The Emerging Role of Oral Peptide Therapeutics in Dermatology

Peptide drugs are emerging as a new frontier across medicine and have recently found a space in dermatology. These therapeutic agents are composed of short chains of amino acids, typically fewer than 50, and bridge the gap between small molecule drugs and larger protein biologics.¹ Currently, over 60 peptide-based therapeutic treatments are FDA-approved, with over 500 still in development. One of the most well-known examples is semiglutide, marketed under brand names of Wegovy, Ozempic, and Rybelsus.²

Historically, however, peptide therapies have been limited by poor membrane permeability and limited oral bioavailability, making injection the primary route of administration.^3,4 This paradigm is now shifting with advances in oral peptide technology and the introduction of agents such as icotrokinra (Icotyde; Johnson & Johnson) into the dermatology space. Overall, oral peptide therapy represents a rapidly evolving frontier that dermatologists cannot afford to overlook.

Background: Peptides in Medicine

Peptide therapies may be derived from endogenous molecules, such as insulin or GLP-1 analogs, or designed synthetically to target specific biological pathways.3 Their applications span across systems, with roles in immune modulation, anti-inflammatory signaling, and cell growth regulation.

Immunomodulatory peptides can precisely alter immune responses by mimicking endogenous signaling molecules or directly interacting with immune cells, enhancing tumor-specific immunity or restoring immune tolerance in autoimmune diseases.^5,6 Anti-inflammatory peptides exert their effects through multiple mechanisms, including regulation of inflammatory mediator release, modulation of MAPK and NF-κB signaling pathways, and reduction of oxidative stress.⁷ These peptides also interfere with cytokine signaling pathways, further contributing to their role as immunomodulators.⁸

Cell growth-regulating peptides are among the most well-established therapies, functioning by binding to specific membrane receptors to stimulate or inhibit cell proliferation directly or through modulation of endocrine or paracrine growth factor secretion.⁹ Glucagon-like peptides (GLP-1 and GLP-2) further regulate cell proliferation and apoptosis in tissues throughout the body, including the pancreas and gastrointestinal tract.¹⁰ Together, these diverse mechanisms highlight the versatility of peptide therapies in modulating immune, inflammatory, and cellular processes, underscoring their growing potential as targeted therapeutics.

Limitations of Peptide Therapies

Traditional peptide therapies face several significant limitations, including poor oral bioavailability, rapid enzymatic degradation, short half-lives, and limited membrane permeability. Collectively, these challenges necessitate frequent parenteral administration, which can reduce patient adherence.¹⁶

Oral delivery is particularly challenging due to peptide denaturation in the low pH of the stomach, enzymatic degradation by gastrointestinal proteases, and limited transport across tight junctions, resulting in a bioavailability of less than 2%.16 These constraints have important clinical implications, often requiring frequent injections that may increase the risk of adverse effects.¹⁷

In addition, cost remains a substantial barrier to access, with disparities driven by factors such as insurance type, high out-of-pocket costs, and prior authorization requirements.¹⁸

Breakthrough of Oral Peptide Technology

A major breakthrough in peptide therapeutics has been the development of oral delivery systems for agents that previously required injections. Oral peptide delivery is primarily enabled by permeation enhancer technologies that help overcome the barriers of enzymatic degradation and poor intestinal permeability.

One of the most clinically successful approaches utilizes sodium-N[8-(2-hydroxybenzoyl)amino] caprylate (SNAC), which facilitates transcellular absorption through a unique mechanism involving membrane defect formation and local pH buffering.¹⁹ Despite these advances, oral bioavailability remains low, averaging around 1%, and it is compensated with high doses and strict administration conditions.²⁰

The landmark approval of oral semiglutide (Rybelsus; Novo Nordisk) in 2019 for type 2 diabetes marked a major breakthrough, followed by oral octreotide (Mycapssa; Chiesi) in 2020 for acromegaly.²¹ Success in endocrinology is now being translated into advances in dermatology.

Oral peptides may offer an advantage with improved patient compliance through convenience and non-invasive, daily pill administration, which is appealing to needle-averse patients. Additional advantages include avoidance of injection-site reactions, higher target specificity, and rapid metabolism, allowing predictable “on/off” effects.

However, oral peptide delivery remains challenging due to enzymatic degradation and poor absorption.¹⁶ Many agents require the strict fasting or “wake-and-take” administration, which may limit adherence.

Peptides in Dermatology

Dermatologists may also be familiar with commercially available oral peptide supplements and cosmetic peptides, including collagen peptides and bioactive peptide nutraceuticals marketed for skin, hair, and nail health. Unlike FDA-approved oral peptide therapeutics, these products are generally regulated as dietary supplements rather than medications and typically lack standardized efficacy and pharmacokinetic data.²² Most recently,icorokinra has emerged as the first oral peptide therapy approved for dermatologic use, specifically used for moderate to severe plaque psoriasis in patients 12 years and older.²³

This oral interleukin-23 receptor antagonist peptide selectively blocks IL-23 signaling, bridging the gap between targeted efficacy of injectable biologics and the convenience of oral administration. This represents a significant advancement in dermatology, where monoclonal antibody biologics like dupilumab (Dupixent; Sanofi/Regeneron Pharmaceuticals) and secukinumab (Cosentyx; Novartis) have transformed the treatment of conditions like atopic dermatitis, psoriasis, and hidradenitis suppurativa. While highly effective, these therapies require injections. Icotrokinra is administered once daily on an empty stomach, offering a potentially favorable alternative to injectable regimens.¹⁵

Education for Dermatologists

Although peptide-based therapeutics are not new to medicine, the recent emergence of orally bioavailable peptide agents has introduced a relatively novel therapeutic class within prescription dermatology. As oral peptide drugs continue to expand into inflammatory and immune-mediated skin disease treatment, dermatologists are likely to become increasingly familiar with this modality, both through prescription therapeutics and broader exposure to peptide-based products already common in dermatologic and aesthetic practice.

Practical considerations for peptide therapies in dermatology include appropriate patient selection, monitoring, and counseling to optimize patient adherence and outcomes. Clinicians should monitor for therapeutic efficacy and potential adverse effects while educating patients on administration requirements and expected timeline for response.

For icotrokinra specifically, special consideration is warranted for patients with renal impairment. Although no dose adjustment is required, close monitoring is recommended.¹⁵ Insurance coverage and access remain significant barriers, often requiring prior authorization and contributing to delays in care. Looking ahead, expansion of the oral peptide pipeline in dermatology is expected to broaden therapeutic options, with emerging indications and the potential for combination regimens to enhance efficacy.

Conclusion

While not new to medicine, oral peptide therapy is a newer class of drugs in the dermatology space. Advancements in oral peptide molecular biology, chemistry, and delivery technologies have allowed significant progress and application to a variety of conditions, including inflammatory skin diseases like psoriasis. For dermatologists, staying informed is essential–not only to critically evaluate emerging data, but also to responsibly integrate these innovations into daily practice.

Sarita Pattisam is a third-year osteopathic medical student at the Ohio University Heritage College of Osteopathic Medicine in Dublin, Ohio.

Shannon Trotter, DO, is a board-certified dermatologist and principal investigator at DOCS Dermatology Group in Columbus, Ohio, clinical instructor at the Ohio University Heritage College of Osteopathic Medicine, and the host of the Derm-it Trotter! Don’t Swear About Skincare podcast.

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