Dajun Yang, Chairman & CEO, Ascentage Pharma Group International
The narrative that small molecules are being displaced is, I think, significantly overstated. The excitement around cell therapies, antibody-drug conjugates, and ribonucleic acid-based approaches is well-founded and these are genuinely important advances, but small molecules retain unique advantages that are often underappreciated.
Oral bioavailability remains a major advantage. Both of our approved drugs, olverembatinib for chronic myeloid leukemia and lisaftoclax for chronic lymphocytic leukemia and small lymphocytic lymphoma, are taken orally. For patients living with these conditions, many of whom may be on treatment for years or even decades, that matters enormously for quality of life and for sustained adherence in a way that infused biologics simply cannot match. The ability to cross the central nervous system, via the blood-brain barrier, is another area where small molecules have a real structural advantage, while remaining a major limitation for larger modalities.
Perhaps most strikingly, the emergence of protein degraders like proteolysis-targeting chimeras is extending the reach of small molecules into targets previously considered undruggable. We are advancing our Bruton’s tyrosine kinase degrader, a drug designed to eliminate that protein entirely rather than simply inhibit it, into global Phase I trials. Unlike conventional inhibitors, it eliminates the target protein rather than simply inhibiting it, offering a potential way to overcome drug resistance.
Far from being overshadowed, small molecules continue to evolve into increasingly sophisticated therapies. Small molecules also generally involve less complex manufacturing and regulatory requirements than biologics or cell therapies, supporting broader global commercialization.
Peng Lu, Chief Medical Officer, Pharvaris
There has certainly been significant excitement around newer modalities, and rightly so – they are expanding what is scientifically possible. However, I would not say small molecules have been overshadowed. Rather, we are seeing a more balanced recognition of where each modality can deliver the greatest value.
The oral bioavailability of small molecules continues to offer clear advantages as a route of administration: oral therapies decrease the burden of treatment by potentially allowing for more convenient, discreet, and faster administration. They also benefit from relatively straightforward and scalable manufacturing processes, broad tissue penetration, and a lower risk of immunogenicity compared with more complex modalities.
Importantly, advances in medicinal chemistry and structure-based drug design have also significantly improved our ability to create highly potent small molecules, reducing off-target effects and narrowing the perceived gap between small molecules and more complex modalities.
For me, it is less about competition between modalities, and more about selecting the right tool for the biological and patient needs.
Daniel Vitt, Chief Executive Officer, Immunic Therapeutics
I would not say they have been overshadowed – every technology and modality has its role. The field is finding a natural balance where each modality is used where it brings the most value.
Small molecules remain essential, particularly when targeting intracellular pathways or regions like the central nervous system. In multiple sclerosis, for example, targets such as the nuclear receptor-related 1 (Nurr1) protein are located inside the cell, which makes small molecules the most practical and often the only viable option. They also offer advantages in terms of oral administration, scalability and overall accessibility for patients.
At Immunic, our investigational therapy vidofludimus calcium reflects this approach by combining neuroprotective and anti-inflammatory effects in an oral small molecule.
Ann Cleeves, VP of Application Science, BioPharmics Division, Optibrium
Small molecules have clear advantages, including (relative) ease of optimization for oral dosing, tractability for computational modelling ranging from virtual screening to lead optimization spanning affinity/selectivity enhancement, and ADMET improvement. Rather than being overshadowed, it might be better to think of the small-molecule modality being expanded. Improvements in experimental methodology now commonly provide high-affinity macrocyclic peptide lead compounds using phage- and mRNA-display. Medicinal chemistry teams can now tackle complex macrocycles coming from such experimental screening approaches to design selective, potent, and orally available compounds such as Merck's bridged PCSK9 macrocyclic MK-0616 (Enlicitide). Computational methodology has enhanced our ability to model the behavior of such compounds, especially in the context of biophysical data from NMR and X-ray crystallography or Cryo-EM. The small-molecule concept had largely conformed to the rule-of-5 complexity/property limits, but it is now expanding beyond the RO5 space.
Piet Wigerinck, Chief Scientific Advisor, Fibrocor Therapeutics
It is clear that newer modalities often have a faster path to clinical validation and breakthrough innovation. But for most chronic diseases, the preferred treatment remains simple: one pill a day. That is what physicians, caregivers, and patients prefer because it is convenient, effective, and accessible worldwide, regardless of access to specialized medical care.
That is where small molecules continue to have a clear advantage. The opportunity is to develop the best once-daily oral therapies in areas opened up by breakthrough scientific advances. Small molecules also face fewer reimbursement hurdles because they fit more easily into health care systems that have evolved around oral medicines over the past 50 years.
Jerry McMahon, CEO, STORM Therapeutics
Small molecules haven’t been overshadowed; they remain highly relevant, particularly where precise modulation of intracellular biology is required. At STORM, we focus on targets within RNA-modifying pathways that are inherently suited to small molecule intervention. Advances in drug discovery technologies are improving how we identify and optimize these compounds, while deeper biological insight continues to reveal new, tractable targets where small molecules can provide differentiated, scalable therapeutic benefit.
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