Arcturus Therapeutics (NASDAQ:ARCT) presented preliminary Phase II data for ARCT-810, its mRNA therapeutic candidate for ornithine transcarbamylase, or OTC, deficiency, while outlining plans to introduce a next-generation delivery platform into the program.
OTC deficiency is a urea-cycle disorder in which deficient OTC enzyme activity can lead to toxic ammonia accumulation. Chief Medical Officer Alan Cohen said the condition affects roughly 10,000 people across the United States and Europe. Current management includes protein restriction, fluid intake and ammonia-scavenger medicines, while liver transplantation remains the only cure for severe patients.
Preliminary ARCT-810 Phase II findings
Cohen said ARCT-810 was generally safe and well tolerated across repeated dosing. The study reported no serious adverse events, no adverse events of special interest and no hyperammonemia events. All participants experienced at least one treatment-emergent adverse event, though most were mild to moderate. The most common events were headache, transaminitis and infusion-related reactions, each reported in two of eight participants.
Two grade-three events, both asymptomatic transaminitis, resolved without intervention after study treatment stopped, according to Cohen. One patient discontinued after an intravenous infiltration and injection-site reaction that the company characterized as a procedural event rather than a systemic drug effect.
Across both dose cohorts, mean first-morning fasting ammonia levels were generally similar to or lower than baseline, according to the presentation. Arcturus said all participants achieved and maintained normal plasma ammonia levels after dosing. Glutamine, another biomarker used to assess nitrogen burden and urea-cycle activity, declined in all participants. Mean glutamine levels fell by roughly 15% to 25% from pre-treatment levels, the company said, before returning toward baseline during the one-month period after treatment discontinuation.
The company also reported that participants generally consumed more protein during treatment than at baseline, despite instructions to maintain stable protein intake. Cohen said this observation, together with stable or lower ammonia and lower glutamine levels, supported the view that ARCT-810 increased urea-cycle activity and protein tolerance.
Marshall Summar, a former founding member and executive committee member of the Urea Cycle Disorders Consortium, said the glutamine findings were particularly meaningful because glutamine is used in long-term monitoring of patient stability. He characterized the on-treatment reduction and return toward baseline after treatment stopped as appearing to be a drug effect rather than normal variability.
LUNAR 2.0 platform and ARCT-2601
Arcturus also introduced LUNAR 2.0, a lipid nanoparticle delivery platform designed to improve endosomal escape of mRNA after it enters liver cells. Chief Scientific Officer Pad Chivukula said the company’s prior work suggested that only 2% to 5% of mRNA entering cells escapes the endosome, with the remainder degraded.
In non-human primate studies, Arcturus reported that LUNAR 2.0 generated approximately 40-fold higher protein expression than the company’s first-generation LUNAR lipid using a human erythropoietin mRNA payload. In a separate primate study using human OTC mRNA, the company said LUNAR 2.0 produced 38-fold more OTC protein than the lipid used in ARCT-810.
The new platform has been incorporated into ARCT-2601, which uses the same OTC mRNA sequence as ARCT-810 but a modified formulation. Chivukula said non-GLP rodent safety, primate tolerability and biodistribution studies did not identify findings that differentiated ARCT-2601 from ARCT-810. He noted that the GLP studies were still pending, with results expected in November.
Following a June Type C meeting, Arcturus said the FDA agreed that ARCT-2601 could be added as an arm to the ongoing ARCT-810 study. The company plans to evaluate safety, pharmacokinetics and biomarkers in three to six patients age 12 and older with elevated baseline ammonia. Arcturus said it intends to integrate ARCT-2601 into the existing study by year-end, subject to the necessary steps and data.
Management said the greater potency could support lower doses, less frequent administration and shorter infusion times. ARCT-810 is currently described as a 0.5 mg/kg infusion in a 250-mL bag administered over about three hours. The company said it is targeting a near-term ARCT-2601 profile of 0.3 mg/kg in roughly 40 mL over about one hour, while exploring a more concentrated, lower-dose formulation that could potentially be administered through a syringe pump in under five minutes.
Pediatric development and potential endpoints
Arcturus said its initial clinical focus for ARCT-2601 will be pediatric OTC patients with the greatest unmet need, particularly children from birth through age six with severe disease. Cohen said the company may also consider enrolling children ages six to 11 as it finalizes trial design. Management indicated a Phase II/III pediatric study is planned for the second half of 2027.
In discussions with analysts, Chief Executive Officer Joe Payne said FDA feedback had elevated the importance of ammonia as an endpoint, particularly in pediatric patients, while glutamine may be an acceptable endpoint in adults. Cohen added that future longer-duration studies could assess metabolic stability, protein tolerance and possible changes in ammonia-scavenger use.
Additional liver-focused programs
Beyond OTC deficiency, Arcturus outlined preclinical liver-focused programs in phenylketonuria, or PKU, and gout. The company said it is also acquiring myNEO, a computational immunology company based in Ghent, to support mRNA construct design and screening for potential immunologic hotspots.
For PKU, Arcturus presented mouse and primate data for an mRNA encoding phenylalanine hydroxylase. The company said an optimized sequence maintained phenylalanine within a target range for six to seven days after a single 1 mg/kg dose in PKU mice. In primates, a 0.5 mg/kg administration produced human PAH protein levels equivalent to 44% of endogenous human PAH levels at day two and 16% at day seven, according to the company.
Arcturus also described a gout program intended to deliver mRNA encoding uricase, an enzyme humans do not naturally produce. Chivukula said the company plans to use computational screening to address the potential immunogenicity of uricase before selecting a development candidate.
About Arcturus Therapeutics (NASDAQ:ARCT)
Arcturus Therapeutics Holdings Inc is a biotechnology company focused on developing medicines based on messenger RNA (mRNA) and other RNA technologies. The company’s platform includes LUNAR, a lipid-mediated delivery system designed to transport nucleic acid medicines into targeted cells, and STARR, a self-amplifying mRNA technology intended to produce therapeutic proteins from relatively small doses of RNA.
Arcturus is developing RNA-based candidates for rare diseases, infectious diseases, and other conditions.
