The Totality-Of-The-Evidence Approach to the Assessment of Sandoz Erelzi™, an Approved Etanercept Biosimilar by the FDA

1. The Totality-Of-The-Evidence Approach to
the Assessment of Sandoz Erelzi™, an
Approved Etanercept Biosimilar by the FDA
Prepared by:
Osaid Al Meanazel
Ph.D. student, King Saud University, Saudi Arabia

2. Contents
Introduction
Development of Erelzi™
• Analytical characterization
• Preclinical program
• Clinical confirmation of biosimilarity
• PK studies
• Confirmatory study in patients with moderate-to-severe plaque-type psoriasis
Conclusion
References

3. Introduction
• The development and
approval of biosimilars is
based on the “totality-of-the-
evidence” concept, whereby
all physicochemical,
functional, preclinical, and
clinical data for a biosimilar
and reference medicine are
evaluated, compared, and
shown to be highly similar.

4. • The term biosimilar or SEB, therefore, is a regulatory term reserved to
describe products that are approved following a stringent regulatory
pathway in which this complete data package is evaluated.
• Etanercept was among the first TNFis to be approved for use in
rheumatic diseases, used as monotherapy or in combination with
methotrexate, etanercept offers rapid and sustained clinical
treatment responses, reducing the signs and symptoms of disease.

5. • Erelzi (etanercept-szzs) for all indications included in the reference
product label, including rheumatoid arthritis (RA), plaque psoriasis
(PsO), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and
polyarticular juvenile idiopathic arthritis (JIA).

6. Development of Erelzi™
• Analytical characterization
Reference etanercept is produced by recombinant DNA technology in a Chinese hamster
ovary (CHO) mammalian cell expression system.
A CHO expression vector was therefore redesigned to allow expression of Erelzi™ from a
single gene encoding the same amino acid sequence as reference etanercept.
After cloning in different CHO cell types and evaluation of hundreds of subclones, a final
subclone was selected based on product quality, titer, and genetic integrity and stability.
Master and working cell banks of the final clone were established and a manufacturing
process typical for monoclonal antibodies and fusion proteins was developed, finalized,
and validated

7. Two strengths of Erelzi™ were developed, consistent with the reference medicine: 25
mg/0.5 mL and 50 mg/1.0 mL.
 Due to intellectual property reasons, the Erelzi™ formulation contained citrate and lysine
buffer components instead of phosphate and arginine, which are used in the reference
formulation.
The quality attributes of Erelzi™ and reference etanercept were compared based on
physicochemical and in vitro functional assays.
Biochemical attributes such as primary structure, higher order structure (secondary and
tertiary), carbohydrate structure, size, charge, hydrophobicity, and other attributes,
including product-related variants and impurities, were evaluated using various
orthogonal methods.

8. Because product-related impurities can impact the efficacy, safety and/or
immunogenicity of a biologic, they should be controlled and maintained at
as low a level as possible.
Etanercept molecules that contain alpha-galactosylated N-glycans are
considered potential immunogenic impurities, which must be closely
monitored.
A normal-phase, HPLC analysis confirmed that the alpha-galactosylated N-
glycans of Erelzi™ were within the range of reference etanercept and below
the upper limit defined by the maximum amount of impurities measured in
batches of reference etanercept.

9. Erelzi™ contained essentially the same active ingredient as reference
etanercept in terms of primary structure, secondary, and tertiary
structure, molecular mass/size, charge, protein content, glycosylation,
size, and amino acid modifications.
analytical studies not only provide evidence for a high level of
comparability between Erelzi™ and reference etanercept, but also
confirm that the characteristics of reference etanercept sourced from
the EU and US are indistinguishable.

13. • Preclinical program
The preclinical program of Erelzi™ consisted of five studies:
1. dose-finding PD study in mice
2. four comparative studies of PD, PK, and toxicity, including local tolerability
and immunogenicity, between Erelzi™ and reference etanercept.
The results from the preclinical studies reduce any residual
uncertainties and support the totality-of-the-evidence demonstrating
similarity between Erelzi™ and reference etanercept.

15. • Clinical confirmation of biosimilarity
For a biosimilar, the aim of clinical studies is not to establish safety
and efficacy de novo, as this has already been done with the
reference molecule, but to confirm the “sameness” of the biosimilar
to the reference medicine, which has already been established
analytically and in preclinical models.
Phase I PK studies in healthy volunteers, as well as data from a phase
III confirmatory efficacy and safety study in patients with moderate-
to-severe chronic plaque-type psoriasis.

17. • PK studies
the primary PK study was a randomized, double-blind, cross-over, singlecenter study, designed to
compare the PK, safety, and immunogenicity profiles of Erelzi™ and reference etanercept in
healthy adults.
Across all PK studies, Erelzi™ was generally well tolerated.
Immunogenicity, as determined by the formation of antietanercept antibodies, was assessed
using a three-step procedure comprising a validated electrochemiluminescence assay (screening
and confirmatory assays) for binding antibodies and a validated competitive ligand-binding
neutralization antibody assay.
The assessment of immunogenicity and PK in normal, healthy volunteers further supports the
demonstration of no clinically meaningful differences between the two medicines and completes
the third stage of the totality-of-the-evidence pyramid

18. • Confirmatory study in patients with moderate-to-severe plaque-type
psoriasis
The goal of the confirmatory study is to use a clinical indication,
primary endpoint, and study duration that has the best chance of
detecting differences in efficacy or safety differences between the
biosimilar and reference product, should they exist.
should be in the patient population most susceptible to developing
an immune response .

19. Plaque-type psoriasis was considered to represent a highly sensitive
indication to detect potential differences between Erelzi™ and reference
etanercept .
confirmatory study was conducted to demonstrate equivalent efficacy and
similar safety and immunogenicity between Erelzi™ and reference
etanercept in patients with moderate-to-severe chronic plaque-type
psoriasis .
there were no differences in safety and immunogenicity between patients
who transitioned from the reference medicine to the biosimilar at Week 16
compared with those who continued treatment with the reference
medicine for the duration of the 52 week study.

21. Conclusion
• For biosimilars, physicians need to be aware that the complete data
package (analytical, preclinical, and clinical data) is considered by
regulatory agencies when concluding whether a proposed biosimilar is
approvable as a biosimilar or not.
• The extent to which biosimilar products are used in daily clinical practice
will largely depend on the confidence placed in them by physicians, nurses,
patients, payers, pharmacists, and regulators.
• For the benefits of biosimilars to be fully realized, high-quality,
comprehensive data on the real-world effectiveness, safety,
immunogenicity, and value for money of biosimilars and reference
medicines are needed.

22. References
• Hofmann HP, Kronthaler U, Fritsch C, et al. Characterization and non-clinical assessment of the
proposed etanercept biosimilar GP2015 with originator etanercept (Enbrel). Expert Opin Biol Ther
2016;16:1185-95.
• von Richter O, Skerjanec A, Afonso M, et al. GP2015, a proposed etanercept biosimilar:
Pharmacokinetic similarity to its reference product and comparison of its auto-injector device
with pre-filled syringes. Br J Clin Pharmacol 2016: published online 27 October 2016, doi:
10.1111/bcp.13170.
• Afonso M, Kollins D, Macke L, et al. Pharmacokinetics and safety of GP2015, a proposed
etanercept biosimilar, administered subcutaneously by an autoinjector or prefilled syringe in
healthy male subjects. Ann Rheum Dis 2016;75(Suppl 2):233.
• Griffiths CE, Thac¸i D, Gerdes S, et al. The EGALITY study: a confirmatory, randomised, double-
blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept
biosimilar, versus the originator product in patients with moderate to severe chronic plaque-type
psoriasis. Br J Dermatol 2016: published online 27 October 2016: doi: 10.1111/bjd.15152
• Strand, V., Girolomoni, G., Schiestl, M., Mayer, R.E., Friccius-Quecke, H. and McCamish, M., 2017.
The totality-of-the-evidence approach to the development and assessment of GP2015, a
proposed etanercept biosimilar. Current Medical Research and Opinion, (just-accepted), pp.1-23.

23. NOTE
• Ocrevus (generic name, ocrelizumab) is a humanized monoclonal antibody that
was approved by the U.S. Food and Drug Administration on March 28, 2017.
Ocrevus was developed by Genentech, a member of the Roche Group, as a
treatment for people with multiple sclerosis (MS).
• The treatment targets B-lymphocytes, a type of immune cell, that express a
protein called CD20 on their surface, giving the drug an immunosuppressive
function. It is designed to reduce the rates of immune system attacks on
myelinated neurons, the main trigger of the disease.
• Ocrevus is the first FDA-approved therapy that treats both relapsing multiple
sclerosis (RRMS) and, in a true breakthrough, primary progressive multiple
sclerosis (PPMS), a disease form that previously had no approved treatments.
https://multiplesclerosisnewstoday.com/ocrevus-ocrelizumab-primary-progressive-
relapsing-multiple-sclerosis/