W7 Biologicals and Biosimilars (GP) Flashcards
What are biological drugs?
What are examples? (6)
Applications? (4)
- Biologics are any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources.
- The first biologic drug approved in 1982 (humanised insulin)
- Different types of biologicals:
o peptides
o proteins
o antibodies (e.g. DPT vaccines)
o nucleic acids (e.g. RNA-vaccines)
o cell-based therapies
o carbohydrates - Applications: cancer, rheumatoid arthritis
inflammatory bowel disease, infectious disease
Chemical vs Biological drug:
Weight, structure, source?
Stability, Immunogenicity?
chemical:
* Low Molecular weight (180 Dalton)
* Simple, well defined
* By Chemical synthesis (1st, 2nd, 3rd structure)
* Usually stable
* Usually unexpected
biological:
* High Molecular weight (150k Dalton)
* Complex
* Made or derived from a biological source
* Sensitive to handling and storage conditions
* Higher potential
What are the Various expression systems for producing Biologicals? (4)
- Prokaryotes - Escherichia coli
- Yeast strains - Saccharomyces cerevisiae, Hansenulla polymorpha and Pichia pastoris
- Transgenic plants (tobacco, cereals, legumes, fruits, and vegetables)
- Mammalian cells- best option
In order of complexity, cost, time, high quality:
From biologicals to biosimilars
- Manufacturing process of these products are often covered by Intellectual Property (IP)
- After this is expired, other companies can use the same process to prepare a version of the product
- These are called biosimilars or follow-up proteins (mainly in US)
- Compared to the reference or originator product
What is the defintion of a biosimilar?
A new biological product that has been developed to be similar to an existing biological product (“reference” or “originator”)
A biosimilar medicine is a biological medicine which has been shown not to have any clinically meaningful differences from the originator medicine in terms of quality,
safety and efficacy.
Concept of similarity: (3)
The nature of biological drugs and their manufacturing process leads to unique attributes in the product being produced:
- Manufacturing conditions (e.g., medium batch, manufacturing sites, pH)
-
Post-translational modifications (e.g., glycosylation)
(Example: Bacterial cells do not have the ability to perform complex posttranslational modifications including glycosylation which will affect the folding of the protein.) -
Amino acid sequence e.g. Plant derived products
-In eukaryotic cells, there are 20 a.a both essential and nonessential, some essential a.a are missing in plant-derived products
Biosimilars nomenclature:
- ‘Core name’ + suffix
rituximab
rituximab-pvvr
rituximab-abbs - Suffix: 4 letter, lower case, no recognizable
meaning - Totally different names from reference
product (pharmaceutical companies) - Identify reference/biosimilar relationship
oTherapeutic category
o Dosing - Differentiate products
o Accurate product identification
o Prevent inadvertent substitution - Trackability of adverse reactions
Biosimilars approval
Who are the 2 regulatory bodies?
- Different regulatory bodies (EMA-European Medicines Agency, FDA-Food and Drug Administration)
- First approved biosimilar - Somatropin (Omnitrope® - 2006), in Germany (EU)
Approval process:
What must a manufacturer demonstrate for a medicine to be approved?
- The MHRA (Medicines and Healthcare products Regulatory Agency) outlines guidance on the licensing of biosimilar products in the UK
- MHRA is closely working with EMA (European Medicines Agency)
- Same standards of pharmaceutical quality, safety and efficacy that apply to all biologics.
-
For a biosimilar medicine to be approved, the manufacturer must demonstrate that the biosimilar has no clinically meaningful differences in safety and efficacy from the
reference medicine (abbreviated pathways)
Approval process:
Biosimilar products must present a complete characterisation of the molecules as compared to the innovator.
This includes:
- Primary structures (amino acid composition)
- Higher order structures (secondary,
tertiary and quaternary structures) - Post-translational modifications
- Intentional chemical modifications (e.g.,
- PEGylation sites, protein deamination and oxidation
Biosimilars market (for info)
- Number of Biosimilar medicines is increasing over the years
- Growing global market (10% of sales)
What are the Impact of biosimilars? (benefits)
- Reduced time drug development
- Reduced costs of drug development
- Final cost of the final product
- More options available
o for affordability (chronic diseases)
o loss of clinical efficacy over time
(e.g., antibody biosimilars)
Biosimilar applications? (6)
When are they used:
- Auto-immune diseases
- Blood disorders
- Diabetes
- Oncology
- Growth Deficiency
- Female infertility
Insulin as a biological:
what are the properties?
structure?
- Insulin is produced by the pancreas
- Insulin injections are needed for Type 1 diabetes therapy
- Initially purified from bovine or porcine pancreas
- Biosynthetic human insulin
- Produced by recombinant DNA technology
- Humulin, the first ever biological (1982)
- Insulin is a small globular protein containing two chains, A (21 residues) and B (30 residues)
- Disulfide bonds between cysteine residues help stabilising the structure of the protein
Ways to produce/obtain insulin?
- Recombinant DNA technology via individual chains (A) or proinsulin (B)
- Mostly E. coli (bacteria) and Saccharomyces cerevisiae (yeast)
- Plant-based approach (oilseeds of plant Arabidopsis thaliana)
- Insulin analogues
- Rapid-acting analogues
- Insulin Lispro → proline-lysine inversion on the B-chain
- Insulin Aspart → aspartic acid/proline substitution on the B-chain
- Long-acting analogues
- Insulin Glargine → asparagine/glycine
substitution of the A-chain and addition two arginine residues on the B-chain
Insulin Biosimilars:
- Recombinant DNA technology (to introduce the amino acid substitutions)
- Proinsulin (B) primarily used for preparation of insulin analogues
What is Omnitrope?
- Omnitrope® is a biosimilar of Genotropin® (reference biologic)
- Genotropin contains the active ingredient somatropin
- Somatropin = Biosynthetic human growth hormone
- Hormone replacement therapy
- Daily injection to treat growth-hormone-related disorders
- Growth hormone deficiency (GHD), Turner syndrome, Prader-Willi syndrome
- Ready-to-use prefilled liquid cartridges
How is Omnitrope produced?
- Growth hormone is prepared via recombinant DNA technology starting from the human gene (A)
- Using E. coli or transgenic tobacco plant (B)
- Protein expression and purification (C)
- Scaling-up (D) and formulation (E)
Structure of Omnitrope?
- Omnitrope® contains a human growth hormone variant produced by recombinant DNA- technology
- This hormone is a polypeptide chain of 190 amino acid residues (primary sequence)
- with 2 disulfide bridges (not essential for the
biological activity of the molecule) - 4 alpha helices arranged in anti-parallel distinctive manner (secondary structure)
Rheumatoid arthritis therapies:
- Disease = Rheumatoid arthritis (RA) is a chronic inflammatory disease
- Biological products = monoclonal antibodies (MABs) targeting pro-inflammatory cytokine tumour necrosis factor alfa (TNF-α)
- Five anti-TNF-α therapies available in the UK
Certolizumab pegol - Cimzia®
Adalimumab - Humira®
Etanercept - Enbrel®
Golimumab - Simponi®
Infliximab - Remicade®
Adalimumab biosimilars:
- Biosimilars available for three of these anti-TNF drugs (adalimumab, infliximab, and etanercept)
- Adalimumab - Humira® (approved in 2003)
- Five biosimilars released since then
As a future pharmacist … things to consider:
- Substitution at the pharmacy level without consulting the prescriber is not permitted for biological medicines, including biosimilars.
- Interchangeability: switching from reference medicines to their biosimilar versions, as well as switching from one biosimilar to another
biosimilar/reference product. - An interchangeable biological product is a biosimilar product that meets additional standards of interchangeability (additional criteria to be added in the approval paperwork)
- An interchangeable biosimilar can be substituted by a pharmacist for its reference product without involving the prescribing health-care provider.
- Prescribing by brand name
- E.g., prescription of Insulin glargine needs to specify the specific product
‘Lantus’ (reference biological) or biosimilars - Guidance published by the European Medicines Agency (EMA) in 2012
- Same guidance provided by the British National Formulary (BNF)
- cost-saving potential of biosimilar drugs
- diverging perceptions about biosimilars
- patient’s education of biologicals and biosimilars
- patient’s perspective on switching biosimilars
True or False?
Are Biosimilars the ‘generic version’ of biologicals?
=False
They are highly similae but not exactly the same.
