Tamilogene Laherparapvec Environmental Risk Assessment
Transcript Of Tamilogene Laherparapvec Environmental Risk Assessment
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 1
Tamilogene Laherparapvec
Environmental Risk Assessment Dossier Version provided for use in Belgian Public Consultation
June 2016
Amgen Ltd 240 Cambridge Science Park Milton Road, Cambridge CB4 0WD
United Kingdom
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 2
CONFIDENTIALITY STATEMENT
Information and data contained herein are proprietary and confidential.
This information should not be disclosed to any third party without the prior written consent
of Amgen Inc.
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 3
Table of Contents
1. Identification of Characteristics which may Cause Adverse Effects ........................ 9
1.1 Characteristics of the Parental Virus, Modified Virus and the Receiving Environment ............................................................................... 9
1.1.1 Characteristics of the Parental Virus ........................................... 9
1.1.2
Characteristics of the Genetically Modified Virus Talimogene Laherparepvec....................................................... 12
1.1.3 Characteristics of the Receiving Environment ........................... 14
1.2 Characteristics which may Cause Adverse Effects.................................... 14
1.2.1 Effects on Human Health .......................................................... 14
1.2.2 Effects on the Environment ....................................................... 19
1.3 Conclusions .............................................................................................. 20
2. Evaluation of Potential Consequences / Magnitude of Effect ................................ 21
2.1 Direct Effects of the Transmission of Talimogene Laherparepvec to an Unintended Human Recipient .......................................................... 21
2.1.1 Magnitude of Effect ................................................................... 21
2.1.2
Consequences of Transmission of Talimogene Laherparepvec to an Unintended Individual .............................. 22
2.2 Indirect Effects of the Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Human Recipient............... 29
2.2.1 Magnitude of Effect ................................................................... 29
2.2.2
Consequences of Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Individual................................................................................... 30
2.3 Conclusions .............................................................................................. 31
3. Evaluation of Likelihood of Occurrence of Identified Adverse Effect ..................... 31
3.1 Likelihood of Direct effects of the transmission of Talimogene Laherparepvec to an unintended human recipient..................................... 31
3.1.1 Manner, Scale and Environment of Release ............................. 31
3.1.2
Potential Mechanisms of Exposure and Risk Management Measures ............................................................ 32
3.1.3
Available Data Relating to Virus Shedding and Human Exposure to Talimogene Laherparepvec................................... 33
3.1.4 Conclusion ................................................................................ 34
3.2 Likelihood of Indirect Effects of the Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Human Recipient................................................................................................... 34
3.3 Overall Conclusions .................................................................................. 35
4. Estimation of Risk Posed by Each Identified Characteristic .................................. 35 4.1 Risk Associated with the Parental Organism (wild type HSV-1) ................ 35 4.2 Risk Associated with the Transmission of Talimogene Laherparepvec to an Unintended Recipient .............................................. 38
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 4
4.3 Risk Associated with the Transmission of a Genetic Variant Talimogene Laherparepvec to an Unintended Recipient ........................... 39
5. Application of Management Strategies for Risks................................................... 41 5.1 Design of Viral Construct .......................................................................... 41 5.2 Control of Release .................................................................................... 42 5.3 Transportation Precautions ....................................................................... 42 5.4 Handling and Administration Precautions.................................................. 43 5.5 Cleaning and Waste Management ............................................................ 45 5.6 Communication of Risks and Precautions ................................................. 47 5.7 Monitoring Activities .................................................................................. 47 5.8 Conclusions .............................................................................................. 47
6. Determination of Overall Risk of the GMO ............................................................ 48
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 5
Term/Abbreviation %CV °C α-TIF AML APCs BHK BSL-1 BSL-2 cDNA cGMP CMV CNS CRO CT DMEM DNA DOT ECACC ELISA FAM FBS FDA FITC gC, gD, gH, gG, gL GCP GFP GLP GM-CSF GMP GTAC GxP
hCMV IE
List of Abbreviations
Explanation
co-efficient of variation
Degrees Celsius
alpha-transinducing factor
Acute Myelogenous Leukemia
Antigen Presenting Cells
baby hamster kidney
Biosafety Level 1
Biosafety Level 2
complementary deoxyribonucleic acid
Current Good Manufacturing Practices
cytomegalovirus
Central Nervous System
Contract Research Organization
Computed Tomography
Dulbecco Modified Eagle Medium
Deoxyribonucleic Acid
US Department of Transport
European Collection of Cell Cultures
Enzyme-Linked ImmunoSorbent Assay
6-carboxyfluorescein
Fetal Bovine Serum
Food and Drug Administration of the United States
fluorescein isothiocyanate
Glycoproteins (type C, D, H, G, or L)
Good Clinical Practice
Green Fluorescent Protein
Good Laboratory Practice
Granulocyte Macrophage Colony Stimulating Factor
Good Manufacturing Practice
Gene Therapy Advisory Committee
Good Practice guidelines, where “x” may be “M” for manufacturing, or “C” for clinical, or “L” for laboratory, etc.
Human Cytomegalovirus Immediate Early
Page 1 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 6
Term/Abbreviation hGM-CSF HGMP HHV-1 HIV HSV HSV-1 HSV-2 HVEM IRL IRS i.l. i.t. i.v. IATA IC50 ICH IPIM IEX IgG, IgM IMP LATs LD50 mGM-CSF
MHC I or II MOI miRNA mRNA MVL MVSS NF12 NSN OncoVEX GM-CSF OOS
Explanation
Human Granulocyte Macrophage Colony Stimulating Factor
Human Genome Mapping Project
Human Herpes Virus Type 1
Human Immunodeficiency Virus
Herpes Simplex Virus
Herpes Simplex Virus, Type 1
Herpes Simplex Virus, Type 2
herpesvirus entry mediator
long internal repeated sequence
short internal repeated sequence
Intralesional
Intratumoural
Intravenous
International Air Transport Association
Inhibitory Concentration At 50%
International Conference on Harmonization
Investigational Product Instruction Manual
Ion Exchange Chromatography
Immunoglobulin G or M
Investigational Medicinal Product
Latency-Associated Transcripts
median lethal dose
Murine Granulocyte Macrophage Colony Stimulating Factor
Major Histocompatability Complex Type I or Type II
Multiplicity of infection
micro ribonucleic acids
Messenger Ribonucleic Acid
Micro Virology Laboratories
Master Viral Seed Stock
U.S. National Formulation 12
New Substances Notification
OncoVEX virus expressing hGM-CSF
Out Of Specification
Page 2 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 7
Term/Abbreviation PAP PCR PFU Ph Eur PKR PPE QA QC QMS QP qPCR RNA RT S s.c. SCCHN SDS SEC SEM SOP TAMRA TFF TK TRL TRS UK UL USP US U.S. VHS
Explanation prostatic acid phosphatase Polymerase Chain Reaction Plaque Forming Unit European Pharmacopoeia Protein Kinase R Personal Protective Equipment Quality Assurance Quality Control Quality Management System Qualified Person Quantitative Polymerase Chain Reaction ribonucleic acid real-time short Subcutaneous Squamous Cell Cancer of the Head and Neck sodium dodecyl sulfate Size Exclusion Chromatography Skin, Eyes and/or Mouth Standard Operating Procedure tetramethylrhodamine Tangential Flow Filtration Thymidine Kinase long terminal repeated sequence short terminal repeated sequence United Kingdom long unique region United States Pharmacopeia short unique region United States virion host shutoff protein
Page 3 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 8
Introduction Talimogene laherparepvec (JS1/ICP34.5-/ICP47-/hGM-CSF), formerly known as OncoVEXGM-CSF, is a disabled recombinant herpes simplex type 1 virus (HSV-1). Talimogene laherparepvec was generated by modifying the wild type HSV-1 genome (new isolate JS1) to functionally delete both copies of ICP34.5 and the ICP47 gene from the viral backbone and to insert an expression cassette encoding the human granulocyte macrophage colony-stimulating factor (hGM-CSF) gene in both ICP34.5 regions.
Full Technical and Scientific Information on the GMO (talimogene laherparepvec) are provided in a separate document in accordance with Annex IIIA of Directive 2001/18/EC.
Objective The objective of this Environmental Risk Assessment (ERA) is to identify and evaluate potential adverse effects of talimogene laherparepvec on human health and the environment which conducting a clinical trial with the GMO may exert, in accordance with Annex IIA of Directive 2001/18/EC.
Talimogene laherparepvec is intended as an investigational medicinal product in a proposed phase 1, multicenter, open-label, single-arm study to evaluate the safety of the investigational medicinal product when injected into liver tumours (Protocol 20140318). Talimogene laherparepvec is intended for intrahepatic injection into hepatocellular carcinoma (HCC) and metastatic liver tumors (non-HCC) by a trained medical professional in a medical study site facility.
Injections will be performed using the coaxial injection technique under ultrasound or CT guidance. A needle of larger diameter than the talimogene laherparepvec dosing syringe needle (introducer needle) will first be inserted into the lesion. Talimogene laherparepvec will be administered via a filled dosing syringe through the introducer needle.
Methodology This ERA has been performed according to the precautionary principle using the methodology set down in Commission Decision 2002/623/EC. These general principles are:
Identified characteristics of the GMO and its use which have the potential to cause adverse effects should be compared to those presented by the non-modified organism from which it is derived and its use under corresponding situations;
The ERA should be carried out in a scientifically sound and transparent manner based on available scientific and technical data;
The ERA should be carried out on a case-by-case basis;
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 9
An analysis of the ‘cumulative long-term effects’ relevant to the release and the conduct of the clinical trial.
1.
Identification of Characteristics which may Cause Adverse Effects
1.1
Characteristics of the Parental Virus, Modified Virus and the
Receiving Environment
1.1.1
Characteristics of the Parental Virus
Wild type HSV-1 is a globally endemic pathogen of humans, which is usually initially
transmitted in childhood via nonsexual contact, though it may be acquired in young
adulthood through sexual contact. The seroprevalence in adults is estimated to be
70% in developed countries and 100% in developing countries (Gupta et al, 2007).
Orolabial herpes has an infection rate of approximately 33% in developing countries and
20% in developed countries (Chayavichitsilp et al, 2009).
Its mode of transmission is through direct contact with infected secretions or mucous membranes/skin with lesions from an asymptomatic or symptomatic patient shedding the virus (Jerome & Morrow, 2007; Chayavichitsilp, 2009; Whitley, 2006). Transmission of HSV-1 can also occur by respiratory droplets (Whitley, 2006).
HSV-1 survives in the environment in the host species (humans) as a persistent infection or as a latent infection in the nucleus of some infected cells (principally neurons of the trigeminal ganglion), where it may remain inactive indefinitely, or be reactivated giving rise to secretion of virus and sometimes (though not always) clinical symptoms.
Several wild type HSV-1 mediated conditions may occur, as summarised below.
Herpes labialis/cold sores: Primary infections with HSV-1 are acquired usually in childhood and may be asymptomatic or subclinical (Drew, 2004; Jerome & Morrow, 2007; Kimberlin, 2005). Symptomatic primary infections present mainly as gingivostomatitis, with fever, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema and vesicular and ulcerative painful lesions involving the buccal mucosa, tongue, gums, and pharynx (Drew, 2004; Jerome & Morrow, 2007; Kimberlin, 2005; Miller & Dummer, 2007). Ulcers heal without scarring within 2-3 weeks (Drew, 2004; Jerome & Morrow, 2007). Recurrent infections have generally milder symptoms and clinical course (Jerome & Morrow, 2007). Recurrent lesions due to HSV-1 occur mainly on a specific area of the lip (vermillion border of the lip), and are called “cold sores” or “fever blisters” (Drew, 2004; Kimberlin, 2005). The lesions heal in approximately 8-10 days (Kimberlin, 2005).
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 10
Herpetic whitlow: Characterised by formation of painful vesicular lesions on the nail or finger area (Drew, 2004), and more commonly seen in healthcare professionals (eg. dentists).
Infections of the eye: Characteristic dendritic ulceration occurs on conjunctiva, and cornea (Drew, 2004). HSV infection may cause other ocular diseases, including blepharitis/dermatitis, conjunctivitis, dendritic epithelial keratitis, and corneal ulceration (Green & Pavan-Langston, 2006).
Encephalitis: Serious infections of the CNS, affecting both children and adolescents (Whitley, 2006). Encephalitis is a rare complication, affecting approximately 1 in 500,000 people per year (Rozenberg et al, 2011). It may occur due to primary or latent infection with HSV-1 virus (Drew, 2004; Whitley, 2006). HSV encephalitis affects one temporal lobe, leading to focal neurologic signs and edema. The disease can be fatal (mortality rate of 70%), if left untreated (Drew, 2004; Whitley, 2006).
Genital herpes: Genital herpes is caused mainly by HSV-2, although HSV-1 has become as common as HSV-2 in primary genital infections in developed countries. It is transmitted sexually through genital-genital or oro-genital contact.
Antiviral medicinal products like acyclovir, valacyclovir, and famciclovir can be used to inhibit wild type HSV-1 replication (Drew, 2004; Usatine & Tinitigan, 2010). The standard antiviral drug used against HSV-1 is acyclovir. Inhibition of viral replication by acyclovir depends on the viral thymidine kinase (TK) gene, which catalyzes the first step necessary to convert acyclovir from an inactive to an active form. Valacyclovir and famciclovir can be used to inhibit wild type HSV-1 replication (Usatine & Tinitigan, 2010). In rare cases, HSV can mutate its viral kinases to gain resistance to acyclovir. In these cases, the anti-viral drug Foscarnet (phosphonoformic acid) which does not require activation by viral kinases can be used. Foscarnet directly inhibits the viral DNA polymerase.
Effects in special populations (neonates and immunocompromised individuals) are discussed below.
Neonatal HSV infection causes significant morbidity and mortality despite significant advances in treatment (reviewed in Kimberlin, 2004; Thompson & Whitley, 2011). The current estimated rate of occurrence of neonatal HSV disease in the United States is approximately 1 in 3,200 deliveries. The majority of neonatal HSV infections are caused by HSV-2, but approximately 15 to 30 percent are thought to be caused by HSV-1 Neonatal Herpes Simplex Virus Infections (Rudnick & Hoekzema, 2002). HSV infections
EudraCT: 2014-005386-67 Page 1
Tamilogene Laherparapvec
Environmental Risk Assessment Dossier Version provided for use in Belgian Public Consultation
June 2016
Amgen Ltd 240 Cambridge Science Park Milton Road, Cambridge CB4 0WD
United Kingdom
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 2
CONFIDENTIALITY STATEMENT
Information and data contained herein are proprietary and confidential.
This information should not be disclosed to any third party without the prior written consent
of Amgen Inc.
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 3
Table of Contents
1. Identification of Characteristics which may Cause Adverse Effects ........................ 9
1.1 Characteristics of the Parental Virus, Modified Virus and the Receiving Environment ............................................................................... 9
1.1.1 Characteristics of the Parental Virus ........................................... 9
1.1.2
Characteristics of the Genetically Modified Virus Talimogene Laherparepvec....................................................... 12
1.1.3 Characteristics of the Receiving Environment ........................... 14
1.2 Characteristics which may Cause Adverse Effects.................................... 14
1.2.1 Effects on Human Health .......................................................... 14
1.2.2 Effects on the Environment ....................................................... 19
1.3 Conclusions .............................................................................................. 20
2. Evaluation of Potential Consequences / Magnitude of Effect ................................ 21
2.1 Direct Effects of the Transmission of Talimogene Laherparepvec to an Unintended Human Recipient .......................................................... 21
2.1.1 Magnitude of Effect ................................................................... 21
2.1.2
Consequences of Transmission of Talimogene Laherparepvec to an Unintended Individual .............................. 22
2.2 Indirect Effects of the Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Human Recipient............... 29
2.2.1 Magnitude of Effect ................................................................... 29
2.2.2
Consequences of Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Individual................................................................................... 30
2.3 Conclusions .............................................................................................. 31
3. Evaluation of Likelihood of Occurrence of Identified Adverse Effect ..................... 31
3.1 Likelihood of Direct effects of the transmission of Talimogene Laherparepvec to an unintended human recipient..................................... 31
3.1.1 Manner, Scale and Environment of Release ............................. 31
3.1.2
Potential Mechanisms of Exposure and Risk Management Measures ............................................................ 32
3.1.3
Available Data Relating to Virus Shedding and Human Exposure to Talimogene Laherparepvec................................... 33
3.1.4 Conclusion ................................................................................ 34
3.2 Likelihood of Indirect Effects of the Transmission of a Genetic Variant of Talimogene Laherparepvec to an Unintended Human Recipient................................................................................................... 34
3.3 Overall Conclusions .................................................................................. 35
4. Estimation of Risk Posed by Each Identified Characteristic .................................. 35 4.1 Risk Associated with the Parental Organism (wild type HSV-1) ................ 35 4.2 Risk Associated with the Transmission of Talimogene Laherparepvec to an Unintended Recipient .............................................. 38
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 4
4.3 Risk Associated with the Transmission of a Genetic Variant Talimogene Laherparepvec to an Unintended Recipient ........................... 39
5. Application of Management Strategies for Risks................................................... 41 5.1 Design of Viral Construct .......................................................................... 41 5.2 Control of Release .................................................................................... 42 5.3 Transportation Precautions ....................................................................... 42 5.4 Handling and Administration Precautions.................................................. 43 5.5 Cleaning and Waste Management ............................................................ 45 5.6 Communication of Risks and Precautions ................................................. 47 5.7 Monitoring Activities .................................................................................. 47 5.8 Conclusions .............................................................................................. 47
6. Determination of Overall Risk of the GMO ............................................................ 48
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 5
Term/Abbreviation %CV °C α-TIF AML APCs BHK BSL-1 BSL-2 cDNA cGMP CMV CNS CRO CT DMEM DNA DOT ECACC ELISA FAM FBS FDA FITC gC, gD, gH, gG, gL GCP GFP GLP GM-CSF GMP GTAC GxP
hCMV IE
List of Abbreviations
Explanation
co-efficient of variation
Degrees Celsius
alpha-transinducing factor
Acute Myelogenous Leukemia
Antigen Presenting Cells
baby hamster kidney
Biosafety Level 1
Biosafety Level 2
complementary deoxyribonucleic acid
Current Good Manufacturing Practices
cytomegalovirus
Central Nervous System
Contract Research Organization
Computed Tomography
Dulbecco Modified Eagle Medium
Deoxyribonucleic Acid
US Department of Transport
European Collection of Cell Cultures
Enzyme-Linked ImmunoSorbent Assay
6-carboxyfluorescein
Fetal Bovine Serum
Food and Drug Administration of the United States
fluorescein isothiocyanate
Glycoproteins (type C, D, H, G, or L)
Good Clinical Practice
Green Fluorescent Protein
Good Laboratory Practice
Granulocyte Macrophage Colony Stimulating Factor
Good Manufacturing Practice
Gene Therapy Advisory Committee
Good Practice guidelines, where “x” may be “M” for manufacturing, or “C” for clinical, or “L” for laboratory, etc.
Human Cytomegalovirus Immediate Early
Page 1 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 6
Term/Abbreviation hGM-CSF HGMP HHV-1 HIV HSV HSV-1 HSV-2 HVEM IRL IRS i.l. i.t. i.v. IATA IC50 ICH IPIM IEX IgG, IgM IMP LATs LD50 mGM-CSF
MHC I or II MOI miRNA mRNA MVL MVSS NF12 NSN OncoVEX GM-CSF OOS
Explanation
Human Granulocyte Macrophage Colony Stimulating Factor
Human Genome Mapping Project
Human Herpes Virus Type 1
Human Immunodeficiency Virus
Herpes Simplex Virus
Herpes Simplex Virus, Type 1
Herpes Simplex Virus, Type 2
herpesvirus entry mediator
long internal repeated sequence
short internal repeated sequence
Intralesional
Intratumoural
Intravenous
International Air Transport Association
Inhibitory Concentration At 50%
International Conference on Harmonization
Investigational Product Instruction Manual
Ion Exchange Chromatography
Immunoglobulin G or M
Investigational Medicinal Product
Latency-Associated Transcripts
median lethal dose
Murine Granulocyte Macrophage Colony Stimulating Factor
Major Histocompatability Complex Type I or Type II
Multiplicity of infection
micro ribonucleic acids
Messenger Ribonucleic Acid
Micro Virology Laboratories
Master Viral Seed Stock
U.S. National Formulation 12
New Substances Notification
OncoVEX virus expressing hGM-CSF
Out Of Specification
Page 2 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 7
Term/Abbreviation PAP PCR PFU Ph Eur PKR PPE QA QC QMS QP qPCR RNA RT S s.c. SCCHN SDS SEC SEM SOP TAMRA TFF TK TRL TRS UK UL USP US U.S. VHS
Explanation prostatic acid phosphatase Polymerase Chain Reaction Plaque Forming Unit European Pharmacopoeia Protein Kinase R Personal Protective Equipment Quality Assurance Quality Control Quality Management System Qualified Person Quantitative Polymerase Chain Reaction ribonucleic acid real-time short Subcutaneous Squamous Cell Cancer of the Head and Neck sodium dodecyl sulfate Size Exclusion Chromatography Skin, Eyes and/or Mouth Standard Operating Procedure tetramethylrhodamine Tangential Flow Filtration Thymidine Kinase long terminal repeated sequence short terminal repeated sequence United Kingdom long unique region United States Pharmacopeia short unique region United States virion host shutoff protein
Page 3 of 3
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 8
Introduction Talimogene laherparepvec (JS1/ICP34.5-/ICP47-/hGM-CSF), formerly known as OncoVEXGM-CSF, is a disabled recombinant herpes simplex type 1 virus (HSV-1). Talimogene laherparepvec was generated by modifying the wild type HSV-1 genome (new isolate JS1) to functionally delete both copies of ICP34.5 and the ICP47 gene from the viral backbone and to insert an expression cassette encoding the human granulocyte macrophage colony-stimulating factor (hGM-CSF) gene in both ICP34.5 regions.
Full Technical and Scientific Information on the GMO (talimogene laherparepvec) are provided in a separate document in accordance with Annex IIIA of Directive 2001/18/EC.
Objective The objective of this Environmental Risk Assessment (ERA) is to identify and evaluate potential adverse effects of talimogene laherparepvec on human health and the environment which conducting a clinical trial with the GMO may exert, in accordance with Annex IIA of Directive 2001/18/EC.
Talimogene laherparepvec is intended as an investigational medicinal product in a proposed phase 1, multicenter, open-label, single-arm study to evaluate the safety of the investigational medicinal product when injected into liver tumours (Protocol 20140318). Talimogene laherparepvec is intended for intrahepatic injection into hepatocellular carcinoma (HCC) and metastatic liver tumors (non-HCC) by a trained medical professional in a medical study site facility.
Injections will be performed using the coaxial injection technique under ultrasound or CT guidance. A needle of larger diameter than the talimogene laherparepvec dosing syringe needle (introducer needle) will first be inserted into the lesion. Talimogene laherparepvec will be administered via a filled dosing syringe through the introducer needle.
Methodology This ERA has been performed according to the precautionary principle using the methodology set down in Commission Decision 2002/623/EC. These general principles are:
Identified characteristics of the GMO and its use which have the potential to cause adverse effects should be compared to those presented by the non-modified organism from which it is derived and its use under corresponding situations;
The ERA should be carried out in a scientifically sound and transparent manner based on available scientific and technical data;
The ERA should be carried out on a case-by-case basis;
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 9
An analysis of the ‘cumulative long-term effects’ relevant to the release and the conduct of the clinical trial.
1.
Identification of Characteristics which may Cause Adverse Effects
1.1
Characteristics of the Parental Virus, Modified Virus and the
Receiving Environment
1.1.1
Characteristics of the Parental Virus
Wild type HSV-1 is a globally endemic pathogen of humans, which is usually initially
transmitted in childhood via nonsexual contact, though it may be acquired in young
adulthood through sexual contact. The seroprevalence in adults is estimated to be
70% in developed countries and 100% in developing countries (Gupta et al, 2007).
Orolabial herpes has an infection rate of approximately 33% in developing countries and
20% in developed countries (Chayavichitsilp et al, 2009).
Its mode of transmission is through direct contact with infected secretions or mucous membranes/skin with lesions from an asymptomatic or symptomatic patient shedding the virus (Jerome & Morrow, 2007; Chayavichitsilp, 2009; Whitley, 2006). Transmission of HSV-1 can also occur by respiratory droplets (Whitley, 2006).
HSV-1 survives in the environment in the host species (humans) as a persistent infection or as a latent infection in the nucleus of some infected cells (principally neurons of the trigeminal ganglion), where it may remain inactive indefinitely, or be reactivated giving rise to secretion of virus and sometimes (though not always) clinical symptoms.
Several wild type HSV-1 mediated conditions may occur, as summarised below.
Herpes labialis/cold sores: Primary infections with HSV-1 are acquired usually in childhood and may be asymptomatic or subclinical (Drew, 2004; Jerome & Morrow, 2007; Kimberlin, 2005). Symptomatic primary infections present mainly as gingivostomatitis, with fever, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema and vesicular and ulcerative painful lesions involving the buccal mucosa, tongue, gums, and pharynx (Drew, 2004; Jerome & Morrow, 2007; Kimberlin, 2005; Miller & Dummer, 2007). Ulcers heal without scarring within 2-3 weeks (Drew, 2004; Jerome & Morrow, 2007). Recurrent infections have generally milder symptoms and clinical course (Jerome & Morrow, 2007). Recurrent lesions due to HSV-1 occur mainly on a specific area of the lip (vermillion border of the lip), and are called “cold sores” or “fever blisters” (Drew, 2004; Kimberlin, 2005). The lesions heal in approximately 8-10 days (Kimberlin, 2005).
Environmental Risk Assessment Talimogene Laherparepvec
EudraCT: 2014-005386-67 Page 10
Herpetic whitlow: Characterised by formation of painful vesicular lesions on the nail or finger area (Drew, 2004), and more commonly seen in healthcare professionals (eg. dentists).
Infections of the eye: Characteristic dendritic ulceration occurs on conjunctiva, and cornea (Drew, 2004). HSV infection may cause other ocular diseases, including blepharitis/dermatitis, conjunctivitis, dendritic epithelial keratitis, and corneal ulceration (Green & Pavan-Langston, 2006).
Encephalitis: Serious infections of the CNS, affecting both children and adolescents (Whitley, 2006). Encephalitis is a rare complication, affecting approximately 1 in 500,000 people per year (Rozenberg et al, 2011). It may occur due to primary or latent infection with HSV-1 virus (Drew, 2004; Whitley, 2006). HSV encephalitis affects one temporal lobe, leading to focal neurologic signs and edema. The disease can be fatal (mortality rate of 70%), if left untreated (Drew, 2004; Whitley, 2006).
Genital herpes: Genital herpes is caused mainly by HSV-2, although HSV-1 has become as common as HSV-2 in primary genital infections in developed countries. It is transmitted sexually through genital-genital or oro-genital contact.
Antiviral medicinal products like acyclovir, valacyclovir, and famciclovir can be used to inhibit wild type HSV-1 replication (Drew, 2004; Usatine & Tinitigan, 2010). The standard antiviral drug used against HSV-1 is acyclovir. Inhibition of viral replication by acyclovir depends on the viral thymidine kinase (TK) gene, which catalyzes the first step necessary to convert acyclovir from an inactive to an active form. Valacyclovir and famciclovir can be used to inhibit wild type HSV-1 replication (Usatine & Tinitigan, 2010). In rare cases, HSV can mutate its viral kinases to gain resistance to acyclovir. In these cases, the anti-viral drug Foscarnet (phosphonoformic acid) which does not require activation by viral kinases can be used. Foscarnet directly inhibits the viral DNA polymerase.
Effects in special populations (neonates and immunocompromised individuals) are discussed below.
Neonatal HSV infection causes significant morbidity and mortality despite significant advances in treatment (reviewed in Kimberlin, 2004; Thompson & Whitley, 2011). The current estimated rate of occurrence of neonatal HSV disease in the United States is approximately 1 in 3,200 deliveries. The majority of neonatal HSV infections are caused by HSV-2, but approximately 15 to 30 percent are thought to be caused by HSV-1 Neonatal Herpes Simplex Virus Infections (Rudnick & Hoekzema, 2002). HSV infections