New modality drugs are innovative therapeutic approaches that attempt to leverage cutting-edge science to target diseases in novel ways, addressing unmet medical needs and offering potential cures for conditions previously considered untreatable.
Oliver Culley is a senior scientist at CN Bio where his work focuses on modeling metabolic-dysfunction-associated steatohepatitis in the PhysioMimix MPS system. With over 15 years of experience in academia and industry, Culley’s background is in cell and molecular biology with a focus on high-content imaging and in vitro assay design. Drug Discovery News spoke with Culley to discuss the ever-evolving challenges of developing new modality drugs and how technological innovations can aid their development.
What are new modality drugs and why are they important for advancing drug development and therapies?
Innovative therapeutic modalities are revolutionizing disease treatment, offering improvements over traditional approaches. These include a range of technologies such as antibodies, protein peptides, cell therapy, gene therapy, vaccines, and RNA therapeutics – paving the way for novel, safer, and more effective treatments for previously untreatable diseases.
While small molecules have been instrumental in significant medical advancements for decades, the growing focus on new therapeutic modalities stems from the need to address more complex disease mechanisms and tackle previously intractable conditions. These advanced therapies offer greater specificity and the potential for more effective treatments with fewer side effects, expanding the possibilities for disease intervention.
According to the 2024 New Drug Modalities Report (Boston Consulting Group), new modalities represent $168 billion in pharma/biotech projected pipeline value, up 14% from 2023. By 2029, their analysts project that 9 of the top 10 drugs will be new modalities.
What are the primary challenges when developing complex therapies?
The inherent complexity of new therapeutic modalities, designed to target intricate biological processes, presents significant challenges across the entire development process, from initial design and targeted delivery to manufacturing and safety evaluation. While safety is paramount for all pharmaceuticals, these advanced therapies often exhibit unique toxicology profiles and potential long-term effects that demand careful investigation and, in some cases, remain incompletely understood.
A major challenge for new modalities is their high specificity to humans, consequently requiring a more human-centric approach to development. Often, an appropriate nonhuman species is not pharmacologically viable for nonclinical testing, or the most relevant option is costly and ethically undesirable nonhuman primates. Therefore, more human-relevant new approach methodologies are required to overcome their development challenges and unlock their full potential.
Additional challenges relate to the delivery of emerging drug types like peptides, proteins, and large oligonucleotide molecules because they often have poor oral bioavailability due to their size, making oral administration challenging.
This requires innovative delivery systems to improve absorption and reach therapeutic levels in the body; researchers are actively developing methods to overcome this barrier to enable the oral delivery of these new drug modalities.
How can technological innovations support the development of safe and efficacious new modality drugs?
The pharmaceutical industry's primary goal is to develop safe and effective drugs. Recent decades have seen a general improvement in drug safety due to stricter regulations, more advanced testing methods, and a greater emphasis on safety throughout the drug development process.
Emerging technologies like artificial intelligence (AI) and organ-on-a-chip (OOC) hold the potential to further enhance both safety and efficacy. AI can predict drug-target interactions, enabling earlier identification of potential issues, even before pre-clinical development. OOC platforms can be used to more accurately model complex diseases and human biology to overcome the inter-species limitations of animal models. Their use allows researchers to assess drug uptake, effectiveness, and safety before costly and time-consuming clinical trials.
What ethical considerations arise with new modality drugs (e.g., gene editing modalities)?
Whilst there is a plethora of ethical considerations around the use of gene editing therapies, including safety, unintended consequences and long-term effects, discrimination, the potential for a slippery slope towards enhancement versus therapy, etc., these represent one class amongst many. Other approaches are much less contentious because they are reversible, such as better targeting of existing drugs, i.e., antibody-drug conjugates, RNA interference therapies that cause gene knockdown and mRNA therapies that instruct cells to produce proteins.
What novel delivery systems (e.g., biodegradable scaffolds, nanocarriers) are being developed to improve the precision and safety of new modality drugs?
New therapeutic modalities offer the advantage of precisely targeting disease processes. This increased precision, often achieved through mechanisms like antibody-drug conjugates, protein degraders (PROTACs), or RNA interference, allows for more focused treatment and potentially fewer side effects than traditional therapies. A prime example is the use of RNAi therapeutics to treat liver diseases. These therapies must overcome the cell's natural defenses, which prevent external RNA from entering.
A key advancement in this area has been the development of N-acetylgalactosamine (GalNAc) siRNA conjugates for liver delivery. The tri-GalNAc component binds to the asialoglycoprotein receptor, highly expressed on hepatocytes, resulting in rapid endocytosis. Given the expression of this receptor on human hepatocytes, more advanced in vitro assays that model the human liver are required to study the update and delivery of RNAi.
The longevity (multiple weeks) and enhanced physiological relevance of primary human OOC assays compared to standard 2D hepatocyte assays can be used to investigate the efficiency (uptake and gene knockdown) of the GalNAc strategy as well as help determine dosing strategy, for example, single versus repeated dose.
How can new modalities be further integrated into precision medicine, allowing for real-time adaptation based on patient biomarkers?
Personalized medicine moves beyond the "one-size-fits-all" treatment model, prioritizing individual patient differences even within the same disease. This approach is especially critical for developing therapies for rare diseases. Omics technologies, such as metabolomics and proteomics, can provide comprehensive patient disease profiles, generating biomarkers that predict treatment response and inform therapeutic design.
Going forward, advanced in vitro assays like OOC represent a great platform for exploring personalized medicine as they are designed for primary human cell use. Their ability to decipher population and individual differences is powerful.
A diverse range of donors is available to purchase from specialized vendors to explore variances in drug response or identify patient susceptibilities to drugs due to differences in sex, ethnicity, genetics, disease, etc.
Most OOC platforms are designed for research and development purposes only so they cannot be used for diagnostics, however, the combination of OOC and omics technologies can be adopted to test, inform, and further refine therapeutic strategies.
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