The development and application of bioanalytical testing methods for large molecule drugs can be complex, especially when you consider our industry’s constantly evolving regulatory compliance standards. Challenges in meeting accuracy, sensitivity, and timeline needs often add another level of complication. At BioAgilytix we work to overcome these complexities and challenges every day. I recently had the opportunity to lead a team working on a particularly difficult clinical phase anti-drug antibody (ADA) assessment for an innovative therapy designed to treat a serious chronic condition. The new therapy uses PEGylated molecules to extend its half-life to minimize dosing frequency. Maintaining systemic levels of the therapeutic for this type of therapeutic over the chronic use is expected to afford the best clinical benefit, as such a suspension of treatment to minimize drug interference was considered not in the best interest of the clinical subjects. A multitude of factors, related to specifics of the therapeutic and the needs of the clinical project team, prompted the need for a well-considered ADA assessment.
The Challenges and Benefits of Using PEGylated Molecules
To understand why the assessment of ADAs was so vital for this drug, it is important to understand PEGs and PEGylation. PEGylation describes the process of modifying a biological molecule using polyethylene glycol (PEG), a non-toxic polymer. The physical and chemical changes that occur through PEGylation result in a change in the pharmacokinetic behavior of the drug by extending the half-life of the therapeutic. Additionally in many cases, it can improve drug solubility, increasing drug stability. While PEGylation typically impacts therapeutics positively, a significant portion of the general population has pre-existing anti-PEG antibodies, possibly due to environmental exposure during their lifetime. Most often these antibodies are clinically benign, but there have been incidences where they play a role in affecting severe adverse reactions after the administration of the drug and may impact the efficacy of the treatment. As such, regulatory agencies are now requiring the monitoring of anti-PEG prevalence and attenuation when a patient is exposed to PEGylated therapeutics as a part of clinical development.
Assessing Immunogenicity Using a Unique Approach
Because of increased regulatory scrutiny, my team needed to evaluate the immunogenicity of the new PEGylated therapeutic with an approach that would ultimately maximize drug tolerance while maintaining excellent of sensitivity. Projects like this call for a novel approach because the tried and true methods that suffice for the vast majority of ADA assessments do not achieve the level of sensitivity and drug tolerance this particular PEGylated drug required.
To arrive at an innovative way to tackle this assessment, we combined our collective knowledge of antibody enrichment and the limitations of traditional immunoassay platforms with our extensive capabilities in working with statistics for dealing with pre-existing antibodies to set appropriate cut points. It also proved instrumental that we, as a team, have considerable experience with varied therapeutics and PEG configurations, ranging from short chain 5K to long chain branching PEGs. Ultimately, we were able to establish a meaningful approach and bring it from proof of concept to a regulatory compliant and defendable approach for the client. In fact, the method is proving out and providing important safety information that, coupled with efficacy data, is helping to further the project’s clinical development phase.
The Impact of PEGylated Drugs
By working through this challenge, we were able to be a part of developing a drug that is meeting an unmet need in the medical community. PEGylated drugs have already found a great deal of success treating chronic diseases like leukemia, rheumatoid arthritis, and Crohn’s disease, and will undoubtedly prove useful for the treatment of many previously difficult-to-treat conditions.
As an innovative bioanalytical CRO, BioAgilytix is here to partner with you in your efforts to bring impactful novel drugs to market. We have extensive experience dealing with evolving regulatory requirements and coming up with new ways to approach large molecule challenges. Speak to one of our scientists today to find out how we can support your ADA and immunogenicity projects.