3.) Biosimilars Flashcards
What was the trigger for the FDA to impose standards re. the chemical composition of medicines?
Snake Oil:
- Imported Chinese remedy for RA; mixture of fatty acids including eicosapentaenoic acid
- Used by Chinese labourers on American railways (late 1800s)
- American imitation ‘snake oil’ passed off as genuine Chinese Snake Oil by ‘grifters’: hence ‘Snake Oil Salesman’ (conman)
»> FDA stipulation guarantees legitimacy of medicine
»> Regulation of what is sold as drugs, if medicines are as described
What set Pharmacopeia Standards must be met for generics manufacturers?
- Chemical formula (synthesis)
- Methods of identification
- Formulation
- Excipients
- Disintegration test/bioavailability (compare to OG branded patent drug)
»> No tests required in man to confirm availability, efficacy and safety (as done by Pharma in PI/PII/PIII development previously)
Define ‘Biologicals’.
Large protein-based drugs:
- Antibodies/fusion proteins produced by recombinant technologies in living cells
- Targeted at cell surface receptors and enzymes for chronic conditions (chronic nature means biologics account for 20% cost of drugs)
Why are ‘generic’ biologics termed ‘biosimilars’ instead of generics?
Production/synthesis routes form the basis of a drug patent; this is not straightforward and easily reproducible in biologics:
- Thus the end product produced by a generic/alternative company are not exact duplicates (different organisms from which the drug is produced, post-translational modifications, and more)
- Inherent variability also exists between OG reference biologics too
- Hence termed ‘biosimilar’
»> Production process of the OG branded drug remains confidential even after the patent expires
How do set pharmacopeia standards differ WRT sMW generics and biosimilars?
Identical aside from the first requirement, and an additional ting:
- Recombinant production (living cells, substrates used for maintaining culture, isolation etc) vs Chemical formula/synthesis
»> Defining ‘recombinant production’ does not equate to easy replication by generics (as opposed to relatively straightforward set synthesis routes with generics)
»> Tests are required in man to confirm availability, efficacy and safety with biosimilars (different from sMW generics)
What is erythropoietin/EPO?
A glycoprotein cytokine hormone that stimulates proliferation of RBCs in the bone marrow.
Does recombinant human EPO differ from natural EPO?
- Recombinant EPO (e.g. epoetin alfa) is practically identical to endogenous EPO
- Though epoetin consists of several forms (alfa/beta etc) which have different biological properties
What is recombinant EPO indicated to treat? How may treatment improve QoL?
Treatment of anaemia (due to poor EPO production) associated with:
- CKD
- Cancer
- Others
Benefits: • Fewer blood transfusions • Improved exercise capacity • Slower progression of CKD? (improved kidney perfusion) • Potential CVS benefits
What standards were the widely prescribed epoetin biosimilar samples (from 13 countries) compared to re. epoetin alfa reference?
- Physical characteristics
- In vitro & in viva activity
- Impurities (bacterial endotoxin)
What factors in the Recombinant production standard for biologics make biosimilars more difficult to manufacture and replicate than sMW generics?
What factors if not explicitly detailed can potentially influence activity?
Generics:
- Just follow chemical formula/synthesis
Biosimilars:
Fixed factors -
• Choice of sequence
• Cloning
Variable factors - • Expression in host cell • Fermentation • Purification • Formulation
How can ‘Expression in host cell’ in the production of biosimilars influence biosimilar activity? Give an example.
Different organisms may express the biologic differently e.g. in GCSF (granulocyte colony stimulating factor):
- Chinese Hamster ovary cells = glycosylated
- E. coli = non-glycosylated
How can the Fermentation process in the production of biosimilars influence biosimilar activity? Give an example.
Fermentation tank size affects glycoside ‘fingerprint’:
- Size of vat results in biologically different proteins
- Patent must stipulate the size of vat and scaling up/down required
How can the Purification/Formulation process in the production of biosimilars influence biosimilar activity? Give an example.
Supposed purification/conjugation for therapeutics may actually precipitate immunogenicity:
- Eprex (Epoetin Alfa) was originally isolated from human blood and bound to human serum albumin (HSA)
- Due to theoretical concerns that HSA may transmit variant Creutzfeldt-Jakob disease, in 1998 the EU stipulated that HSA in Eprex was changed to a synthetic compound, polysorbate 80 (Tween 80), which looked visually similar
- Patients were then observed to fall ill and anaemic (who were undergoing dialysis for CKD etc too)
- Was seen that patients developed antibodies/immunogenicity due to polysorbate 80
- Also prevented endogenous EPO to act (immunogenicity to recombinant EPO and endogenous EPO)
»> Peak times
What were the results of the comparison of epoetin biosimilar samples (from 13 countries) to epoetin alfa reference?
Varying physical characteristics and content:
- pH: 7/31 exceeded specifications
- Total protein and EPO content: 1/31 was under for total protein, 2/31 exceeded EPO
- In vivo potency: ranged 48-163% in mice, 7/31 failed to meet spec
- Bacterial endotoxin: 2/31 (sterility compromised)
How does glycosylation affect the activity of darbepoetin alfa?
Glycosylation:
- Extends half-life and biological activity
- Thus fewer doses required: good for patient adherence
- Location of glycosylation dictates if it has a beneficial or detrimental effect (post-translational modifications)
