Biosimilars today or tomorrow?

Transcription

1 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

2 Biopharmaceuticals help treat severe diseases RHEUMATOID ARTHRITIS First RCT of a biological agent in 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 HIVrelated anemia. IBD Infliximab first biological agent approved in CANCER Several biologics including this image of Trastuzumab (a monoclonal antibody) treat cancers.

3 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

4 A highly complex manufacturing process Fermentation cells produce the protein defined by the vector Purification removing the impurities Design the gene sequence Place gene sequence inside a vector The Process is the Product Place vector inside a specific cell IgG1 antibody >1000 amino acids ~150,000 daltons >20,000 atoms Highly complex protein with 3 or 4 levels of structure

5 Increasing use and cost of biologics biologics fastest growing segment of pharmaceutical revenue ; expanding indications, utilisation, pipeline % 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

6 The driving force for biosimilar development

7 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

8 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);

9 The Patent cliff : A driving force behind biosimilar development References: 1. Calo-fernandez B. Pharmaceuticals 201:5(12);

10 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

11 Biosimilars will always be different from original

12 Differences can lead to unwanted immunogenicity Product Change Consequence Eprex (epoetin alfa ) HX575 (biosimilar for epoetin alfa) New formulation Leaching or organic compounds from rubber stoppers in syringes New indication Immunogenic aggregates induced by tungsten from supplier of syringes Neutralization of drug and endogenous protein Immune response against erythroblasts Pure red cell aplasia (200 cases) Neutralizing antibodies to EPO in 2/337 subjects Pure red cell aplasia in one subject

13 What do we need to know? How much similarity do we need

14 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;

15 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

16 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)

17 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 noninferiority/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

18 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

19 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

20 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

21 What do regulators require?

22 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

23 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 % 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

24 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

25 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

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

27 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

28 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

29 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