Insulin is the most high-profile peptide therapeutic in the world. First discovered in 1921 and used clinically the following year, the drug has improved the lives of millions of people suffering from diabetes.
More recently, the therapeutic potential of peptides has expanded considerably with over 110 peptide drugs approved worldwide, 46 of which gaining approval since 2004. Their versatility, high specificity, and potent bioactivity have prompted researchers to explore their use in addressing complex diseases. Among the most noteworthy is the development GLP-1 receptor agonists such as semaglutide and tirzepatide.
However, these short chains of amino acids can be tricky to develop, particularly in oncology, metabolic disorders, and infectious diseases, where they may be most effective. The following tips can help sponsors enjoy a smooth development journey for peptide-based therapeutics and ensure that new uses of this promising drug type can replicate insulin’s past century of success.
1. Address the Stability and Deliverability of Peptide Therapeutics
Peptides are susceptible to enzymatic degradation within the body. This makes it challenging to deliver them orally, limits their duration in the bloodstream, and increases the difficulty of developing effective peptide drugs.
Fortunately, advances in formulation science have brought fresh strategies to improve the pharmacokinetic properties of peptide-based therapeutics. Attaching stabilizing molecules (PEGylation), forming ring-shaped structures (cyclization), adding fat-like groups (lipidation), and using advanced delivery systems have all been used to help peptides remain in the body longer and work more effectively. However, even when stability and deliverability have been addressed, other issues stubbornly continue to present challenges.
2. Tackle Immunogenicity Issues of Peptide Therapeutic Development
In both laboratory and clinical settings, many peptide-based therapies have triggered the body’s immune response to produce anti-drug antibodies (ADAs). This has been shown to rarely affect the drug’s performance in the body: more than 90% of clinical cases with ADA presence show no meaningful impact on the drug’s pharmacokinetics (PK) or pharmacodynamics (PD), yet confirming this dynamic is a critical consideration for any new therapeutics of this type.
Predicting immune response early on in the development process – while vital – can be complex. Factors like peptide chain length or the incorporation of non-porteinogenic amino acids cannot consistently predict the likelihood of an immune reaction. This complicates early risk assessments, making focused attention on immunogenicity and its impact on PK and PD activity crucial for conducting safe and effective studies.
3. Nail the Core Safety Studies for Peptide Development
Robust nonclinical safety assessments are crucial to making peptide drug development less risky and more efficient. These tests are commonly conducted and theoretically easy, but must be conducted carefully and in compliance with regulatory guidelines.
These core safety studies include:
- Repeated-dose toxicity studies: establish what happens when a drug is administered repeatedly over time and identify harmful effects that build up.
- Toxicokinetics: measure absorption, distribution, metabolism, and excretion.
- Safety pharmacology: examines how drugs affect critical systems.
- Genetic toxicology: assess how the drug might damage DNA.
Additional tests may be required, depending on the drug’s intended administration and target, including phototoxicity, local toxicity, and reproductive toxicity assays. Taking a comprehensive approach to these basic safety studies ensures future patients are protected and costly regulatory delays are avoided.
4. Ensure in vivo Species Selection is Right
Species selection for nonclinical in vivo studies of peptide-based therapeutics is particularly crucial. Investing the energy and expertise into getting this choice right can help reduce the risk of failed studies and regulatory delays further down the line.
Ultimately, the correct species is not just the one that is least costly or most easily sourced, but that which provides the most meaningful translational insights. Study designs should prioritize models with metabolic profiles and target engagement characteristics as close to those of humans as possible. This ensures relevance of study findings for clinical populations and supports regulatory alignment.
5. Carefully Consider Genotoxicity
Evaluating the genetic safety of peptide drugs is a crucial step in their development, and it’s important to consider both the peptide’s cellular uptake and chemical composition. For those peptides with cell-permeating properties or non-natural amino acids, researchers may need to conduct additional in vitro and in vivo genotoxicity testing.
The best course of action is to take genotoxicity testing step by step, starting with evaluating known moieties, pharmacological relevance, and potential DNA interactions.
A Final Word
The peptide-based therapeutics of the future could soon rival insulin’s impact on the world, but their development requires nuance and patience. To ensure these drugs reach their full potential, researchers must optimize nonclinical strategies to reflect their unique biochemical and pharmacological properties. By incorporating the latest advancements in program designs and considering peptide-specific challenges, developers can unlock the broader clinical promise of peptide drugs across a wider range of therapeutic areas. Partnering with a lab partner experienced in peptide characterization and translational study design can ensure enhanced program efficiency, mitigate risk, and support the rigorous standards required for efficient and successful development.
