Inc in depth biosimilars clinical perspective

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Inc in depth biosimilars clinical perspective

  1. 1. a closer look at our industry from thought leaders at INC ResearchDEVELOPMENT OF BIOSIMILARS,A CLINICAL PERSPECTIVEBy Hans-Peter Guler, MDSenior Vice President, Clinical Development, Endocrinology and CardiovascularINC ResearchINNOVATOR PROTEINS AND FOLLOW-ON BIOLOGICSWith the advent of modern biotechnology, the first recombinant proteins were manufactured starting in the late 1970sand early 1980s. They were tested in nonclinical and clinical development programs and recombinant insulin and growthhormone reached the market in the United States in 1982 and 1985, respectively. These initial ground breaking drugswere followed later by erythropoietin (1989), G-CSF (1991), interferons, fusion proteins, monoclonal antibodies andvaccines. In 2009, the worldwide market for recombinant therapeutic proteins reached a volume of $128 billion. Today,numerous medical conditions in endocrinology, nephrology, oncology, hepatology and in autoimmune/inflammatory diseases(multiple sclerosis, rheumatoid arthritis and others), are treated with recombinant proteins. Many patents of the “pioneercompounds” have expired or will expire soon. As a result of the increased treatment applicability of recombinant proteins,a demand for generic options has emerged.Development of generic proteins called “follow-on biologics” or “biosimilars” has started and should result in reduced costdue to increased competition which in turn will improve accessibility to these drugs. Currently, the worldwide biosimilarmarket is less than $100 million, but by 2014 it is estimated to grow to approximately $2 billion.The development of biosimilars is not unlike that of most small molecule drugs where generics follow the innovator drugsonce the patents have expired. However, there are very significant differences in the development of biosimilars as comparedto most small molecule generics. Due to their complex, high molecular structure, synthesis, purification and characterizationof proteins, it is a much more complicated process than with small molecules.PRODUCTION OF THERAPEUTIC PROTEINSProteins cannot be produced using classical, step-wise chemical synthesis; this would be far too cumbersome on an industrialscale. Rather, proteins must be produced using microorganisms (E.coli, different yeast species) plants or animal cells thatare “re-programmed” to express a foreign protein. Initially, the master cell bank is used as a seed and then expandedto a much larger number of working cells placed in a fermentor. The protein is expressed inside the cell or secreted intothe broth, the “soup” in the fermentor. Subsequently, the protein needs to be recovered and purified. In some cases thisinvolves correct “folding” of the protein, which means that the three dimensional structure of the protein has to beadjusted to its biologically active form.Each of these steps can lead to subtle variations of the three-dimensional structure of the molecule, its glycosylation,its sialic acid content and other physico-chemical properties, including new impurities such as endotoxins. Hence, arecombinant protein, unlike a small molecule drug, is only similar to the innovator protein. Consequently, second generationrecombinant proteins will never be identical to the originally approved drug products, which is why these products arecalled follow-on biologics or biosimilars. www.incresearch.com indepth - Biosimilars • February 2011
  2. 2. Furthermore, although assays for the analysis of proteins can detect some of the differences between the innovator drugand the follow-on, it is likely that some differences cannot be detected and are overlooked. Also, in many cases imprecisebioassays with their inherent large inter- and intra- assay variation must be used to test the potency of proteins. For example,the strength testing of erythropoietin includes an in vivo assay in mice where reticulocyte count is the read-out.IMMUNOGENICITYAdding further complexity, once the recombinant protein enters the body, the immune system will detect even smalldifferences between it and the body’s own protein. Antibodies may be formed that may or may not have a blockingeffect on the therapeutic protein but also may neutralize the effects of the endogenous protein such as the body’s ownerythropoietin. The most prominent example of complications generated at least in part by antibodies is a biosimilar oferythropoietin (Eprex). Use of Eprex was associated with pure red cell aplasia (PRCA) in patients with anemia secondaryto chronic renal failure. This occurred almost exclusively when Eprex was administered by the subcutaneous route, whena certain type of uncoated rubber stopper was used to seal the vial, and after a change in formulation was made (albuminwas substituted with polysorbate-80 and glycine).The majority of the PRCA cases clustered in France, Canada, Spain, and the UK. Only very few cases were reportedfrom Germany, Italy or the United States. Other erythropoietin products or even the same product administered by theintravenous route did not show clinically significant case numbers of PRCA. This example shows that safety issues specificallylinked to one particular biosimilar product produced and formulated in a specific way can become clinically importantboth from a safety and an efficacy standpoint. Therefore, comprehensive immunogenicity data is crucial for each biosimilardevelopment program.REGULATORY REQUIREMENTS FOR BIOSIMILARSThe philosophy behind all regulatory requirements is that each biosimilar must go through a so-called comparability exercisein order to be approvable for marketing. This means that from product characterization to nonclinical data to clinical data,the product must be similar to an earlier approved product. In all cases, the biosimilar must be similar to a recombinantprotein of the innovator, pioneer generation. This is fundamentally different from generic drugs where proof of chemicalidentity along with pharmacokinetic (PK) studies is sufficient for a marketing application in most cases.There is an established regulatory framework for the development of biosimilars in the European Union (see references).This framework of guidances was developed to omit unnecessary repetition of studies but still assure sufficient data to writean adequate label. An overarching guidance for biosimilars has been issued and specific guidelines for recombinanterythropoietin, insulin, growth hormone, and G-CSF have been issued. The approved biosimilar drug products have createdregulatory precedence and help in developing other biosimilars.Interestingly, studies carried out by one route of administration (for example intravenous use of erythropoietin in chronicrenal failure) will allow claims by the intravenous route in other indications. This is called extrapolation of study data.In this case, extrapolation of data allows for use of the biosimilar erythropoietin in chemotherapy associated anemia incancer patients or in patients prior to major elective surgery in order to reduce the need for blood transfusions. www.incresearch.compage 2 indepth - Biosimilars • February 2011
  3. 3. In the United States, a regulatory framework comparable to the European guidances is being developed. The PatientProtection and Affordability Act, passed earlier in 2010, defines a regulatory pathway for biosimilars in the United States(351k), but the implementation of the act must now be accomplished. The 351k pathway to approval would be shorterthan the regular BLA pathway, particularly with regards to the registration studies.Criteria for “similarity” and “interchangeability” (a more stringent standard) must be created and the extent of datato support these claims needs to be defined. Interchangeability is a term not used in the European guidance documentsand would mean that a biosimilar product can be prescribed in place of the innovator product just like it is done withgeneric small molecule drugs. Achieving interchangeability is a powerful incentive for biosimilar companies but willundoubtedly require more extensive studies than demonstrating similarity.The rules for extrapolation of data for a drug studied in one indication but potentially used in another will have to bedefined. There is an ongoing discussion of whether sponsors could alternatively use the regular BLA pathway (351a) forapproval of biosimilars. This pathway does not require a sponsor to disclose any data until the FDA advisory board or, ifthere is no advisory board meeting, until approval of the application. In the case of the new 351k pathway, the sponsoris required to notify the manufacturer of the reference compound as soon as the FDA accepts the marketing application.This has important intellectual property implications.CLINICAL REQUIREMENTS FOR APPROVAL OF BIOSIMILARS IN EUROPEApproved biosimilars in the EU include epoetin (erythropoietin), somatotropin (growth hormone, GH), and filgrastim (G-CSF).A brief summary of the clinical requirements for each of these drugs is provided below:Erythropoietin biosimilars: The applicable guidance specifies that sponsors must demonstrate clinical efficacy and safetyin patients with chronic renal failure with two adequately powered, randomized parallel group studies, one using thesubcutaneous route and the other using the intravenous route. One study should be a “correction phase study” and theother a “maintenance phase study.”Alternatively, one large trial using one route of administration and PK bridging studies for the other route of administrationcan be used. Six month efficacy data and 12-month safety data must be presented. Immunogenicity data particularly forthe subcutaneous route but also the intravenous route is very important. Formation of antibodies against erythropoietinsis not common and if detected during the pre-marketing phase would be considered a serious issue.Somatotropin biosimilars: A single dose subcutaneous cross-over PK study in healthy volunteers is needed and shouldinclude pharmacodynamic parameters such as IGF-1. At least one adequately powered, randomized, parallel group,comparative study in growth deficient children is required to demonstrate efficacy. Treatment naïve children withGH-deficiency are recommended and the study duration must be six to 12 months. The efficacy study is sufficient to showsafety and must include immunogenicity data. www.incresearch.compage 3 indepth - Biosimilars • February 2011
  4. 4. Filgrastim biosimilars: A single dose subcutaneous and intravenous cross-over PK study in healthy volunteers is needed.The key pharmacodynamic parameters are absolute neutrophil and CD34+ counts. The recommended setting to demonstratecomparable clinical efficacy is in the prophylaxis of severe neutropenia in a homogenous group of subjects undergoingcancer chemotherapy. If appropriate, the data can be extrapolated to indications other than the one studied. Antibodies tofilgrastim occur infrequently, as these subjects are immune-compromised; however, post-marketing data on immunogenicityare still required.Insulin biosimilars: To show efficacy, a single-dose subcutaneous cross-over study and a cross-over hyperinsulinemic,euglycemic clamp study are needed. Clamp studies are conducted in specialized laboratories and allow for a quantitativeestimate of how the body disposes of and uses glucose in the liver, muscles, and fat tissue. No further efficacy data isrequired if the data from these studies show comparability. To demonstrate safety, immunogenicity data for six to 12 months(using the subcutaneous route) are required. Antibodies against insulin are common but most often do not affect bloodglucose control.Monoclonal antibodies: A concept paper issued by EMA is currently circulating among interested parties and a guidancefor monoclonal antibodies will be developed based on this discussion. It is expected that the new guidance will coverimmunomodulators, including anti-TNF-alpha antibodies, cytotoxic antibodies such as anti-CD20, anti-EGFR, anti-Her2compounds, as well as antimicrobial monoclonal antibodies such as anti-RSV molecules. Monoclonal antibodies arestructurally very complex and may have several functional domains within a single molecule; this will pose uniquechallenges as to how similar the biosimilars have to be compared to the innovator protein. Trial design will have to bedefined. Another discussion point is the choice of endpoints for the clinical studies: should it be the most sensitive endpointor the clinically most relevant endpoint?RISK MANAGEMENT PLANThe timing, nature and clinical consequences of immunogenicity of biosimilar drugs are not predictable. The lessonlearned from the epoetin experience is that clinically significant adverse effects may be detected only after marketingapproval once the product is used widely. Hence, all biosimilar programs must include a detailed post-marketing riskmanagement plan with immunogenicity assessments. The risk management plan (RMP) has to include identification/characterization, risk monitoring, risk minimization/mitigation strategies, communication, and monitoring activities toensure effectiveness of risk minimization. The RMP is individually tailored to each product depending on the specific dataavailable at the time of the marketing authorization.NON-APPROVALRefusal of a marketing application by EMA illustrates key points not to be missed in the development of a biosimilar. Anexample is the case of a biosimilar INF-alpha-2 where Roferon-A was the reference product. The regulator concluded thatcomparability between the biosimilar and reference product was not adequately demonstrated as there were quantitativeand qualitative differences in the impurity profile, a lack of sufficient validation in the manufacturing process, an inabilityto adequately assign drug product shelf-life, and a failure to demonstrate clinical comparability. Among other issues in www.incresearch.compage 4 indepth - Biosimilars • February 2011
  5. 5. the clinical data base was the inadequate documentation of immunogenicity. Assays and methods to assess antibodyresponse were incomplete. Only the occurrence of antibodies was reported and no data for total, binding or neutralizingantibody titres were submitted. It is not surprising that these latter deficiencies were considered very important anddecisive in light of the history with pure red cell aplasia with epoetin.CONCLUSIONCost reductions with biosimilars are not as substantial as with generic small molecule drugs. Savings on the order of 60%can be achieved in some developing countries but may be only 10 to 25% in a developed country such as the UK. Estimatesfor the United States indicate that $3.5 billion could be saved in the first year after approval of a biosimilar and upto $71 billion over 10 years in case of approval of an epo, GH, insulin, and interferon biosimilar. Biologics will alwaysbe substantially more costly than small molecule drugs and introducing biosimilars is a worthwhile effort that appears tobe profitable for sponsor companies. Increased access to less costly biosimilar drugs will allow more patients to betreated with life saving medicines.For more information, please visit www.incresearch.com.ABOUT THE AUTHORHans-Peter Guler, MD has over 20 years of experience in clinical research. Prior to joining INC Research, Dr. Guler served asChief Medical Officer/VP Clinical Development at Phenomix for 6 years, after having held positions of increasing responsibilitywith Regeneron Pharmaceuticals, Inc., Chiron Corp. and Ciba-Geigy Corp. His work in clinical research included studiesat all stages from first-in-man to large registration trials. Indications studied included diabetes mellitus, obesity, rheumatoidarthritis, hepatitis C, asthma, sepsis, cardiovascular disease, and renal failure. Prior to accepting his first job in industry,he conducted some of the early studies with recombinant insulin-like growth factor I in academia. He is an author ofover 30 peer reviewed articles. Dr. Guler trained in Switzerland and received his M.D. from the University of Zurich.REFERENCES• Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins, European Medicines Agency, 13 December 2007 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf• Guideline on Similar Biological Medicinal Products, European Medicines Agency, 30 October 2005 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf• Concept Paper on the Development of a Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies, European Medicines Agency, 22 October 2009, http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/11/WC500014438.pdf www.incresearch.compage 5 indepth - Biosimilars • February 2011

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