Insulin Biosimilar Overview:

Opportunity and Risk

Pradana Soewondo
Division of Metabolism and Endocrinology,
Department of Internal Medicine Faculty of Medicine
University of Indonesia / Cipto Mangunkusumo
National Referral Hospital Jakarta, Indonesia
Terminology: generics vs biosimilars
Protein science

Chemical product Biologic

e.g. Aspirin® e.g. insulin

Chemical synthesis Different manufacturing processes

always result in different products

Branded
Originator
chemical
product
= Generic
biologic ≠ Biosimilar

Adapted from Krämer I. J Endocrinol Invest 2008:31;479–88.

 Biologics are produced by living
organisms Insulin biosimilars

• Biologics
– Medicinal products with active substances produced by, or extracted from,
biological sources and for which characteristics are directly linked to a specific
manufacturing process
– Includes originator biologics, biosimilars and other biologics

Registered Originator biologics

according to • Biologic that has been granted market access on the basis of a full
(non-abbreviated) dossier
specific
regulatory Biosimilars
requirements • Attempted “copy” of a originator biologic
• Biologic that has been granted market access on the basis of an
abbreviated dossier
In absence of • Also called: similar biological medicinal product (EU), follow-on
biologic (US), subsequent entry biologics (Canada)
regulatory
framework Other biologics
3
 Specific challenges associated with
insulin biosimilars
Insulin biosimilars
• Diversity of therapeutic insulins has increased over time
• Insulin manufacturing becoming more sophisticated
–Specific regulatory guidelines (e.g. EU)
• Established for recombinant human soluble insulin (short acting)
• Aspects of particular importance to insulin biosimilars
–PK/PD profiles key to demonstrating comparability to
originator; clinical efficacy studies needed if not demonstrated
–Immunogenicity
–Critical intra-individual dose response
–Mitogenicity
–Insulin administration devices
• First insulin biosimilars: Unsuccessful submission in EU
(Marvel)

4
 Human insulin is complicated by its
tertiary structure Insulin biosimilars

Human insulin is composed of two different chains linked

by two disulfide bonds

A-chain

B-chain

Source: Mayer et al. Arch Physiol Biochem 2008;1:1–8

5
 Insulin analogues further complicated by amino acid
substitutions
Insulin biosimilars

Insulin glargine contains one substituted and two added amino acids

A-chain Replacement of Asp A21

B-chain

Two additional Arg

Insulin glulisine contains two substituted amino acids

A-chain

B-chain

Replacement of Asp B3 Replacement of Lys B29

Source: Mayer et al. Arch Physiol Biochem 2008;1:1–8
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 Protein synthesis

Primary Secondary Tertiary Quaternary

Amino acid Alpha, beta Folding Polypeptide
sequence sheets arrangement

• Protein synthesis is a complex process involving multiple steps

 Complexity of therapeutic insulins has
increased over time
Insulin biosimilars

1921 1940 1960 1980 2000

Nobel Prize Nobel Prize Nobel Prize
1923 1958 1977

Long-acting
analogue
PZI NPH
Insulin insulin Human
discovered insulin

Lente
Rapid-acting
insulins
analogue

Nobel Prizes: 1923 Banting & Mac Leod, 1958 F. Sanger, 1977 R.Yalow; NPH: neutral protamine Hagedorn
insulin; PZI: Protamine zinc insulin

8
 Insulin:
Manufacturing has become more sophisticated
Insulin biosimilars

Semi- Short-acting
synthetic insulin
human insulin analogue
Pork/beef
insulin Long-acting
Recombinant insulin
production human insulin analogue

PZI: Protamine zinc insulin; Source: Burnham. Calif Med 1951:75;412–415; Leichter. Clinical Diabetes 2003:21;39–42; Levinson 2003.
Medicine
9 and Health Rhode Island: Available at: http://findarticles.com/p/articles/mi_qa4100/is_200304/ai_n9205228; Accessed 3 March
2009
 Insulin:
Manufacturing is a complex, multi-step process
Insulin biosimilars

• Choice of expression system is key in the

manufacture of insulin biologics
–E. coli (inclusion bodies)
–S. cerevisiae (secretion)
• Specific expression system affects
–By-product formation
–Folding processes
–Membrane transport
–Cleavage process
–Post-translational modifications
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 Insulin:
Manufacturing is a complex, multi-step process
Insulin biosimilars

• Upstream processing
–Approximately 2,000 possible biochemical reactions in
1 µL cytoplasmic volume (e.g. E. coli)
–Specific cultivation conditionsa
–Specific process equipment
• Downstream processing
–Removal of cultivation by-products, impurities and
related compounds
–Formation of new related compounds depending on
selected process technologies and sequence
Source: aSauer et al. Process 2005;5:50–51
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 Insulin: Manufacturing is a complex,
multi-step process
Insulin biosimilars

• By-product profile influenced by folding and cleavage

E. coli cell
5. Isolation of cells Typical
Inclusion body operations for
6. Cell disruption via inclusion body
homogenizer processes

Fusion protein Folding

7. Isolation and
purification of fusion conditions
protein influence
Preproinsulin by-product
8. Folding S S

S
S
S
S
pattern

9. Enzymatic cleavage Cleavage

S S

S
S
S
enzyme:
S

specificity &
10.Prepurification and InsulinS
concentration via
S
selectivity
S
S S
S
adsorption
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Insulin:
Manufacturing is a complex, multi-step process
Insulin biosimilars

• Purity is determined by chromatography steps

S S
Ion-exchange S
chromatography
S
S
S Chromatography
defines purity
S S
Reversed-phase S
S
S
chromatography S

Fibrillation
Insulin tendency
Crystallization
and lyophilization

Blending / filling

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 Differences between generics and biosimilars
Generics Biosimilars
Small molecule Large complex molecule

Product characteristics Often very stable Stable with special treatment

Taken orally Device used

Produced in living organisms

Highly sensitive to manufacturing changes

Production Chemical synthesis

High production costs

Significant R&D investment

Limited clinical trials
Development
(Bioequivalence) Limited clinical trials

Shorter registration procedures (EU, Pathway defined by EMA, USA

Regulation USA)
“Substitutability” status “Comparability” status

Detailing to specialist physicians required

No or limited detailing to physicians

Low price reduction

Marketing High price reduction
Price sensitivity is product specific

Substitution in pharmacies Substitution not allowed

Heinemann
14 and Hompesch J Diabetes Sci Technol 2011: 741–754
 Immunogenicity is one of the most important
safety issues for biosimilars
Insulin biosimilars

• All biologics are potentially immunogenic

• Product quality may influence immunogenicity
(e.g. impurities, aggregates)
• Minor differences in manufacturing process may
influence immunogenicity
• Immunogenicity cannot be predicted and needs
long-term safety monitoring to be established
• Immunogenicity may have significant clinical
consequences
Source: Kuhlmann et al. Nephrol Dial Transplant 2006:21 (Suppl 5);v4–v8; Schellekens. Nephrol Dial Transplant 2003;18:1257–1259
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 All biologics are potentially
immunogenic
Insulin biosimilars

Mechanisms of antibody production

Reaction to antigens Breakdown of immune tolerance

(classical immune response) (breakdown of B cell tolerance)

• Occurs slowly, following long treatment,

disappears after treatment withdrawal
• Mechanism not completely characterized
• May be caused by impurities and
aggregates

*With the exception of granulocyte colony stimulating factor; Source: Schellekens. Clin J Am Soc Nephrol 2008:3;174–178
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 Immunogenicity of insulin biosimilars may be influenced
by fibrillation and impurities
Insulin biosimilars

• Immunogenicity may be influenced by

–Fibrillation: a type of protein aggregation in which
multiple protein monomers organized into fibrils
• Insulin molecules known to form fibrils
–Impurities
• Any peptide that is not the exact recombinant protein can be
considered as an impurity

• Immunogenicity of insulin biosimilars must be

carefully
monitored to avoid PK/PD profile modification
Source: Covic et al. Nephrol Dial Transplant 2008;23:3731–3737
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 Assessment of immunogenicity is critical
to ensure safety of insulin biosimilars
Insulin biosimilars

Post-
translational Impurities
modifications
Protein
structure Formulation
(1°, 2°, 3°
and 4°)
Immunogenicity
of insulin
biosimilars

Insulin used in a wide range of patient populations

Biosimilars may be granted marketing authorization with limited data

Assessment and monitoring of immunogenicity is critical for insulin biosimilars

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Critical intra-individual dose response of insulin heightens
importance of consistent efficacy
Insulin biosimilars

• PK and PD comparability with the originator

biologic is of paramount importance when
dealing with a substance like insulin
• Comparability and consistent efficacy is key
to avoiding hypoglycaemia
• Consistent efficacy of particular importance
as insulin dose varies day by day

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 Insulin administration devices add to
the complexity of insulin biosimilars
Insulin biosimilars

Insulin
biosimilar
? ?
Disposable pen ? ? Syringes/needles

Cartridges for
Insulin pump
reusable pen

*Presentation refers to both formulation and packaging (i.e. cartridge, concentration, excipients)
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 Insulin administration devices are tested with a
specific insulin presentation*
Insulin biosimilars

• Device accuracy and safety is evaluated at

several levels
Regulatory

Device
Surveillance
Development

Marketing Device
Supply Chain quality

Device
production

*Presentation refers to both formulation and packaging (i.e. cartridge, concentration, excipients)
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 Several aspects of administration devices
controlled by rigorous legal framework
Insulin biosimilars

• Guidelines provided by FDA, EMA, ISO

– Dose accuracy
– Dose visibility
– Correct dosage after storage in
a range of environmental
conditions
– Proper function following a drop
from 1 m at various orientations
– Durability of labels and
distinguishing marks

• Each administration device is tested with a

specific insulin presentation*
*Presentation refers to both formulation and packaging (i.e. cartridge, concentration, excipients); Source: EMA website:
http://www.ema.europa.eu/; FDA website: http://www.fda.gov/; ISO website: http://www.iso.org/iso/home.htm
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 Issues to consider when evaluating a biosimilar insulin
or insulin analogue
Insulin biosimilars

Issue Evaluate

Reliability of supply • Stock position

• Clinical trials using different batches

• Appropriate design
Clinical efficacy
• Results can be generalized

• Safety and tolerability profiles compare to

reference
• Precautions or contraindications provided
Clinical safety
• Serious adverse event reporting
and tolerability
• Immunogenicity
• Post-marketing pharmacovigilence

Adapted from: Krämer, Sauer. Br J Diabetes & Vas Dis 2010;10:163–171; Krämer et al. EJHP Practice 2008:14;73–76
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Biosimilar Usage- ASIA
Jade Registry June 2015
Presented on June 6, 2015 by Prof Julianna Chan (Hong Kong)

Biosimilar insulin use is prevalent in Asia which is

associated with worse glycemic control despite higher
insulin dose. Pharmacological vigilance studies are
needed to evaluate their long term effects on clinical
outcomes.
Key Findings
Biosimilar Usage- ASIA
Jade Registry June 2015

Total of 81, 953 T2D patients enrolled on the registry from 11

countries (Hong Kong, India, China, Philippines, Indonesia,
Korea, Malaysia, Singapore, Taiwan, Vietnam, Thailand)

19,600 patients or 23.9% on insulin; Insulin BiosimIlar usage @

6.9%

Biosimilar insulin users were younger (mean+SD:56.2+11.4 vs.

57.9+11.8)

had higher HbA1C (9.4+2.3 vs originator (9.0+2.2) despite using

higher insulin dosage (0.50 vs. 45 units/kg)
Biosimilar usage was over 10%
HbA1C were 9.7 +2.7 Biosimilar vs.
Had higher BMI vs originator (26.5+5.0 vs 25.8+4.5) 9.2+2.5 Originator

Insulin Dosages were 0.52 for biosimilar

Higher waist circumference with biosimilar and 0.35 for originator.
Conclusion:
Biosimilar Usage- ASIA
Jade Registry June 2015

Biosimilar insulin use was independently associated with

higher insulin dose and HbA1c.

The association with lower incidence of hypoglycemia

was attenuated after adjusting for confounding variables.
Basalin Pen
(Gan and Lee, China)

- Demonstrated to meet ISO 11608-1:2000 requirements

for dose accuracy with higher dosage variability
observed compared with SoloSTAR and ClickSTAR pens1

- Additionally, the device does not have a “last dose stop”

safety feature to prevent dialling more than the
remaining dose in the pen.1
- max 60 unit
- Adjust by 1unit
- Plastic body
- Cartridge dose scale shown: 220 unit
- Body is quite big not easy to hold

1. Friedrichs A et al. Dose accuracy and injection force of different insulin glargine pens. J
Diabetes Sci Technol. 2013; 7(5):1345-1353.
Glaritus Pen
(Wockhardt, India)

- Demonstrated to meet ISO 11608-1 requirements for

dose accuracy with higher dosage variability observed
compared with SoloSTAR and ClickSTAR pens1

- Both the device do not have a “last dose stop” safety

feature to prevent dialing more than the remaining dose
in the pen.1

- The Glaritus dispo pen requires significantly increased

injection force as compared with SoloSTAR and ClickSTAR
pens1

1. Friedrichs A et al. Dose accuracy and injection force of different insulin glargine pens. J
VN- The product was Diabetes Sci Technol. 2013; 7(5):1345-1353.
withdrawn, because the
MOH asked for some clinical
data which they were not
able to provide.
 Insulin biosimilars: Key considerations
Summary

• Biosimilars are not generics

• Small differences in manufacturing may result in different products
• Concerns focus on biosimilar quality, efficacy and safety
• The most important safety issue is immunogenicity
• Clinical trial and pharmacovigilance data are essential to monitor potential
immunogenicity
• Production and therapeutic use of insulin and insulin analogue biosimilars pose
specific challenges not faced by other biologics
• All potential biosimilars should be required to provide relevant
preclinical and clinical data for marketing authorization
• Regulatory authorities recognize the potential risks of biosimilars and are open to
external input

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GLB.DIA.11.12.04 02/12