Oral Peptide Therapeutics: A Sea of Opportunity or a Dry Well?

Proteins and peptides are the building blocks of life and have in recent years become a very promising basis for targeting a range of diseases. Over the past thirty years, and especially the last 10 years, there has been a rapid growth in the development of therapeutic proteins, with a dramatic increase in the number of peptide or protein-based drugs on the market.

The advent of peptide-based therapeutics can be traced to the success of the initial protein biologics, with proteins and peptides now being utilized in numerous indications, including cancer, autoimmune diseases, neurological, and endocrine disorders. Currently, there are more than 200 approved therapeutic proteins and over 100 peptides on the market, accounting for approximately 10% of the pharmaceutical market at a value of $40 billion per year.

There are many reasons for the rapid growth of peptide therapeutics. Peptides serve a highly specific set of functions in the body that cannot be mimicked by simple chemical compounds. Thus, when compared with small-molecule drugs, peptides are able to exhibit increased potency and selectivity due to specific interactions with their targets. As a result, peptides have the potential for decreased off-target side effects and decreased systemic toxicity. Moreover, because the body naturally produces peptides, peptide-based therapeutics are often well-tolerated and are less likely to elicit immune responses.

Though peptide therapeutics offer numerous advantages, and the growth of such drugs is strong, there remains a significant gulf between “market actual” and “market potential”. This is largely attributable to challenges with the route and method of delivery of peptide drugs.

Most peptide drugs are administered via injectable routes such as subcutaneous, intravenous, and intramuscular administration. This is due to the challenges of oral delivery of proteins and peptides. First, the digestive system recognizes these molecules as food and looks to break them down through digestion. Also, intact peptides and proteins have higher molecular weights and contain both hydrophilic and hydrophobic appendages in their structure. These properties make it difficult for peptides to be absorbed by the intestine.

While the market for injectable proteins is strong and growing, alternative administration forms are gaining increasing traction. This trend is guided by three dynamics – patient compliance, prescriber preference and market expansion. As one can appreciate, the low patient acceptability of frequent injections, limits the potential opportunity of peptide-based drugs.

So, why isn’t there a pill for that?

Long hailed as the ‘Holy Grail’ of drug delivery, orally administered peptides offer vast potential but also present considerable development challenges.

In short, the oral peptide formulation must remain intact in the highly acidic environment of the stomach. Once through the stomach, the tablet design must then promote dissolution in the higher pH environment of the small intestine, while simultaneously protecting the peptide payload from degradation by protease enzymes. Finally, mechanisms must be present which facilitate the absorption of the peptide into the relatively impermeable intestinal epithelium.

While this may seem daunting on the surface, there has been significant investment in the development of oral peptide dosage forms by specialized drug delivery companies. This is based on the clear advantages that such medications offer patients, prescribers and pharmaceutical developers, alike. Oral leuprolide demonstrates this potential.

Leuprolide, marketed under the brand name LUPRON DEPOT®, has demonstrated in the clinic and practice to be an efficacious treatment for endometriosis. A daily oral leuprolide tablet could offer a more patient-friendly alternative to monthly depot injections, potentially encouraging physicians and patients to utilize the medication earlier and more often. Market research suggest such a product could produce revenues in excess of $600 million annually in the U.S.

In developing its oral leuprolide tablet, biotechnology company Enteris BioPharma, utilized a technology platform designed to provide protection against the harshness of the digestive system and then promote absorption of the leuprolide into the bloodstream. Results from a Phase 2a clinical trial of the drug, Ovarest®, produced a pharmacodynamic response similar to LUPRON DEPOT injection.

Adding to the growing excitement around oral peptides, another pharmaceutical company, Novo Nordisk, just announced that it submitted applications to the FDA for its oral formulation of semaglutide, a once-daily glucagon-like peptide receptor agonist therapy (GLP-1) for the treatment of Type 2 diabetes. Traditionally, GLP-1 therapies are administered via injections. If cleared by the FDA, it could create a market worth billions of dollars.

Ultimately, not all peptide therapeutics are appropriate for oral administration due to various constraints, from physiochemical to economic. However, for those that meet the necessary criteria, advances in formulation technologies coupled with favorable market dynamics will continue to improve the quality of patients lives by increasing convenient use of these powerful therapeutics.


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