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