Therapeutic Goods Administration
First Round CER report: 19 October 2014Second Round CER report: 4 January 2015
AusPAR Attachment 2
Extract from the Clinical Evaluation Report for ledipasvir / sofosbuvir
Proprietary Product Name: Harvoni
Sponsor: Gilead Sciences Pty Ltd
About the Therapeutic Goods Administration (TGA)
· The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices.
· The TGA administers the Therapeutic Goods Act 1989, applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.
· The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
· The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
· To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au.
About the Extract from the Clinical Evaluation Report
· This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities.
· The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted.
· For the most recent Product Information (PI), please refer to the TGA website https://www.tga.gov.au/product-information-pi>.
Copyright
© Commonwealth of Australia 2015
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
Therapeutic Goods Administration
Contents
Common abbreviations 5
1. Background 12
1.1. Submission type 12
1.2. Drug class and therapeutic indication 12
1.3. Dosage forms and strengths 12
1.4. Dosage and administration 12
2. Clinical rationale 13
3. Contents of the clinical dossier 13
3.1. Scope of the clinical dossier 13
3.2. Paediatric data 14
3.3. Good clinical practice 14
4. Pharmacokinetics 14
4.1. Studies providing pharmacokinetic data 14
4.2. Summary of pharmacokinetics for sofosbuvir 15
4.3. Summary of pharmacokinetics for ledipasvir 17
4.4. Summary of pharmacokinetics for sofosbuvir/ledipasvir 22
4.5. Evaluator’s overall conclusions on pharmacokinetics 24
5. Pharmacodynamics 24
5.1. Studies providing pharmacodynamic data 24
5.2. Summary of pharmacodynamics 25
5.3. Evaluator’s overall conclusions on pharmacodynamics 26
6. Dosage selection for the pivotal studies 26
7. Clinical efficacy 26
7.1. Chronic Hepatitis C Genotype 1 26
8. Clinical safety 39
8.1. Studies providing evaluable safety data 39
8.2. Pivotal studies that assessed safety as a primary outcome 39
8.3. Patient exposure 40
8.4. Adverse events 40
8.5. Laboratory tests 43
8.6. Post-marketing experience 45
8.7. Safety issues with the potential for major regulatory impact 45
8.8. Other safety issues 46
8.9. Evaluator’s overall conclusions on clinical safety 46
9. First round benefit-risk assessment 46
9.1. First round assessment of benefits 46
9.2. First round assessment of risks 48
9.3. First round assessment of benefit-risk balance 48
10. First round recommendation regarding authorisation 49
11. Clinical questions 49
11.1. Pharmacokinetics 49
11.2. Pharmacodynamics 49
11.3. Efficacy 49
11.4. Safety 49
12. Second round evaluation 49
13. Second round benefit-risk assessment 53
13.1. Second round assessment of benefits 53
13.2. Second round assessment of risks 53
13.3. Second round assessment of benefit-risk balance 53
14. Second round recommendation regarding authorisation 53
Common abbreviations
Abbreviation / Meaning /3TC / Lamivudine
ABC / Abacavir
ADME / Absorption, distribution, metabolism, and elimination
AE / Adverse event
ALAG / Absorption time lag
ALT / Alanine aminotransferase
ARV / Antiretroviral
AST / Aspartate aminotransferase
ATV / Atazanavir
ATV/r / Atazanavir and ritonavir
AUC / Area under the plasma/serum/PBMC concentration versus time curve
AUCtau / Area under the plasma/serum/PBMC concentration versus time curve over the dosing interval
BA / Bioavailability
BCRP / Breast cancer resistance protein
BCS / Biopharmaceutics Classification System
BID / Twice daily
BMI / Body mass index
BOC / Boceprevir
BSEP / Bile salt export pump
CatA / Cathepsin A
CES1 / Carboxyl esterase 1
CHC / Chronic Hepatitis C
CI / Confidence interval
CLDQ-HCV / Chronic Liver Disease Questionnaire HCV Version
CL/F / Apparent oral clearance
Cmax / Maximum observed plasma/serum/PBMC concentration of drug
CNS / Central nervous system
COBI / Cobicistat
CPT / Child-Pugh-Turcotte classification
CRCL / Creatinine clearance
CsA / Cyclosporine (cyclosporin A; ciclosporin)
Ctau / Observed drug concentration at the end of the dosing interval
CWRES / Conditional weighted residual
CYP / Cytochrome P450 enzyme(s)
DAA / Direct-acting antiviral
DCV / Daclatasvir
DDI / Drug-drug interaction
DNA / Deoxyribonucleic acid
DRV / Darunavir
DV / Dependent variable
EC50/90 / Half-maximal/90% effective concentration
ECG / Electrocardiogram
EFV / Efavirenz
eGFR / Estimated glomerular filtration rate
Emax / Maximum effect
ESRD / End-stage renal disease
ETR / End of Treatment response (undetectable plasma HCV-RNA at the end of therapy)
EU / European Union
EVG / Elvitegravir
FACIT-F / Functional Assessment of Chronic Illness Therapy – Fatigue
FBC / Full blood count
FDA (US) / Food and Drug Administration
FDC / Fixed-dose combination
FMO / Flavin monooxygenase
FOCE / First order conditional estimation
FTC / Emtricitabine
FU-X / Follow-up visit “X” weeks after completion of all treatment
GGT / Gamma-glutamyltransferase
Gilead / Gilead Sciences, Inc.
GLSM / Geometric least squares mean
GS-5885 / Ledipasvir (LDV)
GS-7977 / Sofosbuvir (SOF)
GS-9451 / Vedroprevir (VDV)
GT / Genotype
GT1-HCV / Genotype 1 Hepatitis C Infection
H2RA / H2-receptor antagonist
HbA1c / Hemoglobin A1c
HBV / Hepatitis B virus
HCC / Hepatocellular carcinoma
HCV / Hepatitis C virus
HINT1 / Histidine triad nucleotide binding protein 1
HIV / HIV-1 human immunodeficiency virus, type 1
HRV / Human rhinovirus
HTA / Host targeting antiviral
IC50 / half-maximal inhibitory concentration
ICH / International Conference on Harmonization (of Technical Requirements for Registration of Pharmaceuticals for Human Use)
IFN / Interferon
IL28 / Interleukin 28
IL28B / Interleukin 28B gene
IND / Investigational New Drug (Application)
IPRED / Individual predicted concentration
IQ / Interquartile
IRES / Internal ribosome entry site
ISS / Integrated summary of safety
iVSR / Integrated virology study report
IWRES / Individual weighted residual
LC/MS/MS / Liquid chromatography/tandem mass spectrometry
LDV / Ledipasvir (GS-5885)
LiPA / Line probe assay
LLOQ / Lower limit of quantitation
LOD / Limit of detection
MATE1 / Multidrug and toxin extrusion protein 1
MedDRA / Medical Dictionary for Regulatory Activities
MELD / Model for End Stage Liver Disease
mRNA / Messenger ribonucleic acid
MRP2 / Multidrug resistance-associate protein 2
NI / Nucleoside inhibitor
NNI / Non-nucleoside inhibitor
NOAEL / No observed adverse effect level
NOEL / No observed effect level
NS (3/4A/5A/5B) / Nonstructural protein (3/4A/5A/5B)
OATP / Organic anion transporting polypeptide
OC / Ortho Tri-Cyclen Lo
OCT / Organic cation transporter
PD / Pharmacodynamic(s)
PEG / Pegylated interferon
Peg-IFN / Pegylated interferon
Pgp / p-glycoprotein
PI / Protease inhibitor
PK / Pharmacokinetic(s)
PPI / Proton pump inhibitor
PRED / predicted concentration
QD / Once daily
QTc / QT interval corrected for heart rate
QTcB / QT interval corrected for heart rate using the Bazett formula
QTcF / QT interval corrected for heart rate using the Fridericia formula
QTcI / QT interval corrected for heart rate using subject-specific correction factor
QTcN / QT interval corrected for heart rate using population-specific correction factor
RAL / Raltegravir
/r / Boosted with ritonavir
RAV / Resistance-associated variant
RBV / Ribavirin
RGT / Response-guided therapy
RNA / Ribonucleic acid
RPV / Rilpivirine
RSV / Respiratory syncytial virus
RTV / Ritonavir
SAE / Serious adverse event
SD / standard deviation
SE / Standard error
SF-36 / Short Form 36 Health Survey
SMV / Simeprevir
SOF / Sofosbuvir (GS-7977)
SVR / Sustained virologic response
SVRXX / Sustained virologic response “XX” weeks following completion of all treatment
TAD / Time after dose
TDF / Tenofovir disoproxil fumarate
TE / Treatment experienced
TFV / Tenofovir
TGV / Tegobuvir
TN / Treatment naïve
TND / Target not detected
TVR / Telaprevir
UGT / Uridine disphosphate glucuronosyltransferase
ULN / Upper limit of the normal range
UMP-CMP / Uridine monophosphate-cytidine monophosphate
URTI / Upper respiratory tract infection
USP / United States Pharmacopeia
VDV / Vedroprevir, GS-9451
VPC / Visual predictive check
vRVR / Very rapid virologic response
WPAI: Hep C / Work Productivity and Impairment: Hepatitis C
1. Background
1.1. Submission type
This is a Category 1, Type A application to register Harvoni (90 mg ledipasvir / 400 mg sofosbuvir) fixed dose combination tablets.
1.2. Drug class and therapeutic indication
Ledipasvir (LDV) is a new chemical entity that inhibits HCV replication through NS5A. In cell-based replicon assays it has high potency, selectivity and specificity for HCV.
Sofosbuvir (SOF) is a pro-drug of 2ʹ-deoxy-2ʹ-fluoro-2ʹ-C-methyluridine monophosphate. It is converted to the active form in the hepatocyte. It inhibits HCV replication by inhibiting RNA replication through inhibition of NS5B.
The proposed indication is:
Harvoni is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adults.
1.3. Dosage forms and strengths
The submission proposes registration of the following dosage forms and strengths:
Harvoni (90 mg ledipasvir/ 400 mg sofosbuvir) Fixed-Dose Combination Tablets, Bottle
1.4. Dosage and administration
The recommended dose of Harvoni tablets is one tablet, taken orally, once daily with or without food.
Duration of Treatment:
· For treatment-naïve patients without cirrhosis the recommended duration of treatment with Harvoni is 8 or 12 weeks.
· For treatment-naïve patients with cirrhosis and treatment-experienced patients without cirrhosis the recommended duration of treatment with Harvoni is 12 weeks.
· For treatment experienced patients with cirrhosis the recommended duration of treatment with Harvoni is 24 weeks.
Elderly: no dose adjustment is warranted for elderly patients.
Renal impairment: no dose adjustment of Harvoni is required for patients with mild or moderate renal impairment. The safety of Harvoni has not been assessed in patients with severe renal impairment (eGFR < 30 mL/min) or end stage renal disease (ESRD) requiring haemodialysis.
Hepatic impairment: no dose adjustment of Harvoni is required for patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B or C).
2. Clinical rationale
As stated in the Clinical Summary:
“Chronic HCV infection is a global health problem with an estimated 170 million individuals infected worldwide. In the US, an estimated 3.2 million people have chronic HCV infection. Chronic HCV infection leads to approximately 16,000 deaths each year in the US. In Europe, an estimated 7.3 to 8.8 million people have chronic HCV infection leading to approximately 86,000 deaths each year. Up to 85% of individuals infected with HCV fail to clear the virus and progress to chronic infection: over the ensuing 20 years, as many as 20% of patients with chronic HCV infection are estimated to develop complications, including cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). Complications from chronic HCV infection are responsible for approximately half of all liver transplants; HCV is therefore the most frequent indication for orthotopic liver transplantation.”
“For genotype 1 HCV infection (subtypes 1a or 1b), which represents the majority of all cases of chronic HCV infection in the US (70% to 75%, predominantly subtype 1a) and Europe (69%, predominantly subtype 1b), the current standard treatment for treatment-naive patients is 12 to 24 weeks of an oral protease inhibitor (PI) combined with 24 to 48 weeks of Peg-IFN+RBV, with duration of therapy guided by on-treatment response.” However, up to 50% of patients are not eligible for these treatments, and there are also serious disadvantages to these treatments, including poor tolerability, frequent adverse effects and high pill burdens.
Hence “there remains a significant unmet medical need for simplified treatment regimens that are more effective than the current standard of care, with better safety/tolerability profiles.”
3. Contents of the clinical dossier
3.1. Scope of the clinical dossier
The submission contained the following clinical information:
Module 5
· 25 clinical pharmacology studies, including 24 that provided pharmacokinetic data and one that provided pharmacodynamic data. The pharmacokinetic studies were: Study GS-US-256-0110, Study GS-US-337-0101, Study GS-US-256-0101, Study GS-US-0108, Study GS-US-334-0111, Study GS-US-256-0102, Study GS-US-248-0117, Study GS-US-344-0101, Study GS-US-344-0108, Study GS-US-119-0113, GS-US-169-0105, Study GS-US-248-0102, Study GS-US-248-0104, Study GS-US-248-0107, Study GS-US-248-0125, Study GS-US-248-0127, Study GS-US-256-0129, Study GS-US-334-0101, Study GS-US-334-0146, Study GS-US-334-0148, GS-US-337-0127, Study GS-US-337-0128, Study GS-US-344-0102, and Study MK-5172-pn023. The pharmacodynamic study was: Study GS-US-344-0109
· The pharmacokinetic studies were supplemented by 16 reports of in-vitro studies: Study AD-256-2094, Study AD-256-2095, Study AD-256-2096, Study AD256-2097, Study AD-256-2098, Study AD-256-2109, Study AD-256-2132, Study AD-256-2133, Study AD-256-2134, Study AD-256-2139, Study AD-256-2140, Study AD-256-2143, Study AD-256-2144, Study AD-256-2146, Study AD-256-2150, and Study AD-256-2108
· Three population pharmacokinetic analyses: Pop-PK of GS331007, Pop-PK of SOF and Pop-PK of LV