Biosimilars the Current Status
Dr. Indrajit AgrawalHOD Rheumatology, Paras Hospitals Gurgaon
Disclosures
Paid consultancy with Roche, J&J, INTAS, Sun , Torrent and Reliance.
Broad Outlines Opportunities
Research & Development
Immunogenicity
Interchangeabilty
Data on currently available Biosimilars in India.
Design the gene sequence
Place gene sequence inside
a vector
Place vector inside a specific
cell
Fermentation – cells produce the protein defined
by the vector
Purification – removing the
impurities
Highly complex protein with 3 or
4 levels of structure
IgG1 antibody>1000 amino acids~150,000 daltons>20,000 atoms
Highly Complex Manufacturing Process
WHO Definition
“Biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product”
Similarity is defined as, “absence of a relevant difference in the parameter of interest”
Biosimilars are highly similar versions of marketed biologic medicines and are supported by appropriate analytical, immunogenicity testing and non-clinical and clinical trials to demonstrate that they are suffficiently “similar” in quality, efficacy, and safety to their reference (originator) biologics. Intended copies of biologics can be defined as copies of already licensed biologic products that have not met the requirements of the WHO, EMA, or FDA to establish biosimilarity. In other words, intended copies are products for which the manufacturer intended to make a copy but did not follow a comparative development pathway with the reference medicine.
Definition of Biologic Agents
Spot the Difference…
Reference Drug/Innovators Biosimilars
Challenges to the Integration of Biosimilars into Clinical Practice
• The WHO International Non-proprietary Name (INN) system was first adopted more than 50 years ago
• Currently no international cohesiveness on biosimilar naming exists and thus impacts on pharmacovigilance
• The WHO INN-BQ system proposes a way by which biosimilar products can be identified and distinguished from the reference product and other biosimilars• Non-glycosylated biosimilars should share the same INN of the reference
product• Glycosylated biosimilars, are more complex and have different glycoform
profiles, should have a Greek letter suffix added to the INN
?
Patient and Healthcare Provider Expectations of a Biosimilar
• Same pharmacological action and antigen binding
• Equivalent efficacy to reference product
• Equivalent safety and tolerability to reference product• Including immunogenicity
• Dissimilar (lower) in price when compared to reference products
Biologics in DevelopmentInnovators
Average cost to develop 1.5 to 2.5 billion USD
Taken into account failures during development may cost up to 5 billion USD
Takes at least 10 years to develop
Biosimilars Development cost about 100 to
200 million USD Manufacturing facility cost 25 to
30 million USD Takes about 5 to 8 years to
develop
Opportunity Patent expired
Infliximab Etanercept Rituximab
Patent soon to expire Toclizumab (Actemra)—EU 17( US expired ) Golimumab (Simponi)---Sept 2018
Total US sales for Biologics is 200 billion USD (about 50% of world sale)
Source: WSJ, FT, Google
Challenges faced by Biosimilar developers From the Regulatory authorities
Expectations form the doctors & patients
Investigators prefer to work with a new agent
Litigations and court orders
Competitions from other bosimilar developers
Marketing & Promotions
Challenges offered by the Innovator companies Lowering cost
Patent extension
Development of second generation Bio-better
Delivery system modification
IPR (Intellectual Property Rights), infringement
Implications for developing world Remicade – 300mg average (approx 4lacs pa)
Simponi---50mgs (5lacs pa)
Enbrel----50mgs (4-5lacs pa)
If cost is reduced by 50% then the saving will amount to few thousand Crs.
ImmunogenecityMurine Chimeric Humanized Fully Human
Less Immunogenic
Immunogenicity Anti Drug Antibodies ( HACA, HAHA )
All the ADA may not result in lack of efficacy
Antibodies binding to Fab component
Antibodies binding to Fx component
Formation of immune complexes
Immunogenicity Depends on the route of administration
Underlying auto immune diseases
Age of the patient
Comorbidities and concomitant medications
Formulation and storage
Contaminants
Biological Product Complexity
The Challenge for Comparing Safety
The Challenge for Comparing Safety
EULAR Recommendations: Phase III
Switching At present switching is only one way from Innovator to Biosimilar. There is
absence of regulatory requirements for multiple switching between Innovator and Biosimilar products.
Quite impossible to design any study incorporating multiple switches.
Concern about immunogenicity and consequent efficacy.
Lack of published data.
Budget Impact with switching The budget impact of swtiching patients to CT-P13 for RA in the UK, Italy,
France and Germany is estimated to save €233-433 million over 5 years and more than 7500 additional patients can be treated
In practice, it has been shown that the overall uptake of TNFi has increased suggesting that additional patients are being treated
In the UK, the National Institute for Health and Care Excellence (NICE) has produced guidance for rheumatologists to initiate treatment with the least expensive drug and in Belgium and Germany, there is a quota system of physicians needing to prescribe up to 40% in biosimilars
TNF inhibitors
ACR20 response
ACR20 Response Intacept(n=81)
Innovator(n=25)
Number of patients who achieved ACR20 68 21
Number of patients who did not achieve ACR20 13 4
Total number of patients 81 25Percent of patients who
achieved ACR20 83.95% 84.00%
p – Value 1.00
ACR50 response
ACR50 Response Intacept(n=81)
Innovator(n=25)
Number of patients who achieved ACR50 43 9
Number of patients who did not achieve ACR50 38 16
Total number of patients 81 25Percent of patients who
achieved ACR50 53.09% 36.00%
p – Value 0.1716
CHANGE IN DAS-28
DAS28Mean DAS-28
score at baseline
Mean DAS-28 score at End of
Study
Mean Change in DAS-28 score from baseline
Intacept (n=81) 5.76 3.60 2.16
Innovator (n=25) 5.91 3.77 2.14
p-value 0.9408
High Moderate Low remission0
10
20
30
40
50
60
70
80
90
100
7.41
54.32
22.2216.05
4
72
12 12
DAS-28 Categorization at End of Study
Test Arm-A
Reference Arm-B
Perc
enta
ge o
f Pati
ents
Baseline Week 2 Week 4 Week 8 Week 120.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
DAS-28 SCORE AT EACH STUDY VISIT
DAS-
28 S
core
Exemptia (adalimumab)
Exemptia- Indian clinical data Multicentric, randomized, active controlled parallel study
Aim: to evaluate efficacy and safety of exemptia in patients of rheumatoid arthritis
Duration: 12 weeks
120 biologic naïve RA patients
Exemptia + methotrexate(60)
Reference product+ methotreaxate(60)Randomization
Primary end point: ACR20
Other end point: change in DAS 28 (CRP)
ACR 70 & ACR50
Results:
Both groups were well matched with regards to baseline characterstics
No statistically significant difference in two groups with regards to ACR response
ACR 20 ACR 50 ACR 700%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Perc
enta
ge
Change from baseline in DAS28Visit 2 (day 28) Visit 4 (day 56) Visit 5 (day 84)
-2.5
-2
-1.5
-1
-0.5
0
Safety Association to study drug
Exemptia N= 14%
Reference productN= 17%
Total N= 31%
Not related 5 (35.7) 11 (64.7) 16 (51.6)
Possible 2 (14.3) 2 (11.8) 4 (12.9)
Probable 7 (50.0) 2 (11.8) 9 (29.0)
Definite 0 2 (11.8) 2 (6.5)
ConclusionThe results demonstrated biosimilarity with respect to efficacy, tolerability and safety of exemptia and reference product in RA
Take Home MessagesSubstantial Cost Saving
Immunogenicity and batch to batch variation are common
Switching trials need to be performed
Registry is mandatory for the Pharmacovigilance
Thank you
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