Industry Insights: Clinical and regulatory momentum across nucleic acid modalities, with advances in ALS and obesity

Leal Therapeutics dosed the first patient in the Phase 1/2 trial of ASO drug in ALS [1]

Leal Therapeutics announced that the first participant has been dosed in NeurALS, a Phase 1/2 trial of LTX-002 in adults with amyotrophic lateral sclerosis (ALS). LTX-002 is an investigational, intrathecally delivered antisense oligonucleotide (ASO) targeting SPTLC1, a core subunit of serine palmitoyltransferase (SPT), whose excessive activity drives the accumulation of ceramides and sphingolipids implicated in motor neuron toxicity across both genetic and sporadic ALS. By reducing SPT activity, LTX-002 is designed to restore healthy sphingolipid balance in the central nervous system (CNS), an approach shown to be protective in preclinical models. NeurALS (NCT07660614) is a randomized, blinded, placebo-controlled study assessing safety, tolerability, and pharmacokinetics, with exploratory endpoints including cerebrospinal fluid target engagement markers, plasma neurofilament light chain, and the ALSFRS-R rating scale.

Trace Neuroscience initiated a global clinical development program for ASO drug in ALS [2]

Trace Neuroscience announced the initiation of its global clinical development program for TRCN-1023, an investigational ASO designed to restore UNC13A protein function in ALS, a genetically validated target relevant to 97% of patients. Administered intrathecally, TRCN-1023 binds UNC13A mRNA to guide formation of functional protein, potentially improving synaptic transmission and nerve-muscle function. The program comprises the Phase 1/2 FUNCTION ALS trial, a randomized, double-blind, placebo-controlled study that has received clinical trial authorization in the UK and Netherlands and expects to enroll approximately 30 participants across North America and Europe, and LAUNCH ALS, an investigator-initiated trial in China conducted with Tenacia Biopharmaceutical at Beijing Tiantan Hospital, in which the first patients were dosed earlier this month.

Trace Neuroscience initiated a global clinical development program for ASO drug in ALS; Clinical trials and research. Credit: Trace Neuroscience.

Wave Life Sciences initiated the Phase 2a trial evaluating GalNAc-siRNA drug in obesity [3]

Wave Life Sciences announced initiation of the Phase 2a multidose portion of its INLIGHT trial evaluating WVE-007, an investigational GalNAc-small interfering RNA (siRNA), as monotherapy in individuals with obesity (body mass index (BMI) 35–50 kg/m²) and comorbidities. WVE-007 is designed to silence INHBE mRNA, an obesity target supported by human genetics, using Wave’s Stereopure SpiNA chemistry. In the ongoing Phase 1 single-dose portion, a 240 mg dose produced clinically meaningful reductions in visceral fat (−14%; p<0.05), total fat (−5%), and waist circumference (−3%) at 6 months, and was well tolerated up to 600 mg, supporting once- or twice-yearly dosing. The placebo-controlled (3:1) Phase 2a portion will enroll participants across the USA and Europe over 12 months.

Resalis Therapeutics dosed the first participant in a Phase 1b study of ASO drug in obesity [4]

Resalis Therapeutics announced dosing of the first participant in a Phase 1b study of RES-010, an investigational ASO targeting microRNA-22 (miR-22), a regulator of metabolic dysfunction, designed to deliver fat-selective weight loss with lean mass preservation in obesity. The candidate is positioned to address limitations of glucagon-like peptide-1 (GLP-1) medicines, namely lean mass loss and rebound weight gain after discontinuation. The randomized, placebo-controlled, sequential multiple ascending dose study will enroll up to 36 overweight and moderately obese adults at a single site in Australia, across up to three cohorts receiving once-weekly subcutaneous injections over a 12-week treatment period, with an optional safety follow-up of up to 6 months. Endpoints comprise safety, tolerability, and pharmacokinetics, alongside efficacy, pharmacodynamic, and biomarker measures.

Praxis Precision Medicines received FDA Breakthrough Therapy Designation for ASO in developmental and epileptic encephalopathy [5]

Praxis Precision Medicines announced that the US FDA has granted Breakthrough Therapy Designation to elsunersen (PRAX-222), an ASO designed to selectively decrease SCN2A gene expression for the treatment of seizures associated with SCN2A developmental and epileptic encephalopathy (SCN2A-DEE) caused by gain-of-function variants, a rare genetic epilepsy with no approved disease-modifying therapies. The designation was supported by the randomized, sham-controlled Phase 1/2 EMBRAVE Part A trial in nine pediatric patients aged 2–12 years, in which elsunersen produced a 77% sham-adjusted reduction in monthly seizures (p=0.015), with benefit sustained in the open-label extension for up to 1 year and no drug-related serious adverse events. The pivotal EMBRAVE3 study, converted to a single-arm registrational design following FDA alignment, is enrolling approximately 30 patients. Elsunersen is being developed in collaboration with Ionis Pharmaceuticals.

Atrium Therapeutics received FDA clearance of its IND application for siRNA candidate in PRKAG2 syndrome [6]

Atrium Therapeutics announced that the FDA has cleared its Investigational New Drug (IND) application for ATR-1072, enabling initiation of the Phase 1/2 Corventis trial in PRKAG2 (protein kinase AMP-activated non-catalytic subunit gamma 2) syndrome, a rare, autosomal dominant, early-onset cardiomyopathy with no approved disease-modifying therapies. ATR-1072 is a siRNA that uses the company’s precision cardiac delivery technology to silence mutant PRKAG2 mRNA, normalize AMP-activated protein kinase activity, and reduce pathogenic glycogen accumulation, potentially improving heart function. Corventis is an open-label, multicenter study enrolling approximately 37 participants across a multiple-ascending-dose part and a single-arm expansion cohort at the recommended Phase 2 dose. First enrollment is expected by the end of 2026, with proof-of-concept data anticipated in the second half of 2027.

Atrium Therapeutics received FDA clearance of its IND application for siRNA candidate in PRKAG2 syndrome; Regulatory changes and updates. Credit: Adobe Stock.

CDW Holding reported preclinical data for spleen-targeted LNP-LANFA delivery platform [7]

CDW Holding announced in vivo murine data for LNP-LANFA, a next-generation lipid nanoparticle (LNP) delivery technology under joint development by its subsidiary A Biotech and Neoregen Biotech, designed to overcome the immunogenicity and hepatotoxicity limitations of conventional LNPs. Whereas conventional LNPs accumulate preferentially in the liver, imaging studies showed LNP-LANFA reduced liver accumulation by 62% and increased splenic delivery by 28%, improving the spleen-to-liver ratio 3.4-fold, from 0.79 to 2.68. Enhanced splenic targeting may benefit vaccines, cancer immunotherapies, and immunomodulating therapies that depend on efficient delivery to immune cells.

Confluence Genetics launched its Cas-CLEAR CRISPR oncology platform [8]

Confluence Genetics announced the launch of Cas-CLEAR (Collaterally Enhanced Activated Ribonuclease), a CRISPR-based oncology platform, with lead programs in hepatocellular carcinoma (HCC), including HBV-derived HCC. Unlike gene-editing systems that cut DNA at a single site, Cas-CLEAR uses Cas12a2 nucleases to recognize cancer-specific genetic signatures and trigger broad collateral cleavage of cellular DNA and RNA, selectively eliminating cells carrying the target signature while sparing healthy cells.

Confluence Genetics launched its Cas-CLEAR CRISPR oncology platform; Research and development highlights. Credit: Adobe Stock.

Ribo and Madrigal Pharmaceuticals reached the first candidate nomination milestone in their siRNA partnership for MASH [9]

Suzhou Ribo Life Science, through its subsidiary Ribocure Pharmaceuticals, and Madrigal Pharmaceuticals announced achievement of the first candidate drug nomination milestone in their siRNA partnership targeting metabolic dysfunction-associated steatohepatitis (MASH), a liver disease with substantial unmet need. The milestone will be followed by initiation of IND-enabling studies to support planned clinical development. The collaboration pairs Madrigal’s clinical expertise in MASH with Ribo’s siRNA discovery and delivery capabilities and spans multiple preclinical, liver-directed assets, broadening the therapeutic landscape for the indication.

Vect-Horus entered a collaboration with Servier to develop brain-targeted oligonucleotide therapeutics for rare CNS diseases [10]

Vect-Horus announced a research evaluation and exclusive license option agreement with Servier to develop targeted oligonucleotide therapeutics for rare CNS diseases. The collaboration will apply Vect-Horus’s proprietary VECTrans platform to transport Servier’s oligonucleotides across biological barriers to the brain, addressing a key delivery challenge in neurological disorders. During an initial option period, the parties will conduct joint research evaluation activities, after which Servier will hold an exclusive option to advance selected compounds into clinical development and commercialization.

Jokūbas Leikauskas, Commissioning Editor, Nucleic Acid Insights, holds a background in science communication and digital publishing, focusing on advancing the nucleic acid therapeutics field by commissioning and shaping high-impact, open access content for Nucleic Acid Insights. He leads the development of interviews, expert articles, and industry perspectives that highlight emerging advances across mRNA, DNA, oligonucleotide, and drug delivery modalities. Jokubas is driven to translate complex scientific topics into engaging, accessible content while maintaining strong connections across the nucleic acids community.

References

1. Leal Therapeutics. Leal Therapeutics doses first patient in NeurALS Phase 1/2 trial of LTX-002 for amyotrophic lateral sclerosis (ALS).

2. Trace Neuroscience. Trace Neuroscience initiates global clinical development program for TRCN-1023, an antisense oligonucleotide designed to restore UNC13A function for the treatment of ALS.

3. Wave Life Sciences. Wave Life Sciences announces initiation of Phase 2a portion of INLIGHT trial of WVE-007 (INHBE GalNAc-siRNA) for obesity and cardiometabolic diseases.

4. Resalis Therapeutics. Resalis announces initiation of Phase 1b clinical study evaluating RES-010 as treatment to address unmet needs in obesity.

5. Praxis Precision Medicines. Praxis Precision Medicines receives FDA Breakthrough Therapy Designation for elsunersen for the treatment of seizures associated with SCN2A developmental and epileptic encephalopathy caused by gain of function variants.

6. Atrium Therapeutics. Atrium Therapeutics announces FDA clearance of Investigational New Drug application for ATR-1072 for treatment of PRKAG2 syndrome.

7. CDW Holding. Next-generation drug delivery technology LNP-LANFA achieves groundbreaking preclinical results in animal studies.

8. Business Wire. Confluence Genetics launches Cas-CLEAR, a new CRISPR technology platform for cancer therapy.

9. Ribocure. Ribo and Madrigal reach first major milestone in advancing novel siRNA therapies for MASH.

10. Vect-Horus. Vect-Horus announces collaboration and license option agreement with Servier to develop targeted oligonucleotide therapeutics for rare CNS diseases.