Peptides in practice: what it takes to advance these therapies to clinic

Peptide therapeutics are rapidly emerging as a transformative class of medicines, bridging the molecular divide between small molecules and biologics. These short chains of amino acids exhibit high specificity, potent bioactivity and broad versatility – characteristics that are increasingly valuable in addressing complex diseases. Peptides have found utility across oncology, metabolic disorders and infectious diseases, offering new opportunities where traditional modalities fall short.

However, the expanding potential of peptide-based therapeutics highlights distinct challenges for their development. Advances in stability, delivery and safety assessment are reshaping capabilities, while evolving frameworks for nonclinical studies and development programmes provide a clearer roadmap for success.

Therapeutic value and clinical progress

Peptides can be categorised into several classes, including natural peptides (that occur naturally in the body), synthetic peptides (made synthetically in the lab), macrocyclic peptides (whose structure makes them behave differently than other peptides) and disulfide-rich versions (stabilising disulfide chemical bonds). These molecules can be especially useful in treating complex diseases due to their ability to mimic endogenous ligands – the body’s own signalling chemicals – and connect with a wide range of targets, especially G protein-coupled receptors (GPCRs), which help control many bodily functions.

Between 2004 and 2017, 46 peptide‑based drugs received regulatory approval, underscoring significant clinical momentum.

Between 2004 and 2017, 46 peptide‑based drugs received regulatory approval, underscoring significant clinical momentum. More recently, the peptide landscape has continued to expand. By mid‑2024, over 110 peptide‑based therapeutics had been approved worldwide, including noteworthy high-profile GLP-1 receptor agonists such as semaglutide and tirzepatide.¹ Their high target specificity and often favourable safety profiles combine with structural flexibility, enabling a broad range of chemical modifications that further reinforce peptides’ potential for treating a wide variety of complex diseases.

Challenges in development: stability, delivery and immunogenicity

Despite their promise, peptide therapeutics pose distinct challenges in the development process, especially concerning stability, delivery and immunogenicity.

Peptides are inherently susceptible to enzymatic degradation within the body, making them difficult to deliver orally and limiting their duration of activity in the bloodstream. While these issues have made it challenging to develop and use peptide drugs effectively in the past,²advances in formulation science have established strategies to improve their pharmacokinetic properties. Attaching stabilising molecules (PEGylation), forming ring-shaped structures (cyclisation), adding fat-like groups (lipidation) and using advanced delivery systems have helped peptides last longer in the body and work more effectively.

In both laboratory and clinical settings, many peptide-based therapies have been shown to trigger the body’s immune system to produce anti-drug antibodies (ADAs).

Immunogenicity, however, continues to present a distinct challenge. In both laboratory and clinical settings, many peptide-based therapies have been shown to trigger the body’s immune system to produce anti-drug antibodies (ADAs). While this response is quite common, it rarely affects how the drug behaves in the body: more than 90 percent of clinical cases with ADA presence showed no meaningful impact on the drug’s pharmacokinetics (PK) or pharmacodynamics (PD).³ Predicting this immune response early on, however, is difficult. Factors like peptide chain length or the incorporation of non-proteinogenic amino acids don’t consistently indicate the likelihood of an immune reaction, which complicates the early risk assessments needed to develop safe and effective studies.

Toxicological considerations and nonclinical study design

A robust nonclinical safety assessment is pivotal to overcome these challenges and derisk peptide drug development. It is also critical that each element of the process is aligned with current International Council for Harmonisation (ICH) guidelines tailored to the unique features of peptide therapeutics, including M3(R2), S6(R1), S9 and S7 series documents.

Core safety studies

To ensure the safety of new peptide drugs before clinical applications, scientists must perform a robust programme of nonclinical studies. These tests reveal how drugs behave in the body and the potential risks they may pose. The core tests include:

• Repeated-dose toxicity studies – these show what happens when the drug is given repeatedly over time, helping to identify any harmful effects that build up
• Toxicokinetic studies – these measure how the drug is absorbed, distributed, broken down and cleared from the body
• Safety pharmacology studies – these examine how drugs affect critical systems like the central nervous, cardiovascular and respiratory systems
• Genetic toxicology studies – these check whether the drug might damage DNA and increase the risk of cancer.

Depending on the drug’s intended administration and target, additional studies may be needed. These can include tests for phototoxicity, local toxicity and reproductive toxicity. Designing and conducting the right combination of tests provides a more thorough understanding of the drug’s safety profile. A comprehensive approach helps protect future patients and supports regulatory approval.

In vivo species selection

Species selection for nonclinical in vivo studies is particularly important. Nonclinical study design should prioritise models with metabolic profiles and target engagement characteristics that closely resemble those of humans to ensure translational relevance and regulatory alignment. For example, the safety evaluation of semaglutide encompassed repeated-dose studies across multiple nonclinical models of varying durations, supplemented by comprehensive safety pharmacology and genotoxicity assessments.

Genotoxicity considerations

When evaluating the genetic safety of peptide drugs, it is important to consider the peptide’s cellular uptake and chemical composition. Peptides with cell-permeating properties or those with non-natural amino acids may warrant additional in vitro and in vivo genotoxicity testing. A step-by-step approach is the best course of action, starting with evaluating known moieties, pharmacological relevance and potential DNA interactions.

A final word

Peptides are positioned to play a central role in addressing diseases with high unmet need for treatment. However, their development demands nuanced approaches, including optimised nonclinical testing strategies to reflect their unique biochemical and pharmacological properties.

Incorporating the latest advancements in programme design with a nuanced understanding of peptide-specific challenges can unlock broader clinical potential across a wide range of therapeutic areas. Collaborating with a laboratory partner experienced in peptide characterisation and translational study design further enhances programme efficiency, mitigates risk and supports the rigorous standards required for successful development.

References:

1. Elsayed YY, Kühl T, Imhof D. (2025). Regulatory Guidelines for the Analysis of Therapeutic Peptides and Proteins. Journal of Peptide Science, 31(3), e70001. https://doi.org/10.1002/psc.70001
2. Baral KC, Choi KY. (2025). Barriers and Strategies for Oral Peptide and Protein Therapeutics Delivery: Update on Clinical Advances. Pharmaceutics, 17(4), 397. https://doi.org/10.3390/pharmaceutics17040397
3. Shankar, et al. (2014). Assessment and Reporting of the Clinical Immunogenicity of Therapeutic Proteins and Peptides—Harmonized Terminology and Tactical Recommendations. The AAPS Journal, 16(4), 658. https://doi.org/10.1208/s12248-014-9599-2