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Peptide Therapeutics: Current Status And Future Directions

Peptide Therapeutics: Current Status And Future Directions

Peptides are recognized for being highly selective and efficacious and, at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D), and approximately 140 peptide therapeutics are currently being evaluated in clinical trials. Given that the low-hanging fruits in the form of obvious peptide targets have already been picked, it has now become necessary to explore new routes beyond traditional peptide design. Examples of such approaches are multi-functional and cell penetrating peptides, as well as peptide drug conjugates. Here, we discuss the current status, strengths, and weaknesses of peptides as medicines and the emerging new opportunities in peptide drug design and development.

More than 7000 naturally occurring peptides have been identified, and these often have crucial roles in human physiology, including actions as hormones, neurotransmitters, growth factors, ion channel ligands, or anti-infectives 1, 2, 3, 4. In general, peptides are selective and efficacious signaling molecules that bind to specific cell surface receptors, such as G protein-coupled receptors (GPCRs) or ion channels, where they trigger intracellular effects. Given their attractive pharmacological profile and intrinsic properties, peptides represent an excellent starting point for the design of novel therapeutics and their specificity has been seen to translate into excellent safety, tolerability, and efficacy profiles in humans. This aspect might also be the primary differentiating factor of peptides compared with traditional small molecules. Furthermore, peptide therapeutics are typically associated with lower production complexity compared with protein-based bio-pharmaceuticals and, therefore, the production costs are also lower, generally approaching those of small molecules. Thus, in several ways, peptides are in the sweet spot between small molecules and bio-pharmaceuticals.

Naturally occurring peptides are often not directly suitable for use as convenient therapeutics because they have intrinsic weaknesses, including poor chemical and physical stability, and a short circulating plasma half-life. These aspects must be addressed for their use as medicines. Some of these weaknesses have been successfully resolved through what we term the 'traditional design' of therapeutic peptides as described below (see Fig. 1 for a full SWOT analysis of peptides as therapeutics). Besides traditional peptide design, a range of peptide technologies has been emerging that represent the opportunities and future directions within the peptide field. These include multi-functional and cell penetrating peptides, as well as peptide drug conjugates and technologies focusing on alternative routes of administration. Here, we present a chain of thoughts leading to the conclusion that peptides offer enormous growth potential as future therapeutics.

Peptide drug market
During the past decade, peptides have gained a wide range of applications in medicine and biotechnology, and therapeutic peptide research is also currently experiencing a renaissance for commercial reasons. For example, the peptide-based medicine Lupron™ from Abbott Laboratories for the treatment of prostate cancer and more, achieved global sales of more than US$2.3 billion in 2011. In addition, Lantus™ from Sanofi (which is really at the border between a peptide drug and a small bio-pharmaceutical) reached sales of US$7.9 billion in 2013. Currently, there are more than 60 US Food and Drug Administration (FDA)-approved peptide medicines on the market and this is expected to grow significantly, with approximately 140 peptide drugs currently in clinical trials and more than 500 therapeutic peptides in preclinical development. An overview was presented in a recent review by Kaspar and Reichert.

In terms of value, the global peptide drug market has been predicted to increase from US$14.1 billion in 2011 to an estimated US$25.4 billion in 2018, with an underlying increase in novel innovative peptide drugs from US$8.6 billion in 2011 (60%) to US$17.0 billion (66%) in 2018. The most recent example of a novel peptide drug class is the group of glucagon-like peptide-1 (GLP-1) agonists for the treatment of type 2 diabetes mellitus (T2DM), which reached total sales of over US$2.6 billion in 2013, with Victoza™, the most prominent member of the class, reaching blockbuster status. A status of the top-selling peptide therapeutics was given in a recent report from Transparency Market Research.

The main disease areas currently driving the therapeutic use of peptide drugs are metabolic diseases and oncology. The former can be characterized by the epidemic growth in both obesity and T2DM, the latter by a rising mortality and need for chemotherapy replacement, as well as cancer supportive care. The use of peptide therapeutics in the treatment of diabetes and obesity is probably why North America currently represents the largest share of the peptide drug market, with the Asian market expected to have the largest growth. The movement of the pharmaceutical industry into rare diseases and orphan drugs has also been extended to peptides, and marketed examples in this area include teduglutide, a GLP-2 receptor 2 agonist for short bowel syndrome, and pasireotide, a somatostatin receptor agonist for the treatment of Cushing's syndrome. Moreover, there seems to be a current trend towards the disease areas of infectious diseases and inflammation, where several peptides are undergoing clinical testing.

Currently, most peptide drugs are administered by the parental route and approximately 75% are given as injectables. However, alternative administration forms are gaining increasing traction, including oral, intranasal, and transdermal delivery routes, according to the respective technology developments. One example of an alternative administration route evaluated for application to peptides is the transbuccal delivery via the combination of gold nanoparticles (Midatech) and the PharmFilm™ (Monosol Rx) technology. Accordingly, Midasol Therapeutics is currently carrying out clinical development of a transbuccal delivery system that utilizes insulin-passivated gold glyconanoparticles. Another example is the TopAct™ technology platform from ActoGeniX, which might enable oral delivery of peptides directly expressed in the gastrointestinal tract.

The use of alternative administration forms could also enable greater usage of peptide therapeutics in other disease areas, such as inflammation, where topical administration of peptides could be the basis for highly efficacious novel treatments. Although not within the scope of this article, peptides are often excellent biomarkers and, therefore, can also be used for diagnostic purposes. Finally, peptides have also found an application as vaccines.

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