Safety of biologics therapy

Brian A. Baldo

Safety of
Biologics Therapy
Monoclonal Antibodies, Cytokines,
Fusion Proteins, Hormones, Enzymes,
Coagulation Proteins, Vaccines,
Botulinum Toxins

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Safety of Biologics Therapy



Brian A. Baldo

Safety of Biologics Therapy
Monoclonal Antibodies, Cytokines,
Fusion Proteins, Hormones, Enzymes,
Coagulation Proteins, Vaccines,
Botulinum Toxins


Brian A. Baldo (Retired)
AUA(Pharmacy); BSc(Hons); PhD
Formerly:
Royal North Shore Hospital of Sydney
Head, Molecular Immunology Unit
Kolling Institute of Medical Research and

University of Sydney
Sydney, NSW, Australia

ISBN 978-3-319-30470-0
ISBN 978-3-319-30472-4
DOI 10.1007/978-3-319-30472-4

(eBook)

Library of Congress Control Number: 2016943849
© Springer International Publishing Switzerland 2016
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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The publisher, the authors and the editors are safe to assume that the advice and information in this book
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Printed on acid-free paper
This Springer imprint is published by Springer Nature
The registered company is Springer International Publishing AG Switzerland


Dedicated to the memories of my mother
and father and to Gail MacDiarmid for the

cherished years of support, partnership,
and mutual devotion



Preface

In writing this book, the author’s primary intention was to produce an up-to-date
text book on approved biologic therapies as far as that is possible in this time of
rapidly evolving and seemingly ever-expanding developments in biotherapeutic
research and the introduction of new and novel biopharmaceuticals. Emergence of
the disciplines of genomics and proteomics, together with molecular biological
approaches to elucidate the functions of single genes, continues to reveal the complexities and multifaceted nature of diseases such as cancer, autoimmunity, and
metabolic disorders and to identify potential targets for the development of new
drug therapies. Targeted approaches, long practiced in relation to peptide hormones
and enzymes, now so often drive the extraordinary interest in, and development of,
monoclonal antibody, fusion protein, and cytokine therapies. Added stimulus has
been provided by regulatory authorities in efforts to encourage the development of
diagnostic agents and treatments for rare diseases previously neglected because of
inadequate financial returns from very small markets. In particular, The US Food
and Drug Authority (FDA) Office of Orphan Products Development provides incentives for the study and development of products for so-called orphan diseases, that
is, diseases with fewer than 200,000 patients in the USA. This initiative has, for
example, transformed the extent and nature of the research and development of
enzymes as replacement therapies for lysosomal storage diseases and led to the
introduction of monoclonal antibody therapy for the rare paroxymal nocturnal
hemoglobinuria and atypical hemolytic uremic syndrome by targeting complement
C5. These advances, among many others presented in this monograph, would almost
certainly not have been made in the absence of recombinant DNA technology,
today’s sequencing methods, application of modern bioinformatics, and parallel
proteome analyses by application of techniques such as mass spectroscopy.

An attempt has been made to cover those biologics that are currently the main
product classes with regulatory approval in the USA and/or European Union and
which show every indication of remaining important therapies over at least the next
decade and beyond. Due to considerations of established therapeutic relevance and
space constraints, coverage has been almost totally restricted to products given regulatory approval. This is reflected in the three chapters devoted to monoclonal
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Preface

antibodies, the dominant biotherapeutic agents in terms of diversity of target recognition and approved indications, and the products with the highest global sales revenue in today’s biopharmaceutical market. Although there are well over 300
monoclonal antibodies in development, coverage here at June 2016 is restricted to
the 50 (counting alemtuzumab [MabCampath® and Lemtrada®] and Denosumab
[Prolia® and Xgeva®] as two not four antibodies) currently approved by the FDA or
European Medicines Agency or both. Unsurprisingly, recombinant preparations
dominate the different categories of approved biologics, and because of their inherent advantages including production of large quantities of pure human materials
without the need to purify crude extracts, their ease of genetic and chemical manipulation to reduce side effects and accentuate or reduce selected properties, consistency of supply, minimal batch-to-batch variation, reduced cost of production, and
their safety of manufacture, this is certain to continue. Coverage is extended to the
relatively small number of cytokines approved for therapy out of more than 130 of
these known pleiotropic immune modulators of immune and inflammatory responses
and to the growing list of approved fusion proteins most of which are made up of an
effector peptide (such as a cytokine, growth factor, etc.) linked to an antibody Fc
fusion partner or human albumin. Known, studied, and used as therapies for many
years, peptide and glycoprotein hormones, now mainly as recombinant products,
are examined in some detail together with other related and/or modified hormone
products produced to effect therapeutic improvements, alter pharmacokinetic and
pharmacodynamic properties, or reduce adverse effects. In addition to enzymes as
replacement therapies for lysosomal storage diseases, a number of other enzymes

indicated for disorders as diverse as cystic fibrosis, Dupuytren’s contracture, vitreomacular adhesion, myocardial infarction, and acute lymphocytic leukemia are
examined. Descriptions, approved indications, and usage, of 22 approved coagulation or clotting factor preparations, essential for maintaining homeostasis, are
reviewed together with the clotting cascade, an emphasis on safety aspects, and new
product developments. Vaccination, an indispensable public health measure
described as “the greatest triumph of modern immunology and the most successful
exploitation of our knowledge of the workings of the immune response,” has nevertheless not always been afforded the respect it deserves in modern medical practice.
While vaccines are not free of associated adverse events, those that have been
recorded together with the known and suspected effects induced by additives and
possible contaminants are examined for all 46 approved vaccine preparations presented. Botulinum neurotoxins, surprising in their sheer number of clinical applications (a few approved, many not), which now include muscular, neurologic,
gastrointestinal, urologic, ophthalmic, and oropharyngeal disorders, have exceeded
the most optimistic early estimates of their usage. This already large list of approved
and potential indications is currently being further enlarged by evaluations in offlabel treatments outside controlled clinical trials. Such relatively uncontrolled activity is a reminder of the need to remain aware of the potentially extreme toxicity of
the botulinum neurotoxins and to record and report adverse events when they occur.
In the light of the seemingly exorbitant costs associated with many of today’s biologic therapies, follow-on biologics or biosimilars offer the promise of fostering


Preface

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competition, allowing the treatment of more patients at lower cost, and helping to
lower ever-increasing government health costs. Difficulties in achieving the required
comparability or similarity, safety evaluations, and eventual regulatory approval are
considered in the book’s final chapter.
While efforts have been made to unify the text by cross-referencing and interconnecting common or related subjects, no comprehensive and scrupulous referencing
to the original literature that is standard for scientific papers has been undertaken
since this would have considerably increased the size of the book and been at odds
with its intended organization and textbook style. As a reasonable compromise and
with the aim of assisting the reader to locate original sources and extend understanding, carefully selected suggestions for Further Reading have been included at
the end of each chapter. The chapters on cytokines, fusion proteins, and enzymes are

based on the author’s previous publications for Springer. These publications, quoted
in the Further Reading lists, provide a comprehensive reference list for Chaps. 5, 6,
and 9. Further Reading selections for these and other chapters have been selected to
guide the interested reader to the most significant studies in the original literature
and preview potentially important future developments.
It is with sincere appreciation and thanks that the author acknowledges the skills,
dedication, cooperation, and help, given by long-standing collaborator Dr. Nghia
H. Pham in the joint preparation of numerous tables and a widely diverse range of
figures, many of the latter demonstrating individuality and produced with some artistry as well as relevance, scientific accuracy, and dedication to detail.
In conclusion, with biologic therapies continuing to demonstrate extraordinary
growth in the origin and nature of the agents employed, the introduction of new
disease targets, the enlarging range of approved indications, and the increasing
understanding of each agent’s spectrum of associated risks and adverse events, the
continued development and innovation seen in biologic therapies over the last few
years seem certain to be sustained. Given this ongoing expansion of new knowledge, research, and development in therapeutic biologics, the author remains open
and ready to consider all comments in an ongoing effort to remain abreast of new
developments, improve the book, and correct any errors.
Sydney, Australia

Brian A. Baldo



Contents

1

2

Approved Biologics Used for Therapy

and Their Adverse Effects ......................................................................
Biologics ...................................................................................................
US Guidelines .......................................................................................
European Guidelines .............................................................................
Biologics and Small Molecule Drugs ...................................................
Protein Therapeutics .............................................................................
Some Complexities of Protein Therapeutics:
Perceived Advantages and Some Problems ..........................................
The Evolving Biologics Market ............................................................
Adverse Drug Reactions ...........................................................................
Definitions .............................................................................................
Terminology: Adverse Reactions and Adverse Events .........................
Classification of Adverse Drug Reactions ............................................
Syndromes That May Be Associated with Biologic Therapies.............
Summary ...................................................................................................
Further Reading ........................................................................................
Monoclonal Antibodies: Introduction ...................................................
Monoclonal Antibodies for Therapy .........................................................
Evolution of Therapeutic Monoclonal Antibodies:
From Mouse to Man..................................................................................
Technological Advances in the Production
of Monoclonal Antibodies.........................................................................
Hybridoma Technology and Immortalization
of Human B Cells..................................................................................
Phage Display .......................................................................................
Transgenic (Knockout) Mice ................................................................
Monoclonal Antibodies from Single Human B Cells
by Gene Cloning ...................................................................................

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IgG Antibody Subclasses ..........................................................................
Glycosylation of Monoclonal Antibodies .................................................
Antibody-Dependent Cell-Mediated
and Complement-Dependent Cytotoxicities .............................................
Nomenclature for Monoclonal Antibodies................................................
Breakdown of Antibody Type and Approved Indications
for the Currently Approved Monoclonal Antibodies ................................
Antibody-Drug Conjugates .......................................................................
Future Prospects of Monoclonal Antibody Therapy .................................
Summary ...................................................................................................
Further Reading ........................................................................................
3

Monoclonal Antibodies Approved for Cancer Therapy ......................
Approved Monoclonal Antibodies for Cancer Therapy............................
Catumaxomab .......................................................................................
Blinatumomab .......................................................................................
Monoclonal Antibodies Targeting CD20:
Rituximab, Ibritumomab, Ofatumumab,
and Obinutuzumab ................................................................................
Brentuximab Vedotin ............................................................................
Alemtuzumab ........................................................................................
Monoclonal Antibodies Targeting Epidermal
Growth Factor Receptor: Cetuximab, Panitumumab,
and Necitumumab .................................................................................
Bevacizumab .........................................................................................
Ramucirumab ........................................................................................
Monoclonal Antibodies Targeting Human Epidermal
Growth Factor 2 (HER2): Pertuzumab, Trastuzumab,
and Ado-trastuzumab Emtansine ..........................................................

Denosumab ...........................................................................................
Ipilimumab ............................................................................................
Siltuximab .............................................................................................
Monoclonal Antibodies Targeting Programmed
Cell Death Protein 1 (PD-1): Pembrolizumab and Nivolumab ............
Dinutuximab .........................................................................................
Daratumumab........................................................................................
Elotuzumab ...........................................................................................
Recent Approval: Atezolizumab ...........................................................
Range of Side Effects of Monoclonal Antibodies Used
for Cancer Therapy ...................................................................................
Types I–IV Hypersensitivities and Cytopenias .....................................
Infusion Reactions and Cytokine Release Syndrome ...........................
Pulmonary Adverse Events ...................................................................
Cardiac Adverse Events ........................................................................
Mucocutaneous Reactions to Monoclonal
Antibodies Targeted to Epidermal Growth Factor Receptor.................

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Other Rare Adverse Events Following Antitumor
Monoclonal Antibody Therapy ............................................................. 128
Summary ................................................................................................... 129
Further Reading ........................................................................................ 138
4

Other Approved Therapeutic Monoclonal Antibodies ........................
Monoclonal Antibodies Targeted to Human Tumor
Necrosis Factor: Adalimumab, Certolizumab Pegol,
Infliximab, and Golimumab ......................................................................
Boxed Warnings and Precautions for Adalimumab,
Certolizumab Pegol, Infliximab, and Golimumab ................................
Adalimumab..........................................................................................
Certolizumab Pegol...............................................................................
Infliximab ..............................................................................................
Golimumab ...........................................................................................
Abciximab .................................................................................................
Integrin Recognition by Abciximab ......................................................
Indications, Warnings, Precautions, and Adverse Events .....................
Immunogenicity of Abciximab .............................................................
Alemtuzumab ............................................................................................
Basiliximab ...............................................................................................
The IL-2 Receptor and Mechanism of Action of Basiliximab ..............
Basiliximab Indications, Warnings, Precautions,
and Adverse Events ...............................................................................
Immunogenicity of Basiliximab ...........................................................
Belimumab ................................................................................................
BLys and Belimumab............................................................................
Belimumab Warnings, Precautions, and Adverse Events .....................

Immunogenicity of Belimumab ............................................................
APRIL, Lupus, and Atacicept ...............................................................
Canakinumab ............................................................................................
CAPS and the Mechanism of Action of Canakinumab.........................
CAPS Diseases and Approved Indications for Canakinumab ..............
Warnings, Precautions, and Adverse Events for Canakinumab ............
Denosumab ...............................................................................................
Eculizumab ...............................................................................................
Approved Indications ............................................................................
Paroxysmal Nocturnal Hemoglobinuria, Atypical
Hemolytic Uremic Syndrome, and Mechanism of Action
of Eculizumab .......................................................................................
Warnings, Precautions, and Adverse Events .........................................
Immunogenicity of Eculizumab............................................................
Monoclonal Antibody Integrin Inhibitors: Natalizumab
and Vedolizumab .......................................................................................
Natalizumab ..........................................................................................
Vedolizumab .........................................................................................

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Omalizumab ..............................................................................................
Approved Indications ............................................................................
Mechanism of Action of Omalizumab ..................................................
Safety of Omalizumab ..........................................................................
Palivisumab ...............................................................................................
Ranibizumab .............................................................................................
Raxibacumab.............................................................................................
Anthrax and Background to the Development of Raxibacumab ..........
Mechanism of Action of Raxibacumab.................................................
Indications and Usage of Raxibacumab ................................................
Safety of Raxibacumab .........................................................................
Secukinumab .............................................................................................
Mechanism of Action of Secukinumab .................................................
Approved Indications and Safety of Secukinumab ...............................
Tocilizumab...............................................................................................
IL-6 and Mechanism of Action of Tocilizumab ....................................
Approved Indications and Safety of Tocilizumab.................................
Ustekinumab .............................................................................................
IL-12 and IL-23 and Immune-Mediated Diseases ................................
Mechanism of Action of Ustekinumab .................................................
Indications and Safety of Ustekinumab ................................................
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors:
Alirocumab and Evolocumab ...................................................................
Alirocumab: Indications and Safety......................................................
Evolocumab: Indications and Safety ....................................................
Idarucizumab.............................................................................................
Mechanism of Action of Idarucizumab.................................................
Indications and Safety of Idarucizumab ...............................................
Mepolizumab ............................................................................................

Mechanism of Action of Mepolizumab ................................................
Indications and Safety of Mepolizumab ...............................................
Recent Approvals: Obiltoxaximab, Ikexizumab, Reslizumab ..................
Summary ...................................................................................................
Further Reading ........................................................................................
5

Cytokines .................................................................................................
Introduction ...............................................................................................
General Characteristics .........................................................................
Classification of Cytokines ...................................................................
Adverse Effects of Individual Approved Recombinant
Cytokine Analogs ..................................................................................
Individual Approved Cytokines ................................................................
Interferon Alfa .......................................................................................
Interferon Beta ......................................................................................
Interferon Gamma .................................................................................

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Contents

Colony-Stimulating Factors: Filgrastim, Sargramostim,
and Tbo-Filgrastim................................................................................
Oprelvekin.............................................................................................
Becaplermin ..........................................................................................
Palifermin..............................................................................................
Aldesleukin ...........................................................................................
Anakinra................................................................................................
Epoetins.................................................................................................
Bone Morphogenetic Proteins...............................................................
Metreleptin ............................................................................................
Ancestim ...............................................................................................
Concluding Remarks.................................................................................
Summary ...................................................................................................
Further Reading ........................................................................................
6

Fusion Proteins ........................................................................................
Desired Properties and Composition of Chimeric Fusion Proteins ..........
Fc Fusion Proteins.................................................................................
Fc Fusion Proteins as Glycoproteins.....................................................
IgG Subclasses of Fc Fusion Proteins: Increasing
and Decreasing Effector Function.........................................................
Origin, Nature, Mechanism of Action, and Usage
of Fc Fusion Proteins ................................................................................
Etanercept .............................................................................................
Belatacept..............................................................................................

Abatacept ..............................................................................................
Rilonacept .............................................................................................
Aflibercept.............................................................................................
Romiplostim..........................................................................................
Alefacept ...............................................................................................
Factor VIII Fc Fusion Protein ...............................................................
Factor IX Fc Fusion Protein..................................................................
Dulaglutide............................................................................................
Atacicept ...............................................................................................
Safety of Approved Fc Fusion Proteins ....................................................
Etanercept .............................................................................................
Belatacept Safety ..................................................................................
Abatacept ..............................................................................................
Rilonacept .............................................................................................
Aflibercept Safety .................................................................................
Romiplostim..........................................................................................
Alefacept ...............................................................................................
Albumin Fusion Proteins ..........................................................................
Albiglutide ............................................................................................
Factor IX Albumin Fusion Protein........................................................

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Albumin Fusion Proteins in Late Stage Development..........................
Albumin Fusion Proteins in the Early Stage of Development ..............
Denileukin Diftitox ...................................................................................
The Immunogenicity of Therapeutic Fusion Proteins:
Attempts to Help Recognize Patients at Risk ...........................................
Diagnosis of Hypersensitivities to Fusion Proteins,
Premedication, and Desensitization ..........................................................
Concluding Remarks.................................................................................
Summary ...................................................................................................
Further Reading ........................................................................................
7

Peptide Hormones ...................................................................................
Insulin .......................................................................................................
Diabetes Mellitus ..................................................................................
Production of Insulin.............................................................................
Structure of Insulin ...............................................................................
Release of Insulin..................................................................................
Insulin Binding to Its Receptor and Ensuing Signaling ........................
Different Available Insulin Preparations ...............................................

Sodium-Glucose Co-transporter 2 Inhibitors ........................................
Warnings, Precautions, and Adverse Events
Associated with Insulin Use..................................................................
Glucagon ...................................................................................................
Structure and Mechanism of Action of Glucagon.................................
Indications and Adverse Effects of Glucagon .......................................
Glucagon Hypersensitivity....................................................................
Glucagon-Like Peptide 1 ..........................................................................
Glucagon-Like Peptide 2 ......................................................................
Glucagon-Like Peptide 1 and the Incretin Effect..................................
GLP-1 Receptor Agonists .....................................................................
Safety of GLP-1 Receptor Agonists......................................................
Immunogenicity of GLP-1 Receptor Agonists .....................................
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors (Gliptins) ..........................
Pramlintide ................................................................................................
Human Growth Hormone .........................................................................
Structure and Mechanism of Action of Growth Hormone ....................
Indications and Usage of Somatropin ...................................................
Adverse Events to Somatropin..............................................................
Immunogenicity of Growth Hormone ..................................................
Pegvisomant: A Growth Hormone Receptor Antagonist ......................
Insulin-Like Growth Factor 1 ...................................................................
Structure and Mechanism of Action .....................................................
IGF-1 and Growth Stimulation .............................................................
Mecasermin ...........................................................................................

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Somatostatin..............................................................................................
Synthetic Analogs of Somatostatin .......................................................
Approved Indications for Somatostatin Analogs ..................................
Warnings and Precautions for Somatostatin Analogs ...........................
Adverse Events to Somatostatin Analogs .............................................
Vasopressin ...............................................................................................
Physiologic Actions of Vasopressin ......................................................
Vasopressin Gene and Hormone Structure ...........................................
Vasopressin Receptors ..........................................................................
Safety of Vasopressin Therapy ..............................................................
Desmopressin ........................................................................................
Terlipressin ............................................................................................
Vaptans: Vasopressin Receptor Antagonists .........................................
Oxytocin....................................................................................................
Indications .............................................................................................
Oxytocin Structure ................................................................................

Oxytocin Receptors...............................................................................
Safety of Oxytocin ................................................................................
Safety of Carbetocin .............................................................................
Safety of Atosiban .................................................................................
Adrenocorticotropic Hormone ..................................................................
Structure, Function, and Indications of ACTH .....................................
Adverse Events to Cosyntropin ............................................................
Gonadotropin-Releasing Hormone ...........................................................
Structure of GnRH ................................................................................
GnRH Neurons and Secretion ...............................................................
GnRH Receptor.....................................................................................
GnRH Agonists and Antagonists ..........................................................
Safety of GnRH Analogs ......................................................................
Parathyroid Hormone ................................................................................
Structure and Action of Human Parathyroid Hormone.........................
Parathyroid Hormone Receptors and Signaling ....................................
Safety of Parathyroid Hormone ............................................................
Summary ...................................................................................................
Further Reading ........................................................................................

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Glycoprotein Hormones .........................................................................
Follicle-Stimulating Hormone ..................................................................
Structure and Mechanism of Action .....................................................
Indications and Usage of Follicle-Stimulating Hormone .....................

Warnings, Precautions, and Adverse Events .........................................
Luteinizing Hormone ................................................................................
Structure and Mechanism of Action .....................................................
Indications and Usage of Lutropin Alfa ................................................

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Warnings, Precautions, and Adverse Events
Associated with Lutropin Alfa ..............................................................
Human Chorionic Gonadotropin...............................................................
Structure and Mechanism of Action .....................................................
Indications and Usage of Chorionic Gonadotropin ..............................
Warnings, Precautions, and Adverse Events .........................................
Thyroid-Stimulating Hormone..................................................................
Structure and Mechanism of Action .....................................................
Indications and Usage of Thyrotropin Alfa...........................................
Warnings, Precautions, and Adverse Events .........................................
Thyrostimulin........................................................................................

Summary ...................................................................................................
Further Reading ........................................................................................
9

Enzymes Approved for Therapy ............................................................
Introduction ...............................................................................................
Toward Successful Enzyme Replacement Therapy:
Gaucher Disease........................................................................................
Approved Enzymes as Replacement Therapy
for Lysosomal Storage Diseases ...............................................................
Other Enzymes Approved for Therapy .....................................................
Tissue Plasminogen Activators .............................................................
Asfotase Alfa.........................................................................................
Asparaginase .........................................................................................
Collagenase ...........................................................................................
Dornase Alfa .........................................................................................
Glucarpidase .........................................................................................
Hyaluronidase .......................................................................................
Ocriplasmin ...........................................................................................
Pegademase Bovine ..............................................................................
Pegloticase ............................................................................................
Rasburicase ...........................................................................................
Streptokinase .........................................................................................
Safety of Approved Enzymes Used as Therapy
for Lysosomal Storage Diseases ...............................................................
Agalsidase Beta for Fabry Disease .......................................................
Alglucosidase Alfa for Pompe Disease .................................................
Recombinant Enzymes Used to Treat Gaucher Disease:
Imiglucerase, Taliglucerase Alfa, and Velaglucerase Alfa ....................
Sebelipase Alfa for Lysosomal Acid Lipase Deficiency .......................

Laronidase for MPS I ............................................................................
Idursulfase for MPS II ..........................................................................
Elosulfase Alfa for MPS IVA ................................................................
Galsulfase for MPS VI ..........................................................................

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Adverse Events Caused by Other Approved Enzymes .............................
Tissue Plasminogen Activators .............................................................
Asfotase Alfa.........................................................................................
L-Asparaginase .....................................................................................
Collagenase ...........................................................................................
Dornase Alfa .........................................................................................
Glucarpidase .........................................................................................
Hyaluronidase .......................................................................................
Ocriplasmin ...........................................................................................

Pegademase Bovine ..............................................................................
Pegloticase ............................................................................................
Rasburicase ...........................................................................................
Streptokinase .........................................................................................
Antibody Responses to Enzymes ..............................................................
Other Therapies for Lysosomal Storage Diseases.....................................
Stem Cell Transplantation .....................................................................
Substrate Reduction Therapy ................................................................
Chaperones............................................................................................
Gene Therapy ........................................................................................
Living with Enzyme Replacement Therapy..............................................
Summary ...................................................................................................
Further Reading ........................................................................................

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Blood Coagulation...................................................................................
Platelet Activation and von Willebrand Factor .........................................
The Kallikrein-Kinin System and Coagulation.........................................
The Clotting Cascade ................................................................................
Factor XII and Coagulation ......................................................................
Factor VIII.................................................................................................
B-Domain Deleted Recombinant Factor VIII .......................................
Turoctocog Alfa ....................................................................................
Simoctocog Alfa....................................................................................
Susoctocog Alfa ....................................................................................
Clotting Factor Fusion Proteins ................................................................
Factor VIII Fc Fusion Protein ...............................................................
Factor IX Fc Fusion Protein..................................................................
Factor IX Albumin Fusion Protein........................................................
Safety of Approved Blood Coagulation Preparations ...............................
Inhibitors in Hemophilia and Bypass Therapy .....................................
Factor VIIa ............................................................................................
Factor VIII Full Length Preparations ....................................................
Moroctocog Alfa: B-Domain Depleted Factor VIII..............................
Other B-Domain-Depleted Factor VIII Preparations:
Turoctocog Alfa, Simoctocog Alfa and Susoctocog Alfa .....................
Factor VIII Fc Fusion Protein ...............................................................

479
479
489
490
494
495
495
496
497
498
498
498
499
500
500
500
502
503
503
504
504


xx

Contents

Factor IX Fusion Proteins .....................................................................
Factor XIII A-Subunit ...........................................................................
Von Willebrand Factor/Coagulation Factor VIII Complex ...................

Antihemophilic Factor/Von Willebrand Factor Complex .....................
Recombinant Von Willebrand Factor ....................................................
Factor Eight Inhibitor Bypassing Activity (FEIBA),
Anti-inhibitor Coagulant Complex .......................................................
Prothrombin Complex Concentrate ......................................................
Fibrinogen Preparations to Control Bleeding .......................................
Summary ...................................................................................................
Further Reading ........................................................................................
11

12

505
505
506
506
507
507
507
507
508
512

Vaccines ....................................................................................................
Vaccines: Definition, Attenuation, and Subunit, Acellular,
Carbohydrate, Conjugate and DNA Vaccines ...........................................
Currently Approved Vaccines: Description, Indications, Warnings,
Precautions, and Adverse Events ..............................................................
“Allergy”/Adverse Reactions to Vaccines and Added Components .........
Allergic Reactions to Egg Proteins in Vaccines ....................................

Allergic Reactions to Gelatin in Vaccines.............................................
Aluminium Adjuvants ...........................................................................
Reactions to Other Vaccine Additives...................................................
Cutaneous Reactions to Vaccinations .......................................................
Injection Site Reactions ........................................................................
Cutaneous Hypersensitivity Reactions to Vaccines ..............................
Other Dermatologic Reactions ..............................................................
Summary ...................................................................................................
Further Reading ........................................................................................

515

Botulinum Neurotoxins ..........................................................................
Botulinum Neurotoxin Serotypes .............................................................
Toxin Structure and Mechanisms of Action..............................................
Structure of Botulinum Neurotoxin BoNT ...........................................
Structure and Absorption of Botulinum Neurotoxin Complex .............
Mechanism of Action at the Neuromuscular Junction ..........................
Therapeutic Applications of Botulinum Neurotoxin.................................
Nomenclature and Equivalence of Different
Botulinum Toxin Preparations ..............................................................
Approved Indications of FDA Registered Botulinum Neurotoxin
Preparations...........................................................................................
Other Possible Indications for Botulinum Neurotoxins ........................
Adverse Effects of Botulinum Neurotoxin ...............................................
Warnings and Precautions .....................................................................
Adverse Events Following Therapeutic and Cosmetic
Use of Botulinum Neurotoxin...............................................................

559

559
560
560
561
563
565

515
536
540
541
543
544
546
549
549
551
552
552
556

565
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572
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575


Contents

13

xxi

Immunogenicity and Clinical Relevance of Botulinum Neurotoxin ........
Anti-Neurotoxin Antibodies..................................................................
Detection and Measurement of Neutralizing Antibodies ......................
Summary ...................................................................................................
Further Reading ........................................................................................

579
579
580
582
585

Biosimilars ...............................................................................................
The Continuing Evolution of Biosimilars .................................................
Naming of Biosimilars and Pharmacovigilance Considerations ..............
Biobetters ..................................................................................................
Biosimilars in the Immediate Future.........................................................
Summary ...................................................................................................
Further Reading ........................................................................................

587
587
589
593
593

594
596

Index ................................................................................................................. 597


Chapter 1

Approved Biologics Used for Therapy
and Their Adverse Effects

Biologics
“Biologics” in this book refer to therapies that are prepared from materials made or
expressed in living organisms. They may simply be isolated proteins such as
enzymes and blood products or, as is increasingly the case, preparations produced
by recombinant DNA technology. Biologics, sometimes also referred to as “biotherapeutics” or “biopharmaceuticals,” are covered by a number of different definitions depending on the perspective of the interested party, with researchers from
different disciplines, biotechnologists, chemists, clinicians, legislators, and regulatory agencies, to name only a few, requiring or excluding aspects that reflect their
interest and involvement. Whereas a biologist, chemist, or clinician may see a biologic used for therapy as material derived from, or related to, a living organism, for
example, cells, cell extracts, or molecules composed of protein, peptide, complex
carbohydrate, lipid, or nucleic acid, a regulatory authority will also consider how
such agents are to be classified and assessed for characterization, manufacturing,
and control; product development; identity, purity, and potency; and so on. In other
words, in a regulatory context, “biologics” does not necessarily correspond to common usage or usage in everyday medical research and likewise for the terms
“biotechnology medicine/drug,” “biological medical product/drug,” and “biopharmaceuticals,” used outside the regulatory environment.

US Guidelines
In 1902, in the Biologics Control Act passed by the US Congress, biologics and
biologic products were defined as “any virus, therapeutic serum, toxin, antitoxin or
analogous product applicable to the prevention, treatment or cure of diseases or injuries of man.” Although this definition has changed over time, uncertainties, difficulties, and impreciseness have remained for agencies, many groups, and individuals
© Springer International Publishing Switzerland 2016

B.A. Baldo, Safety of Biologics Therapy, DOI 10.1007/978-3-319-30472-4_1

1


2

1

Approved Biologics Used for Therapy and Their Adverse Effects

concerned and/or working with biologic therapeutics. In particular, the term
“analogous” has remained undefined and open to varying degrees of relatedness.
Since 1902, the Congress has expanded the list of biologics to include other products
including vaccines, blood products, and some other proteins, but polypeptides prepared by chemical synthesis remained excluded. In the 1938 Federal Food, Drug, and
Cosmetic Act, “drug” was defined as a substance for the investigation, prevention, or
cure of disease, but no guidance was forthcoming to distinguish biologic and nonbiologic drugs. However, in 1944, the Congress did declare that a requirement for a
new drug application (NDA) did not apply to biologics. The latter are now marketed
under the provisions of the Public Health Service Act requiring a Biologics License
Application (BLA) showing the agent is “safe, pure, and potent.” By 1947, hormones
had been excluded from the list of biologics, and with the arrival of the new age of
biotechnology in the mid- to late 1980s, US Food and Drug Administration (FDA)
issued a policy statement saying that agents would be regarded as biologics “based
on the intended use of each product on a case-by-case basis.” Following an Intercenter
Agreement, in June 2003, the FDA transferred some of the therapeutic biologic products that had formerly been reviewed and regulated by the Center for Biologics
Evaluation and Research (CBER) to the Center for Drug Evaluation and Research
(CDER). Therapeutic biological products transferred to the CDER include monoclonal antibodies (mAbs), cytokines, fusion proteins, some enzymes, growth factors,
non-vaccine immunomodulators, and therapeutic proteins derived from animals,
plants, and microorganisms and recombinant versions of these products. Remaining
with the CBER are cellular products of human, animal, or bacterial origin; gene

therapy products such as nucleic acids, viruses and genetically engineered microorganisms; vaccines; allergenic extracts; antitoxins, antivenins, and venoms; and blood,
blood components, and plasma-derived products. The approved biologics covered in
this monograph are comprised of therapeutic biological products from both the
CDER and CBER lists. In 2012, the FDA issued a draft guidance addressing and
distinguishing the long-standing proposed differences between proteins, peptides,
and chemically synthesized polypeptides. A protein was defined as any alfa amino
acid polymer with a specific defined sequence that is greater than 40 amino acids in
size. From this definition, it followed that peptides have fewer than 40 amino acids
and are therefore not proteins. A chemically synthesized polypeptide was defined as
an alfa amino acid polymer that is made entirely by chemical synthesis and has fewer
than 100 amino acids. Until the draft guidance is finalized, these definitions can be
seen as proposals, but regardless of the definitions finally declared and adopted and
for the coverage of biologics in this volume, peptides with less than 40 amino acids
and chemically synthesized polypeptides (whether they contain fewer or more than
100 amino acids) with regulatory approval for therapeutic use in humans will be
considered first and foremost as biologics regardless of size or method of preparation. In keeping with this approach, peptide hormones (Chap. 7) and glycoprotein
hormones (Chap. 8) are logically included in the coverage of biologics licensed for
marketing as approved therapeutic agents. Note that regardless of the method of
manufacture, hormones require a NDA. In summary, in the US, distinguishing a
product from other drugs and classifying it as a biologic on the basis of existing


Biologics

3

Fig. 1.1 Phases in biological product development under an investigational new drug (ING) application leading to clinical trials with evaluations for safety and efficacy, a Biologics License
Application (BLA) and ultimately licensing and marketing. Reproduced from Vatsan RS, Bross PF,
Liu K, et al. J Immunother Cancer 2013;1:5. />an open access article distributed under the terms of the Creative Commons Attribution License

definitions is not straightforward since detailed legislated guidance has never been
provided. Recently, the FDA has mentioned the application of a so-called bright-line
rule for distinguishing proteins suggesting a much-needed shift from ad hoc to jurisdictional decision-making.
From the early preliminary specifications for product characterization, Fig. 1.1
summarizes the phases in biological product development under an investigational
new drug (IND) application leading on to clinical trials with evaluations for safety
and efficacy, a BLA, and ultimately licensing and marketing.

European Guidelines
From a 2001 Directive of the European Parliament and the Council of Six on the
community code relating to medicinal products for human use, “biological medicines” are defined as “products, the active substance of which is a biological substance.” In turn, a “biological substance” is defined as “a substance that is produced
by or extracted from a biological source and that needs for its characterization and
the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control.” In the European Union, the
European Medicines Agency (EMA) defines a “biological medicinal product” as “a
protein or nucleic acid-based pharmaceutical substance used for therapeutic or
in vivo diagnostic purposes, which is produced by means other than direct extraction
from a native (nonengineered) biological source.” This definition essentially appears
to restrict “biological medicinal products” to recombinant preparations including
mAbs, cytokines, fusion proteins, some hormones (such as insulin, glucagon, growth
hormone), enzymes (e.g., alteplase and enzymes used for enzyme replacement therapy), and coagulation proteins (factors VIIa, VIII, IX, XIII, and antithrombin).