The onset of the genomic era in the early 2000s led to an emphasis on developing innovative chemical approaches to address “undruggable” targets. These targets, characterized by large, shallow pockets, necessitated different chemical modalities like cyclopeptides or macrocycles. Technological advances in structural biology, genomics, and proteomics have significantly enhanced our understanding of protein modulation, leading to innovative treatments.

Latest FDA Approvals and Emerging Trends

In 2023, the FDA approved 55 new drugs, the second-highest number following 59 approvals in 2018. The relatively low approval number in 2022 (37 drugs) appears to have been a temporary anomaly rather than a pandemic-related consequence, as evidenced by the industry’s recovery and the strong pipeline.

The 55 approvals in 2023 include 17 biologics, 5 peptides and 4 oligonucleotides, and 29 small molecules, with a total of 38 new chemical entities (NCEs).

Small Molecules, PROTACs, and More

Small molecules have been central to drug discovery due to their versatility in modulating targets and crossing biological barriers. They are preferred for their ability to be orally bioavailable, targeting both intracellular and extracellular targets. Recent trends include the development of allosteric modulators and covalent inhibitors, which offer increased selectivity and safety margins.

PROTACs and other bifunctional degraders represent a newer modality within the small molecules space. These compounds, larger than traditional small molecules, link two small molecules moieties to target proteins for degradation. Challenges include ensuring oral bioavailability and cell permeability. Companies like Arvinas are pioneering this approach, leading to significant advances in oncology.

Biologics

Biologics, including monoclonal antibodies (mAbs) and antibody–drug conjugates (ADCs), have seen numerous FDA approvals. The agency has now approved well over 100 novel mAbs for cancer, autoimmune and infectious diseases, and inflammatory conditions, among other indications. Biologics offer high affinity, potency, and specificity, resulting in fewer off-target toxicities. They are primarily administered parenterally, with ongoing research into nanomedicine-based strategies for oral delivery.

Biologics face challenges in crossing the blood-brain barrier, limiting CNS applications. Intrathecal (IT) injection is one method to circumvent this barrier. However, biologics are prone to immunogenicity, leading to anti-drug antibodies (ADAs) that can alter efficacy and safety.

Next-Generation Peptides

Peptide therapeutics have a long history, with nearly 90 peptide drugs currently commercialized. Despite high potency and selectivity, development challenges include low membrane permeability and oral bioavailability. Innovations in cyclic and constrained peptides aim to enhance stability and permeability. Recent advances include permeation enhancers and formulation strategies like lipidation and PEGylation to improve the pharmacokinetic (PK) profile.

The approval of Rybelsus, an oral semaglutide for type 2 diabetes, marks a significant milestone in peptide therapeutics. It incorporates a fatty acid moiety for extended half-life and is co-formulated with an absorption enhancer for oral administration.

Oligonucleotide Strategies

Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs) and small interfering RNA (siRNA), have grown significantly, accelerated by the development of RNA-based vaccines. These therapies, with larger molecular weights, are typically administered via IV or subcutaneous (SC) routes due to poor oral bioavailability.

Chemical modifications, such as phosphorothioate linkages, enhance stability and plasma protein binding. Delivery systems focus on non-viral methods to improve cellular uptake and endosomal escape. Recent advancements include stereopure isomers to increase binding affinity and reduce degradation.

Conclusions

The field of medicinal chemistry is undergoing significant transformation with the introduction of diverse chemical modalities. Innovations in formulation technologies are overcoming traditional limitations, enabling effective therapies beyond small molecules. The continued expansion of small molecules modalities and the development of PROTACs, peptides, oligonucleotides, and biologics are driving pharmaceutical innovation and improving patient outcomes.

References

1. U.S. Food and Drug Administration (FDA) – New Drug Therapy Approvals
2. Nature Reviews Drug Discovery – Recent advances in targeting “undruggable” proteins
3. PPD – Five Key Trends Shaping Biopharma and Biotech in 2025
4. Drug Discovery Trends – Core Trends in 2023 FDA Drug Approvals

Originally published by Romesh Collins on LinkedIn. Access the LinkedIn article here.