A6- Biologic medicines and Biosimilars

Question 1

What is biologic medicine?

Answer 1

A biologic medicine is defined in European legislation as “a medicine whose active substance is made by or derived from a biological source”

•In the broadest sense, biological medicines include any substance made in the laboratory from a living organism

Question 2

Examples of biologic medicine?

Answer 2

Examples include insulin, vaccines, stem cell or tissue therapies

Question 3

What are some examples of biological sources?

Answer 3

e micro-organisms, animal cells or human cells

Question 4

Some biologic medicines mimic proteins made naturally in the human body

Examples?

Answer 4

Insulin and growth hormone

Question 5

What are main differences between small molecule drugs and biological products?

Answer 5

Question 6

What are monlconal antibodies in relation to biological drugs

Answer 6

• Monoclonal antibodies (mAbs) are one type of biological drug
• mAbs are engineered to target/neutralise an elevated antigen/overexpressed targets
• Main therapeutic uses in cancer and immune/inflammatory conditions

Question 7

Name some monoclonial antobodies and its use?

Answer 7

• Anti-TNFα – Adalimumab in inflammatory conditions

• Anti-HER2 – Trastuzumab in breast cancer

Question 8

Explain a mAb structure?

Fc

Fab

Sl

Sh

VL

VH

Answer 8

Question 9

How are biologic molecules adminstered

Answer 9

Due to the size of biologic molecules they are mainly administered parenterally

• IV, SC, IM

Question 10

do biologic molecules have a short or prolonged Tmax

Answer 10

• Prolonged Tmax (slow absorption via lymphatic system) • 2-14 days • 50-80% bioavailability
• Small molecule drugs have Tmax in hrs

Question 11

How do mAbs bind to their targets?

Answer 11

• mAbs bind to their targets by specific (Fab) or non-specific binding (Fc) (FcRn and FCγ pathways)

Question 12

Most mAbs can not be exreted by kidneys

Why is this?

How are the excreted?

Answer 12

• Most mAbs are too large to be excreted by kidneys • Biologics <69kDa are excreted by kidneys
• mAbs mostly eliminated by intracellular catabolism by lysosomal degradation to amino acids
• Occur throughout the entire body

Question 13

What is the difference between Linear Pharmokinetics and Non- Linear Pharmocokinetics

Answer 13

• Linear PK – Fc receptor and FcRn
• Non-linear PK - TMDD – target mediated drug disposition

Question 14

Why is the neonatal Fc receptor important?

Answer 14

The neonatal Fc receptor for IgG (FcRn) is responsible for the transfer of passive humoral immunity from the mother to the newborn in rodents and humans. Throughout life, FcRn contributes to effective humoral immunity by recycling IgG and extending its half-life in the circulation

Question 15

Where are neonatal Fc receptor found?

Answer 15

In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother’s milk, leading to its name as the neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother’s IgG to the growing fetus.

Question 16

What is the role of the FcRn receptor?

Answer 16

FcRn functions as a recycling or transcytosis receptor that is responsible for maintaining IgG and albumin in the circulation, and bidirectionally transporting these two ligands across polarized cellular barriers.

learn the pathway!

Question 17

Can mAb stimulate an immune response?

Answer 17

yes

Question 18

TYpes of therapeitic monoclonal ab

Answer 18

Question 19

Nomenclature of biologics

Answer 19

• Prefix (unique and identifies drug)
• Substem A (specifies the target)
• Substem B (identifies the sequence from which the Ab derived)
• Suffix (type of drug)

Question 20

What is biosimilar?

Answer 20

A biosimilar is a biological medicine highly similar to another biological medicine already approved in the EU (“reference medicine”) in terms of structure, biological activity and efficacy, safety and immunogenicity profile

Question 21

There are four stages in the development of a biosimilar

What are they?

Answer 21

1) product development and comparative analysis;
2) process development, scale up and validation;
3) clinical trials;
4) Regulatory (EMA and FDA) review and approval.

Question 22

How long does it take for a biosmilar development process

Answer 22

around 5 years

Question 23

Biosimilars

Primary aim in phase I studies show?

Answer 23

comparability in PK between biosimilar and reference product

eg Healthy volunteers (unless specific safety issue)

Question 24

Biosimilars

Phase III biosimilarity trial demonstrates?

Answer 24

similar clinical efficacy between the candidate and reference product

• Adequately powered, randomised, parallel group comparative clinical trial, (preferably) double blind, with equivalence study design, for at least one representative indication
• Choose most homogenous patient population to minimise patient and disease-related factors (e.g. disease severity or prev treatments)

Question 25

Adverse Reactions to Biologics

Immediate

Non-Immediate

Answer 25

Immediate reactions

• Standard infusion reactions (SIRs)
• Hypersensitivity reactions

Non-immediate reactions

• Target/Biologic specific
• Can affect any organ system

Question 26

Standard infusion reaction

When does it occur?

Symptoms?

Intensity?

Answer 26

• Within first hour of infusion
• Fever, shaking chills, MSK pain, nausea, vomiting, diarrhoea and skin rashes
• Usually moderate intensity but can be fatal

Question 27

Hypersensitivity reactions are degranulation of ____ ____ and __________

Answer 27

mast cells and basophils

Question 28

Symptoms and signs of hypersensitivity reactions?

Answer 28

Pruritus, urticaria and angioedema