Navigating FDA Guidance with Abzena’s Expertise
Peptide-based therapeutics have emerged as a major focus in pharmaceutical development, driven by their success in treating metabolic disorders, diabetes, and obesity. Structurally similar to naturally occurring neurotransmitters, growth factors, or ion channel ligands, these drugs offer high specificity and potency, making them ideal candidates for targeting complex physiological pathways.
One of the most prominent examples is Ozempic (semaglutide), a GLP-1 receptor agonist that has gained global attention for its dual use in treating type 2 diabetes and promoting weight loss. As interest in peptide-based therapeutics soars, so too does the urgency to develop safe, effective, and regulatory-ready alternatives. As Ozempic is expected to come off patent in the next few years, with key patents expiring in 2032 in the US and as early as 2026 in Canada and parts of Asia, this opens the door for manufacturers to develop generic versions of this revolutionary drug.
However, gaining regulatory approval for peptide generics isn’t as simple as copying the sequence. Today, immunogenicity testing is a critical component of the development and approval pathway, especially for manufacturers hoping to avoid full-scale clinical trials. That’s where Abzena comes in.
What is Immunogenicity and Why Does it Matter?
Immunogenicity refers to a drug’s ability to provoke an immune response, including the production of anti-drug antibodies (ADAs). While peptide drugs often resemble endogenous proteins and are assumed to be low-risk, small changes introduced during synthesis, degradation or formulation can significantly impact their immune profile.
Understanding and mitigating these risks requires assessment of both major arms of the immune system:
- Adaptive Immunity: the adaptive immune response is precise and memory-driven. In the context of peptide drugs, this response involves the activation of CD4+ T cells, which can lead to the activation of B cells and the formation of antibodies against the drug. These antibodies may:
- Reduce drug efficacy
- Alter pharmacokinetics
- In rare cases, trigger autoimmune-like responses
Adaptive immunity often becomes more significant over longer treatment durations which is exactly the case with long-term use weight loss drugs.
- Innate Immunity: the innate immune system acts as the first line of defence, rapidly responding to foreign signals through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Peptide or process-related impurities, including degradation products or deletions, can act as IIRMIs (innate immune response modulating impurities). These may lead to:
- Cytokine release (e.g., IL-6, TNF-α)
- Undesirable inflammatory responses
- A priming effect that increases adaptive immunogenicity
For regulators, assessing both innate and adaptive responses is essential for determining whether a generic peptide drug is truly safe for use in patients without triggering unwanted immune responses.
FDA Guidance: What Developers Need to Know
In May 2021, the FDA released a guidance document, “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin.” This document lays out the scientific and regulatory expectations for submitting an Abbreviated New Drug Application (ANDA) for synthetic peptide drugs. The guidance currently applies to five reference products: glucagon, liraglutide, nesiritide, teriparatide, and teduglutide.
Key requirements include:
- Demonstrate sameness of the active ingredient through physicochemical and functional characterization
- Match or improve impurity profiles relative to the reference listed drug (RLD)
- Ensure no new peptide-related impurity exceeds 0.5%
- Provide justification and data that any new impurity does not impact immunogenicity, including:
- Lack of T-cell epitopes
- No increased aggregation
- No enhanced innate immune stimulation
- Characterize each new impurity and provide data confirming it does not alter the drug’s physicochemical properties, biological activity, or immunogenicity profile
This means that non-clinical immunogenicity data, particularly from well-established in vitro assays, are essential to support approval under the ANDA regulations.
Abzena’s Immunogenicity Assessment Platform
At Abzena, we specialize in helping drug developers navigate these regulatory expectations with a comprehensive suite of fit-for-purpose immunogenicity assays. Our platform is designed to evaluate both innate and adaptive immune responses and is built with FDA guidance front of mind.
Innate Immune Assessment
To evaluate innate immune activation, we employ cytokine release assays using human whole blood, preserving the physiological context of the immune response. These assays are conducted on multiple product batches, including both start-of-life and end-of-shelf-life samples, to capture potential immune variation over time.
Using a high-sensitivity multiplexed Luminex platform, we’re able to measure the activation of a broad panel of toll-like receptors (TLR) by measuring signature cytokine and chemokine release, ensuring a deep understanding of early immune triggers.
Every run includes a suite of positive and negative suitability controls, helping to differentiate between genuine immune stimulation and background noise and delivering high-confidence results aligned with regulatory expectations.
Adaptive Immune Assessment
To assess the adaptive immune response, Abzena offers the EpiScreen™ 2.0 platform, a sophisticated T-cell proliferation assay designed to detect antigen-specific responses with precision. This assay measures antigen-specific CD4+ T cell activation using EdU incorporation at multiple timepoints, allowing us to monitor proliferation in a time course setting.
Because adaptive immunity relies on highly specific cellular recognition, we use flow cytometry to distinguish between naïve and memory T cell populations, ensuring detailed immune profiling. The assay is performed using high-quality leukopak-derived Peripheral Blood Mononuclear Cells (PBMCs) that provide a consistent and genetically diverse pool of donors, each containing physiological levels of immune cell subsets, necessary for reproducible results.
EpiScreen™ 2.0 also incorporates a range of titrated peptide controls selected for their similarity in length and immune relevance to ensure assay sensitivity and specificity. The system is developed in accordance with FDA expectations for cell viability, reproducibility, and sensitivity, making it ideal for submissions under the 2021 peptide drug guidance.
Together, these complementary assays provide a comprehensive picture of immunogenicity risk, enabling developers to identify potential concerns early, refine your formulation or manufacturing strategy, and build a robust data package.
Why Partner with Abzena?
Immunogenicity testing is a regulatory necessity, especially for companies developing peptide drugs.
Abzena offers:
- Extensive experience supporting immunogenicity risk assessment and addressing FDA requests
- Assays developed with reference to FDA guidance
- Capability to test multiple batches and donors under rigorous conditions
- Strategic input on impurity assessment and assay design
Our experts will work with you at every stage to ensure your peptide program meets regulatory expectations and moves forward with confidence.
Ready to Bring Your Peptide Drug to Market?
As peptide drugs like semaglutide begin to approach patent expiry, the opportunity to bring high-quality generic alternatives to market is rapidly emerging. Regulatory expectations are clearly defined, and Abzena offers the tools, scientific insight, and experience to accelerate your program with rigor, safety, and confidence.
To partner with us on your next peptide development program or to learn more about how Abzena’s immunogenicity platform can accelerate your path to market, get in touch with our team today.
