Appendix 1
Medicine Evaluation; Non-Clinical Studies
FINAL
1 PRODUCT DETAILS
File number:
TT50-10853
Product name:
Comirnaty (COVID-19 mRNA vaccine) (Pfizer-
BioNTech) 0.5 mg/mL concentrate for injection (TT50-
10853).
Dose form:
Concentrate for injection
Drug substance and
BNT162b2 [mRNA], 0.5 mg/mL (as 225 µg/0.45 mL)
strength:
Each 0.3 mL dose of the diluted vaccine delivers 30 µg
drug substance.
e Official Information Act 1982
Evaluator: s 9(2)(g)(ii)
By email to s 9(2)(g)(ii)
, Acting Manager Product Regulation, Medsafe 28
Jan 2021 12:27 am
Peer reviewer:s 9(2)(g)(ii)
By email to s 9(2)(g)(ii)
, Acting Manager Product Regulation, Medsafe 28
Jan 2021 10:32 am
Appendix 1
Table of Contents
2
CONTENTS
1
Product details ................................................................................................................... 1
1
Introduction ....................................................................................................................... 5
1.1
Data Update Status ..................................................................................................... 6
2
Formulation ........................................................................................................................ 7
3
Non-Clinical Overview and Conclusions ................................................................ .... ...... 8
3.1
Overview of nonclinical testing strategy ................................................ ..... ............. 8
3.2
Pharmacology .................................................................................... . .................... 10
3.2.1
S Protein Expression............................................................... ........................... 11
3.2.2
Immunogenicity ............................................................... . ............................... 11
3.2.3
Protection .............................................................. . . ....................................... 12
3.3
Pharmacokinetics .................................................. .. ............................................... 14
3.4
Toxicology ....................................................... .. ...................................................... 16
3.4.1
Single Dose Toxicity .......................... ................................................................ 16
3.4.2
Repeat Dose Toxicity .................. .... .................................................................. 16
3.4.3
Genotoxicity and carcinogenicity ....................................................................... 17
3.4.4
Long term studies .......... ................................................................................... 17
e Official Information Act 1982
3.4.5
Reproduction and Developmental Toxicity ....................................................... 17
3.4.6
Local Tolerance .................................................................................................. 18
3.4.7
Immunotoxicity .................................................................................................. 18
3.5
Overview and conclusions. ........................................................................................ 19
3.6
Comment on the nonclinical overview and summaries. .......................................... 19
3.7
Pfizer Responses to EMA and TGA Questions ........................................................... 19
4
Detailed evaluation .......................................................................................................... 32
4.1
Pharmacology ............................................................................................................ 32
4.1.1
Primary Pharmacodynamics .............................................................................. 32
4.1.2
Secondary & Safety Pharmacodynamics ........................................................... 44
4.1.3
Pharmacodynamic Drug Interactions ................................................................ 45
4.2
Pharmacokinetics ...................................................................................................... 45
4.2.1
Absorption ......................................................................................................... 45
4.2.2
Distribution ........................................................................................................ 45
Appendix 1
4.2.3
Metabolism ........................................................................................................ 48
4.2.4
Pharmacokinetic Drug Interactions (nonclinical)............................................... 48
4.3
Toxicology .................................................................................................................. 48
4.3.1
Single-Dose Toxicity (in order by species, by route) .......................................... 48
4.3.2
Repeat-Dose Toxicity ......................................................................................... 48
4.3.3
Genotoxicity ....................................................................................................... 52
4.3.4
Carcinogenicity ................................................................................................... 53
4.3.5
Long-term studies .......................................................................................... ... 53
4.3.6
Reproductive and Developmental Toxicity ........................................ ... ........... 53
4.3.7
Local Tolerance ........................................................................... ..................... 55
4.3.8
Antigenicity ............................................................................ .. ....................... 55
4.3.9
Immunotoxicity .............................................................. . ................................ 55
e Official Information Act 1982
Appendix 1
Limited glossary / abbreviations
Abbreviation
Expansion
ACE2
Angiotensin Converting Enzyme 2 Receptor for
ADE
Antigen Dependent Enhancement
ALC-0159
2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
ALC-0315
((4-hydroxybutyl) azanediyl) bis (hexane-6,1-diyl) bis(2-hexyldecanoate)
Bw;bwt
Bodyweight
DART
Developmental and Reproductive Toxicity
EM
Electron Microscopy
GMT
Geometric Mean Titre
HEK
Human Embryonic Kidney Cells
HCS
Human Convalescent Serum
IM
Intra muscular injection
IFN
Interferon
IL
Interleukin
LNP
Lipid Nano-Particles (specifically LNP8 unless otherwise specified)
MACS
Magnetic Antigen Cell Separation
MOE
Margin of Exposure
mRNA
messenger Ribonucleic acid
modRNA
nucleoside modified mRNA
OP
OroPharyngeal
P2
two proline mutations
pVN50
A measure of the serum antibody Titre (The reciprocal of the serum
dilution resulting in a 50% neutralization of a pseudo-virus). A higher
value indicates a greater response/titre
pVNT
Pseudo Virus Neutralisation Titre
q.s.
Quatum satis
QSAR
Quantative Strutural Activity Relationship
e Official Information Act 1982
RNA
Ribonucleic acid
RBD
Receptor Binding Domain
S protein
SARS-CoV-2 spike glycoprotein
TGA
Therapeutic Goods Administration (Australia)
Th1
T helper type 1 cells
Th2
T helper type 2 cells
TNF
Tumour Necrosis Factor
TTC
Threshold of Toxicological Concern
V8&9
Viral variants of SAR-CoV-2
VAERD
vaccine-associated enhanced respiratory disease
Appendix 1
Non-Clinical Assessment
1
INTRODUCTION
This new medicine application is for a new biological entity, BNT162b2 [mRNA], hereafter
referred to as BNT162b2 (BioNTech code number BNT162, Pfizer code number PF-
07302048), developed by Pfizer and BioNTech. The drug product (COMIRNATY) is an RNA-
based vaccine indicated for the active immunisation of individuals aged 16 (originally 18 in
the TGA application but amended by the applicant) years and over against COVID-19 disease
caused by the SARS-CoV-2 virus.
The vaccine will be administered intramuscularly (IM) in the upper arm (deltoid muscle) as a
series of two 30 μg doses of the diluted vaccine solution (0.3 mL each) according to the
following schedule: a single 0.3 mL dose followed by a second 0.3 mL dose 21 days later
(prime/boost regimen).
The drug substance is a nucleoside-modified mRNA that encodes a prefusion stabilised full-
length variant of the SARS-CoV-2 spike (S) glycoprotein and is manufactured by a cell-free
in
vitro transcription process. The final clinical variant and related developmental variant RNAs
were encapsulated lipid nanoparticles (LNPs), which facilitate entry of the RNA into host
cells. The RNA is translated in the host cells to the S protein, which induces a protective
immune response in the vaccinated individual. The vaccine is formulated as a preservative-
free concentrated suspension for injection, presented in a multi-dose vial. The product is
supplied frozen (-80°C to -60°C) and must be thawed and diluted with sterile sodium
chloride (0.9%) solution prior to administration.
e Official Information Act 1982
s 6(b)(ii)
The LNP component of the Pfizer vaccine formulation contains two novel excipient lipids,
ALC-0159 (2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide) and ALC-0315(4-
hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate). These lipids are a key
aspect of the formulation contributing both to the particle size of LNPs and the stability of
the mRNA in the formulation.
Pages 6- 57 withheld under section 9(2)(b)(ii) of the Act.
