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FDA's Peptide Regulatory Guidelines

Jul 30, 2024

4 min read


Written by Johnathon Anderson, Ph.D., a research scientist specializing in regenerative medicine and serving as an Associate Professor at the University of California Davis School of Medicine


What are the FDA's Peptide Regulations?

The FDA's peptide regulations provide recommendations to support the pharmaceutical industry in the development of peptide drug products. Upon finalization, the FDA's peptide guidance will articulate the FDA’s current stance on critical clinical pharmacology considerations such as hepatic impairment, drug-drug interactions (DDIs), QT prolongation risk, and immunogenicity risk, with a focus on their effects on the peptide drug product’s pharmacokinetics (PK), safety, and efficacy.


FDA peptide regulations

What Are Common Peptide Sources and Drug Development Challenges?

Peptides are most commonly produced solid-phase synthesis for smaller peptides, or produced via recombinant expression for larger peptides and proteins.


As signaling molecules, peptides influence a diverse range of physiological functions. Recent advances in drug development have aimed at enhancing the absorption, distribution, metabolism, and excretion (ADME) properties of peptides. Some of these strategies include:


peptide ADME

Structural modifications are sometimes used to optimize ADME properties of peptide therapies. Examples of such modifications are:

  1. Cyclization

  2. Pseudo-peptide bond formation

  3. Incorporation of unnatural amino acids

  4. Conjugations (e.g., PEGylation)


Additionally, formulation innovations like liposomes are sometimes applied to improve therapeutic efficacy and pharmacokinetics.


FDA’s Peptide Regulatory Framework

Peptide drugs exhibit characteristics of both small and large molecules, which require a tailored regulatory strategy from the FDA for their safe development. The FDA’s guidance does not focus on any specific peptide drug product but encourages industry sponsors to consult the appropriate FDA review division for questions about regulatory requirements.

 

FDA peptide regulations

FDA Peptide Guidance Interpretation

FDA’s guidances, unless cited as regulatory mandates, should be treated as recommendations rather than enforceable requirements. When the FDA uses terminology like “should”, this signifies a suggestion on their part rather than a mandate. In contrast, the FDA’s statutory or regulatory requirements explicitly state mandatory compliance.

 

Clinical Pharmacology Considerations for Peptide Therapies

Developing peptide drug products requires a hybrid approach, which incorporates aspects of both small-molecule and biologic drug development programs due to their dual characteristics. Below is an outline of the critical clinical pharmacology considerations for peptide drug products, including immunogenicity, hepatic impairment, drug-drug interactions, and QT interval prolongation.

 

peptide pharamcology

Immunogenicity Risk and Clinical Impact Assessments

1. Immunogenicity Risk Assessment

Peptide drug products can potentially possess immunogenicity risks, which require detailed assessments to ensure their safety and efficacy. These immunogenicity evaluations should investigate:

·        Product-specific factors: Molecular size, structure, and purity.

·        Process-specific factors: Host cell proteins and impurities.

·        Subject-specific factors: Disease state and genetic predisposition.

·        Study-specific factors: Dosing regimen and administration route.

It should be noted that immunogenicity concerns primarily arise from impurities or aggregates for peptides under eight amino acids. Sponsors are advised to conduct early discussions with the FDA to align immunogenicity evaluations with development objectives.

 

peptide immunogenicity

2. Clinical Immunogenicity Assessment

For immunogenicity assessments, a tiered approach is recommended by the FDA.

·        Develop assays for anti-drug antibody (ADA) detection, including specificity for endogenous counterparts if sequence homology exists.

·        Evaluate ADA titers, neutralizing activity, and their effects on pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety.

·        Investigate both within-subject and between-subject comparisons to analyze immunogenicity impacts in a comprehensive manner.


3. Clinical Impact Analysis of Immunogenicity

Assessments of the clinical effects of ADAs should focus on a couple of different variables.

·        PK and PD: Variations before and after ADA emergence.

·        Correlation of ADA titers and their neutralizing activity within therapeutic outcomes.


Hepatic Impairment

Peptide Metabolism in Hepatic Impairment

Peptides are primarily degraded by ubiquitous proteases. This results in minimizing liver’s metabolic role in clearance. However, specific peptide characteristics may result in hepatic impairment.

·        Substantial hepatic metabolism (>20%): Increased plasma exposure risks.

·        Structural modifications: Cyclic peptides (e.g., cyclosporine) susceptible to liver enzyme metabolism.

·        Biliary excretion (>20%): Elimination changes impacting plasma levels.

·        Lipid conjugation: Albumin-binding peptides (e.g., acylated peptides) sensitive to serum albumin levels in hepatic diseases.

·        For peptides targeting liver-associated diseases or exhibiting target-mediated drug disposition, pharmacodynamic assessments should accompany PK studies.

 

Drug Interaction Assessments

1. Pharmacokinetics of Drug Interactions

Peptide drug products are generally not CYP enzyme substrates, as they are typically metabolized by proteolytic enzymes.


Peptide therapies are not actively biodistributed via transport transport proteins. Therefore, peptides are typically unaffected by drug-drug interactions associated with inhibitors or inducers of major transporters.


However, the major exceptions to this are structurally modified peptides such cyclic peptides, which often undergo CYP metabolism or transporter-mediated interactions. Peptides should be assessed in vitro to determine if that have >20% hepatic or biliary elimination, or >25% renal active secretion.

 

2. Pharmacodynamics of Drug Interactions

Peptide therapies can potentially exhibit pharmacodynamic interactions, such as additive effects with concomitant drugs (e.g, vasopressin with catecholamines). Industry sponsors should evaluate these effects, particularly for peptides with mechanisms affecting gastric emptying kinetics or systemic hemodynamics.

 

QT Interval Prolongation

Most naturally occurring peptides pose minimal risks for direct ion channel interactions. However, QT studies may be warranted if mechanistic or clinical data indicate that a given peptide therapy possesses proarrhythmic potential.


Sponsors should propose a QTc risk assessment plan that aligns with the FDA’s recommendations, referencing guidances such as E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential. The timing and scope of this depend on the peptide drug’s risk/benefit profile and overall therapeutic context.

Jul 30, 2024

4 min read

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