By Erika L. Roberts, ELR Lab Services
The FDA has announced a new draft guidance for industry titled Clinical Pharmacology Considerations for Peptide Drug Products. This guidance describes FDA’s recommendations regarding clinical pharmacology considerations for peptide drug product development programs, including hepatic impairment, drug–drug interactions (DDIs), assessing QTc prolongation risk, and immunogenicity risk and impact on the pharmacokinetics (PK), safety, and efficacy assessment. The intent of this draft guidance, when finalized, is to assist industry in the conduct of these development programs. The draft guidance follows the publication last year of a set of concept papers from the European Medicines Agency (EMA) proposing quality guidelines for manufacturing synthetic peptides and oligonucleotides.
FDA considers any polymer composed of 40 or fewer amino acids to be a peptide. Peptides can occur naturally in the body or can be produced in a laboratory through chemical synthesis or recombinant DNA technology using other living systems (e.g., bacteria). A total of eight peptides, two oligonucleotides, and two ADCs containing peptides out of 50 drugs were approved by the FDA during 2021 (which are the most recent statistics available on the FDA’s website). Approval status is still pending on some of those. The continuous approval of peptides reflects the importance of this class of drugs, which offer high specificity, efficacy, and tolerable safety profiles. Peptide drugs have two major drawbacks: their in vivo instability and membrane impermeability. Proteolytic degradation of peptide drugs in serum limits the drug's half-life and reduces the bioavailable concentration.
Most peptide drug products have the potential for immunogenicity. The process for assessing the immunogenicity risk for peptide drug products is like that for therapeutic proteins. Factors such as molecular size and structure, host cell proteins, dosing regimen, and disease state should be taken into consideration when formulating the immunogenicity assessment. Currently, there is a draft guidance already in place titled Immunogenicity Assessment for Therapeutic Protein Products (August 2014). In general, peptide drug products of less than eight amino acids are not expected to be immunogenic unless there is a risk due to impurities or aggregates.
A multitiered clinical immunogenicity assessment of a peptide drug product should be informed by the immunogenicity risk assessment and conducted in a manner consistent with the scientific principles described in the FDA’s guidance mentioned directly above (Immunogenicity Assessment for Therapeutic Protein Products) and Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody Detection (January 2019).
For a peptide drug product with multiple domains, it might be appropriate to develop multiple assays to assess immunogenicity. For a peptide product with sequence homology to an endogenous protein or peptide counterpart, it might also be appropriate to develop an assay to measure cross-reactivity of ADAs between the peptide drug product and endogenous counterpart.
Peptides are generally metabolized and degraded by endopeptidases. Due to the ubiquitous availability of proteases and peptidases throughout the body, proteolytic degradation of many peptides is rapid and not limited to organs typically associated with drug elimination, such as the liver. Therefore, hepatic metabolism rarely plays a significant role in the clearance of peptides. However, emerging evidence suggests that under certain circumstances it might be important to characterize the impact of hepatic impairment on the PK of some peptide drug products. Below are some characteristics that could result in a recommendation for a hepatic impairment assessment, such as conducting a dedicated hepatic impairment study:
- Peptide drug products that are found to be substantially metabolized by liver enzymes (>20 percent of the systemically available drug) based on nonclinical models could have increased plasma exposure due to hepatic impairment.
- Peptide drug products that result from certain modifications, such as cyclic peptides, could render them susceptible to substantial metabolism by liver enzymes.
- Peptide drug products that are substantially eliminated through biliary excretion, as determined by basic pharmacology and nonclinical ADME studies, could have increased plasma exposure due to hepatic impairment, even if hepatic metabolism is not significant.
- Peptide drug products that are conjugated with a lipid group (e.g., fatty acids or cholesterol) can be highly bound to serum albumin and lipids, and their elimination rate could be affected by the levels of serum albumin and lipids.
- Peptide drug products that are being developed for an indication with the liver as a target organ or in cases when the peptide drug product can be characterized as targeting the liver could be affected by hepatic impairment; therefore, whenever appropriate and feasible, pharmacodynamic assessments should be included.
- Peptide drug products that are subject to target-mediated drug disposition may have altered PK in patients with hepatic impairment as a result of changes in target expression.
Assessing Drug Interactions
In general, peptide drug products are primarily metabolized by proteolytic or hydrolytic enzymes such as endopeptidases, aminopeptidases, and carboxypeptidases, or are chemically modified to resist degradation and are not metabolized by cytochrome P450 (CYP) enzymes. Therefore, the disposition of peptide drug products is not anticipated to be affected by inhibitors or inducers of CYP enzymes. In general, peptide drug products are not expected to significantly modulate CYP enzymes and 218 drug transporters. However, there are structural modifications to peptide drug products that could lead to modulation of CYP enzymes and drug transporters. In addition, there are cases where peptides indirectly affect CYP enzymes or transporters. Peptide drug products can exhibit pharmacodynamic interactions with a concomitant drug when the pharmacological effect of one drug is altered by that of another drug. Peptides composed of only naturally occurring amino acids have a low likelihood of direct ion channel interactions, and a thorough QT study is generally not scientifically warranted, unless the potential for proarrhythmic risk is suggested by mechanistic considerations or data from clinical or nonclinical studies.
Given the potential for immunogenicity generally associated with peptide drug product administration, the labeling for such products should include immunogenicity information, consistent with the principles proposed in FDA’s draft guidance Immunogenicity Information in Human Prescription Therapeutic Protein and Select Drug Product Labeling — Content and Format (February 2022). In general, the labeling for peptide drug products that are less than eight amino acids that are without concerns for impurities and/or aggregates does not need to include immunogenicity information because an immunogenicity assessment would likely not be relevant to the assessment of a drug’s safety and effectiveness.
The FDA is accepting comments on the guidance until December 11, 2023, at https://www.regulations.gov/docket/FDA-2023-D-3391.
About The Author:
Erika L. Roberts, MFS, is principal consultant and owner of ELR Lab Services LLC. Having more than 15 years of experience working in many different areas of the pharmaceutical/biotech manufacturing quality environments, she has particular expertise in sterility testing, microbial identification training, HPLC analysis, cGMP training, analytical chemistry, and pharmaceutical regulations. Roberts obtained a master’s in forensic science in 2006 with an emphasis in document examination.