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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
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