Oxford Inflammatory Bowel Disease MasterClass

Biosimilars today or tomorrow?

Dr Vipul Jairath Bsc DPhil MRCP

NIHR Clinical Lecturer

Translational Gastroenterology Unit

University of Oxford

John Radcliffe Hospital

Biopharmaceuticals help treat severe diseases

RHEUMATOID ARTHRITIS First RCT of a biological agent in 1994. Now 9 approved biological agents for RA

DIABETES Synthetically made Human insulin was made available in the 1980’s. Before then, it was made from cows and pigs.

HIV/AIDS Some antiretroviral therapies like Infuvirtide (Fuzeon) prevent the virus from infecting cells while others treat HIV-related anemia. CANCER Several biologics including this image of Trastuzumab (a monoclonal antibody) treat cancers.

IBD Infliximab first biological agent approved in 1998.

Biologicals are different to small molecule drugs

Size: Larger, more complex, heterogeneous structure

Manufacture: Made from unique cell lines under precise conditions using exacting steps to yield a consistent product. Highly sensitive to manufacturing conditions. Small alterations can cause large changes in immunogenicity profile

Drift: Change with time. An unintended change over time which require regulatory and manufacturing control

Stability: Biologicals are sensitive to light, heat, denaturing or degradation

A highly complex manufacturing process

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

The Process is the Product

Increasing use and cost of biologics

2010 - biologics fastest growing segment of pharmaceutical revenue ; expanding indications, utilisation, pipeline

2012 - 32% of all products in drug development and worldwide sales of $142 billion

Biologic firms spend 1/3 of revenue on R&D

Greater R&D costs than chemical drugs

$50,000 per year of adalimumab for Crohn’s disease

Annual price rises for biologics far exceed rate of inflation

The driving force for biosimilar development

What are biosimilars?

In principle the biologic medicines’ equivalent of generics

EMA: Demonstrate similarity based on quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise

US FDA: A product highly similar to the reference product without clinically meaningful difference in safety, purity and potency

WHO: A biotherapeutic similar to an already licensed reference biotherapeutic product in terms of quality, safety and efficacy

Canada: A biologic that enters the market subsequent to a version previously authorized in Canada with demonstrated similarity to a reference biologic

Factors driving biosimilar development

Looming expiration of patents

Technological innovation in biomanufacturing

Better selection of high producing cell lines

Less costly bioreactors

Improved production yields, time and lower costs

Global socioecomomics

Mounting cost pressures on government budgets

Desire to increase access to patients

Regulatory initiatives

EMA in 2006

FDA 2009

Canada, Japan, Korea

References: 1. Calo-fernandez B. Pharmaceuticals 201:5(12);1393-1408

The “Patent cliff”: A driving force behind

biosimilar development

References: 1. Calo-fernandez B. Pharmaceuticals 201:5(12);1393-1408

Biosimilars: Similar ≠ Same

Biosimilars manufactured by different manufacturers will differ from the innovative product and each other

They are not generic biologics

They use a different host cell to develop the biosimilar

The active ingredient of the biosimilar can only resemble as best possible that of the original biologic

How an innovator makes its biologic can never be copied to the last details since it is a trade secret.

Recognised in EMA guidance (CHMP/437/04) “Due to the complexity of biotechnology derived products the

generics approach is scientifically not appropriate for these products”

Biosimilars will always be different from original

Differences can lead to unwanted immunogenicity

Product Change Consequence

Eprex (epoetin alfa ) New formulation

Leaching or organic compounds from rubber stoppers in syringes

Neutralization of drug and endogenous protein

Immune response against erythroblasts

Pure red cell aplasia (200 cases)

HX575 (biosimilar for epoetin alfa)

New indication

Immunogenic aggregates induced by tungsten from supplier of syringes

Neutralizing antibodies to EPO in 2/337 subjects

Pure red cell aplasia in one subject

What do we need to know?

How much “similarity” do we need

How can similarity be assessed?

Analytical studies

Demonstrate the candidate is higher similar to the originator at a structural level

Similar process to those already used for originator biologics after a manufacturing change

ELISAs compare molecular weight and size differences

Gel electrophoresis for glycosylation, aggregation and purity

NMR or spectroscopy for tertiary and quaternary structures

Multiple batches of the reference drug must be analysed to create “goalposts” of acceptable features for the biosimilar

References: 1. Locatelli F. Nephrol Dial Tranplant 2006:21; 13-16.

How can similarity be assessed?

Pre-clinical and Clinical

Animal: this can't predict all biological activity in patients because many immune response are species specific

Human: Pharmacokinetic and/or pharmacodynamic data

Clinical trials

Efficacy trials powered to detect clinically important differences

Equivalence; non-inferiority

Safety data from a sufficient number of participants for sufficient duration to allow comparison of nature and severity of ADRs

Non inferiority and equivalence trials

Non-inferiority: •New intervention is not substantially worse than the standard by more than a detriment of clinical unimportance (i.e. a one-sided comparison)

Equivalence • The difference in performance of the two interventions is within a range small enough to be considered clinically unimportant i.e. the new intervention is not appreciably superior or inferior (i.e. this is a two-sided comparison)

Non inferiority and equivalence trials

The margin of clinical unimportance needs to be small so these trials need large numbers

The importance of rigorous methods In a superiority trial, non-compliance will lead to a conservative

estimate in an ITT analysis

In a non-inferiority/equivalence trial violations will make the groups more similar and hence more likely to conclude non-inferiority/equivalence

There are less incentives for rigorous conduct!

Be wary of the dose used in the standard comparator

Check the patients in the standard arm are typical responders

Importance of clinical trials:immunogenicity and safety

Omnitrope (somatropin): Innovator (genotropin- Pfizer)

60% of enrolled patients developed antibodies to Omnitrope in first phase III study

High concentration of host cell protein in the host cell known to enhance antibody reaction against growth hormone

Resulted in additional purification steps

New phase III studies initiated

Antibody levels sufficiently reduced

EMA Approval

References: 1. EMA/164541/2012

Importance of clinical trials: efficacy and safety

Alpheon (interferon alfa-2a): Roferon-A (Roche)

Differences in the qualitative and quantitative impurity profile could not lead to a similarity conclusion for Alpheon and Roferon-A

Manufacturing processes not adequately validated

A phase III trial demonstrated that patients using Alpheon had a higher relapse rate and higher rate of adverse events that the innovator agent

EMA – Not approved

References: 1. EMA/H/C/000585

Pharmacovigilance

Clinical trials are usually too small to detect rarer AEs, especially if duration is limited

Robust PV programmes can track immunogenicity and unforeseen adverse events

Multiple biosimilars may be available for each innovator biologic. Assigning unique names to each biosimilar would enable:

Clear prescribing and dispensing

Enable tracking of adverse events to the appropriate product

What do regulators require?

EMA guidleine on biosimilars containing mAbs

Pre-clinical studies

A “stepwise” approach on a case by case basis

Step 1 = In-vitro studies

To assess differences in binding or function

Step 2 = Determination of need for in-vivo studies

Usually non-human primate; if not available proceed to human studies

Step 3 = In-vivo studies

PK and PD of the two products should be compared

Immunogenicity in animals does not predict immunogenicity in humans

References: 1. EMA/CHMP/403543/2010; May 2012

EMA guideline: Clinical studies

Clinical studies

Comparative clinical studies should always be conducted. A stepwise approach is needed and extent of programme depends on evidence in previous steps

Step 1 = Pharmacokinetics

Homogeneous population e.g. single dose in healthy subjects

Encouraged to provide supportive PK data from patients

AUC, Cmax, tmax, half-life, volume of distribution

Conventional equivalence margin 80-125%

Step 1 = Pharmacodynamics

Clear dose response relationship

Accepted surrogate marker and can be related to patient outcome

References: 1. EMA/CHMP/403543/2010; May 2012

EMA guideline: Clinical studies

Step 2 = Clinical efficacy

If highly sensitive PD studies cannot be performed, similar clinical efficacy between the similar and reference product should be demonstrated in adequately powered RCTs, preferably double blind equivalence trials

The guiding principle is to demonstrate similar efficacy and safety compared to the reference product, not patient benefit per se, which has already been established by the reference medicinal product

Step 2 = Clinical safety

Type, severity and frequency of ADRs between the two products

Assessment of immunogenicity

Pharmacovigilance and risk management plan (e.g. registries)

References: 1. EMA/CHMP/403543/2010; May 2012

Interchanging, switching or substituting?

Interchangeable

Designation by health authority after biosimilar has proven Same clinical result in any patient as reference product

Switching produces no greater risk in efficacy and safety compared to continuation of reference product

Switching

Prescriber decides that changing a patient’s treatment is appropriate, whether another biologic or biosimilar

Substitution

Enables a pharmacist to substitute a prescribed product by another equivalent, with or without a physician's permission

FDA

References: 1. FDA Biosimilar Guidance Web, Feb 15, 2012

Biosimilars in IBD

ECCO

A biosimilar proven effective for one indication may not necessarily be so for a second indication for which the innovator has been shown to be effective

Specific evidence obtained in IBD should be required to establish efficacy and safety. Efficacy in IBD cannot be predicted by that in other conditions such as RA

RCTs should be large enough to detect common AEs and powered for equivalence

Substitution should only be done with the physician’s approval and patient’s knowledge

Each biosimilar should have a different name

References: 1. Danese, S. ECCO position statement:The use of biosimilar medicines for IBD; JCC Jul 2013

Biosimilars today

35 biosimilar antibodies in RCTs in the EU at end of 2012

June 2013 EMA CMPH recommended two biosimilar infliximab products for EU marketing

Celltrion’s Remsima©

Hospira’s Inflectra©

Celtrion’s Remsima©

Approved for all 6 indications of Remicade

RA, AS, PsA, PsO, CD and UC

Phase I trial conducted in ankylosing spondylitis

Phase III efficacy and safety study performed in RA in patients co-prescribed methotrexate

Biosimilars tomorrow

We will be prescribing them

Decreased cost

Traceability and continuous pharmacovigilance monitoring to ensure patient safety

Quality may even be better

Challenges for the manufacturers

Many questions remain over interchanging/substitution