PEPTIDE THERAPEUTICS – Oral Peptide Therapeutics – Opportunities Abound as Barriers Fall

Proteins and peptides are the building blocks of life and are a very promising basis for targeting a range of diseases. Throughout the past 30 years, and especially the past 10 years, there has been a rapid growth in the development of therapeutic proteins, with a significant increase in the number of protein-based drugs on the market.

As posted on Drug Development and Delivery
Issue: September 2020


Proteins and peptides are the building blocks of life and are a very promising basis for targeting a range of diseases. Throughout the past 30 years, and especially the past 10 years, there has been a rapid growth in the development of therapeutic proteins, with a significant increase in the number of protein-based drugs on the market.

The cornerstone of protein therapeutics was laid with the regulatory approval of insulin by the US Food and Drug Administration in 1982. As the first commercially available recombinant protein, insulin soon became the gold-standard therapy for patients suffering from diabetes. Almost four decades have passed since insulin’s market introduction, and its success has inspired the development of myriad new therapeutic proteins for a wide range of ailments.

The advent of peptide-based therapeutics can be traced to the success of the initial protein biologics, with proteins and peptides now being utilized across numerous indications, including cancer, autoimmune, neurological, and endocrine disorders. Currently, there are more than 200 approved therapeutic proteins and more than 100 peptides on the market, accounting for approximately 10% of the pharmaceutical market at a value of $40 billion per year. With hundreds of protein and peptide drugs in clinical trials and many more in preclinical development, this market is expected to continue to grow substantially throughout the next 5 to 10 years. A significant percentage of this growth is expected to come from peptide-based drugs.

Peptides occupy a therapeutic niche between small molecules and large biologics, and are generally classified as being a chain of amino acids containing 40 amino acids or less. Currently, the disease areas driving the therapeutic use of peptide drugs are oncology, driven by a rising mortality and need for chemotherapy replacement, and metabolic diseases. The treatment of metabolic diseases via peptide therapeutics has largely centered around the epidemic growth in type 2 diabetes. In addition to metabolic disease and oncology, the movement of the pharmaceutical industry into rare diseases and orphan drugs has also been extended to peptides, and peptides are being further targeted at infectious diseases and inflammation.

Peptides serve highly specific functions in the body that are extremely difficult to mimic by small chemical compounds. Compared with small-molecule active pharmaceutical ingredients, 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. Furthermore, peptide therapeutics are typically associated with lower production complexity compared with protein-based biopharmaceuticals and small molecules.

That being said, recent evolution in the advancement of small molecule drug targeting has enabled the introduction of several new technologies that offer considerable promise. Among these are macrocyclic therapeutics, which represent a nexus between classic small molecules and peptides. The growth of these and similar technologies has resulted in a “blurring of the line” between peptide and small-molecule APIs, as more “peptide” drugs incorporate D-amino acids, non-natural amino acids, and are being made as cyclic compounds.

Though peptide and hybrid-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.

Peptides are large, polar, water-soluble biopolymers containing both hydrophilic and hydrophobic appendages in their structure. These properties make it difficult for peptides to be absorbed by the intestines. Peptides also degrade in the stomach and small intestines, given the digestive roles of these organs, so they may not even be available for absorption by the intestines. Simply said, our bodies recognize peptides as food when ingested.

Macrocyclic therapeutics and peptide-like molecules, due to their flexible composition, are resistant to breakdown by proteases in the digestive system. However, as with peptides, macrocyclic and peptide-like therapeutics suffer from poor permeability. As such, oral delivery of these therapeutics is generally not possible without an enabling formulation technology.

Given these barriers, most peptide and peptide-like drugs are administered parenterally, with approximately 75% given via injectable routes, such as subcutaneous, intravenous, and intramuscular administration. While the market for injectables 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, frequent injections, inconsistent blood drug concentrations, and low patient acceptability make parenteral administration of peptide-based drugs less desirable. As a result, pharmaceutical developers continue to explore alternate routes of delivery for peptide therapeutics that have the potential to maintain the drug’s potency, while enhancing the ease of administration, patient compliance, and market penetration.

Against this backdrop, the oral delivery of peptides has caught the imagination of drug developers far and wide. The majority of drugs on the market today are administered as a pill or capsule, and thus, represent the form most patients are accustomed to taking. Orally administered peptides offer vast potential but also present considerable development challenges.


Numerous technologies are currently in development that are designed to enable the oral delivery of peptides. Though each has its unique set of properties and capabilities, all must overcome key obstacles to successfully deliver peptides via the oral route. First, the oral formulation has to remain intact in the highly acidic environment of the stomach. Once through the stomach, the dosage form 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 that facilitate the absorption of the peptide across the relatively impermeable intestinal epithelium. This factor is also critical for peptide-derived therapeutics, which may be protease resistant but are poorly permeable.

However, before any technology is applied to confront these challenges, developers must first target therapeutic peptides that are appropriate for oral delivery. Practical considerations, such as whether the orally delivered drug will enhance patient compliance, increase treatment options, and boost marketability, should have priority since, without clear medical and business advantages, there is little motivation to transition from an injectable.

Yet, even if these boxes are checked, oral delivery may not be an option unless one can achieve therapeutically relevant bioavailability. Numerous factors impact bioavailability, some of which technology can mitigate.

Illustrative of the challenges and potential of orally delivered, peptide-derived therapeutics are the ongoing development of an oral leuprolide tablet for the treatment of various endocrine disorders and the clinical development of an oral formulation of difelikefalin, a peripherally acting kappa opioid receptor agonist (KORA). Both oral formulations were engineered utilizing a technology platform, Peptelligence®, developed by Enteris BioPharma, a biotechnology company that specializes in the oral delivery of peptide and small molecule therapeutics.

Leuprolide, marketed under the brand name LUPRON DEPOT® (leuprolide acetate for depot suspension), has demonstrated in the clinic and practice to be an efficacious treatment for certain endocrine diseases. However, the drug’s parenteral route of administration limits its utilization due to the irreversibility of the depot injection, which stays in the body for 30 to 90 days, and the pain and inconvenience of the injections. 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.

Difelikefalin (KORSUVATM), is under development by Cara Therapeutics and is the subject of several clinical studies in a number of indications. Initially, Cara Therapeutics advanced difelikefalin as an intravenous agent for the treatment of postoperative pain. The company is also developing IV difelikefalin for chronic kidney disease-associated pruritus (CKD-aP), which recently completed a Phase 3 clinical trial.

In order to advance a non-parenteral formulation of difelikefalin, Cara has partnered with Enteris to develop an oral formulation of the drug (Oral KORSUVATM). Cara initially developed oral difelikefalin for the treatment of CKD-aP. In December 2019, Cara reported that a Phase 2 clinical trial of oral difelikefalin for the treatment of CKD-aP produced positive top-line results. In addition to CKD-aP, Cara has initiated additional oral difelikefalin programs targeting chronic liver disease-associated pruritus (CLDaP) and atopic dermatitis-associated pruritus (AD-aP). Each oral difelikefalin program is currently the subject of individual Phase 2 clinical trials, as reported by Cara.

In developing oral peptides, Enteris BioPharma utilizes its Peptelligence platform to provide protection against the harshness of the digestive system and then promote absorption of each API into the bloodstream. First, to overcome the stomach’s highly acidic environment, the oral tablets were encapsulated in an enteric coating (Figure 1). Simple in concept, an enteric coating is a polymer barrier applied to an oral medication that prevents its dissolution in the gastric environment.

figure one

Enteric coatings work by presenting a surface that is stable at the highly acidic pH found in the stomach, yet dissolves at the higher pH of the small intestine and at locations within the intestinal tract to enable optimal drug absorption. A variety of materials can be utilized as an enteric coating, provided the material shields the peptide drug in the stomach and enables its release in the intestine where absorption into the bloodstream can occur.

Protecting against the acidic gastric environment and enabling dissolution in the small intestine is but the first hurdle that must be addressed. The next, limiting proteolytic degradation in the jejunum, is a considerably more difficult (and critical) proposition as peptides, including leuprolide, are highly vulnerable in the soluble form to peptidases in the lumen prior to reaching the systemic circulation. As noted previously, non-natural peptides are generally tolerant of breakdown by proteases in the digestive system; however, the ability to significantly limit this effect is important to ensuring optimal bioavailability.

Though it is difficult to completely inhibit the actions of luminal proteases, scientists at Enteris BioPharma utilized protease inhibitors to create a protective microenvironment for its oral leuprolide tablet. Without such protective measures, the protease enzymes would immediately act upon the leuprolide, breaking it down for ingestion into the bloodstream; no different than protein consumed as food.

Despite the clear need for protease inhibitors in the oral delivery of a peptide, caution must be heeded when selecting a protease inhibitor, as many are not considered safe for use as excipients and inhibition of such a ubiquitous biological function can be risky. Developers, therefore, are encouraged to utilize technologies that limit the effects of such inhibitors to the GI lumen locally, and transiently, to avoid systemic toxicity.

Though shielding against the digestive system is paramount to administering a peptide orally, success in developing an efficacious oral peptide (one that elicits the desired therapeutic response comparable to or exceeding the standard of care) ultimately hinges on whether the API is absorbed through the intestine and enters the bloodstream as an intact chemical species. This may be the most challenging barrier to oral peptide delivery.

As peptides reach the intestinal epithelium, they first encounter an exogenous mucus gel layer containing proteases and antibodies, which together reduce the rate of diffusion to the epithelial surface. Attempts to overcome mucoadhesion have focused on incorporation of mucolytics or use of hydrophilic PEGylated nanoparticles, which avoid entrapment in mucus glycoprotein meshes. An alternative approach is to exploit mucoadhesion to increase the residence time of the dosage form in the small intestine.

However, greater success has been achieved via the use of permeability enhancers. Often, these are surfactants or emulsifying agents, such as acyl carnitines, sucrose esters, or anionic surfactants. Such permeability enhancers function by enabling the transport of peptide molecules through the epithelium via passive movement across the epithelial tight junctions (Figure 2).

figure 2

In developing oral peptides, Enteris’ Peptelligence platform utilizes a combination of enhancers. The first, citric acid, is more commonly recognized as a protease inhibitor because of its ability to modulate pH levels. However, citric acid also functions as a potent permeation enhancer by making the mucus layer less viscous, thus removing a diffusion layer to permeation. Additionally, citric acid makes the tight junctions more porous through multiple pathways, enhancing paracellular transport.

In combination with citric acid, Enteris employs surfactants, such as lauroyl-L-carnitine, as enhancers, which work by increasing the number of loose tight junctions. Citric acid makes these loose tight junctions even more porous. Thus, the two excipients work together.


Even after overcoming these obstacles, the successful development of an oral peptide must accept that the bioavailability of an orally delivered peptide will be less than that of a comparable dose of a parenterally delivered peptide. Even the best oral peptide formats are known to have relatively low bioavailabilities of ≤10%. As such, higher doses are required to obtain the same therapeutic effect in an oral formulation.

Given such differentials, developers must carefully consider the practicality of transitioning a peptide to an oral form based on the cost per goods. Simply put, the cost of the additional API (and production) must be less than the expected market expansion for an oral formulation.

While this may seem discouraging 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.

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 drive interest across the entire prescription drug spectrum for safe and effective orally administered peptide therapeutics.

dr john s vrettos

Dr. John S. Vrettos is the Senior Principal Scientist and Head of Formulation Development at Enteris BioPharma, a privately held, New Jersey-based biotechnology company offering innovative formulation solutions built around its proprietary drug delivery technologies. Dr. Vrettos earned his BA in Chemistry from Haverford College, his PhD in Biophysical Chemistry from Yale University, and was a National Academy of Sciences/National Research Council Postdoctoral Fellow at NIST. He has more than 17 years of experience in protein, peptide, and small molecule drug formulation and delivery.