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Why Aren’t More Oligonucleotide Drugs Getting to Market?
Interest in oligonucleotide-based therapeutics has steadily increased over the last decade, particularly following the successful use of the Pfizer mRNA vaccine to protect populations from SARS-CoV-2. Our market research has identified 430 active oligonucleotide research programs spanning six therapeutic areas, with 448 drugs in development focusing on three major modalities: antisense oligonucleotides (ASOs), messenger ribonucleic acids (mRNAs), and short-interfering ribonucleic acids (siRNAs). However, the vast majority of these products remain in purgatorial preclinical and clinical development phases.
Despite the growing body of evidence supporting the efficacy of oligonucleotide therapeutics, drug developers encounter challenges bringing their products to market due to bioanalytical testing bottlenecks. Few biotech companies possess the capabilities, budget, or regulatory experience to handle these assays in-house.
So, Why Not Outsource?
Many small companies hesitate to outsource because they fear losing control over essential analytical testing processes. Experiences with oversubscribed large contract research organizations (CROs) including long wait times and opaque services may have been discouraging as well.
We propose finding CRO partners that will provide open communication and flexible approaches, because developing bioanalytical methods for oligonucleotides requires iterative R&D experimentation, data analysis, and optimization.
It is essential to have reliable quantification methods with sensitivity and selectivity, particularly during toxicokinetic (TK) and pharmacokinetic (PK) studies. These methods provide critical information about the absorption, distribution, metabolism, and excretion patterns in vivo as well as the safety and efficacy of the product.
Challenges in Bioanalytical Method Development
1. Analytical Sensitivity: Oligonucleotides often exhibit low concentrations in biological matrices, necessitating high analytical sensitivity to detect and quantify them accurately. The challenge lies in developing sensitive methods that can reliably measure oligonucleotide concentrations even at these low levels, minimizing the risk of false negatives or incomplete data.
2. Selectivity and Specificity: Differentiating the therapeutic oligonucleotide from endogenous oligonucleotides and other interfering substances is critical for reliable PK and TK analysis. Achieving selectivity and specificity is a complex task, especially considering the potential for off-target binding and interference from similar biomolecules or metabolites.
3. Sample Preparation and Stability: Due to their susceptibility to degradation by nucleases and other factors, oligonucleotides require careful sample preparation and handling to maintain their integrity during PK and TK studies. Ensuring stability throughout the analysis process is crucial for obtaining accurate and reliable data.
Achieving High Sensitivity and Selectivity Is Crucial for Bioanalytical Success
Take our high-resolution mass spectrometry (HRMS) method for Inclisiran, a double stranded siRNA product, for instance. In particular, our implementation of ion-pairing reagents during the mobile phase improved ionization and chromatographic separation significantly. This demonstrated the method’s ability to overcome matrix effects and solidified its suitability for absolute qualification and comprehensive profiling.
Consistent sensitivity for chromatographic readings at each extracted sample from matrix with injection volume of 5 µL, indicated that the method was highly reproducible and sensitive, achieving a lower limit of quantification (LLOQ) of 50 ng/ml. This LLOQ was within expected parameters and is highly suggestive of selectivity with minimal risk of off-target binding in vivo.
Transparent CRO Partnership Provides Detail Necessary for Regulatory Success
Direct communication of results enabled our clients to go further with their analyses, obtaining quantitative data on sense and antisense strands that would not have been possible without an agile and flexible approach. Likewise, because our lab team is directly in client meetings, speaking scientist to scientist, we are able to clearly understand our clients’ concerns regarding finite sample volume and develop methods that required minimal injection volumes.
Drug development is evolving, and our client base is expanding as companies recognize the importance of transparent communication and flexibility among collaborators to overcome research bottlenecks, particularly in the dynamic biologics market. With 300+ validated methods, 11 successful regulatory audits, and 168 active global customers, our core focus on quality, speed, and flexibility is proving successful.
Learn more www.sannova.net.
For more information contact: Charlie Zogzas, PhD, SVP of Business Development, [email protected].
