Biosimilars and the New Drug Development Paradigm laboratory tests versus clinical trials

Arnold G. Vulto FCP PharmD PhD

Professor of Hospital Pharmacy & Practical Therapeutics

Erasmus University Medical Center, Rotterdam, The Netherlands

a.vulto@erasmusmc.nl

2nd MENA Regulatory conference on Bioequivalence, Biowaivers,

Bioanalysis, Dissolution and Biosimilars

Amman, 17 September 2015

The question I will address today

Why would a doctor prescribe a biosimilar and/or a pharmacist dispense a biosimilar?

The decision to prescribe a drug is a yes/no decision, black or white.

This first talk is on the background why physicians have reservations to prescribe biosimilars.

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Who is Arnold Vulto?

A practising hospital pharmacist, not a lawyer or regulator

Member of ErasmusMC Medical Ethical Review Board

We see and run all drug trials

Got involved in biosimilars as early as 2004 via Eur J Hosp Pharmacy

How to guide hospital pharmacists in this difficult area

2008 Founder of GaBI, together with Huub Schellekens and Lasia Tang

To provide transparency to cost-effective medicines

2013 Co-founder of the Dutch Biosimilar Initiative

Independent platform to promote efficient use of medicines

My motto: For each patient the best medicine at the best price

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Conflict of Interest

I declare no personal financial interest in any pharmaceutical bussiness

I entertain friendly relationships with all innovative and generic / biosimilar companies

As a co-founder I have a societal – but not financial - interest in the advocacy of cost-effective treatments via the Generics & Biosimilar Initiative (GaBI)

My employer – Erasmus University Hospital - receives any speakers honoraria if they let me speak at scientific or commercial meetings (like this one).

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Agenda

1. What are biosimilars?

2. How are biosimilars developped?

A paradigm shift

3. Biosimilars: not a container-principle

3 “generations” of biosimilars

4. Indication extrapolation

Is “totality of evidence” a valid principle?

5. Why would a physician prescribe a bisimilar?

6. Take home message

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Biosimilars: What are we talking about?

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The only true definition of a biosimilar as of September 2015: A biosimilar is a pharmaceutical product, that as such has been licensed

via the WHO regulatory pathway (=minimum global standard)

What does that mean? It is a version of an already licensed biotech-drug, for which similarity has

been proven in an extensive comparability exercise, encompassing physical, chemical, biological and pharmacological properties, including efficacy and safety

This excludes all kinds of bio-questionables in existence in other regions of the world that have not been endorsed via the WHO pathway as a biosimilar. Reference to such products as if biosimilars may be inferior is thus WRONG.

List of EU-licensed biosimilars (1/1/2015)

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How are biosimilars developped?

“Reversed engineering” and “reversed body of evidence”

An existing drug (“reference-product”) is disassembled and characterised in great detail

The resulting protein is cloned and expressed in a polyclonal cellsystem.

Hundreds of cells are scrutinised for the best similarity

The best cell-molecule combinations are worked up in an extensive physical-chemical test battery

Next comparison in animal experiments and more advanced test systems

If resemblance is > 99,9% sure, similarity is CONFIRMED in a small trial.

This limited trial is performed in a representative and sensitive indication.

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This is a new drug development paradigm, in which the “similarity excercise” is key

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Clinical trials

PK / PD

Pre-clinical

Analytical

Integration of data from multiple analytical and biological tests provides complete understanding

Primary structure

Posttranslational modifications

Higher order structure

Impurities

Σ Combination of attributes

Biological activity

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• Combined data from ~40 different methods provide information on multiple attributes (orthogonality)

• Every attribute is evaluated more than once (redundancy)

Berkowitz SA, et al. Nat Rev Drug Discov 2012; 11(7): 527–540

The sensitivity of analytical methods has increased enormously: Mass spectrometry example

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Physicochemical characterisation of Celltrion’s biosimilar infliximab Vs Remicade

A multitude of state-of-the-art analysis

Identical primary structure (amino-acid sequence etc.)

Indistinguishable higher order structure

Peptide mapping (chromatography)

Higher order structure analysis

Antibody conformation array

Crystalline micrographs

Size exclusion chromatography

Iso-electro focussing looking for isoforms

Etc etc

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With a real innovative drug we need to explore unknown territory Uncertainty is by nature large

Research is focussed on reducing uncertainty in knowledge and on proof of efficacy and safety

In biosimilars we compare with an existing drug, we know already for 10 – 15 years Uncertainty is relatively small

Research is focussed on the confirmation of similarity (and not proof of efficacy or safety)

What is the essential difference in approach?

The role of clinical trials in biosimilar development

Not for proof of efficacy

Confirmation of similarity

Laboratory tests (fingerprinting) are more sensitive to find small difference

The stronger the pre-clinical evidence, the smaller the requirements for clinical trials.

Physicians have been trained in the principles of Evidence Based Medicine, with the controlled clinical trial as golden standard for proof of efficacy.

This is not the case for biosimilars (and therefore difficult to accept)

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Agenda

1. What are biosimilars?

2. How are biosimilars developped?

A paradigm shift

3. Biosimilars: not a container-principle 3 “ generations” of biosimilars

4. Indication extrapolation

Is “totality of evidence” a valid principle?

5. Why would a physician prescribe a bisimilar?

6. Take home message

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Three Generations of Therapeutic Proteins / biosimilars

Generation 1: substitution products (“replacement therapy”)

Like hormones, growth factors

Generation 2: proteins with a distinct pharmacologcial effect

Like TNF-alfa inhibitors

Generation 3: proteins with a more remote clinical effect

Targeted therapies in oncology

First generation: proteins mimicking biological functions

Mostly hormones

Insulin

Follicle stimulating hormone

Growth hormone

Coagulation factors and thrombolytic agents

Hematopoietic growth factors

Pharmacological effects:

almost instantaneous or visible within days

Mostly a simple dose-effect relationship

1st generation biosimilar replacement therapy

Examples of such effects

Insulin: glucose goes down

FSH: ovulation occurs

Growth hormone

Initially effect on “biomarkers”

On the longer term: increased length growth

Coagulation factors: stop bleeding

Thrombolytic agents: dissolve blood clots

Hematopoietic growth factors:

increase in white or red blood cell count

2nd generation: Therapeutic proteins with a pharmacological action

These proteins do not mimic a biological function, but act mostly as an pharmacologcial antagonist e.g. binding a circulating protein or blocking a receptor

The clinical effect may be visible and measurable within days or weeks

Example: TNF-alpha inhibitors like infliximab and etanercept.

Second generation of EU licensed biosimilar

Active Substance Brand Name Approval Date

Infliximab (CT-P13) Inflectra Remsima

September 2013 September 2013

Approved indications Supported by clinical research:

• Ankylosing spondylitis • Rheumatoid arthritis

Extrapolated indications: • Psoriatic arthritis • Psoriasis • Crohn’s Disease • Ulcerative colitis

Due to patent restrictions, the product could only be marketed after February 2015

www.gabionline.net (1/09/2015)

(The best patentdeal of the century)

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Will be extended

3rd generation: therapeutic proteins with a remote clinical effect

These protein drugs provide a statistical chance on benefit some time in the future (e.g. trastuzumab, rituximab).

Now we need deep trust in the principles of similarity.

On what is the purported clinical effect based?

Can we expand the use in other types of cancer?

Doctors may be very reluctant to accept clinical similarity of these molecules (“You can’t gamble with patients’ lives”)

As yet, these are theoretical questions: as yet no biosimilar of this type has been granted marketing authorization.

More complex molecules require also deeper understanding of the similarity principles

Different generations are confronted with different emotions

First generation biosimilars are a no-brainer They work, and have a proven safety track record

Second generation biosimilars: Are now available in the greater part of Europe

The current knowledge base looks promising

Extrapolation of indications under debate among professionals

Third generation biosimilars: Difficult to say: as yet no product in registration (August 2015)

Agenda

1. What are biosimilars?

2. How are biosimilars developped?

A paradigm shift

3. Biosimilars: not a container-principle

3 “generations” of biosimilars

4. Indication extrapolation Is “ totality of evidence” a valid principle?

5. Why would a physician prescribe a bisimilar?

6. Take home message

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DIA meeting Berlin

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Extrapolation is not a free ride It is based on rigorous scientific principles

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Extrapolation of indications: how does that work?

If the comparability exercise in a battery of tests shows that biosimilar and reference product behave the same, biosimilarity is assumed

This means that the biosimilar will work for the same conditions as the reference product

It is the ultimate conclusion of the comparability exercise

A limited trial is used to confirm these expectations

This conflicts with traditional “evidence based” thinking, where the clinical trial is the ultimate proof of efficacy and saftey

Result of > 30 years education in “evidence based medicine”

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Extrapolation of indications with Inflectra / Remsina (Source: EPAR para 2.6.3.)

Based on an extensive review on mode of action in different indications

Indeed, mode of action of infliximab is complex and partly unknown

Major effect: binding to soluble / membrane bound TNF

Possibly also other actions, like direct cytotoxicity (ADCC)

In inflammatory bowel disease it is unknown which “mixture” is best

CTP-13 is virtually identical to Remicade ®

Somewhat less fucosylation; likely clinically irrelevant

The best in-vitro models support similarity

There was a very small series of IBD patients treated

Follow up in post-marketing surveillance (as with any other new drug)

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ECCO survey on concerns of GE-physicians (2013)

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Immunogenicity: - Analytical data cannot predict immunogenicity - Issues around methodology used to detect Anti-drug-antibodies Safety:

- manufacturer may not have assessed differences between attributes biosimilar vs originator

- subtle changes may have profound effects on immunogenicity Trial sensitivity:

- appropriate statistics / margins to capture clinically relevant differences in phase 3 trials ?

Extrapolation: - safety and efficacy data transferable to other indications ? - different effects / distribution of mAbs in different tissues ? - role of other confounding factors eg. co-medication (eg MTX) ? - different safety profiles in different populations ? Molecular stability : - what if originator and biosimilar drift apart over time ?

Agenda

1. What are biosimilars?

2. How are biosimilars developped?

A paradigm shift

3. Biosimilars: not a container-principle

3 “generations” of biosimilars

4. Indication extrapolation

Is “totality of evidence” a valid principle?

5. Why would a physician prescribe a bisimilar? 6. Take home message

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Acceptance of a new drug

Affinity with the existing product (Innovator brand) (= current value, including habit)

Versus Attractiveness of the alternative (biosimilar) (= it implies a change with uncertain outcome)

Without an incentive for change,

A physician will not change it’s prescribing habits

Drug prescribing is highly emotion and information driven Where to obtain convincing information?

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We perceive an information gap

EMA’s EPAR (50+ pages) is difficult to read / understand for a busy healthcare professional

Need support to understand the comparability excercise

Is a snapshot in time with no updates

No access to risk management information / PSUR’s

Research findings should be published and made accesible

Please use open-access publications

Clinical trials scattered and not easily accesible 39

Take home message: what we need to do

Educate health-care professionals on

How the similarity excercise works

Science based and transparant

Paradigm shift

Classical “evidence based’ thinking is not valid for biosimilars

Focus on high-tech analytical techniques and science

Clinical trial for confirmation, not for proof

How extrapolation of indications is justified

Acceptance by prescribers will be dependent on the understanding of the development model and accepting principles of extrapolation

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Thank you for your attention

Contact: a.vulto@erasmusmc.nl 41

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