Dual-Target RNAi Therapy Reports Positive Clinical Results; Long-Acting GLP-2 Analog Receives CHMP Positive Opinion | TIDES Weekly

The global peptides and oligonucleotides (TIDES) sector is witnessing a wave of clinical and regulatory breakthroughs, with dual-target RNAi therapies demonstrating robust lipid-lowering effects, a long-acting GLP-2 analog advancing toward European approval, and major pharmaceutical companies forging strategic partnerships to push nucleic acid therapeutics into the central nervous system.

ARO-DIMER-PA: Dual-Functional RNAi Therapy Reports Positive Phase 1/2a Interim Data

Arrowhead Pharmaceuticals has announced interim topline results from its Phase 1/2a clinical trial of ARO-DIMER-PA, an investigational RNAi therapeutic designed to simultaneously silence two key genes involved in lipid metabolism—PCSK9 and APOC3—using a single RNAi molecule. The candidate is being developed for the treatment of atherosclerotic cardiovascular disease (ASCVD) associated with mixed hyperlipidemia.

Unlike conventional RNAi drugs that target a single gene, ARO-DIMER-PA employs a dual-functional design that enables concurrent suppression of both PCSK9 and APOC3 expression. This approach addresses a critical unmet need in patients with mixed lipid abnormalities who often require multiple therapies to manage their cardiovascular risk.

The newly disclosed data stem from a single-dose assessment. Results demonstrated sustained pharmacodynamic effects on both targets, with serum PCSK9 levels showing an average maximum reduction of 72% and APOC3 levels declining by an average maximum of 88%.

The lipid and lipoprotein profile improvements were equally striking. Low-density lipoprotein (LDL) cholesterol decreased by an average maximum of 54%, triglycerides dropped by 73%, non-high-density lipoprotein (non-HDL) cholesterol fell by 61%, and apolipoprotein B was reduced by 50%. Arrowhead indicated that additional data from the program will be presented at upcoming medical conferences.

Zeydovio: Long-Acting GLP-2 Analog Receives CHMP Positive Opinion

Zealand Pharma's Zeydovio (glepaglutide), a long-acting glucagon-like peptide-2 (GLP-2) analog, has moved one step closer to European market approval after receiving a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). The drug is recommended for the treatment of adult patients with short bowel syndrome (SBS).

Glepaglutide is designed to improve intestinal absorption function, thereby reducing the dependence of SBS patients on parenteral support (PS). The CHMP's positive opinion is primarily based on data from the Phase 3 EASE-1 clinical trial, supplemented by interim results from long-term extension studies EASE-2 and EASE-3, as well as mechanistic data from the EASE-4 study.

The EASE-1 trial enrolled 106 SBS patients with intestinal failure who required parenteral support at least three days per week. Participants were randomized to receive glepaglutide 10 mg once weekly, twice weekly, or placebo, with the primary endpoint being the change in weekly PS volume from baseline at 24 weeks.

At 24 weeks, patients in the twice-weekly glepaglutide group achieved a mean reduction of 5.13 liters in weekly PS volume from baseline, compared with a 2.85-liter reduction in the placebo group—a difference that was statistically significant (p=0.0039).

In the twice-weekly dosing group, 65.7% of patients achieved at least a 20% reduction in weekly PS volume, meeting the predefined clinical response threshold. Additionally, 51.4% of patients reduced their weekly PS days by at least one day, and five patients completely discontinued parenteral support and achieved intestinal autonomy.

Zealand Pharma has previously reported that glepaglutide demonstrated favorable overall safety and tolerability in clinical studies. If approved by the European Commission, the drug would offer a new treatment option for SBS patients dependent on long-term parenteral support.

QurCan/Lilly: Multi-Project Collaboration on Nucleic Acid Therapies for Neurological Diseases

In the field of nucleic acid drug delivery, QurCan Therapeutics has entered into an exclusive multi-project research collaboration with Eli Lilly and Company to develop nucleic acid therapies targeting central nervous system (CNS) and peripheral nervous system (PNS) diseases.

Rather than focusing on a specific nucleic acid molecule, the partnership leverages QurCan's polymer-lipid nanoparticle (PLNP) delivery platform built on Target-Engineered Responsive Polymer (TERP) technology to explore the delivery of various nucleic acid payloads to the nervous system.

Under the collaboration terms, QurCan will utilize its TERP platform to optimize candidate nucleic acid drugs, while Lilly will take responsibility for subsequent research, clinical development, and commercialization of selected programs. QurCan will receive an upfront payment and a strategic investment from Lilly. For each collaborative project, QurCan is also eligible for research support fees and up to $237 million in research, development, and commercialization milestone payments.

The TERP platform is designed to support repeated systemic administration of nucleic acid drugs while delivering payloads to disease-relevant specific cell populations. According to QurCan, the platform can deliver various types of nucleic acid molecules, including mRNA, DNA, and oligonucleotides. While liver-targeted delivery has become relatively mature, delivering nucleic acid therapeutics to the CNS and PNS remains a significantly greater challenge.

Additional TIDES Developments

Beyond the headline developments, several other TIDES-related programs are advancing through clinical stages:

SpliSense has initiated a Phase 2b trial of SPL84, an antisense oligonucleotide targeting the CFTR gene for the treatment of cystic fibrosis. Alveus Therapeutics has launched the Phase 2 PRESERVE trial to evaluate ALV-100, an antibody-peptide fusion protein that acts as a GIP receptor antagonist and GLP-1 receptor agonist, for chronic weight management in obesity. Phio Pharmaceuticals has announced a key development milestone for PH-762, an siRNA therapy targeting PDCD1 for cutaneous squamous cell carcinoma, with an FDA submission supporting the next stage of clinical development in the United States.

Integrated Platform Supporting Oligonucleotide Drug Development

As oligonucleotide therapeutics continue their rapid expansion, establishing reliable in vitro metabolic stability evaluation systems has become a critical foundation for early-stage drug development. Unlike traditional small molecules, oligonucleotide drugs are primarily metabolized by endonucleases and exonucleases, requiring specialized assessment approaches.

WuXi AppTec's DMPK team has built a systematic in vitro metabolism research platform that employs a multi-model collaborative strategy to comprehensively evaluate the stability and degradation behavior of oligonucleotide drugs. The platform provides critical data support for candidate molecule optimization and preclinical decision-making.

Drawing on years of oligonucleotide DMPK research experience, WuXi AppTec has established an in vitro stability model system covering multiple biological matrices, including plasma, serum, liver and kidney S9 fractions, tissue homogenates, hepatocytes, and lysosomes. Researchers can select appropriate models based on molecular structure characteristics and therapeutic targets to more accurately simulate in vivo degradation environments.

By comparing metabolic rates and metabolite formation across different models, the team can systematically elucidate oligonucleotide clearance pathways in both the circulatory system and target tissues, while supporting cross-species difference assessments to improve the predictive capability of in vitro results for in vivo behavior.

Through continuous optimization of incubation systems, matrix selection, and experimental parameters, combined with mechanistic studies and standardized processes, WuXi AppTec's DMPK team can identify metabolic risks at early development stages, guide molecular modification strategies, and support subsequent pharmacokinetic and safety studies—providing robust scientific support for advancing oligonucleotide drugs from discovery through clinical development.

Disclaimer: This article is for informational purposes only. The views expressed do not represent the position of WuXi AppTec, nor do they constitute endorsement or opposition to any viewpoints presented. This article is not a treatment recommendation. For treatment guidance, please consult a qualified healthcare provider.