Biopharmaceuticals and Biosimilar Drugs

Dr. Mohit KulmiPG Resident

Dept. of PharmacologySAIMS, Indore

History of Biotechnology• Biotechnology is in some ways as old as human history.

• It was just during the early 20th century when the term biotechnology came into use.

• The term was coined in 1917 by Karl Ereky, a Hungarian engineer & professor who described a technology based on converting raw materials into a more useful product.

• At that time, the newly categorized field was focused on food production, addressing such issues as malnutrition & famine.

Contd…

• The Field soon expanded its focus to medical uses, led by the 1940s introduction of penicillin made through a fermentation process,• greatly impacted countless lives over a half-century ago.

• Today, Biologic medicines are making significant impact on the lives of patients with serious illnesses throughout the world.

• It Hold promise to cure diseases like Cancers, Alzheimer’s, Multiple sclerosis, Arthritis & Cardiovascular disorders.

Definition of Biotechnology• A standard definition of biotechnology was not reached until the United Nations & World Health Organization accepted the “1992 Convention on Biological Diversity” & defined biotechnology as:

• “Any technological application that uses biological systems, living organisms or derivatives thereof, to make or modify products & processes for specific use”

Biopharmaceuticals

• Biopharmaceuticals drugs structurally mimics compounds found within the body and are produced using biotechnologies. • Biopharmaceuticals make up about one-third of drugs currently in development and refer to pharmaceutical substances derived from biological sources.• These are medical drugs produced using biotechnology especially genetic engineering or hybridoma technology or via biopharmaceutical techniques such as • Recombinant human technology, • gene transfer and• antibody production methods.

Contd…• Biopharmaceuticals have changed the treatment ways of many diseases like diabetes, malignant disorders;

• since these can be tailored for specific medical problems in different individuals.

•With biotechnology, any drug can be genetically modified using cell fusion or deoxyribonucleic acid (DNA)-recombinant technologies to alter specificities for individual diseases.

Biosimilars

What are biosimilars?

•Legally approved subsequent versions of innovator biopharmaceutical products made by a different sponsor following patent & exclusivity expiry of the innovator product.

• Because of structural & manufacturing complexities, • these biological products are considered as similar, • but not generic equivalents of innovator biopharmaceuticals.

• After the expiration of patent(s) for the first approved biopharmaceuticals,• ‘copying’ and marketing of these biological substances• can be offered by other biotech companies and might possibly, as•with generics, reduce cost to patients and society.

Definitions & Interpretations of Biosimilar Products

Term By DefinitionSBP (Similar Biologic Product)

WHO Similar to an already licensed reference biotherapeutic product in terms of quality, safety & efficacy

FOB (Follow-On Biologic)

US-FDA

Highly similar to the reference product without clinically meaningful differences in safety, purity and potency

SEB (Subsequent Entry Biologic)

Canada

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

Based on these different definitions, there are three determinants in the definition of the biosimilar product:

1. It should be a biologic product.

2. The reference product should be an already licensed biologic product.

3. The demonstration of high similarity in safety, quality & efficacy is necessary.

Similarity should be demonstrated using a set of comprehensive comparability exercises at the quality, non-clinical & clinical level.

AimThe aims of development of a biopharmaceutical are:

• It should be clinically effective, and

• it should be approvable by regulatory authorities and commercially viable.

ScopeBiologic medicines are currently prescribed to treat a wide variety of conditions, including:

1. Blood conditions: leuko/neutro/pancytopenias2. Cancers: colon & breast ca or NHL3. Immune system disorders: rheumatoid

arthritis,4. Psoriasis & crohn’s disease5. Neurological disorders: multiple sclerosis6. More than 400 biologics are in clinical trials7. These include therapies for cancers,

alzheimer’s 8. Disease, heart disease, diabetes, HIV/AIDS & 9. Autoimmune disorders.

Manufacturing of Biopharmaceuticals• Recombinant Protein formation

• Cell Therapies

• Viral Vaccines

Examples: Recombinant proteinModifying the selected cell

Growing a cell line from the original modified cell

Cultivating them to produce the desired protein

Separating the protein from the cells

Purifying the collected protein

Cell therapy

Cells of animal

or human origin

Isolation of cells

Expansion

Purification

Cells for implant

ation

Vaccine against viral infection

Production of carrier system

Inoculation with virus

Elimination of reproducibility and infectivity

Purification

Virus fragment

Differences between chemical generics & biosimilars -

Heavier

• Unlike structurally well-defined, low molecular weight chemical drugs, biopharmaceuticals are:

• High molecular weight compounds with complex three dimensional structure

• For example, the molecular weight of Aspirin is 180 Da whereas Interferon-β is 19,000 Da.

Larger

• Typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs.

• Possesses fragile three-dimensional structure as compared to well-characterized one-dimensional structure of chemical drug.

Difficult to define structure

• Small Molecule drugs → easy to reproduce & specify

by mass spectroscopy & other techniques.

• Lack of appropriate investigative tools to define

composite structure of large proteins.

Complex manufacturing processes•Manufacturers of biosimilar products will not have access to manufacturing process of innovator products→Proprietary knowledge.

• Impossible to accurately duplicate any protein product.

•Different manufacturing processes use different cell lines, protein sources & extraction & purification techniques → heterogeneity of biopharmaceuticals

• Versatile cell lines used to produce the proteins have an impact on the gross structure of the protein

• Such alterations may significantly impact: • Receptor binding, Stability, Pharmacokinetics & Safety

• Immunogenic potential of therapeutic proteins→ Unique safety issue→ Not observed with chemical generics

Overview of the main differ ences betweenchemical and biological drugs

Chemical Biological

Produced by chemicalSynthesis

Produced by living cell cultures

Low molecular weight High molecular weight

Well-defined structure Complex, heterogeneousstructure

Mostly process-independent

Strongly process-dependent

Completely characterised Impossible to fully characterisethe molecular composition andheterogeneity

Stable Unstable, sensitive to externalconditions

Mostly non-immunogenic Immunogenic

Impact Safety & Effectiveness of biologic

Quantity of Acid–base variants & Glycosylation

Alterations in the three-dimensional structure of the Protein

Significant changes in behaviour of the cells & changes in the protein

Even small changes in production (Minor equipment/ Environmental variations)

• To assure high quality & consistency in final product, production process requires a high level of monitoring & testing throughout the process

• A biologic drug typically has around 250 in-process tests during manufacturing, compared to around 50 tests for small molecule drugs.

Biopharmaceutical classification system• Biopharmaceutical classification system (BCS) is a drug development tool that deals with the contributions of three major factors,

1. dissolution, 2. solubility and 3. Intestinal permeability,

According to BCS, drug substances are classified into different classes.

• Class I: high solubility-high permeability;

• Class II: low solubility-high permeability;

• Class III: high solubility-low permeability;

• Class IV: low solubility-low permeability.

Types of biopharmaceuticalsBiopharmaceuticals are being developed to fight cancer, viral infections, diabetes, hepatitis and multiple sclerosis and these can be grouped into various categories.• i) cytokines • ii) enzymes • iii) hormones • iv) clotting factors • v) vaccines • vi) monoclonal antibodies• vii) cell therapies • viii) antisense drugs, and • ix) peptide therapeutics.

Cytokines• Cytokines are hormone-like molecules that can control reactions between cells. They activate cells of the immune system such as lymphocytes and macrophages. • Interferon is potent glycoprotein cytokine that acts against viruses and uncontrolled cell proliferation. • The FDA has approved a recombinant variant of IL-2, aldesleukin (Proleukin), for treating renal cell carcinoma• An IL-1 blocker, anakinra (Kineret), has been approved for treatment of rheumatoid arthritis.• Another, rilonacept (Arcalyst), has been approved

Granulocyte-macrophage colony-stimulating factor• (GM-CSF) stimulates the bone marrow to produce neutrophils and macrophages, and is used for chemo and radio therapy that suppresses bone marrow function.

EnzymesFor example, • Alteplase (Activase, TPA) (dissolves blood clots);

•Dornase alfa (Pulmozyme) (a recombinant DNAse I that digests DNA in the mucous secretions in lungs);

• Imiglucerase (Cerezyme) - a recombinant glucocereborsidase for Gaucher’s disease, bone destruction and enlargement of the liver and spleen.

• Factor IX (Alphanine SD,Benefix, Bebulin VH, Profilnine SD, Proplex T) belonging to peptidase family S1, is one of the serine proteases of the coagulation system. Deficiency of this protein causes hemophilia B.

Hormones: • These chemicals transfer information and instructions between cells in animals and plants.• Examples include insulin (Insugen, Humulin, Novolin),•Human growth hormone (Ascellacrin, Crescormon),•Glucagon, growth hormone, gonadotrophins (Ovidrel)

Clotting factors: • These include any factor in the blood that is essential for the blood to coagulate.

Monoclonal antibodies:

Monoclonal antibodies are produced by hybridoma technology. Examples include

• Infliximab (Remicade), adalimumab (Humira), rituximab (Rituxan, MabThera). •Monoclonal antibodies now account for approximately one third of all new treatments. •Their applications include the treatment of breast cancers, leukemia, asthma, rheumatoid arthritis, psoriasis, chronic gastrointestinal inflammatory disease and transplant rejection. •First fully human monoclonal antibody was launched in 2003 (Humira) in UK-removing potential for immunogenic reactions.

Cell therapies: • Cell therapy describes the process of introducing new cells into tissues in order to treat a disease.• Several stem cell therapies are routinely used to treat disease today. • Adult stem cell transplant e.g. peripheral blood stem cells and umbilical cord blood stem cell transplant. •Umbilical cord blood stem cell transplants are less prone to rejection than either bone marrow or peripheral blood stem cells.

Antisense drugs:

• Antisense drug is a medication containing part of the non-coding strand of messenger RNA (mRNA).

• Antisense drugs work at the genetic level to interrupt the process by which disease-causing proteins are produced.

• Antisense oligonucleotides are emerging as a novel approach to cancer therapy, and used alone or in combination with conventional treatments such as chemotherapy and radiation.

Peptide therapeutics:

• Peptide therapeutics represents a novel class of therapeutic agents. • Currently, only selected cationic antimicrobial peptides have been licensed, and only for topical applications.• Ex – Gramicidin S• Polymyxin B• Bracitracin• Rabbit alpha defensin•Human beta defensin • Bacterial nisin.

Techonologies used in the processPEGylation• It is the process of covalent attachment of poly ethylene glycol or PEG polymer chains to another molecule, normally a drug or therapeutic protein.

• PEGylation has been proven as a powerful new drug delivery technology.

•Main aims being to extend the circulation time and the avoidance of immunogenicity or toxicity.

Five PEGylated biopharmaceuticals:1. Pegademase bovine (Adagen) PEG- bovine

adenosine deaminase, used to treat cross-linked severe combined immunogenicity syndrome, as an alternative to bone marrow transplantation and enzyme replacement by gene therapy,

2. Pegaspargase (Oncaspar) PEGylated L-asparaginase for the treatment of acute lymphoblastic leukemia in children.

3. Pegylated interferon alfa-2a (Pegasys) or pegylated interferon alfa-2b (PegIntron) PEGylated interferon alpha for use in the treatment of chronic hepatitis C and hepatitis B,

4. Pegfilgrastim (Neulasta) PEGylated recombinant methionyl human granulocyte colony-stimulating factor for severe cancer chemotherapy induced neutropenia, and

5. Doxorubicin HCl (Doxil) PEGylated liposome containing doxorubicin for the treatment of cancer.

were commercialized.

Bio-crystallization• The benefits of protein crystallization in biopharmaceutical processing include

• i) Streamlining the manufacturing process and making biopharmaceuticals less expensive,

• ii) Crystals are the most concentrated form and is beneficial for drugs such as antibodies, which require high doses at the delivery site

• iii) Protein crystallization may significantly improve some aspects of protein handling, and change the way biopharmaceuticals are produced, formulated, and delivered,•

• iv) Reduced chemical degradation and as such may enhance drug efficacy over prolong period,

• v) Ability to achieve high concentration, low viscosity formulation and controlled release protein delivery

• Protein crystals have shown significant benefits in the delivery of biopharmaceuticals to achieve high concentration, low viscosity formulation and controlled release protein delivery.

Transgenics• A potentially controversial method of producing biopharmaceuticals involves transgenic organisms, particularly plants and animals that have been genetically modified to produce drugs. • Transgenic plants are an attractive platform for the production of biopharmaceuticals since they offer bio-safety, lower cost of goods and flexibility. •One potential approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk (or blood or urine).

• The first such drug manufactured from the milk of a genetically-modified goat was antithrombin (ATryn).

Biopharmaceutical manufacturing• The process of manufacturing a biopharmaceutical product entails two major steps that are referred to as upstream and downstream processing.

•Upstream processing skills include those associated with the culture and maintenance of cells and

•Downstream processing skills included those associated with the chemical and physical separations necessary for the isolation and purification of the product itself, from the complex culture mixture.

• In biopharmaceutical manufacturing,

• process development accounts for 30% of costs,

• upstream processing for 20%.

•However, the highest outlay in biopharmaceutical manufacturing is attributed to downstream processing, which is responsible for a massive 40% of the total costs incurred

Uses of biopharmaceuticalsErythropoietin: • Erythropoietin is the hormone responsible for inducing red blood cell production by the body’s bone marrow. •Drugs such as epoietin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) • increased the production of red blood cells. They are used to treat• anaemia associated with chronic kidney failure, • cancer• chemotherapy, and • antiretroviral HIV therapy

Interferon-α :

• Imatinib (Gleevec) is a 2-phenylaminopyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase (TK) enzymes. • It occupies the TK active site, leading to a decrease in activity.

• IMATINIB is used in chronic myelogenous leukemia,• gastrointestinal stromal tumors and a number of other malignancies.

• Interferon-β : This is used for treatment of relapsing multiple sclerosis.

Monoclonal antibody: The newest monoclonal antibody approved for the treatment of rheumatoid arthritis is rituximab (Rituxan). Like infliximab (Remicade), it is a chimeric mouse/human monoclonal antibody that is given by intravenous infusion.

Colony stimulating factors: Colony-stimulating factors are medications used to increase the number of WBCs. Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used for treatment of febrile neutropenia in systemic lupus erythematosus (SLE) and other systemic rheumatic diseases.

Glucocerebrosidase: This is used for treatment of Gaucher’s disease which is the most common glycolipid storage disorder, • It is caused by a hereditary deficiency of the enzyme glucocerebrosidase.

• Recombinant human glucocerebrosidase, produced by Chinese hamster ovary cells in tissue culture, became available in 1994 and has replaced the placenta-derived product.

• These therapies have revolutionized the care of patients with Gaucher’s disease, reversing many of the pathological consequences of this disease, and preventing further progression

Issues of concern with use of biosimilarsEfficacy issues

•Differences between the bioactivity of the biosimilars & their innovator products.

• Example

• 11 epoetin alfa products from 4 different countries (Korea, Argentina, China, India) differ in efficacy due to difference in the production process.

• Some studies compared quality parameters (purity, content & efficacy) of several biosimilar brands taken from the Indian market & with those of the innovator drug products and showed -

•Marked lack of comparability between biosimilars & innovator products

• Significant difference in the level of purity was observed among various brands of biosimilars as per European & Indian Pharmacopoeia standards

Safety issues• Concerns regarding immunogenicity

• Example

• ↑ in no. of cases of Pure Red Cell Aplasia associated with specific formulation of epoetin α

• Caused by the production of neutralizing antibodies against endogenous epoetin.

• Most of the cases in patients treated with Eprex→

• Biosimilar of epoetin α

• Cause→ subtle changes in manufacturing process,

•↑ immunogenicity and thus the adverse effects.

Pharmacovigilance• Due to limited clinical database at the time of approval→

• Vigorous pharmacovigilance is required.

• Immunogenicity is a unique safety issue.

• Adverse drugs reactions monitoring data should be exhaustive.

Regulatory framework in IndiaSimilar biologics are regulated as per: • The Drugs and Cosmetics Act, 1940

• The Drugs Cosmetics Rules, 1945

• Rules for the manufacture, use, import, export & storage of hazardous microorganisms/genetically engineered organisms or cells, 1989. •Notified under the Environment Protection Act

• Apart from Central Drugs Standard Control Organization (CDSCO), the office of Drug Controller General of India (DCGI) two other competent authorities are involved in the approval process

1. Review Committee on Genetic Manipulation(RCGM)

• Works under Department of Biotechnology (DBT)

• Regulates import, export, carrying out research, preclinical permission, No objection certificate for clinical trial (CT) .

2. Genetic Engineering Approval Committee (GEAC)

• Functions under the Department of Environment (DoE)

• Statutory body for review & approval of activities involving large scale use of genetically engineered organisms & their products

• India is one of the leading contributors in the world biosimilar market

• Over 50 biopharmaceutical brands have got marketing approval.

• Potential to replicate success of Indian Generic Industry

India has inherited advantages of: • Cost effective manufacturing •Highly skilled, reasonably priced workforce •Huge market• Key benefit→ Reduce cost by 20-25%

Few Biosimilars Approved in IndiaActive

substance

Product name

Launch date in India

Company

Epoetin alfa

Epofit/Erykine

Aug 2005

Intas Biopharma-

ceuticalsDarbopoetin alfa

Cresp Aug 2010

Dr Reddy’s Laboratorie

sInsulin glargine

Basalog 2009 Biocon

Reteplase Mirel 2009 Reliance Life Scienes

Rituximab Reditux Apr 2007

Dr Reddy’s Laboratorie

s

Conclusion• In light of limitations of cost and lack of long-term safety and efficacy data, newer agents for the time being are recommended for use as second- or third-line agents in patients.

• Biopharmaceutical products are considerably more expensive than traditional ones, largely due to the high-cost technology required for production.

• Technologies must be developed to bring the cost of manufacture down,

• It’s more viable to manufacture biopharmaceuticals with large market size and high market growth like India.

• Advantages of biopharmaceuticals include fewer side effects and more potent effect on target cells.

• Biopharmaceuticals’s greatest potential lies in gene therapy and genetic engineering.

• Biotechnological medicines shall become an important part of future healthcare landscape.