I had the privilege of attending the TIDES conference in Boston from May 12th to 14th. TIDES is always a standout event where attendees can hear about the latest advances in oligonucleotide and peptide therapeutics, along with valuable insights into the evolving landscape of drug development and manufacturing. This year was no exception, with a strong gathering of industry leaders, researchers, and solution providers sharing both cutting-edge science and practical perspectives across the field.
Many talks focused on new synthetic strategies for peptides and oligonucleotides, including hybrid liquid- and solid-phase synthesis, enzymatic synthesis, and complete liquid-phase synthesis.
The first keynote presentation on May 12th was focused on efficacy and process improvement for a next-generation tritagonist peptide drug, currently in clinical trials, that targets three metabolic pathways—GLP-1, GIP, and glucagon receptors. The talk highlighted synthetic challenges and optimization strategies. Strategies to reduce PMI (Process Mass Intensity) and solvent usage by deploying new synthetic processes were presented.
This was followed by another excellent presentation by a member of a company that develops peptide-based drugs targeting inflammation, hematology, and metabolic disorders, both independently and in partnership with other pharmaceutical companies. This person discussed the development of the next-generation metabolic peptide PN-477, which can be administered via both subcutaneous and oral routes, and the challenges and possible solutions for developing an oral version of the drug.
The next presentation was on key innovations in oligonucleotide manufacturing, including pathways and challenges for moving from chemical synthesis to full enzymatic synthesis.
The afternoon session started with an excellent presentation focused on improvements in drug delivery methods and the speaker’s contributions to the field. The presentation included many fascinating stories and anecdotes, along with innovative methods of drug delivery to increase bioavailability and reduce product degradation before reaching its target, such as “leopard tortoise”-inspired insulin delivery, aerosol-based inhalation therapy, and the design of nanoparticle carriers coated with polyethylene glycol (PEG).
Another interesting presentation, on personalized CRISPR gene-editing therapy, spoke of different choices of delivery vehicles for lowering LDL cholesterol levels in patients, including lipid nanoparticles (LNPs) for gene-editing drugs. The presenter talked about regulatory pathways for applying variant-specific LNP editor drug products targeting a single gene under a single IND or umbrella clinical trial and shared the results of their interactions with the FDA. This new approach may open avenues for other personalized medicines; however, the presenter noted that, while the IND is being submitted, the clinical trial has not yet opened.
Between and after the presentations, there were lively discussions and interactions in the poster and exhibit hall, where more than eighty posters were presented by scientists from academia and industry, with topics ranging from preclinical studies and CMC development to analytical control strategies and process improvement/optimization.
On May 13th, I was intrigued by a presentation about biomanufacturing of oligonucleotides using enzymatic catalysis and how its use could lead to better yield, higher selectivity, and simpler workflows. On another interesting topic, the speaker demonstrated the application of machine learning to identifying differentiated target mechanisms that can be used to design oligonucleotide therapeutics. The speaker also demonstrated how this platform can be used to accurately predict in vivo toxicity in rodents. The use of AI/ML will improve the speed and accuracy of the discovery stage of modern therapeutics.
This was followed by excellent presentations about new approaches to in vivo gene editing. The presenter discussed the development of a non-viral delivery platform using LNPs to deliver RNA payloads to edit hematopoietic stem cells (HSCs) and T-cells in vivo. Data from studies in humanized mice and rhesus monkeys are very promising and may open new therapeutic avenues for patients. The presenter discussed the development of the PRINT (Precise RNA-mediated Insertion of Transgenes) platform where the drug substance is made of mRNA—Addition Therapeutics’ proprietary plug-and-play template RNA—loaded into an LNP delivery vehicle. The presenter described the mechanism of RNA-mediated insertion of transgenes to induce highly durable DNA changes and also explained how this platform can be particularly useful when traditional AAV gene therapy may not work due to potential safety risks for patients with adverse immune responses to AAVs, offering the possibility of combining the best aspects of RNA therapeutics and gene therapy.
The day was capped with an exciting presentation that discussed the development of a cell-based platform for designing, optimizing, and manufacturing mRNA therapeutics. This innovative company uses in-silico modeling along with high-throughput screening to generate cell-based mRNA and promises to produce mRNA at large scale without requiring chromatographic purification. This exciting new approach provides an alternative to traditional IVT-based mRNA manufacturing processes.
On the last day of the event, May 14th, there were several intriguing presentations in the morning session. A few among them were about developing stereopure siRNA, or “SpiNA,” which has shown promising results for fat loss in mice without muscle loss.
The afternoon session included presentations on challenges and possible solutions in the development of oral peptides. Due to instability of peptides in the human GI tract, bioavailability is low. Possible solutions included leveraging permeation enhancers and modeling approaches to determine key parameters that can improve oral absorption.
One of the speakers discussed analytical control strategies for therapeutic peptides and directed the audience to several USP chapters, such as <1503> and <1504>, that provide guidance. The speaker presented the regulatory expectations for using bioassays for peptides, noting that while bioassays may be necessary in early development and discovery stages, they may be removed and replaced with physicochemical methods with appropriate scientific justification. The speaker also discussed the use of 1-D and 2-D NMR spectroscopy for identification of peptides and related impurities, particularly for determining higher-order structure and generating structural fingerprints.
TIDES showcased both the pressing challenges and rapid advancements in the peptide and oligonucleotide space. A recurring theme was the need for process innovation, alternative manufacturing strategies, and more robust control frameworks. The conference also highlighted the significant promise of next-generation “-tide” therapeutics enabled by emerging technologies and platforms.
