1

Sundar Ramanan, Ph.D.Vice President, Global Regulatory Affairs

May 13, 2019

Patient-first, Science-based Regulatory Approaches for Insulins

Biocon – Pioneer in Affordable Access to Biologics

40 years in Biotechnology

Expertise in multiple expression systems (e.g. Yeast, E.coli, CHO, SP2/0)

In 2019, Biocon’s products will improve ~2.6 million livesa

Glargine & rHI: ~2.5 million lives

Pegfilgrastim: ~ 26,000 lives

Adalimumab: ~ 24,000 lives

Trastuzumab: ~ 20,000 lives

“For us a blockbuster is being accessible to a billion patients” Kiran Mazumdar-Shaw

Patents filed*

~1,315Patents granted*

~1,100Registered

Trademarks*

~630

Biologics taken from Lab to Market

2 Novels & 6 Biosimilars

8

cGMP approvals from International regulatory agencies*

25+

Countries where our products are available

~120

Key regulatory approvals from US, EU, Japan, France, Brazil, Mexico, Turkey, GCC etc.

a. Number of lives is calculated based on volume supplied

Expertise in Insulins: > 15 years of serving patient needs

Insulin: 40+ countriesa

Insulin Glargine: 60+ countriesa,b

a. List of countries on fileb. Marketing authorization holder is Mylan in some countriesc. https://wayback.archive-it.org/7993/20170405222944/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf

Biocon has the Science, Scale, Scope, Technology, and years of real world safety data

> 2 Billion doses; ~730 Million patient days exposure

rHuman InsulinInsulin Glargine

One of the largest Insulins provider

FDA precedentc: Use of 7.5 Million patient days of exposure toward the Totality of Evidence for the US approval of Zarxio®

Insulins• rHI, Basal and Rapid acting • Vials, pens and cartridges• Disposable and reusable pens

Question 1 (a): Considerations for BiosimilarityOutline

4

1. Molecular complexity - Insulins can be completely characterized

2. Efficacy & Safety can be evaluated using in-vitro functional assays

3. Clinical pharmacology can also include efficacy (valid PD marker) and safety assessment

4. Minimal residual uncertainty with regards to immunogenicity

5. Considerations to address residual uncertainty with regards to immunogenicity

a) Utilize existing/available clinical evidence

b) Immunogenicity is not correlated with Insulin dose increase or adverse reactions

c) Consider uniqueness of Insulins in practice

d) Recommend specific clinical trial to address any product or patient related factors

6. Other considerations

Q1 (a): Considerations for Biosimilarity

Insulins are simple proteins – can be completely characterized

Image Source: BioEngage - https://www.amgenbiosimilars.com/expertise/highly-specialized-knowledge/

• Scientific and regulatory expectation must reflect the complexity of molecule

• Physiochemical & Functional assays are adequate to characterize the product and impurities

• Analytical characterization can adequately identify all residual risks (i.e. no unknown risks)

Consideration 1: Insulins are small and simple proteins

Q1 (a): Considerations for BiosimilarityConsideration 2: In-vitro methods can adequately assess the safety of Insulins

Physicochemical characteristics• Amino acid sequence• Secondary/HOS• Impurities and Variants

Biological activity

Efficacy

Safety

Metabolic Activity• Insulin Receptor B Binding• Insulin Receptor B

Phosphorylation• Glucose Uptake• Adipogenesis• Inhibition of stimulated lipolysis

Mitogenic Activity• Insulin Receptor A Binding• Insulin Receptor A

Phosphorylation• IGF-1 Receptor Binding• Cellular Proliferation

Efficacy & Safety can be determined using functional assays

STRUCTURE FUNCTION

rHuman InsulinCell growth & proliferation

P PGlucose

GLUT-4 Vesicle

GLUT-4

MAP Kinase/ERK Signalling PathwayPI-3K Signalling

Pathway

Cell Survival & Proliferation

Synthesis-Lipids,

proteins, glycogen

α α

β β

Insulin

1

4

2

3

α α

β β

IGF-1 receptor

1

2

Insulin receptor

3

Q1 (a): Considerations for BiosimilarityConsideration 3: Minimal residual uncertainty remains (Immunogenicity)

Immunogenicity

Clinical

Pharmacology

• PK comparability

• Validated PD

marker (GIR)

Non Clinical

• In-vitro Assays can

assess functions

with adequate

sensitivity (Efficacy

& Safety)

Quality(Analytical Similarity)

Structure-Function• Complete characterization is

possible

Totality of evidence required for biosimilarity can be addressed via Structure-Function analysis and PK/PD Comparability. Minimal uncertainty remains on Immunogenicity.

Residual Uncertainty

Insulin Antibodies (IA’s) and Insulin Resistancea:

- Multiple studies have shown absence of a correlation between IA’s & Insulin resistance

- In long-term follow-up studies of children with type 1 diabetes, neither the presence of insulin autoantibodies (IAA’s) nor the development of IA’s caused an increased need for insulin dose requirements

Insulin Antibodies (IA’s) and Hypoglycemiab:

- Many clinical studies have shown absence of significant correlation between IA’s and average glycemia

Q1 (a): Considerations for Biosimilarity

Insulin Antibodies are not correlated with (1) loss of efficacy or (2) safety issues

a. Radermecker et al., 2009, Diabetes Metab Res Rev 25:491–501; Lassmann-Vague et al., 1995, Diabetes Care 18:498–503; Salardi et al., 1995 Acta Paediatr 84:639–645;Tominaga et al., 1992, Diabetes Res. Clin. Pract. 18: 143–151; Fernandez et al., 1996, Diabet. Med 13:686–687; Keilacker et al., 1982, Metab. Res 14:227–232; Martinka et al., 1998, Vnitr Lek 44:577–581.

b. Wredling et al., 1990, Scand J Clin Lab Invest 50:551–557; Dozio et al., 1996, Diabetes Care 19:979–982; Francis et al., 1985, Diabet Med 2:89–94; Hubinger et al., 1988, Diabetes Res 7:65–69. Sakata et al., 1986, Immunol Invest 15:791–799.

Consideration 3: Insulins Immunogenicity & Risk to Patient Safety

Product Specific Factorsa:

- The insulin molecule is well established to have multiple T cell epitopes that can elicit an adaptive immune response

- Net immune response is a balance between opposing (effector & regulatory) T-cell responses

- Given identical AA sequence and T-cell epitopes are linear peptides, switch between the reference product & biosimilar is not expected to result in differential T-cell response

- Higher Order Structure (HOS) using NMR and X-ray crystallography can ascertain any structural difference with high degree of certainty

- In cases where the formulation is identical, no risks from excipients exist

Patient-related factorsb:

- Multiple long term clinical studies in T1DM ( >70% of patients had baseline anti-insulin antibodies [AIA]) and T2DM patients evaluating AIA formation after exposure to human Insulin and Insulin analogues indicate that AIA does not have a major impact on patient safety and efficacy

Q1 (a): Considerations for Biosimilarity

a. James, 2017 Diabetes 66: 2940-2941; Kurki et al., 2017, BioDrugs, 31(2):83-91.b. Data on file

Consideration 3: Insulins Immunogenicity & Risk to Patient Safety

Product and Patient-related factors suggest that AIA’s don’t cause a loss of efficacy or safety issues

One trial (N, ~300) can address any residual immunogenicity risks

TEAR rates from multiple studies have shown no impact on efficacy, safety or dosing

Comparative results should be viewed in the totality of evidence- Immunogenicity assessment should include NAb and its effect on glucodynamic effect (e.g., HBA1C and/or Insulin dose)

- Injection site reaction should also be evaluated

Q1 (a): Considerations for Biosimilarity

A single 300-patient study should be adequate to address any product and/or patient-related immunogenicity risks

Consideration 3: Recommendations to address any immunogenicity risks

Admelog FDA Medical Review 2017; Admelog EPAR 2017; Darwahl et al SORELLA 2 Results 2018; Garg et al SORELLA 1 Results 2017, Ilag et al, 2016, Basaglar FDA Medical Review 2014; Lusduna EPAR 2016

Q1 (a): Considerations for Biosimilarity

Products with multiple concentration:• Safety & Immunogenicity assessment of

one concentration is sufficient, along with a PK/PD assessment for an additional concentration based on scientific justification.

a. Humulin N, 70/30, R formulations US-PI; http://pi.lilly.com/us/HUMULIN-N-USPI.pdf; https://pi.lilly.com/us/humulin-r-pi.pdf; https://pi.lilly.com/us/humulin-r-pi.pdf (accessed 5/6/2019)

Consideration 4: Other considerations toward totality of evidence

Low concentration High concentration

PK / PD

Safety

Immunogenicity

PK/PD

Products with multiple formulations:• Immunogenicity assessment of the

formulation with the highest theoretical risk is sufficient.

• Safety & Immunogenicity can be extrapolated to other formulations.

Formulation 1(e.g. Soluble)

Formulation 2(e.g. Suspension)

Formulation 3(e.g. Mix)

Extrapolation Form 1

Extrapolation Form 2

Immunogenicity assessment in

one theoretically high risk

formulationSam

e A

dve

rse

R

eact

ion

*

Q1 (a): Considerations for Biosimilarity

Safety & Immunogenicity data from clinical trials with a different reference product (for OTC products) should be considered toward the totality of evidence for biosimilarity

Consideration 5: Other considerations toward totality of evidence

For OTC products, Safety and Immunogenicity data for the biosimilar product from foreign controlled study (even if the reference product is different) should be considered toward the totality of evidence, with scientific justification

Pharmacovigilance data must be considered toward the totality of evidence, with scientific justification

Question 1 (b): Considerations for InterchangeabilityOutline

1. Insulin is the only protein to be designated as OTC

2. Biosimilarity + Any given patient + Risk of diminishing efficacy

3. Additional considerations

Humulin N® Novolin N®

Novolin N

Humulin N

Novolin N

Humulin N

Despite large differences in the Product Characteristics• Under emergency situations the FDA allows rHI to be switched between manufacturers2

• Effective Therapeutic Range is the Same & Wide (dosage is Identical, unit-per-unit basis)• Designated as OTC by the FDA

Pharmacodynamics1 Humulin R Novolin R Humulin N Novolin N Humulin 70/30 Novolin 70/30

Onset 30 min 30 min NA 1-2 hr 50 min 30 min

Peak 3 hr 1.5 - 3.5 hr 6.5 hr NA 3.5 hr NA

Duration of Action NA NA NA 24 hr 23 hr up to 24 hr

1. Data from the respective RLD US PI2. https://www.fda.gov/Drugs/EmergencyPreparedness/ucm085213.htm

NA = Not available

Humulin is manufactured by Eli Lilly and Novolin is manufactured by Novo Nordisk

Q1 (b): Considerations for InterchangeabilityConsideration: Only therapeutic proteins with OTC rating (r-Human Insulin)Different characteristics that could impact PD does not result in clinically meaningful differences

Q1 (b): Considerations for InterchangeabilityConsideration: No incremental risk for interchangeability

No additional need for evidence between Biosimilarity & Interchangeability

QUALITYAnalytical Similarity

NONCLINICAL(Efficacy & Safety)

CLINICAL PHARMACOLOGY

(human PK/PD; Efficacy & Safety)

CLINICAL CONFIRMATION(Immunogenicity)

Same clinical effect for any given

patient

Risk in safety terms of diminished

efficacy

• Every patient currently takes the drug that is titrated to their needs

• Comparison of GIR equivalence proves drug is effective in any given patient

• Unlike mAb’s, loss of efficacy due to AIA is not a concern for diabetic patients

• Unlike mAb’s (weekly, monthly or longer), Insulins are injected daily (i.e. a single switch or a three switch study is not needed)

There are multiple reference products or biosimilars available to patients today, and these products are frequently switched with each other because of an OTC rating or other drivers, therefore:

- When a biosimilar is approved, it should be deemed as interchangeable to all the reference products

Q1 (b): Considerations for InterchangeabilityConsideration: Uniqueness of Insulins

Q2: Unique scientific considerations for continuous infusion pumps

All product related factors have been adequately addressed via totality of evidence for biosimilarity/interchangeability

No additional or incremental risk exists from the product

Product Compatibility studies are needed (i.e. compatibility study and extractable/leachable study)

Additional clinical studies do not add any value for the patients or address any specific safety risks

Product compatibility testing and Extractable/Leachable studies are adequate to ensure safety. No additional studies are needed.

Q3: Patient Experience

Patient experience data should be linked with clinical outcomes, i.e. safety, efficacy etc.

Patient preference data, should be limited to clinical outcomes

Policies should allow patient experience and/or patient preference data to be utilized toward enabling approval, access and/or adoption of biosimilars

Patient experience should allow for a greater access to biosimilars

Q4: Information resources for patients, clinicians, pharmacists, and other stakeholders

Level playing field for both the reference product and biosimilars – Any false and/or misleading information campaign should have meaningful consequences

– FDA must ensure that the promotional materials not include language that is suggestive or negative about biosimilars

Any educational and promotional materials casting aspersions on the biosimilarity and/or interchangeability should be discouraged

Enhanced education on storage and handling should mitigate Loss of Efficacy (LoE)– We request the FDA to discourage attribution of LoE to either the reference products, biosimilars or due to switching

between the two, without convincing evidence

FDA should enable fair, transparent, evidence based communication

Conclusions

Insulins are simple proteins and the regulatory requirements should be proportional to the complexity

Residual uncertainty can be accurately identified and quantified

Such residual uncertainty can adequately be addressed in a single clinical trial

The totality of evidence required for a biosimilar or interchangeable insulin is the same

–All biosimilar Insulins should be approved as Interchangeable products

Compatibility studies are necessary and sufficient to address any risks related to continuous infusion pumps

Patient experience data should enable quicker access to biosimilars

Patient-first, Science-based regulations ensure efficient development of biosimilar and interchangeable Insulins.