World Journal of Pharmaceutical Research Sen et al. World Journal of Pharmaceutical SJIF ImRepactsearch Factor 6.805
Volume 5, Issue 9, 1841-1866. Review Article ISSN 2277– 7105
BIOSIMILARS AS BIOACTIVE MOLECULAR CLONE
1Prof. Dr. Dhrubo Jyoti Sen*, 2Jahangir Nabi, 2Pooja Raj and 2Jainik Khamar
1Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India. 2Delhi Institute of Pharmaceutical Sciences & Research (DIPSAR), Mehrauli-Badarpur Road, Puspvihar, Sector-3, New Delhi-110017, India.
ABSTRACT Article Received on 24 July 2016, Biologics are 200 to 1,000 times the size of a small molecule (generic)
Revised on 12 August 2016, drug and far more structurally complex. Additionally, biologics and Accepted on 01 Sept 2016 biosimilars are manufactured in living cells, then extracted and DOI: 10.20959/wjpr201610-7121 purified, whereas small molecule drugs and generics are manufactured
purely via chemical synthesis. These fundamental differences in *Corresponding Author complexity and large-scale manufacturing are at the core of why Prof. Dr. Dhrubo Jyoti Sen
Department of biosimilars are not equal to generics. Biologics and biosimilars are
Pharmaceutical Chemistry, produced in living cells with a multi-step process. Initially, a basic Shri Sarvajanik Pharmacy protein structure is ―translated‖ from a DNA sequence and then College, Gujarat modifications, including changes and additions, are made to that basic Technological University, protein structure. These later changes and additions are called post- Arvind Baug, Mehsana- 384001, Gujarat, India. translational modifications. The impact of post-translational modifications on a product is similar to the impact of a farming environment on growing tomatoes. The look and taste of the same type of tomatoes will vary in different farm environments because of the quality of the soil, use of fertilizers, type of irrigation and weather elements like rain, air, sunlight. Similarly, differences in biological systems (e.g., type of living cell with slightly different cellular environments) used to manufacture biosimilars may cause different types and levels of modifications, which in turn may affect the quality, safety or effectiveness of the product. So, whereas a generic can be identical to a small molecule reference product, biosimilars cannot and are not required to be exactly like the biologic reference product. Given the expected differences, regulatory authorities have outlined robust data requirements to demonstrate similarity. Biosimilar manufacturers will generally need to generate data from lab testing, non-clinical testing and
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clinical testing to show that the biosimilar they have developed will provide the same therapeutic benefit and risks to patients as the reference product.
KEYWORDS: Darbepoetin alfa, Etanercept, Epoetin alfa, Somatropin, Trastuzumab, Adalimumab, Pegfilgrastim, Filgrastim, Infliximab, Rituximab, Bevacizumab, Lispro, Glargine.
INTRODUCTION The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be ―biosimilar‖ to or ―interchangeable‖ with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be ―biosimilar‖ if data show that, among other things, the product is ―highly similar‖ to an already-approved biological product.
Figure-1: Similar
A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product and has no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products. An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product. FDA requires licensed biosimilar and interchangeable biological products to meet the Agency‘s rigorous standards www.wjpr.net Vol 5, Issue 9, 2016. 1842
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of safety and efficacy. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.[1]
Figure-2: Biosimilar
A biosimilar (also known as follow-on biologic or subsequent entry biologic) is a biologic medical product which is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval. Unlike with generic drugs of the more common small-molecule type, biologics generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Follow-on manufacturers do not have access to the originator's molecular clone and original cell bank, nor to the exact fermentation and purification process, nor to the active drug substance, although they do have access to the commercialized innovator product. Overall, it is harder to ascertain fungibility between generics and innovators among biologics than it is among totally synthesized and semi-synthesized drugs, which is why the name "biosimilar" was coined to differentiate these drugs from small-molecule generics. A simple analogy is that it is harder to say that two wines are "sufficiently interchangeable", because of differences in yeast strain, weather, grape harvest, or terroir, than it is to say that two soda pops are "sufficiently interchangeable" because they contain the same flavoring powder and salts.
Drug related authorities such as European Medicines Agency (EMA), Food and Drug Administration (FDA) and Health Canada hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies that demonstrate that the biological product is highly www.wjpr.net Vol 5, Issue 9, 2016. 1843
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similar to the reference product notwithstanding minor differences in clinically inactive components, animal studies (including the assessment of toxicity) and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) are sufficient to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. In case of a monoclonal antibody-containing medicinal product, such as Remsima, extensive physicochemical and biological characterization for it and its reference product Remicade (Infliximab) was conducted in order to demonstrate their highly similar properties. Consequently, EMA has granted a marketing authorisation for only a few biosimilars since 2006 including a monoclonal antibody which is recently approved. Meanwhile, on March 6, 2015, the FDA approved the United States's first biosimilar product, the biosimilar of filgrastim called filgrastim-sndz (trade name Zarxio) by Sandoz.
Figure-3: Infliximab biosimilar
Figure-4: Filgrastim biosimilar
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The European regulatory authorities led with a specially adapted approval procedure to authorize subsequent versions of previously approved biologics, termed "similar biological medicinal products", or biosimilars. This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product. In the United States, the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. Since 2004 the FDA has held a series of public meetings on biosimilars. The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Patient Protection and Affordable Care Act signed by President Obama on March 23, 2010. The FDA has previously approved biologic products using comparability, for example, Omnitrope (Somatropin) in May 2006, but this like Enoxaparin (Heparin) was also to a reference product, Genotropin, originally approved as a biologic drug under the FD&C Act.[2]
Figure-5: Omnitrope
On March 6, 2015, Zarxio obtained the first approval of FDA. Sandoz‘s Zarxio is biosimilar to Amgen‘s Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an ―interchangeable‖ may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human www.wjpr.net Vol 5, Issue 9, 2016. 1845
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pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Zarxio is biosimilar to Neupogen.
Cloning of human genetic material and development of in-vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches. Recombinant therapeutic proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.
Figure-6: Recombinant DNA After the expiry of the patent of approved recombinant drugs (e.g., insulin, human growth hormone, interferons, erythropoietin, monoclonal antibodies and more) any other biotech company can develop and market these biologics (thus called biosimilars). Every biological (or biopharmaceutical products) displays a certain degree of variability, even between different batches of the same product, which is due to the inherent variability of the biological expression system and the manufacturing process. Any kind of reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and www.wjpr.net Vol 5, Issue 9, 2016. 1846
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was approved by the EMA. In contrast, it is mandatory for biosimilars to take a both non- clinical and clinical test that the most sensitive clinical models are asked to show to enable detection of differences between the two products in terms of human pharmacokinetics (PK) and pharmacodynamics (PD), efficacy, safety and immunogenicity. The current concept of development of biosimilar mAbs (monoclonal antibody) follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between biosimilar and its reference mAb also at the clinical level. The European Medicines Agency (EMA) has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same. Every biological displays a certain degree of variability. However, provided that structure and function(s), pharmacokinetic profiles and pharmacodynamic effect(s) and/or efficacy can be shown to be comparable for the biosimilar and the reference product, those adverse drug reactions which are related to exaggerated pharmacological effects can also be expected at similar frequencies.[3]
Figure-7: Biosimilars in action
Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan. It is
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difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status. Generally, once a drug is released in the market by FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years afterward re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by EMEA (European Medicines Agency) are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.
Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator‘s product versus antibodies from an biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population. Importantly, provided that structure and function(s), pharmacokinetic profiles and pharmacodynamic effect(s) and/or efficacy can be shown to be comparable for the biosimilar and the reference product, those adverse drug reactions which are related to exaggerated pharmacological effects can also be expected at similar frequencies.
Biological Products Many of today‘s important medications are biological products. Biological products are made from living organisms. The material they are made from can come from many sources, including humans, animals and microorganisms such as bacteria or yeast. Biological products are manufactured through biotechnology, derived from natural sources or, in some cases, produced synthetically.
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Biological products are among the medications used to treat conditions such as rheumatoid arthritis, anemia, low white blood cell counts, inflammatory bowel disease, skin conditions such as psoriasis and various forms of cancer.
Most biological products are more complex in structure and have larger molecules or mixtures of molecules than conventional drugs (also called small molecule drugs). Conventional drugs are made of pure chemical substances and their structures can be identified. Most biologics, however, are complex mixtures that are more difficult to identify or characterize.[4]
Figure-8: Biosimilar and interchangeable biological products
(a) What are biosimilar and interchangeable biological products?: There are two new types of biological products-biosimilar and interchangeable. Biosimilars are a type of biological product that are licensed (approved) by FDA because they are highly similar to an already FDA-approved biological product, known as the biological reference product (reference product), and have been shown to have no clinically meaningful differences from the reference product. An interchangeable biological product, in addition to meeting the biosimilarity standard, is expected to produce the same clinical result as the reference product in any given patient.
(b) Will biosimilars and interchangeable work in the same way as the biological reference product they were compared to?: Yes, biosimilars have no clinically meaningful differences in terms of safety and effectiveness from the reference product they were compared to. In addition, a biosimilar needs to have the same mechanism of action as the reference product it was compared to, which means it will work in the same way as the reference product. The FDA will only approve a biosimilar product if it has the same mechanism of action, route of www.wjpr.net Vol 5, Issue 9, 2016. 1849
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administration, dosage form, and strength as the reference product. Additionally, a biosimilar can only be approved for the indications and conditions of use that have been previously approved for the reference product.
Figure-9: In-vitro testing of biosimilars
An interchangeable biological product, in addition to meeting the biosimilarity standard, is expected to produce the same clinical result as the reference product in any given patient, and for a product that is given to a patient more than once, the risk in terms of safety and effectiveness of alternating or switching between the interchangeable and the reference product is not greater than the risk of using the reference product without alternating or switching. Once a biosimilar or interchangeable has been approved by FDA, patients and health care providers will be able to rely upon the safety and effectiveness of an FDA approved biosimilar just as they would for the reference product that the biosimilar was compared to.
(c) How are biosimilars and interchangeables prescribed?: A biosimilar product can be prescribed by a health care provider in place of the FDA-approved reference product. The health care professional has to write the specific name of the product on the prescription if they want to prescribe the biosimilar. An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product. That means the patient may receive the interchangeable instead of the reference product, even if the health care provider writes the prescription for the reference product. If you are prescribed a biosimilar or interchangeable product, it will work in the same way (i.e., same mechanism of action) as the reference product. www.wjpr.net Vol 5, Issue 9, 2016. 1850
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(d) Are biosimilars generic versions of biological products?: No, generic drugs are copies of brand-name drugs, have the same active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. That means the brand-name and the generic are bioequivalent. Biosimilars are highly similar to the reference product they were compared to, but have allowable differences because they are made from living organisms. Biosimilars also have no clinically meaningful differences in terms of safety, purity, and potency from the reference product.
(e) How are biosimilars approved?: Biosimilars were created under the Biologicals Price Competition and Innovation Act (BCPI) of 2009 and signed into law through The Patient Protection and Affordable Care Act (Affordable Care Act) on March 23, 2010. The BCPI Act created an abbreviated licensure pathway for biological products that are demonstrated to be ―biosimilar‖ to or ―interchangeable‖ with an FDA-licensed (approved) biological product. Under this law, a biological product may be demonstrated to be biosimilar if data show that, among other things, the product is highly similar to an already-approved biological product, also called the reference product, and has no clinically meaningful differences in terms of safety, purity, and potency from the reference product. Therefore, the biosimilar approval relies on the agency‘s previous findings that the FDA-approved reference product is safe and effective.
(f) How does the Agency Determine Biosimilarity or Interchangeability?: The manufacturer must submit an application for a biosimilar or interchangeable biological product that includes, among other things, information demonstrating biosimilarity based upon data from analytical studies, animal studies, and clinical studies such as the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD).
If the manufacturer wants its product to be reviewed as an interchangeable product, the application must also include data or information to show that the proposed interchangeable product is expected to produce the same clinical result as the reference product in any given patient. In addition, when a product will be administered more than once to an individual (as many biological products are), the manufacturer must also demonstrate that the risk in terms of safety or reduced effectiveness of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the
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reference product without alternating or switching. This is in addition to the data described above to demonstrate biosimilarity.[5]
Companies Listed: 3SBio (Shenyang Sunshine Pharmaceutical), Abbott Laboratories, Aché, Actavis, Affitech, Amega Biotech, Amgen Amicus Therapeutics, Anglo Gulf (part of MJ Group), Apotex, Aprogen, ASKA Pharmaceutical, AstraZeneca, Avesthagen, AxiCorp, AzkoNobel, Baxter International, Bayer, Beijing Four Rings Bio-pharmaceutical, Beijing SL Pharmaceutical, Bigpearl Trading (part of Pharmstandard), Bioceuticals Arzneimittel (part of Stada), Biocon, Biogen Idec, BioGeneriX (part of Teva), BioMab, Biomed (part of Pharmstandard), Bionovis, Biopartners (part of Bioton), Biopharmaceuticals and Herbal Medicines Bureau, Biosidus (part of Sidus Pharmaceutical Group), Bioton, Biovel Life Sciences (part of Ranbaxy), Blau Farmacêutica, Boehringer Ingelheim, Bristol-Myers Squibb, Cell Pharm (part of Stada), Celltrion, Central Drugs Standard Control Organization, Chemo Group, China National Pharmaceutical Group (Sinopharm), CinnaGen, Cipla, CJ Corporation, Clinigene International (part of Biocon), CoGenesys (part of Teva), Comisión Federal para la Protección contra Riesgos Sanitarios (Cofepris) [Mexico], Committee for Medicinal Products for Human Use (CHMP) [EU], CT Arzneimittel (part of Teva), CureTech (part of Teva), Daiichi Sankyo, Dainippon Sumitomo Pharma, DaVita, Department of Biotechnology (DBT) [India], Diapin Therapeutics, DM Bio, Dong-A Pharmaceutical, Dr. Reddy's Laboratories, Drug Controller General of India (DCGI), Eden Biodesign (part of Watson), Egis Pharmaceuticals, Eli Lilly, Emcure Pharmaceuticals, EMS, Epitomics, European Medicines Agency (EMA), Ferring Pharmaceuticals, Finox, Food and Drug Administration (FDA), [US], Fosun International, Fresenius Medical Care, Fuji Pharma, Fujifilm, Fundação Ezequiel Dias (Funed) [Brazil], Gan & Lee Pharmaceutical, Gedeon Richter, Genentech (part of Roche), GeneScience Pharmaceuticals, Gennova Biopharmaceuticals (part of Emcure Pharmaceuticals), Genzyme (part of Sanofi), German Remedies (part of Zydus Cadila), Germonta Holdings (part of Bioton), Green Cross Corporation, GSK, Hangzhou Jiuyuan Gene Engineering, Hanwha Chemical, Haselmeier, Hefei-SciGen-Bioton Biopharmaceutical Company, Hemofarm (part of Stada), Hexal (part of Novartis), Hikma Pharmaceuticals, Hospira, Hospira Japan (part of Hospira), Hualida Biotech, Human Genome Sciences (part of GSK), Hypermarcas, IATRICa, iBio, Insmed, Intas Biopharmaceuticals (part of Intas Pharmaceuticals), Intas Pharmaceuticals, International Biotech Center (IBC) Generium, Isotechnika Pharma, Isu Abxis, Itero Biopharmaceuticals, JCR Pharmaceuticals, Johnson & Johnson (J&J), Kissei Pharmaceutical, Korea Food and www.wjpr.net Vol 5, Issue 9, 2016. 1852
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Drug Administration (KFDA), Kwizda Pharma, Kyowa Hakko Kirin, Laboratórios Biosintética (part of Aché), Landsteiner Scientific, Lekko (part of Pharmstandard), LG, LG Chem Investment (part of LG), LG Life Sciences, Lonza, Lupin Pharmaceuticals, MabPharm, Marvel Life Sciences (part of MJ Group), Masterlek (part of Pharmstandard), Medice Arzneimittel Pütter, MedImmune (part of AstraZeneca), Meiji Seika Pharma, Merck BioVentures, Merck & Co., Merck KGaA, Mindar Holdings (part of Bioton), MJ Biopharm (part of MJ Group), MJ Bioton Life Sciences, MJ Group, Mochida Pharmaceutical, Mylan, NeuClone, Nichi-Iko Pharmaceutical, Nippon Kayaku, Nipro Pharma, Nobel Ilac, Norbitec, Nordmark Arzneimittel, Novartis, Novo Nordisk, Organon (part of Merck & Co.), Owen Mumford, Parexel International, Pfenex, Pfizer, Pharmaceuticals and Medical Devices Agency (PMDA) [Japan], Pharmapark (part of Pharmstandard), Pharmstandard, Pharmstandard-Biolek (part of Pharmstandard), PlantForm, Pliva (part of Teva), Polpharma, Polpharma Biologics (part of Polpharma), Probiomed, Prolong Pharmaceuticals, Proquifin, Qilu Pharmaceutical, Quintiles, Ranbaxy Laboratories, Ratiopharm (part of Teva), Reliance GeneMedix (part of Reliance Life Sciences), Reliance Group, Reliance Life Sciences (part of Reliance Group), Rentschler Biotechnologie, Roche, Royal DSM, Safety Syringes, Samsung, Samsung Bioepis, Samsung BioLogics, Sandoz (part of Novartis), Sanofi, sanofi-aventis Nichi-Iko, Savient Pharmaceuticals (part of Ferring), Schering-Plough (part of Merck & Co.), Schnell Biopharmaceuticals, SciGen, Shandong Kexing Bioproducts, Shanghai Celgen Bio- Pharmaceutical, Shanghai Chemo Wanbang Biopharma, Shanghai CP Goujian Pharmaceutical, Shanghai Fosun Pharmaceutical, Shanghai Henlius Biotech, Shantha Biotechnics (part of Sanofi), Sicor Biotech (part of Teva), Sidus Pharmaceutical Group, Silanes, Stada Arzneimittel, State Food and Drug Administration (SFDA) [China], State's Employees´ Social Security and Social Services Institute (ISSSTE) [Mexico], Sundiro Pharma, Syngene (part of Biocon), Teva Pharmaceutical Industries, Teva-Kowa Pharma (part of Teva), The United Laboratories, Therapeutic Goods Administration (TGA) [Australia], TL Biopharmaceutical, Tonghua Dongbao, União Química, University of Michigan, Wanbang Biopharmaceuticals (part of Shanghai Fosun Pharmaceuticals), Watson Pharmaceuticals, Wockhardt, World Health Organization (WHO), Xiamen Amoytop Biotech, Ypsomed, Zao Indar, Zenotech Laboratories, Zuventus Healthcare (part of Emcure Pharmaceuticals), Zydus Cadila.
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Overview Biologics are medicines made from living cells through highly complex manufacturing processes. They must be handled and administered under carefully monitored conditions. Biologics are used to prevent, treat, diagnose, or cure a variety of serious and chronic illnesses including cancer, chronic kidney disease, autoimmune disorders, and infectious diseases. A biosimilar is exactly what its name implies — it is a biologic that is ―similar‖ to another biologic drug already approved by the FDA. Under U.S. law, a biosimilar is approved based on a showing that it is ―highly similar‖ to an FDA-approved biological product, known as a reference product. It may not have any clinically meaningful differences in terms of safety and effectiveness from the reference product. In 2010, Congress approved the Biologics Price Competition and Innovation Act (BPCIA), creating an abbreviated approval pathway for biosimilars, while maintaining incentives for continued medical advances. The legislative intent was to balance the desire for increased competition among biologics from biosimilar products with the need for incentives to support future medical innovation. Congress achieved this balance by providing biopharmaceutical innovators with 12 years of data protection for biologic medicines. To date, the FDA has issued several draft and final guidance documents to assist biosimilar sponsors in generating data to support biosimilar applications. FDA guidance and regulations provide insight into the agency‘s current thinking regarding how it will evaluate biosimilar biological products. The FDA approved in March 2015, the first biosimilar product for marketing in the United States. The world‘s largest two markets for prescription medicines remain a study in contrasts: The European Medicines Agency authorizes 11 biosimilar drugs for market in the nations comprising the EU. Meanwhile in the U.S., the FDA continues to ponder draft guidances for how the agency will evaluate biosimilars.[6]
Aranesp (Darbepoetin alfa: Erythropoietin)
Figure-10: Darbepoetin alfa biosimilars
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Drug developers: Dr. Reddy‘s Laboratories: Cresp® launched 2010 in India as that country‘s only darbopoetin alfa of any kind, and as world‘s first generic darbopoetin alfa, Merck: MK- 2578 development halted in 2010, Stada: Silapo® marketed in EU, where it was authorized December 2007 for anemia that is causing symptoms in patients with chronic renal failure; anemia in adults receiving chemotherapy to treat certain types of cancer and to reduce the need for blood transfusions; and to increase the amount of blood patients with moderate anemia can self-donate before surgery.
Nature and indication: Erythropoiesis-stimulating agent (ESA) for anemia due to chronic kidney disease (CKD) in patients on dialysis and patients not on dialysis; the effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. 2012 sales: $2.040 billion (Amgen), Patent status: Patent set to expire 2016 in EU; 2024 in U.S.
Enbrel (Etanercept: Tumor necrosis factor inhibitor)
Figure-11: Etanercept biosimilars
Drug developers: Avesthagen: Avent™ in preclinical studies as of 2012, BioXpress Therapeutics: Biosimilar in active development, Cipla: Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product, Hanwha Chemical: HD203 ―scheduled for launch,‖ company states on its website without including a date, following submission for marketing approval to South Korea‘s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab), LG Life Sciences: LBEC0101 completed Phase I trial in South Korea, Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea, Protalix Biotherapeutics: PRX-106 in www.wjpr.net Vol 5, Issue 9, 2016. 1855
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preclinical studies, Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China.
Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.
Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis. 2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013. Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029.
Epogen® / Procrit® / Eprex / Erypo (Epoetin alfa; Erythropoietin)
Figure-12: Epoetin alfa biosimilars
Drug developers: Hexal: Epoetin alfa Hexal marketed in EU, where it was authorized August 2007 for anemia, cancer and chronic kidney failure, Hospira: Retacrit® marketed in EU, where it was authorized in December 2007 for anemia associated with chronic renal failure or other kidney problems, adults receiving chemotherapy for some cancers. Also indicated to increase the amount of blood patients with moderate anemia can self-donate before surgery, and to reduce the need for blood transfusions in patients with moderate anemia about to undergo major bone surgery. In U.S., Phase III trial launched last year, Medice: Abseamed® marketed in EU, where it was authorized August 2007 for anemia, cancer, and chronic kidney
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failure, Sandoz: Binocrit® marketed in EU, where it was authorized August 2007 for anemia and chronic kidney. In U.S., the company said October 25, 2012, that it has started patient enrolment in a Phase III clinical trial, comparing safety and efficacy of biosimilar with reference product Epogen® /Procrit® in anemia associated with chronic kidney disease.
Nature and indication: Erythropoiesis-stimulating agent for anemia due to chronic kidney disease in patients on dialysis and not on dialysis; due to Zidovudine in HIV-infected patients; and due to effects of concomitant myelosuppressive chemotherapy, where upon initiation, there is a minimum of two additional months of planned chemotherapy. Also, for reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery. 2012 sales: $2.267 billion, including $1.941 billion for Epogen (Amgen), and $326 million combined for Procrit / Eprex / Erypo (Johnson & Johnson) Amgen also generated. Patent status: Patent set to expire 2015 in U.S.; expired 2004 in EU.[7]
Genotropin (Somatropin or somatotropin: Growth hormone) Drug developers: BioPartners: Valtropin® marketed in EU, where it was authorized April 2006, 12 days after Omnitrope, for pituitary dwarfism and Turner syndrome; authorization withdrawn voluntarily ―for commercial reasons‖ in October 2011, and withdrawn formally in May 2012, Sandoz: Omnitrope® marketed in EU, where it was authorized April 2006 for pituitary dwarfism, Prader-Willi syndrome, and Turner syndrome; the first biosimilar authorized by the European Medicines Agency. In U.K., was the first biosimilar recommended for approval by the National Institute for Health and Clinical Excellence in 2010. In Japan, launched October 2009 as that nation‘s first approved biosimilar.
Nature and indication: Peptide human growth hormone for children with growth failure due to growth hormone deficiency (GHD), Prader-Willi syndrome, small for gestational age, Turner syndrome, and idiopathic short stature; and for adults with either adult onset or childhood onset GHD.
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Figure-13: Somatotropin biosimilars
Pursuing FDA approval since 2009 for additional indication, Replacement of human growth hormone deficiency (Mark VII multidose disposable device); received two complete response letters. ―We are working to address the FDA's requests for additional information,‖ Pfizer stated in its 2012 Financial Report. 2012 sales: $832 million (Pfizer). Patent status: Patents expired 2008 and April 16, 2013 in U.S.
Herceptin (Trastuzumab: Monoclonal antibody that interferes with the HER2/neu receptor)
Figure-14: Trastuzumab biosimilars
Drug developers: Amgen, Synthon, and Watson (now Actavis): Global licensing agreement announced July 18, 2012, for clinical development and testing of biosimilar. Deal followed publication March 2, 2012, of Phase I trial results showing bioequivalence between Synthon‘s biosimilar and Herceptin, BioXpress: Biosimilar in active development, Hanwha Chemical: Biosimilar in development. Hanwha has said it is seeking a partner to commercialize Herceptin and HD203, a biosimilar for Enbrel, Hospira: Biosimilar in active development, Pfizer: PF-05280014 completed Phase I REFLECTIONS B327-01 trial as of www.wjpr.net Vol 5, Issue 9, 2016. 1858
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December 2012, to study the safety and pharmacokinetics of the biosimilar compared to Herceptin. The study yielded ―positive data,‖ hence the company ―is exploring plans to go into Phase III this year, Mikael Dolsten, president of Pfizer‘s Worldwide Research & Development unit, said on the Q4 2012 earnings conference call January 29, PlantForm: Clinical trials in humans expected to begin in 2014. Biosimilar expected to be launched, ―in partnership with a pharmaceutical company,‖ in world markets in 2016, Stada Arzneimittel: Joined with Gedeon Richter in announcing plans August 2011 to collaborate on biosimilars for trastuzumab and rituximab. Richter agreed to buy from Stada trastuzumab for a ―low single-digit million Euros figure,‖ they announce.
Nature and indication: Monoclonal antibody; Human epidural receptor 2 (neu) receptor antagonist for aggressive HER positive metastatic and adjuvant breast cancer, for aggressive HER positive metastatic stomach or gastroesophageal junction cancer. 2012 sales: $6.317 billion (CHF 5.889 billion) (Roche). Patent status: Patents set to expire July 2014 in Europe, and June 2019 in the U.S.
Humira (Adalimumab: TNF inhibiting anti-inflammatory biologic medication) Drug developers: AET BioTech and BioXpress: Biosimilar being co-developed under agreement announced October 25, 2012; companies will be jointly responsible for development, registration, and manufacture of the biosimilar, based on BioXpress technology. AET BioTech will provide further investment in the biosimilar based on committed long-term financing, and oversee any future commercialization of the product, Amgen: Biosimilar in active development, Boehringer Ingelheim: BI695501 completed Phase I trial in New Zealand, studying the biosimilar‘s safety and pharmacokinetics compared to Humira (adalimumab) in October 2012, Fujifilm and Kyowa Hakko Kirin: Companies announce 50–50 joint venture, Fujifilm Kyowa Kirin Biologics, to develop a biosimilar version of Adalimumab for rheumatoid arthritis. The venture is proceeding with preparations to begin clinical trials in Europe in the first half of 2013, the companies said October 24, 2012.
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Figure-15: Adalimumab biosimilars
Nature and indication: Anti-TNF-α monoclonal antibody for moderate to severe rheumatoid arthritis, moderate to severe chronic plaque psoriasis, moderate to severe Crohn‘s disease; moderate to severe ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, moderate to severe polyarticular juvenile idiopathic arthritis. 2012 sales: $9.265 billion (AbbVie). Patent status: Patent set to expire 2016 in U.S.; 2018 in EU.
Neulasta (Pegfilgrastim: PEGylated form of the recombinant human granulocyte colony-stimulating factor)
Figure-16: Pegfilgrastim biosimilars
Drug developers: Hospira: Biosimilar in development, Merck & Co.: MK-6302 said to be in clinical development as of 2011 for neutropenia caused by cancer chemotherapy; no further announcement since then on ‗6302, acquired through acquisition of Insmed in 2009, Teva: Neugranin launch delayed in 2011, when company reached settlement of litigation with Amgen in which it agreed not to sell Neugranin until November 10, 2013 unless it first obtains a final court decision that Amgen patents are not infringed by the biosimilar, Teva: Lipefilgrastin (XM22) meets primary endpoint in Phase III clinical trial of reducing the
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duration of severe neutropenia, in a study designed to evaluate the efficacy and safety of lipegfilgrastim compared to pegfilgrastim, the company said June 6, 2011.
Nature and indication: Leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. 2012 sales: $4.092 billion. Patent status: Patents set to expire August 2015 in EU; October 2015 in U.S.
Neupogen (Filgrastim: granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes) Drug developers: Biocon and Celgene: Nufil marketed in India by Biocon; in active development for EU by joint venture ctArzneimittel: Biograstim® marketed in EU, where it was authorized September 2008 for cancer, hematopoietic stem cell transplantation, and neutropenia, Dr. Reddy‘s Laboratories: Grafeel marketed in India, Hexal: Filgrastim Hexal® marketed in EU, where it was authorized February 2009 for cancer, hematopoietic stem cell transplantation, and neutropenia, Hospira: Nivestim™ marketed in EU, where it was authorized June 2010 for cancer, hematopoietic stem cell transplantation, and neutropenia, Intas/Apotex: Neukine in Phase III development, Merck & Co.: MK-4214 in Phase III clinical development; acquired through acquisition of Insmed in 2009, Ratiopharm: Ratiograstim® marketed in EU, where it was authorized September 2009 for cancer, hematopoietic stem cell transplantation, and neutropenia.
Figure-17: Filgrastim biosimilars
Authorization withdrawn voluntarily March 2011, followed two months later by formal European Commission withdrawal, Sandoz: Zarzio® marketed in EU, where it was authorized February 2009 for cancer, hematopoietic stem cell transplantation, and
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neutropenia In U.S., recruiting patients as of January for a noninterventional, long-term safety data collection of the biosimilar and Filgrastim Hexal® in stem cell donors (NCT01766934), Teva: Tevagrastim® marketed in EU, where it was authorized September 2008 for cancer, hematopoietic stem cell transplantation, and neutropenia.
Nature and indication: Granulocyte colony-stimulating factor (G-CSF) for neutropenia caused by the drugs used to treat cancer. 2012 sales: $1.260 billion (Amgen). Patent status: Patent set to expire December 2013 in U.S.; Patent expired 2006 in EU.
Remicade (Infliximab: Chimeric monoclonal antibody biologic drug that works against tumor necrosis factor alpha (TNF-α)
Figure-18: Infliximab biosimilars
Drug developers: Amgen: Biosimilar in active development, BioXpress: Biosimilar in active development, Celltrion: Ramsima™ (formerly CT-P13) authorized for marketing in Korea on July 20, 2012, for rheumatoid arthritis, ulcerative colitis, Crohn‘s disease, ankylosing spondylitis, and psoriasis. Applied for marketing authorization in EU, Hospira: Biosimilar in active development.
Nature and indication: Tumor necrosis factor (TNF) blocker for moderately to severely active rheumatoid arthritis in adults, in combination with methotrexate; Crohn's disease in children six years and older, and adults who have not responded well to other medicines; rheumatoid arthritis; ankylosing spondylitis; psoriatic arthritis; chronic, severe, extensive, and/or disabling plaque psoriasis in adults; moderately to severely active ulcerative colitis in children six years and older and adults that have not responded well to other medicines. 2012
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sales: $8.215 billion ($6.139 billion Johnson & Johnson + $2.076 billion Merck & Co.). Patent status: Patents set to expire 2014 in Europe, and 2018 in U.S.
Rituxan / MabThera (Rituximab) Drug developers: Amgen: Biosimilar in active development, BioXpress: Biosimilar in active development, Boehringer Ingelheim: BI695500 in Phase III development in U.S., EU, Brazil, Guatemala, Russia, Norway, Ukraine, Argentina, Peru, New Zealand. U.S. study recruiting participants as of April 17, according to ClinicalTrials.gov (NCT01682512)
Celltrion and Hospira: Conducting Phase I trial in South Korea of CT-P10 for RA and another Phase I trial for lymphoma.
Dr. Reddy‘s Laboratory: Reditux® marketed in Bolivia, Chile, India, and Peru, iBio: Announces October 5, 2011, that it produces rituximab in nontransgenic green plants.[8]
Figure-19: Rituximab biosimilars
More recent announcements, however, focus on the company‘s technologies for developing biosimilar and proprietary drugs. On April 26, 2012, announces results of ongoing tests showing that its immunomodulator molecule lichenase (LicKM) enhances vaccine antigens when produced as fusions to LicKM. iBio said it will offer commercial collaborations and product licenses to the immunomodulator, dubbed iBioModulator™, which last month was warded U.S. Patent No. 8,404,252. The iBioModulator has been shown in animal models to increase the strength and extend the duration of immune response to a vaccine antigen, Merck: MK8808 in Phase I development for EU, with trial in Belarus, Pfizer: PF-05280586 set this year to complete a Phase II trial launched March 2012 comparing the biosimilar to Rituxan/MabThera. ―This year, we expect data,‖ Mikael Dolsten, president of Pfizer‘s
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Worldwide Research & Development unit, said on the Q4 2012 earnings conference call January 29. Probiomed: Kikuzubam® marketed in Bolivia, Chile, Mexico, and Peru, Roche: CEO Severin Schwan was quoted in March as pushing back his company‘s anticipated launch of a rituximab biosimilar beyond the 2016 date he had earlier cited in The Wall Street Journal, until the end of this decade, Sandoz: GP2013 in Phase I/II trial for rheumatoid arthritis and non-Hodgkin‘s lymphoma, and a Phase III trial for advanced folicular lymphoma. As of last year, the biosimilar was in Phase II trials in Argentina, Austria, Brazil, France, Germany, India, Italy, Spain, and Turkey, Stada Arzneimittel: Joined with Gedeon Richter in announcing plans August 2011 to collaborate on biosimilars for rituximab and trastuzumab. Stada receives nonexclusive rights to sell Richter-produced rituximab in Europe and the Commonwealth of Independent States, excluding Russia. In addition to an undisclosed payment to Richter, Stada also agrees to pay Richter based on progress of the development of rituximab to a ―low double-digit million Euros‖
Recently discontinued efforts: Teva and Lonza: End planned 544-patient, Phase III clinical trial of TLO11, saying they wanted input from regulators on designing the trial program (October 2012). On April 5, Lonza issues statement denying news reports that it will end its biosimilar joint venture with Teva4, Samsung Biologics: Venture between Samsung and Quintiles halts development of SAIT101, in October 2012, reportedly due to uncertainty over biosimilar regulation in the U.S.
Nature and indication: Chimeric mouse-human monoclonal antibody, for non-Hodgkin‘s lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis. 2012 sales: $7.190 billion (CHF 6.707 billion) (Roche). Patent status: Patents set to expire later this year in EU, and 2018 in U.S.
Figure-20: Bevacizumab biosimilars
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Avastin (Bevacizumab: Angiogenesis inhibitor): Amgen is developing a biosimilar to the breast cancer drug, while Fujifilm and Kyowa Hakko Kirin on October 24, 2012, announce 50–50 joint venture, Fujifilm Kyowa Kirin Biologics, to develop a biosimilar version of Avastin (Roche / Genentech) for cancer indications
Lispro: Biocon and Mylan announed a strategic collaboration February 14 to develop a biosimilar to the generic version of insulin analog Humalog (Eli Lilly).
Figure-21: Lispro biosimilars
Glargine (long-acting basal insulin analogue): Biocon and Mylan on February 14 announced a strategic collaboration to develop a biosimilar to the insulin analog Lantus (Sanofi).
Figure-22: Glargine biosimilars
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