Rising TIDES: The Growth of Peptide and Oligonucleotide Therapeutics

Most pharmaceutical drugs target proteins, with increasing interest in improving both selectivity and indication coverage. Approximately 10–15% of the 20,000 protein-coding genes in the human genome are linked to disease, making proteins attractive targets for therapeutic intervention. However, many of the small-molecule drugs lack the specificity to bind disease-associated proteins with high affinity and selectivity¹. As drug developers aim to address unmet medical needs, they face the challenge that traditional small molecule therapies are often unable to effectively target these “undruggable’” proteins, leaving many conditions without viable treatment options.

To help overcome current inaccessibility, drug developers are increasingly looking for new therapeutic modalities that can interact with previously “undruggable” proteins. Two promising approaches use peptides and oligonucleotides, which offer enhanced specificity and selectivity compared to traditional small molecules. While these modalities are pharmacologically distinct, they are often grouped as “TIDES” due to similarities in their manufacturing processes. Together, these advanced therapies hold the potential to become next-generation treatments with greater efficacy and reduced off-target effects, providing hope for previously untreatable conditions.

 

The rise of TIDES therapeutics

The TIDEs market has evolved rapidly over recent years, driven by increasing knowledge of the molecular mechanisms that underpin common diseases and inform new treatment approaches. This growth has been further enhanced by the focus on developing new therapeutics that fit in the mid-sized drug space between low- and high-molecular-weight compounds, i.e., between small molecules and biologics. Within this area, peptide and oligonucleotide-derived, mid-sized drugs are of particular interest as they offer the ability to target enzymes and receptors, as well as mediate protein-protein interactions².

The overall shift in the pharmaceutical landscape toward complex molecules also reflects the promising future for TIDES therapeutics. In 2023, nine of the 55 FDA-approved drugs were TIDES (five peptides and four oligonucleotides), alongside 17 biologics³. This trend looks set to continue, with the 2024 CPHI Annual Industry Survey predicting that complex molecule approvals will soon outpace small molecule approvals⁴.

Peptides

Therapeutic peptides consist of two to ~50 amino acids linked by peptide bonds. Depending on the number of amino acids, structure, and additional moieties, there are a range of different classes of peptides, including oligopeptides, cyclic peptides, and glycopeptides. Due to their diversity, peptides have applications across the therapeutic spectrum from metabolic disorders and chronic pain to oncology and cardiovascular disease⁵.

Recently, there has been significant interest in glucagon-like peptide-1 (GLP-1) receptor agonists including semaglutide and liraglutide. By activating the GLP-1 receptor, these molecules have a range of therapeutic effects, including increasing insulin production, inhibiting glucagon release, and slowing gastric emptying. Due to their ability to mediate glucose metabolism, GLP-1 agonists were initially developed for type II diabetes management, delivered through subcutaneous injections. More recently, GLP-1 agonist drugs have gained additional popularity as obesity treatments⁶. To support this growth and encourage wider patient uptake, there is a drive to develop new peptide therapeutics with similar effects by oral administration⁷. The wider future for peptide therapeutics is equally promising, with over 150 currently in clinical trials and 400-600 in pre-clinical development, often targeting conditions with currently unmet clinical needs⁸.

Oligonucleotides

Oligonucleotides are nucleic acid polymers that can modulate gene expression and protein production through a range of mechanisms to either reduce the amount of dysfunctional protein or correct protein production. Their specificity arises from complex binding between the designed nucleic acid sequences and target genes, which has made them especially valuable for treating rare genetic diseases. This same precision also positions them as promising tools for addressing more common clinical conditions, such as asthma, cancer and diabetic retinopathy. There has been increasing interest in using oligonucleotides for cardiovascular disease⁹ . There is also significant research into new methods to more effectively sequence and chemically modify oligonucleotides to improve their stability, target affinity, and bioavailability¹⁰.

 

Current TIDES manufacturing landscape

Given the rapid growth of the TIDES market, developers across the industry seek scalable manufacturing processes to support the commercialization of peptide and oligonucleotide therapeutics.

Currently, most TIDES are manufactured using solid-phase synthesis methods. Although these approaches are based on well-understood chemistry and have been continually optimized over several decades, they are still associated with relatively high manufacturing costs. Additionally, due to the volumes of hazardous reagents and solvents required for synthesis and purification, these processes also present sustainability challenges¹¹. Together, these limitations have led developers to begin exploring alternative synthetic approaches. In particular, liquid-phase methods are being developed that can support large-scale production while reducing the need for excess reagents and solvents, consistent with the principles of green chemistry¹².

Chromatographic purification is another essential part of the TIDES manufacturing process that can present complexity. This is primarily due to the number of closely related by-products that may be created during synthesis and must be separated from the final products¹³. As a result, there is a need for new approaches that can simplify separation and support the design and implementation of more robust purification processes. One such approach is the use of solid-form science to enable the crystallization and isolation of intermediates and the final TIDES therapeutic. This method can provide a more scalable and cost-effective alternative to chromatography, as well as increased stability and purity¹⁴.

Accelerating TIDES innovation with CDMO support

Due to the dynamic industry landscape and complexity of TIDES manufacturing, efficiently navigating process development and scale-up can be challenging. This has led to increased demand for support at all stages, from optimizing synthetic approaches to developing suitable chromatographic or crystallization purification methods. As such, contract development and manufacturing organizations (CDMOs) with specialized knowledge and capabilities are playing a pivotal role in supporting TIDES innovation.

At Veranova, we tackle TIDES development and manufacturing challenges to deliver cost-effective and scalable solutions for our customers. We are an experienced CDMO partner in TIDES pipelines with over 10 years of experience in the development to commercial-scale production of nucleotides and drug modifiers, and in the development of peptides and oligonucleotides.

Visit our TIDES webpage to learn more about our capabilities and find out how we can meet your project needs with consistent quality, capacity, security, and efficiency.

 

References

1. Warner, K. D., et al., 2018. Principles for targeting RNA with drug-like small molecules. Nature Reviews Drug Discovery, 17, pp. 547-558.
2. Tamamura, H., Kobabyakawa, T. & Ohashi, N. Mid-size Drugs Based on Peptides and Peptidomimetics: A New Drug Category; Springer Singapore, 2018.
3. Al Shaer, D., et al., 2023 FDA TIDES (Peptides and Oligonucleotides) Harvest. Pharmaceuticals, 17(2):243.
4. CPHI Milan Annual Industry Report, 2024. https://www.cphi-online.com/46/resourcefile/15/13/54/CPHI-Annual-Report-2024-v20241021.pdf (accessed November 2024)
5. Wang, L., et al., 2022. Therapeutic peptides: current applications and future directions. Signal Transduction and Targeted Therapy, 7(1), pp. 1-27.
6. Knudsen, L.B. and Lau, J., 2019. The Discovery and Development of Liraglutide and Semaglutide. Frontiers in Endocrinology, 12(10):155.
7. Wharton S., et al., 2023. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. The New England Journal of Medicine, 389(10), pp. 877-888.
8. Chen, X., et al., 2024. Advancements in therapeutic peptides: Shaping the future of cancer treatment. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer, 1879(6):189197.
9. Makhmudova, U., et al., 2024. Advances in nucleic acid-targeted therapies for cardiovascular disease prevention. Cardiovascular Research, 120(10), pp. 1107-1125.
10. Yin, W. and Rogge, M., 2019. Targeting RNA: A Transformative Therapeutic Strategy. Clinical and Translational Science, 12(2), pp. 98-112.
11. Ferrazzano, L., et al., 2023. From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry. Green Chemistry, 25(4), pp. 1217-1236.
12. Sharma, A., et al., 2022. Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides. Chemical Reviews, 122(16), pp. 13516-13546.
13. Fornstedt, T. and Enmark, M., 2023. Separation of therapeutic oligonucleotides using ion-pair reversed-phase chromatography based on fundamental separation science. Journal of Chromatography Open, 3: 100079.
14. Application of Solid Form and Crystallization Science in Purification Strategies of NCMs. Scientific Updates, November 15, 2023. https://veranova.com/expert-insights/webinar-application-of-solid-form-and-crystallization-science-in-purification-strategies-of-new-chemical-modalities-ncms-including-peptides-and-protacs/ (accessed November 2024).