Biologics and Biosimilars

Delivery Issues with Protein Drugs:

1. Peptide and protein drugs are prone to numerous stability problems 2. Optimization of in vivo efficacy 3. Rapid engulfment by macrophages

Production of Biopharmaceuticals

1. gene is transfected into cell 2. cells grown in a bioreactor 3. protein product is isolated by cell lysis and centrifugation/filtration 4. protein is purified by chromatographic techniques

Novel Drug Delivery Systems:

A range of drug delivery systems have been developed to deliver biologics and small molecular weight drugs

Pharmaceutical Nanotechnology

The design, characterization and production of drug delivery devices that have dimensions between 1 nm and 1000 nm

Dendrimers=

highly branched spherical polymers built from a central core molecule ‒ Each additional layer of branching referred to as a generation

Purple Book Database will list:

biosimilar(s), interchangeable(s), and reference product(s)

Biologics=

medicines derived from a biological source (ie derived from living organisms) also called biopharmaceuticals or biological products

Novel Drug Delivery Systems are designed to:

protect from degradation, facilitate uptake, provide sustained release, and direct molecules to their target

An interchangeable biological product is a biosimilar product that meets additional requirements

"An interchangeable product is expected to produce the same clinical result as the reference product in any given patient." -For products administered more than once, the manufacturer must evaluate the safety and decreased efficacy of switching between products

Antibody-drug Conjugates

Conjugation of a drug molecule to an antibody

Microspheres and Nanoparticles:

Drug incorporated within a biodegradable polymer matrix ‒ Most commonly used polymers are esters of polylactic acid (PLA) and its copolymer with glycolic acid (PLGA). ‒ PLA and PLGA cage must be degraded before the drug is released from the microsphere. • Protects from drug metabolizing enzymes

Regulation of Biologics

Drugs are approved by the FDA under the Federal Food, Drug, and Cosmetics Act (FD&C Act) • Biologics are approved under the Public Health Service (PHS) Act ‒ The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure path for biosimilars and interchangeable biological products

Nanoparticles can be given:

IV

Data Required for Biosimilars:

Biosimilarity based on a totality-of-evidence approach that evaluates: ‒ Analytical studies of structure, function, and bioactivity ‒ Animal studies to assess toxicity ‒ Human clinical studies to assess immunogenicity, pharmacokinetics, and pharmacodynamics

Liposomes

Can carry both water-soluble drugs and lipophilic drugs ‒ Loaded with drug either in their aqueous core or in the bilayer itself

Microspheres can be given:

IM and SQ - can act as a depot dosage form

The goal is to demonstrate biosimilarity between the proposed biosimilar product and the reference product, not to independently establish the safety and effectiveness of the proposed product.

Less data needs to be collected → less cost, faster approval

PEGylated liposomes and micelles

Phagocytic cells that are a primary reason for removal of liposomes and micelles • Attachment of polyethylene glycol to the surface of the system ‒ Hydrophilic coating prevents detection by macrophages in the liver and spleen ‒ Lengthens circulation time extensively relative to uncoated liposomes.

Naming of Biosimilars

The FDA has recommended that reference biologics and biosimilars have nonproprietary names that share a core drug substance name AND a suffix that is unique to each product. • The proposed suffix should be 1) four lowercase letter 2) be unique 3) be devoid of meaning. ‒ Core name: infliximab ‒ Suffix: infliximab-dyyb

Purple Book

The Purple Book is available as a database of FDAapproved biological products, including biosimilar and interchangeable products. Biosimilar information is not available in the Orange Book

True or False, biologics are mainly administered by the parenteral route but some administered through other routes (nasal, respiratory, etc)

True

True or False, there are NO current dendrimers on the market.

True

True or false, Biosimilars and generic drugs are versions of brand name drugs and may offer more affordable treatment options to patients.

True

True or false, Novel Drug Delivery Systems utilize nanotechnology.

True

True or false, each manufacturer uses a unique process or cell system to create a biological product. Production processes are usually proprietary.

True

True or false, it is impossible to produce exactly the same therapeutic protein with identical glycosylation patterns

True

True or false, it is not possible to create an exact copy of a brand name biologic.

True

True or false, unlike micelles that form spontaneously, liposomes must have energy inputted into the system to form

True

True or false, Insulin, glucagon, heparin, human growth hormone, and others were previously regulated as drugs not biologics.

True Starting March 23, 2020, the FDA will transition to regulating these agents (insulin, growth hormone, etc) as biological products (i.e. transition from regulation under FD&C Act to PHS Act) • The transition of insulin and other products from approved drugs to biological products will open products to potential biosimilar and interchangeable competition.

True or false, Biosimilars are not generic drugs.

True ‒ Generic drug molecules are identical to the brand name drug. Generic drugs must demonstrate bioequivalency between the brand and generic. ‒ Biosimilars must be highly similar to the reference product and have no clinically meaningful differences

True or false, 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

True ‒ In WA, the prescriber has indicated "Substitution Permitted" on the prescription. ‒ Only interchangeable biological products can be substituted for brand name biologic. A biosimilar cannot be substituted.

Peptide drugs are made of:

a small number of amino acids - molecular weight between 1 and 5 kDa hundreds of amino acids - molecular weight between 6 and 150 kDa Most protein drugs created in cells through recombinant methods - this is in comparison to small molecule drugs that are produced through chemical synthesis

Which of the following most appropriately defines a biologic? a. A medication that is made of either a protein or a peptide. b. A medication derived from a biological source. c. A medication that has its biopharmaceutics clearly elucidated.

b. A medication derived from a biological source.

Which of the following can be substituted for a brand name biologic without having to contact the prescriber? a. A biosimilar b. An interchangeable biological product c. Either a biosimilar OR an interchangeable biological product

b. An interchangeable biological product

A drug manufacturer is in the process of creating a less expensive version of the brand-name, monoclonal antibody Cimzia. Which of the following difficulties will the manufacturer most likely encounter? a. Contamination of antibody solutions with endotoxins. b. Creation of the same glycosylation patterns on the antibody. c. Creation of the protein with same molecular target as the brand name product.

b. Creation of the same glycosylation patterns on the antibody. nearly impossible to produce exactly the same therapeutic protein with identical glycosylation patterns

What issues does the mononuclear phagocytic system cause for protein drugs? a. Rapid enzymatic degradation b. Engulfment by macrophages in the spleen and liver c. Denaturation of the protein

b. Engulfment by macrophages in the spleen and liver

A pharmaceutical manufacturer is designing a parenteral dosage form to consist of microspheres. They would like to modify their formulation to provide a longer sustained release of drug over many days. Which one of the following approaches would most likely provide this sustained release? a. Decreasing the size of the microspheres b. Increasing the size of the microspheres c. Using a biodegradable polymer matrix

b. Increasing the size of the microspheres

An academic research lab is developing a novel delivery system where a drug can be incorporated into a biodegradable polymer and made into solid spheres that are approximately 1 micron in size. The spheres slowly eroded in vivo to provide sustained release of the drug. Which of the following best describes this system? a. Polymer-drug conjugate b. Micelle c. Microsphere d. Parenteral gel-forming product

c. Microsphere

A pharmaceutical company is developing a novel delivery system where a chemotherapeutic agent is being loaded into a spherical bilayer of phospholipids that have been covalently attached to polyethylene glycol polymers. This allows this delivery system to evade the immune system. Which of the following best describes this system? a. Micelle b. Antibody-drug conjugate c. Liposome d. PEGylated liposome

d. PEGylated liposome

Polymer-drug Conjugates

drug molecules are conjugated to polymers

Liposomes protects against:

drug toxicity and drug metabolizing enzymes

biologics:

often large (MW >1000 g/mol), complex molecules Sometimes biologics are complex combinations of sugars, proteins, or nucleic acids

glycosylation=

post-translational modification of a protein by addition of a sugar molecule

Liposomes consist of:

single bilayer membrane or multiple bilayers

Microspheres=

spherical particles ranging from 100 nm to 1 micron (smaller ones are called nanoparticles) ‒ Can be solid or porous ‒ Can also be hollow (microcapsules)

What is "highly similar"?

‒ A biosimilar manufacturer must demonstrate the product is highly similar to the reference product by analyzing the structure and function of the reference product and proposed biosimilar ‒ May have minor differences in clinically inactive components (i.e. buffer ingredients)

Construction of an antibody-drug conjugate:

‒ Antibody ‒ Linker group ‒ Drug

Dendrimers; drug molecules:

‒ Can be attached to peripheral groups covalently or by electrostatic interactions ‒ Can be encapsulated within the dendrimer

At this time, most polymer-drug conjugates are PEGylated proteins.

‒ Covalent attachment of protein drugs to large polyethylene glycol polymers (40 kDalton)

1. Peptide and protein drugs are prone to numerous stability problems

‒ Denature on exposure to heat, extremes in pH, organic solvents ‒ Aggregation ‒ Deamination

Nanotechnology can allow for:

‒ Enhanced solubility and dissolution ‒ Enhanced drug delivery ‒ Decreased drug degradation ‒ Decreased toxicity

Polymer Conjugation can do the following:

‒ Improve solubility ‒ Enhance bioavailability ‒ Extend half life ‒ Protect against degradation ‒ Promote targeting to specific tissues

2. Optimization of in vivo efficacy

‒ Large MW and very water soluble which results in poor permeability ▪ Move through membranes by endocytosis ▪ Consequently, many administered parenterally (mainly IV, sometimes subcutaneously or IM) ‒ Vulnerable to rapid enzymatic degradation by peptidases

What are "no clinically meaningful differences"?

‒ No clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness). ‒ Demonstrated through human pharmacokinetic and pharmacodynamic studies, an assessment of clinical immunogenicity, and, if needed, additional clinical studies.

Liposomes and Micelles can target liposomes and micelles to tumors or other tissues by:

‒ Passive processes ▪ EPR effect ‒ Active processes ▪ Attaching monoclonal antibodies specific for a tumor or any target cell ▪ Prodrugs cleaved at intended site of action ▪ Many others!

The following are considered biologics:

‒ Peptide and protein drugs ▪ Monoclonal antibodies ▪ Hormones ▪ Insulin ▪ Growth factors ‒ Nucleic acids ‒ Carbohydrates (ie heparin) ‒ Blood-derived products ‒ Vaccines ‒ In vivo diagnostic allergenic products ‒ Immunoglobulin products ‒ Gene therapy products ‒ Products containing cells or microorganisms

Majority of Nanomedicines are administered parenterally. Include:

‒ Polymer-drug conjugates ▪ PEGylated proteins ‒ Antibody-drug conjugates ‒ Dendrimers ‒ Micelle systems ‒ Liposomes ‒ Microspheres and Nanoparticles

Liposomes are classified base on SIZE and NUMBER of lamellae (# of bilayers):

‒ Small unilamellar vesicles (SUV) ‒ Large unilamellar vesicles (LUV) ‒ Multilamellar vesicles (MLV) ‒ Multivesicular vesicles (MVV)

Enhanced Permeability and Retention Effect (EPR)

‒ Solid tumors have poorly differentiated and disorganized capillary systems that are 'leaky' and allow the liposomes to accumulate within the tumor ‒ Release contents by allowing drug to diffuse out of carrier or by degradation of the polymer ‒ Carriers are too large to be absorbed by diffusion through capillary membranes

Construction of polymer-drug conjugates:

‒ Water soluble polymer backbone ▪ Polyethylene glycol (PEG) most widely used ‒ A linker group ▪ Helps to minimize the polymer from blocking therapeutic activity ▪ Can be cleaved by hydrolysis, enzyme degradation, pH ▪ Amides (most common), amines, carbamates, esters ‒ Drug ▪ Most often used for chemotherapies and proteins ‒ Targeting group

3. Rapid engulfment by macrophages

‒ Will adsorb opsonins (complement) resulting in rapid removal from circulation due to engulfment by liver and spleen macrophages ‒ Known as mononuclear phagocytic system

Biosimilar is highly similar to, and has no clinically meaningful differences in safety, purity, and potency from, an existing FDA-approved reference product.

‒ Will have the same safety and effectiveness ‒ The reference product is the biological product already approved by the FDA against which a proposed biosimilar product is compared

Micelle systems

• Use of surfactants to self-assemble into micelles • Polymeric micelles are specially designed micelles made from block copolymers ‒ Amphoteric molecules that contain: ▪ Hydrophobic section ▪ Hydrophilic section