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European Biopharmaceutical Review

Lease of Life

During the development of new or improved drugs, obstacles are often encountered with the short therapeutic half-life that is inherent to many proteins and peptides. Their rapid clearance from the body makes it necessary to deliver higher doses of medications more frequently in order to achieve efficacy, which means patients with chronic conditions are often required to administer drugs as often as twice a day.

As expected, this inconvenient frequency of dosing can impact patient adherence to treatment, creating signifi cant challenges for healthcare providers. This has led to advanced half-life extension technologies based on the natural blood protein, albumin, reaching the market, to optimise the therapeutic window of novel drugs. These can enable dosing regimens to be reduced to as little as once a month, helping to improve patient adherence and overall quality of life.

Defining Half-Life

The half-life of a medicine indicates how long a substance will remain active in the human body. It comprises the period of time that it takes for the concentration of the drug to be reduced by half, postadministration, and determines how often dosing is required to maintain its therapeutic effect. The shorter the halflife of a drug, the faster it will be cleared from the body; subsequently, the drug has to be administered more often by patients to ensure a sustained impact. This is particularly true for biological drugs, which have seen a signifi cant increase in investment in recent years, as their limited side-effects for patients makes them ideal for treating conditions where medication needs to be administered frequently, such as chronic disease.

However, these types of drugs are often hampered by short half-lives, which means that, once administered, they can be cleared from the body in a matter of minutes. Patients with conditions such as diabetes, haemophilia and neutropenia are required to administer higher doses more regularly – often once or twice daily – leading to an inconvenient medication regimen, higher costs and greater risks of undesirable side-effects. Many drugs with a promising therapeutic value may be limited by this factor.

Extension Technologies

If medicines can be engineered to remain active in the body for a more sustained period, it would enable patients to take lower doses, saving both time and money. Furthermore, with the development of new drugs also becoming increasingly difficult, drug companies are researching new ways to increase the effectiveness of novel products, as well as enhancing medicines that are already available on the market. The pharma and biotech sectors are paying increasing attention to half-life extension strategies, with many research institutes and academic papers referencing the growing trend in developing technologies that extend and improve the circulatory half-life of proteins and peptides.

Extending half-life offers pharmaceutical companies new potential to improve the profile of products, while increasing the probability that patients will continue with a particular treatment by making compliance less complicated, and as a result, helping to enhance their quality of life. Until recently, researchers have concentrated their efforts on developing technologies that modulate the serum half-life of protein-based therapeutics to required specifications. However, while success has been found in extending the actual serum half-life, it has not been possible to design flexible protein half-life to deliver more defined pharmacokinetics.

The current, widely used strategies tend to be those that increase hydrodynamic volume (PEGylation) or those that use neonatal Fc receptor (FcRn) mediated recycling (albumin fusions). Although significant progress has been made in the creation of novel technologies, the industry is still looking for solutions that allow companies to tailor their therapies in line with specific medical conditions.

Engineered Albumins

Half-life extension technologies based upon albumin are now presenting new options to the industry. As the most abundant protein found in blood, albumin has an extended circulatory half-life of 19 days in humans, and avoids the degradation mechanisms that affect other biologic therapies. Stable, benign and abundant, it is responsible for transporting all manner of endogenous molecules, from bilirubin, fatty acids, metals, ions and hormones, to exogenous drugs.

It is widely accepted that albumin is recycled in the body due to its interaction with its receptor, known as FcRn. FcRn is a dualbinding receptor that is present on many cell types. It binds both immunoglobulin G (IgG) and albumin at distinct sites, and protects them from intracellular degradation. Specific albumin variants have been designed with altered binding affinities for the receptor, making it possible to modulate the serum half-life of the albumin molecule. By coupling a drug to these variants through genetic fusion or chemical conjugation, the technology confers the degree of extended circulatory half-life onto the drug molecule, allowing for longer-lasting therapeutics. The albumin variants differ from wild-type albumin by a very limited set of alterations, with minimal impact on the immunological profile.

Advanced Control Dosing

Using an albumin-based half-life extension platform provides manufacturers with a highly versatile drug delivery technology that can optimise the pharmacokinetics and efficacy of proteins and peptides, and precisely control when compounds leave the body. The ability to define and enhance the therapeutic window of a product means that dose size and intervals can be controlled by the manufacturer, while patients can be required to self-administer medication as little as once a week, fortnightly, or even once a month.

The benefits of this type of technology are already being applied to peptide and protein drugs used to treat chronic conditions where patients self-administer, while the platform can also be exploited for small molecules in oncology. As the technology is based on the natural protein albumin serving as the drug carrier, it represents a highly soluble, nonimmunogenic, bio-compatible solution that offers a strong safety profile. It also produces more stable circulatory drug concentrations in patients, while the reduced risk of side-effects at the associated lowerdose rate means that the toxicity level of the protein may not be reached. Instead, these technologies allow the drug dose to remain within the therapeutic range, increasing the patient's tolerance to the drug.

In recent years, the pharma industry has had to contend with the added challenges of declining R&D productivity, as well as fierce competition from generics when a drug comes off patent. Albumin can help to address these challenges, as the addition of an albumin molecule to any therapy will render it a novel drug entity, as well as extend its lifecycle.

Ultimate Delivery

Albumin represents the bloodstream's ultimate delivery molecule. The latest advancements in half-life extension technologies based on the protein are offering pharma companies new opportunities to develop more powerful novel therapeutics, while delivering optimum effect and a more competitive edge to products that are already available on the market.

The ability to define how long a drug is active in the body provides unrivalled potential to improve treatments aimed at patients with chronic conditions through reducing the frequency of injections needed to provide therapeutic benefit. This not only makes compliance significantly less complicated, but makes drugs more efficient and therefore more tolerable – all of which translates into a better quality of life for patients.

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Dermot Pearson is Strategic Marketing Director with Novozymes Biopharma UK, with responsibility for market development of the company’s Veltis half-life extension and drug targeting business. His role includes overseeing product development, branding, pricing and lifecycle management, all on a global basis. A member of the company's business unit management team, Dermot has held past roles in R&D, quality and manufacturing.
Dermot Pearson
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