavrinEXPERIMENTALStudy Part 2
Placebo + pegylated interferon alfa-2a + ribavirinACTIVE_COMPARATORStudy Part 2
Interventions
NameTypeDescription
GSK2336805 40 mgDRUG20 mg tablet, round, 10-mm diameter, white to off-white, no markings
GSK2336805 60 mgDRUG30 mg tablet, round, 10-mm diameter, white to off-white, no markings
Pegylated interferon alpha-2aDRUG180 microgram per 0.5 mL prefilled syringe for single use
RibavirinDRUG200-mg tablet, capsule-shaped, light blue, film-coated, and debossed with "200" on 1 side and the logo "3RP" on the other side
TelaprevirDRUG375 mg film-coated tablet
GSK2336805DRUGActive Investigational Drug
Pegylated interferon alfa-2aDRUGStandard of Care drug
GSK2336805 Matching PlaceboDRUGPlacebo of Investigational Drug
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Eligibility Criteria
Age Range18 Years — 70 Years
SexALL
Healthy VolunteersNo
Study Sites34

Inclusion Criteria: * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Male or female aged 18 to 70 years of age, inclusive, at Screening. * Genotype 1 or genotype 4 hepatitis C virus (HCV) infection as assess...

Countries:United StatesBelgiumBulgariaFranceGermanyPuerto Rico
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