review · Pharmaceuticals
In 2024, the United States Food and Drug Administration approved fifty novel drugs, which included four peptide and oligonucleotide therapeutics. These classes of medicines, collectively termed TIDEs, provide vital treatments for complex conditions such as genetic disorders by targeting underlying disease mechanisms rather than merely relieving symptoms. Following the approval of a peptide treatment for Rett syndrome in 2023, peptides were approved to treat Niemann-Pick disease type C in 2024. Recent approvals highlight key chemical strategies to resolve delivery and stability challenges. The prodrug approach, demonstrated by treatments like palopegteriparatide and pegulicianine, enables more precise targeting and lengthens circulation time. In addition, chemical adaptations such as ribose substitutions and targeted delivery platforms have advanced, expanding therapeutic options for hepatic and systemic delivery.
Peptides and oligonucleotides are expanding beyond conventional drug limits to address the root causes of rare and complex genetic disorders. By overcoming long-standing challenges around drug stability and precise tissue delivery, these advanced therapies offer viable, approved treatment pathways for life-threatening conditions that previously had few or no disease-modifying therapeutic options.
The therapeutic strategies described are already at commercial stage, having achieved regulatory approval for clinical use. For biotechnology firms and drug developers, the validated techniques, including prodrug frameworks, ribose modifications, and targeted delivery platforms, offer proven design pathways to enhance the stability, half-life, and tissue-specific delivery of pipeline therapies.
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In 2024, the FDA approved fifty novel drugs, including four peptides and oligonucleotides (TIDEs) (two pepTIDEs and two oligonucleoTIDEs), highlighting their increasing importance as effective alternatives to traditional drug classes. TIDEs provide essential therapies for complex diseases, such as genetic disorders, rather than merely addressing symptoms. In addition to oligonucleotide therapeutics for various genetic conditions, peptides became the first approved treatment for Rett Syndrome in 2023 and were also used to treat Niemann-Pick disease type C (NPC) in 2024. Interestingly, among the strategies employed in recent approvals to enhance stability and/or delivery, the prodrug approach, exemplified by palopegteriparatide and pegulicianine, is emerging as a more targeted and precise therapeutic strategy. Additionally, the Enhanced Stabilization Chemistry (ESC)-GalNAc platform has been expanded for hepatic delivery of a new oligonucleotide drug, olezarsen. Furthermore, novel modifications to the ribose moiety in oligonucleotides, such as the 3'-amino substitution in imetelstat, enhance their stability. This review examines the TIDES approved in 2024 based on their chemical structure, medical targets, modes of action, administration routes, and common adverse effects. In addition, it highlights how the prodrug strategy has improved targeting efficiency and extended the half-lives of the active drugs.
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DOI: 10.3390/ph18030291
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