Biosimilars IN RETINAL DISORDERS -DR AJAY DUDANI

Treatment Options in
Medical Retina: Where do
we stand?
DR. AJAY DUDANI
PROF- K J SOMAIYA MEDICAL COLLEGE
MUMBAI RETINA CENTRE
ZEN EYE CENTRE

Retinal conditions – Current
scenario
Source: https://theophthalmologist.com/issues/0317/its-in-their-bones/

VEGF-A: key mediator of angiogenesis
and vascular permeability.......
The development of antivascular endothelial growth factor (anti-VEGF) has
revolutionised the treatment of a plethora of ocular angiogenic disease processes.
Tah et al. Anti- VEGF Therapy and the Retina – An Update; Journal of Ophthalmology 2015

Evolution of Anti-VEGFs
Hypothesized - a diffusible, hypoxia-
induced, angiogenic “factor X” was
responsible for iris and retinal
neovascularization associated with
ischaemic retinopathies.
initiated phase 1 trials for the
development of an anti-VEGF molecule
(bevacizumab)
Discovered a candidate
glycoprotein and termed
vascular permeability factor
Discovered a tumour-derived factor
named vascular permeability factor
(VPF), which was responsible for
inducing vascular permeability
Decades later
1948 Michaelson
1989 Leung et al.
1990 Keck et al.
The diffusible,
hypoxia induced,
endothelial cell-
specific factor
VEGF
conceivably
represents
Michelson’s
retinal tissue
“factor X”
Elevated levels of
VEGF in ocular
fluids from
patients with active
neovascular ocular
disease were found
compared with
ocular fluids with no
vascularisation.
Simultaneous Research showed
All the
evidence of
angiogenesis
points to the role
of VEGF in ocular
neovascularisatio
n
1997 Genentech

Evolution of Anti-VEGFs....contd
2003 - 2004
Furthermore, with the knowledge that
VEGF played a significant role in
neovascular AMD, FDA approved
pegaptanib (Macugen) was created,
making it the first antiangiogenic
therapy for ocular neovascularisation
Bevacizumab approved for the
treatment of colon cancer in
combination with chemotherapy
– based on successful results
from phases 2 and 3 trials.
2004 - 2005
Believing that bevacizumab would not
efficiently diffuse through the retina to
reach the choroid, Genetech decided
to generate a truncated alternative
molecule (Ranibizumab)
2007
Ranibizumab (Lucentis) was approved based on data
from two large Phase III clinical trials:
• MARINA (minimally classic/occult trial of the anti-
VEGF antibody ranibizumab in the treatment of
neovascular AMD)
• ANCHOR (anti-VEGF antibody for the treatment of
predominantly classic choroidal neovascularisation
in AMD) trials
• 1st Anti-VEGF for intraocular use
2011
Regeneron developed a chimeric fusion
protein (Aflibercept) that acted as a
decoy receptor to sequester VEGF and
thereby block its biological effects
Since its approval in 2006, ranibizumab has revolutionized the treatment of retinal diseases

The evolution of ranibizumab
Innovator
CNV, choroidal neovascularization; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion;
DME, diabetic macular edema; mCNV, myopic CNV; nAMD: neovascular age-related macular degeneration; ROP, retinopathy of prematurity
nAMD
2007
2011
DME
2012
2014
Pre-filled
syringe
Other
CNV
2016
2018
2020
2013
mCNV
2017
2019
BRVO
CRVO

Rbz Innovator : supported by a large amount of
clinical evidence with 17 million injections
across indications
• Rbz Innovator is the only anti-VEGF agent which has:
1. Novartis Pharma AG. Accentrix Summary of Product Characteristics, September 2014; 2. Rofagha S, et al. Ophthalmology 2013;120:2292-9; 3. Novartis Pharma AG. Press
release September 2013. http://www.novartis.com/newsroom/media-releases/en/2013/1731649.shtml; 4. Bloch SB, et al. Am J Ophthalmol 2012;153:209-13; 5. Brand C, et
al. Presented at ARVO, 5 May 2013, Seattle, WA, abstract #3831
Most extensive patient
follow-up program
Patient-years,
from continued
post-marketing,
real-world data, and
pharmacovigilance
studies4,5
Years of
long-term data
available2
ANCHOR
SEVEN-UP
PIER
SAILOR
SUSTAIN MONT BLANC
MARINA
FOCUS
EXTEND EXCITE
GEFAL
HARBOR
WAVE
LUMIÈRE
CATT
IVAN VIEW
BRAMD
COMPASS
LUMINOUS
SAVE
SECURE
LAST
FUSION
HORIZON
PrONTO
Largest number
of clinical trials
Patients included
in the extensive
clinical trials
program3
Largest amount
of patient data
Rbz Innovator has a well-defined efficacy and safety profile supported by
clinical trials and real-world data
Number of indications
approved for treatment1
Largest number of
approved indications
nAMD
Myopic CNV
DME
CRVO
BRVO

Real-world evidence shows over 70,000
patients have been treated with
ranibizumab innovator
Cumulative
number
of
patients
*Except other choroidal neovascularization. †Includes n=401 eyes
1. Cohen SY, et al. Graefes Arch Clin Exp Ophthalmol 2011;249:521–7; 2. Shona O, et al. Clin Exp Ophthalmol 2011;39:5–8; 3. Pushpoth S, et al. Br J Ophthalmol 2012;96:1469–73; 4. Novartis, Data
on file
Cumulative number of patients included in
ranibizumab real-world studies (all indications)*1-4

Anti-VEGFs – Current Status
Innovator biologics like
1. Ranibizumab
2. Aflibercept
3. Bevacizumab (Off-label) are well known and successful.......
In the world of ophthalmology,
Biosimilars
1. Ranibizumab
2. Bevacizumab
Now.......companies are developing anti-VEGF biosimiliars in attempts to get a
foothold in the anti-VEGF market....
Are biosimilars the same as Innovator biologics?

Biologics Are Large, Protein-Based
Therapeutics That Vary in Size and
Complexity
Small Molecule Biologics
Acetylsalicylic
acid1
~ 180 daltons Insulin2
~ 5,700 daltons
Growth hormone3
191 amino acids
~ 22,000 daltons
Monoclonal antibody4
~ 1,300 amino acids
~ 150,000 daltons
Increasing Complexity
1. Aspirin (acetylsalicylic acid) prescribing information, Bayer.
2. Insulin product information, Sigma-Aldrich. www.sigmaaldrich.com/content/dam/sigma-
aldrich/docs/Sigma/Product_Information_Sheet/2/i6634pis.pdf. Accessed February 6, 2017.
3. Online Mendelian Inheritance in Man.
www.omim.org/entry/139250?search=human%20growth%20hormone&highlight=hormone%20growth%20human. Accessed Feburary 6,
2017.
4. Chennamsetty N, et al. mAbs. 2009;1:580-582

What Is a Biosimilar?
• Undergone rigorous analytical and clinical assessment, in
comparison to its reference product
• AND
• Been approved by a regulatory agency according to a specific
pathway for biosimilar evaluation
A biosimilar is a “copy” of a commercially
available biopharmaceutical (reference product)
that no longer is protected by patent which has:
A biosimilar is “highly similar” to its reference
product in physicochemical characteristics,
efficacy, and safety.
Dörner T, et al. Ann Rheum Dis. 2016;75(6):974-982.

Biosimilars Are Not…
Woodcock J, et al. Nat Rev Drug Discov. 2007;6(6):437-442.
→ Structurally different from originally
licensed biopharmaceutical
→ Intended to improve performance
while preserving mechanism of action
→ Examples
Infliximab and adalimumab
Filgrastim and pegfilgrastim
→ Not considered to be biosimilar
Second-Generation
(or Biobetter)
Generic Drugs
→ Small-molecule drugs, that are
less complex than biosimilars
→ Manufacturing process is several
orders of magnitude less complex
→ Regulated under different
legislation

5
‘Similar’ DoesNot Equal ‘Same’
‘‘Similar’ DoesNot Equal ‘Same’
- Let’s look at Manufacturing
Processes

Biologics: Drug Substance
Production Process
START
Vectors to
insert the gene
Gene sequence
coding for
protein
Host cells to
grow the protein
END
Biophysical characteristics
of final drug substance
Lengthy and complex
purification process
Fermentation
with very precise
culture conditions
Factors influencing properties of the molecule:
• Time, pH, temperature, culture media, oxygen
levels/lactic acid accumulation
Properties most frequently affected:
• Carbohydrates, ratios of charged species,
aggregates
Factors influencing properties of the
molecule/product:
• Removal of host cell DNA and proteins
• Removal of fragments and aggregates
• Concentration of the protein
• Final formulation buffer
Liu HF et al. mAbs. 2010;2;(5):480-499
Li F. et al. mAbs 2010;2(5):466-477

Manufacturing Biologics – why is it
so difficult ?
• A biological typically requires around 250 in process
tests during manufacturing as compared to around 50
for routine generics
• To ensure high quality and consistency in final product ,
high level of monitoring and testing required during
production.

Biologics Manufacturing Control at
EveryStep
In ProcessTestingData From EveryProcess Step
CellBank Bioreactor Harvest Chromatography
1, 2, 3
Virus Filter Concentration
Bottling
FinalTests
Purification
Cell Culture Final Dosage Form
Forcomparability, the innovator hasarich testing database from every in process
step of every batch, the biosimilar only hasaccessto the finalproduct

Biosimilars and Twins:
Identical DNA, Minor differences in Features
• Theactive ingredient of abiosimilar can at best only resemblethat of
the innovator product
• How an innovator makesits biologic can never be duplicated down to the
last detail; abiosimilar is made using cells, materials and processesthat
differ from the innovator product
• Thisis true even if abiologic and its biosimilar start from the samegenetic
blueprint, in much the sameway asidentical twins, despite the same
genes, have different fingerprints

Different vectors to
insert the gene
Different host cells to grow
the protein
Different fermentation/culture
conditions
Different downstream processing
Different biophysical characteristics in final
product

Accumulated Experience and Knowledge
Generates Sustainable Quality and Predictability
YEAR 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Innovator
Development
Discovery and
Target Validation
Cell Line,
Process
Development
Process Characterization,
Validation
Process monitoring, Scale and Site changes, Comparability Protocols,
Process consistency Assurance
Characterization of Molecule, Structure
/Function Studies, Justify and Establish
Specifications
Deep understanding of Product Properties, Comparability Protocols to assure consistent product
Non-clinical Studies
Ph 1
clinic
als
Phase 2
Clinicals Phase 3Clinicals
BLA/
MAA Clinical Studies for additional Indications
Pre-Approval SafetyDatabase
Post-Approval Safety Database, Post-Approval Phamacovigilence, Post-
Marketing Observational Stuides, Post-Marketing Safety Studies
YEAR 1 2 3 4 5
Biosimilar
Development
Cell Line, Process
Development,
Characterization
Analytical
Characterization,
Establsih Specifications
Non-
Clinical
Studies
Clinical studies
BLA/
MAA
Pre-Approval SafetyDatabase

5
Small Alterations Can Make a BIG
Difference

Manufacturing Biosimilars
Even small changes in production – minor equipment and
environmental variations can :
• Cause significant changes in behavior of cells
• Change in the fragile 3-dimensional structure of the
protein
• Change in quantity of acid-base variants and
glycosylation
• Impact the safety and effectiveness of the Biologic

23
Concept of Interchangability

Interchangeability
“Biosimilar to the U.S.-licensed
reference biological product …
expected to produce the same
clinical result as the reference
product in any given patient.”
“For a biological product that is administered
more than once to an individual, the risk in
terms of safety or diminished efficacy of
alternating or switching between use of the
biological product and the reference product
will not be greater than the risk of using the
reference product without such alternation or
switch”
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAppli
cations/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 19th Feb 2016
Note : The interchangeable product may be substituted for the reference product without the intervention of the health care
provider who prescribed the reference product.
(biosimilar drug should
neither increase AEs nor
decrease efficacy when
switched from the
reference drug)

5
Approvals

Steps involved in Approval of Similar
Biologic
Physicochemical
data
Pre-clinical
Studies
Clinical (PK/PD)
studies
Confirmatory
clinical safety
and efficacy
studies
Safety and
Immunogenicity
Data
• One or more adequately
powered, randomized,
parallel group, blinded
confirmatory clinical
safety and efficacy trials
are desirable based on
the comparability
established during
preclinical and PK / PD
studies
• Pharmacodynamic
Studies
• Toxicological
Studies
• Both pre-approval and post-
approval assessment of
safety is desired to be
conducted for similar
biologic.
• Regarding pre-approval
safety assessment,
comparative pre-approval
safety data including the
immunogenicity data is
required for all similar
biologics

• Strong need for regulations governing biosimilars
• Implementation of an abbreviated licensure pathway for biological
products presents challenges, given the associated scientific &
technical complexities
• European Union has regulations in place for quite some time for
approving biosimilars
• US & India have recently covered these under their respective Acts
by bringing in applicable guidelines for their evaluation & overall
regulation
Status of Regulations for Biosimilars
Globally

Strength of Evidence
Meta-
analysis
Randomized
Clinical
Trials
Cohort studies
Case control studies
Case reports
Editorials/Expert Opinions
Animal research/ In-vitro studies
1
2
3
4
5
Levels of evidence
http://www.dentalcare.co.uk/dental-professional-education/dental-courses/ce-
311/evidence-based-decission-
making.aspx?ModuleName=coursecontent&PartID=4&SectionID=-1. Accessed on 30th Sept
2016
Currently all the
data of
Ranibizumab
biosimilar fall into
this level
Ranibizumab
Innovator

Occult CNVM 15 YR STUDY –
BILATERAL RAP -45 INJECTIONS
• 82 year old male
• Strong family history of AMD
• LE – Diagnosed with AMD 14 years ago(2001), Underwent 2 TTT’s, 3
PDT’s with IVTA, now has macular scar with Vn of HM
RE – Has had 1 PDT (Nov 2005) for extra foveal RAP lesion and 36
injections of Lucentis in the past 11 year
• OCT MONTHLY
• EXTENT AND TREAT-ONLY INJECT WHEN FLUID
• LUCENTIS TACHYPHYLAXIS?
• RE AFTER SWITCH TO EYLEA -6 EYLEA INJ OVER 5 YRS
• Repeat eylea after 4 months ON PRN BASIS
• LAST EYLEA 2WEEKS AGO AFTER 12 MONTHS
• VISION 6/9 N6
• GEOGRAPHIC ATROPHY

COMPARE PRE AND POST VEGF -RAP
• PRE VEGF EYE—PL
• POST VEGF 6/9 N12
• DOES THE LEAK EVER STOP
• STARTS AS FLOOD
• THEN A DRIZZLE
• ENDS AS A MINOR TRICKLE
• VEGF IS THE DRIVER
• ANTIVEGF IS THE GLUE
• WATERPROOFING THE RETINA
• DR FIXIT

Serial angiography-RE
Sep
2005
(FFA)
May 2006
(ICG)
Oct
2008
(FFA)
RAP LESION

Serial OCTs - PEDs with fluid
Sep 05 – PDT
done
May 06 – post lucentis
– 3 injections at 2
monthly intervals
May 06 – fluid 6
months later –
Lucentis started

Serial OCTs
May 07 – Fluid 8 months
after last injection –
needed injection every 3
months since..
Jan 09 – eg of OCT post
injection
March 09 – fluid in
3 months –
Thickening of
same parafoveal
area every 3
months

Serial OCT’s – Last injection
July13
July 2013 – pre- injection
Feb’13 - extra foveal site

Serial SLO photos
Nov 2010
Mar 2009
Sep 2008
July 2013

ANTI VEGF SIDE -EFFECTS
• DID IT LEAD TO CHORIODAL ATROPHY
• GEOGRAPHIC ATROPHY
• GLAUCOMA
• HEART ATTACK
• HYPERTENSION
• CENTRAL SCOTOMAS
• SLOW READING SPEED
• LOSS OF CONTRAST SENSITIVITY
• EXTENT AND TREAT

Summary
• Anti-VEGF medications have revolutionized the treatment of
exudative AMD over the past 2 decades and patients with a
potentially blinding disease have been able to regain vision.
• While there is still no clear-cut best treatment regimen,
evidence suggests individualized treatments may be safer
and more efficient.
• The "treat and extend" protocol seems to offer the most
favorable alternative to the monthly regimen with a goal
being to extend the interval between visits to maintain an
exudation-free macula with the fewest number of visits and
injections
• There still remain several unanswered questions regarding
nAMD treatment such as the interval by which "treat and
extend" protocols should be extended at each visit, how

Ranibizumab vs biosimilar
Parameter Bio-similar Study Ideal Standard
Duration of
the Study
Just 3 months Minimum of 1 year follow up is necessary and ideally
landmark studies like CATT & IVAN have taken the 2 year
follow up to compare the safety between bevacizumab
and ranibizumab.
Endpoint % of patients with loss of <15 letters Current studies evaluate BCVA gain
Number of
Patients in
the study
The study with Bio-similar has only
100 patients.
Biosimilar arm 75 and ranibizumab
arm 25.
A minimum of 30 patients is required in any arm of a trial
for statistical significance and the ranibizumab arm is
under –represented.
Sample sizes for most H2H studies of Anti-VEGF have
been around 200- 300 patients
Ranibizumab and its biosimilar have been studied in one
single trial and that too in patients of AMD only.
http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=7625&EncHid=&userName=ranibizumab.
Accessed on 19/02/2016

RE-ENACT Study (Retrospective,
Multicentre, Observational study on Wet AMD)
45
Did not capture the complete information on adverse
events in the medical records and hence, not analyzed in
this subgroup

5
Safety??

Recent Report of Eye Inflammation with Rbz
Biosimilar, Company Recalls Batch for QC Testing
48
Patel D. Patients report eye inflammation, Intas recalls its drug batch. The Indian Express. April
3, 2017. http:// indianexpress.com/article/business/companies/undertaking-detailed-analysis-
patients-report-eye-inflammation-intasrecalls-its-drug-batch-4596914/. Accessed April 11, 2017
With some patients reporting
Inflammation in their eyes due to Rbz
Biosimilar, the company has advised the
docs to not to use any drug of this of this
particular batch. It has also recalled this
batch from the market to undergo internal
testing at its QC lab

VRSI Issued Alert on Ranibizumab
Biosimilar Second Time In a Row
49
Dear Members, there had been reports of Intraocular
Inflammation from various parts of India after IV Rbz Biosimilar
of a company. Company has advised not to use Rbz Biosimilar
Inj. of batch no 18020020. VRSI is gathering more facts on this
situation.
It is advised that all members to be alert and exercise
abundance of precaution with other batches of the biosimilar
also. Please report any adverse Incidents to VRSI at
secretaryvrsi@gmail.com

FDA Inspection of Biosimilar Plant
50
Observation-1: Lab reports are deficient in that they do not
include complete record of all data obtained during testing
Observation-2: Appropriate controls are not exercised over
computers or related systems. There was failure to
maintain backup file of data entered into computer or
related system
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/cder
foiaelectronicreadingroom/ucm567595.pdf

51
• Observation-10: Building used in mfgd., processing, packing or
holding of drug products are not free of infestation by birds
• Observation-11: Cell bank were not maintained under appropriate
storage monitoring conditions designed to maintain viability and
prevent contamination and records of the vials from the cell bank and
storage conditions were not maintained
FDA Inspection of Biosimilar Plant
https://www.fda.gov/downloads/drugs/guidancecomplianceregulato
ryinformation/cderfoiaelectronicreadingroom/ucm567595.pdf

USFDA – approved innovator
Manufacturing Site
52
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process

Summary
• With patent expiration of innovator products, biosimilars will
increasingly become available
• Awareness of the deviations between biosimilars &
innovator products in terms of efficacy, safety &
immunogenicity is essential for proper prescription & safety
of the patients
• How similar is similar enough?

Biosimilars IN RETINAL DISORDERS -DR AJAY DUDANI

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