ARCT-810 (LUNAR-OTC): An Investigational mRNA Therapy for Ornithine Transcarbamylase Deficiency

1. Executive Summary

ARCT-810 is an investigational messenger RNA (mRNA) replacement therapy currently under development by Arcturus Therapeutics. It is designed to address Ornithine Transcarbamylase (OTC) deficiency, a rare and potentially life-threatening X-linked urea cycle disorder. The therapeutic strategy involves intravenous administration of ARCT-810, which utilizes the proprietary LUNAR® lipid nanoparticle (LNP) delivery platform to transport functional OTC mRNA to hepatocytes. This approach aims to enable the patient's own liver cells to synthesize the deficient OTC enzyme, thereby restoring or augmenting urea cycle function and mitigating the toxic accumulation of ammonia.[1]

Preclinical studies in relevant animal models of OTC deficiency provided proof-of-concept, demonstrating successful mRNA delivery, functional enzyme expression, correction of biochemical abnormalities, and improved survival.[4] Phase 1 clinical development involved single ascending dose (SAD) studies in healthy adult volunteers (ARCT-810-01) and subsequently in adult patients with stable, mild OTC deficiency (ARCT-810-02). These studies established an initial safety and tolerability profile, characterized the pharmacokinetics of the mRNA and LNP components, and identified infusion-related reactions (IRRs) as a manageable adverse event.[5]

ARCT-810 is currently advancing through Phase 2 clinical development. The ARCT-810-03 study (EudraCT 2021-001081-38) is a randomized, double-blind, placebo-controlled, multiple ascending dose study in adolescent and adult OTC deficiency patients in Europe, with initial cohorts having completed dosing.[3] Concurrently, the ARCT-810-04 study (NCT06488313) is an open-label, multiple ascending dose study enrolling adolescents (aged 12 years and older) and adults with OTC deficiency in the United States, with the first participant dosed in December 2024.[1] These Phase 2 trials are crucial for evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamic effects (via ureagenesis biomarkers) of multiple doses of ARCT-810. Interim data from the Phase 2 program are anticipated in the second quarter of 2025.[12]

The therapeutic candidate has received multiple favorable regulatory designations, including Orphan Drug Designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), Rare Pediatric Disease Designation from the FDA, and an approved Pediatric Investigation Plan (PIP) from the EMA.[1] More recently, in April 2025, ARCT-810 was granted Fast Track Designation by the FDA.[12] These designations underscore the significant unmet medical need in OTC deficiency and recognize the potential of ARCT-810 to address this condition. The collection of these regulatory acknowledgments, combined with the progression to multi-dose Phase 2 studies, suggests a promising trajectory for ARCT-810, contingent upon continued positive clinical data, particularly concerning sustained enzyme activity and tangible clinical benefits. The management of IRRs and the demonstration of durable efficacy with repeated dosing remain key areas of focus for the ongoing clinical program.

2. Introduction to ARCT-810

2.1. Overview and Drug Identification

ARCT-810 is an investigational therapeutic agent classified as a messenger RNA (mRNA) replacement therapy. It is a biotechnology-derived product being developed by Arcturus Therapeutics Holdings Inc..[1] In some company literature and development programs, ARCT-810 is also referred to by the synonym LUNAR-OTC, highlighting its delivery system and target.[2] The DrugBank accession number for ARCT-810 is DB17683.

2.2. Therapeutic Rationale: mRNA Replacement Therapy

The fundamental therapeutic rationale behind ARCT-810 is to address the genetic and enzymatic defect underlying Ornithine Transcarbamylase (OTC) deficiency. This is achieved by delivering a synthetic mRNA molecule that encodes the normal, functional human OTC enzyme directly to the patient's liver cells, specifically hepatocytes.[1] Once inside the hepatocytes, the ARCT-810 mRNA is intended to be translated by the cell's endogenous protein synthesis machinery. This process should lead to the production of active OTC enzyme, thereby restoring or significantly augmenting the deficient urea cycle function.[1] This direct approach of enzyme replacement at the cellular level aims to correct the primary metabolic defect, distinguishing it from current standard-of-care treatments for OTC deficiency, which primarily focus on managing the downstream consequences of the enzyme deficiency, such as the accumulation of toxic ammonia.[1]

The decision to utilize mRNA technology for OTC deficiency represents a strategic choice to pursue a therapy that, while transient in its direct effect (as mRNA is naturally degraded), can be repeatedly administered to maintain therapeutic enzyme levels. This modality avoids the complexities and potential long-term risks associated with permanent genetic modification inherent in some gene therapy strategies. For a chronic metabolic disorder like OTC deficiency, where enzyme activity may need to be sustained or modulated over a patient's lifetime, the ability to re-dose and potentially titrate therapy based on response is a significant consideration. The transient nature of mRNA expression also mitigates concerns about irreversible off-target effects or insertional mutagenesis, which are theoretical risks with certain gene therapy vectors. This could offer a more favorable long-term safety profile, particularly if the therapy is eventually extended to younger pediatric populations who are often most severely affected by OTC deficiency.[18]

Table 1: ARCT-810 Key Drug Information

Feature	Details
Name	ARCT-810
Synonyms	LUNAR-OTC
DrugBank ID	DB17683
Therapeutic Class	mRNA Replacement Therapy
Drug Type	Biotechnology Product
Developer	Arcturus Therapeutics Holdings Inc.
Mechanism of Action Summary	Intravenously administered LNP-encapsulated mRNA encoding human OTC, designed for uptake by hepatocytes to enable endogenous production of functional OTC enzyme and restore urea cycle activity.
Target Indication	Ornithine Transcarbamylase (OTC) Deficiency

3. Ornithine Transcarbamylase (OTC) Deficiency

3.1. Pathophysiology and Genetic Basis

Ornithine Transcarbamylase (OTC) deficiency is the most common inherited disorder of the urea cycle, a critical metabolic pathway responsible for the detoxification of ammonia—a neurotoxic byproduct of protein metabolism—into urea, which is subsequently excreted by the kidneys.[1] The disorder is caused by mutations in the

OTC gene, which is located on the X chromosome. This gene provides the instructions for synthesizing the OTC enzyme, a key mitochondrial enzyme primarily expressed in liver cells.[1]

The OTC enzyme catalyzes the second step in the urea cycle, the condensation of carbamoyl phosphate with ornithine to produce citrulline.[17] A deficiency or dysfunction of this enzyme leads to a blockage in the urea cycle, resulting in the accumulation of ammonia (hyperammonemia) in the bloodstream and tissues. Ammonia readily crosses the blood-brain barrier and exerts significant neurotoxic effects, including the development of cerebral edema and direct neuronal damage.[3] In addition to hyperammonemia, the biochemical profile of OTC deficiency typically includes elevated plasma levels of glutamine and alanine (which act as alternative nitrogen carriers), low plasma levels of citrulline and arginine (downstream products of OTC activity), and markedly increased urinary excretion of orotic acid, a result of carbamoyl phosphate being shunted into an alternative pyrimidine biosynthesis pathway.[17]

Due to its X-linked inheritance pattern, OTC deficiency primarily affects males more severely. However, heterozygous females can exhibit a wide range of clinical severity, from being completely asymptomatic to experiencing severe, life-threatening hyperammonemic episodes. This variability in females is largely attributed to the random pattern of X-chromosome inactivation in their hepatocytes; if the X chromosome carrying the normal OTC allele is predominantly inactivated, a female can have significant enzyme deficiency and clinical disease.[17] This genetic nuance complicates diagnosis and management, particularly in females, but also implies that a therapy capable of restoring enzyme function could benefit a broader spectrum of affected individuals.

3.2. Clinical Manifestations and Unmet Medical Need

The clinical presentation of OTC deficiency is heterogeneous and depends on the degree of residual enzyme activity. Severe, neonatal-onset forms typically manifest within the first few days of life, often after protein feeding is initiated. Symptoms include poor feeding, vomiting, lethargy, tachypnea, hypothermia, irritability, seizures, and rapid progression to coma due to hyperammonemic encephalopathy. Such crises are frequently precipitated or exacerbated by catabolic states like sepsis.[1] Without prompt and aggressive intervention, neonatal-onset OTC deficiency carries a high risk of mortality and severe, irreversible neurological impairment in survivors.[8]

Later-onset forms of OTC deficiency can present at any time from infancy through adulthood. These individuals may experience intermittent episodes of hyperammonemia, often triggered by metabolic stressors such as illness, surgery, or increased dietary protein intake. Symptoms during these episodes can include vomiting, confusion, ataxia, behavioral changes, and lethargy, potentially progressing to coma. Chronic or recurrent hyperammonemia, even if subclinical, can lead to progressive neurocognitive impairment, developmental delay, and psychiatric disturbances.[1] Liver dysfunction can also occur. Even with current medical management, a significant proportion of children who survive OTC deficiency suffer from disabling neurological complications.[8]

The current standard of care for OTC deficiency is primarily aimed at reducing ammonia production and enhancing its removal. This involves a lifelong, highly restrictive low-protein diet, supplementation with essential amino acids and arginine (or citrulline), and the use of nitrogen-scavenging medications such as sodium phenylbutyrate, glycerol phenylbutyrate, or sodium benzoate.[1] These therapies are burdensome for patients and families, require meticulous monitoring, and often do not fully prevent metabolic decompensation or long-term complications. The only curative treatment currently available is liver transplantation, which replaces the deficient enzyme source but carries its own substantial risks, including surgical complications, lifelong immunosuppression, and limited organ availability.[1]

Given these limitations, there is a profound unmet medical need for safer and more effective therapies that can address the underlying enzymatic defect in OTC deficiency. An estimated 10,000 individuals are affected in Europe and the United States alone.[1] The development of a therapy that could restore intrinsic OTC enzyme activity, even partially, could dramatically improve the quality of life and long-term prognosis for these patients by reducing the risk of hyperammonemic crises and their devastating neurological consequences.

4. ARCT-810: Mechanism of Action and Delivery System

4.1. Restoration of OTC Enzyme Function in Hepatocytes

ARCT-810 is an investigational mRNA therapeutic designed to directly address the molecular defect in OTC deficiency. The drug product consists of a synthetic mRNA molecule encoding the normal human OTC enzyme.[1] Following intravenous administration, ARCT-810 is intended to be delivered to hepatocytes. Once inside these liver cells, the mRNA sequence is translated by the host cell's natural protein synthesis machinery (ribosomes) into functional OTC protein.[16] This newly synthesized OTC enzyme is expected to localize to the mitochondria—the site of urea cycle activity—and participate in the conversion of ammonia to urea, thereby restoring or augmenting the deficient metabolic pathway.[1]

A notable feature of the ARCT-810 mRNA construct is the incorporation of three specific amino acid modifications compared to the wild-type OTC enzyme sequence. These engineered changes are intended to enhance the therapeutic properties of the expressed protein, potentially by increasing its in vivo half-life and/or improving its targeting efficiency to the mitochondria.[5] This rational design approach aims to optimize the efficacy of the enzyme replacement beyond simply providing the native sequence.

4.2. The LUNAR® Lipid Nanoparticle (LNP) Delivery Platform

The delivery of the OTC mRNA to hepatocytes is facilitated by Arcturus Therapeutics' proprietary LUNAR® (Lipid-enabled and Unlocked Nucleomonomer Agent RNA) lipid-mediated delivery system.[1] LNPs are multi-component lipid formulations specifically designed to encapsulate and protect nucleic acid payloads, such as mRNA, from degradation by nucleases present in the bloodstream. Furthermore, LNPs facilitate the uptake of the mRNA into target cells.[2] For ARCT-810, the LUNAR® LNPs are engineered for preferential delivery to the liver following intravenous administration.

A critical component of the LUNAR® platform is Arcturus's extensive and proprietary library of ionizable lipids. These lipids are essential for both efficient encapsulation of the negatively charged mRNA during formulation and for facilitating the release of the mRNA from endosomal compartments into the cytoplasm of the hepatocyte after cellular uptake. This endosomal escape is a crucial step, as the mRNA must reach the cytoplasm to be translated by ribosomes.[5] The LUNAR® platform's versatility is demonstrated by its application across Arcturus's broader pipeline, including self-amplifying mRNA (STARR®) vaccines and other therapeutic candidates targeting different tissues and delivery routes, such as inhaled mRNA for cystic fibrosis.[2]

Pharmacokinetic data from early clinical studies of ARCT-810 indicate that the ionizable lipid component of the LUNAR® LNP has a relatively short plasma presence, being detectable for less than 48 hours post-infusion. In contrast, the mRNA payload itself can be detected in plasma for a more extended period, up to 15 days.[5] This differential pharmacokinetic profile—rapid clearance of the delivery vehicle components while the therapeutic payload persists—is an important characteristic for a therapy intended for repeated administration. The transient nature of the LNP components minimizes the risk of lipid accumulation and associated dose-dependent toxicities, which is a critical consideration for the long-term safety of chronically administered LNP-based therapeutics.

5. Preclinical Evidence and Development Rationale

5.1. Proof-of-Concept in Animal Models

The advancement of ARCT-810 into clinical trials was underpinned by compelling preclinical proof-of-concept data. Studies utilizing the spf/ash mouse model, a well-established animal model that recapitulates key features of human OTC deficiency, demonstrated that LUNAR®-formulated OTC mRNA (ARCT-810) could be effectively delivered to liver cells, leading to the expression of functional OTC protein.[4]

This restoration of enzyme activity translated into tangible physiological benefits. Treatment with ARCT-810 resulted in significant improvements in critical biochemical markers of urea cycle function in these mice. Specifically, reductions were observed in plasma ammonia levels, plasma glutamine concentrations, and urinary orotic acid excretion. Furthermore, an improvement in overall ureagenesis capacity was documented.[4] Perhaps most significantly, weekly intravenous administration of ARCT-810 conferred a survival advantage to spf/ash mice, particularly when they were subjected to a high-protein diet—a metabolic challenge that mimics conditions leading to hyperammonemic crises in human OTC deficiency patients.[5] The ability of ARCT-810 to not only correct biochemical defects but also improve survival under metabolic stress provided a strong indication of its potential clinical utility.

5.2. Optimized mRNA Construct and Dose Estimation

The ARCT-810 therapeutic candidate utilizes an mRNA sequence that has been engineered with three specific amino acid changes compared to the wild-type human OTC enzyme. These modifications were rationally designed with the aim of enhancing the in vivo properties of the expressed enzyme, specifically by potentially increasing its protein half-life and improving its targeting to the mitochondria, the subcellular compartment where the urea cycle operates.[5] This proactive protein engineering at the mRNA level suggests an effort to maximize the therapeutic impact of each dose.

Based on the dose-response relationships observed in these preclinical efficacy studies, the Minimal Anticipated Biological Effect Level (MABEL) for ARCT-810 was estimated to be 0.1 mg/kg.[5] This MABEL value served as a critical reference point for the selection of safe starting doses in the subsequent first-in-human clinical trials.

5.3. Strategic Rationale for Clinical Development

The robust preclinical data package, demonstrating successful LNP-mediated mRNA delivery, functional enzyme expression, correction of disease-specific biomarkers, and a survival benefit in a relevant disease model, provided a strong scientific and clinical rationale for advancing ARCT-810 into human trials.[4] The primary development goal is to offer a therapy that addresses the fundamental enzymatic defect in OTC deficiency, thereby providing a disease-modifying treatment rather than merely palliating the symptoms of ammonia accumulation.[2]

Further underscoring the company's confidence in the program, Arcturus Therapeutics reassumed 100% global rights for ARCT-810 in February 2019, following a prior 50/50 collaboration with CureVac AG. At that time, Arcturus announced plans to file an Investigational New Drug (IND) application with the FDA in the fourth quarter of 2019.[4] This strategic move to consolidate control over a flagship rare disease asset often signals a strong internal belief in its potential, likely driven by the encouraging preclinical outcomes.

6. Clinical Development Program

The clinical development of ARCT-810 has progressed through Phase 1 studies in healthy volunteers and OTC deficient adults to the current Phase 2 multiple-dose studies in adolescent and adult patients with OTC deficiency.

Table 2: Overview of ARCT-810 Clinical Trials

Trial Identifier (NCT/EudraCT)	Phase	Brief Title/Objective	Status (as of early-mid 2025)	Region(s)	No. of Participants (Actual/Planned)	Key Population	Primary Endpoints
ARCT-810-01 (Not specified)	Phase 1	SAD in Healthy Volunteers	Completed (2020)	New Zealand	30	Healthy Adults	Safety, Tolerability, PK
ARCT-810-02 (Not specified)	Phase 1b	SAD in OTCD Adults	Completed	Europe	16	Stable, Mild OTCD Adults	Safety, Tolerability, PK
EUCTR2021-001081-38 (ARCT-810-03)	Phase 2	Randomized, Double-Blind, Placebo-Controlled, Nested Single and Multiple Ascending Dose Study in Adolescent and Adult OTCD Participants	Completed (Initial Cohorts)/Ongoing (per company)	UK, EU	8 (initial cohort dosed)	OTCD Adolescents (≥12y) & Adults	Safety, Tolerability, PK
NCT06488313 (ARCT-810-04)	Phase 2a	Open-Label, Multiple Ascending Dose Study to Evaluate Pharmacodynamics and Safety in Adolescent and Adult OTCD Participants	Recruiting	USA	Up to 9	OTCD Adolescents (≥12y) & Adults	Safety, Tolerability, PD (Urea Cycle Biomarkers)

6.1. Phase 1 Studies

6.1.1. ARCT-810-01: Single Ascending Dose Study in Healthy Adult Volunteers

The initial first-in-human evaluation of ARCT-810 was conducted in a Phase 1, single-ascending dose (SAD), randomized (2:1, ARCT-810 to placebo), placebo-controlled study in 30 healthy adult volunteers in New Zealand, completed in 2020.[5] Participants received a single intravenous (IV) infusion of ARCT-810 at doses ranging from 0.1 mg/kg to 0.4 mg/kg, or placebo, administered over 90 minutes. All subjects received premedication with ibuprofen and H1/H2 histamine receptor antagonists.[5]

The primary objective was to assess the safety and tolerability of ARCT-810. Pharmacokinetics (PK) of both the mRNA component and the LUNAR® ionizable lipid were secondary objectives. Exploratory pharmacodynamic (PD) measures, including ureagenesis assays and plasma OTC enzyme activity, were also evaluated, although no significant changes were anticipated in healthy individuals with normal endogenous OTC function.[5]

ARCT-810 was reported to be generally well-tolerated. Observed adverse events (AEs) were predominantly mild and non-serious. There were no significant safety concerns identified from vital signs, physical examinations, electrocardiograms (ECGs), or laboratory assessments. A notable finding was a moderate infusion-related reaction (IRR) in the sentinel subject of the 0.4 mg/kg dose cohort. This event led to a modification of the infusion protocol to a 2-step, 90-minute procedure for subsequent subjects in that cohort, after which no further IRRs were observed at that dose level.[5] Pharmacokinetic analysis demonstrated a dose-proportional increase in ARCT-810 exposure. The mRNA component was detectable in plasma for up to 15 days post-dose, whereas the ionizable lipid component of the LUNAR® delivery system was cleared more rapidly, being detectable for less than 48 hours.[5] As expected, no changes in ureagenesis or plasma OTC activity were seen in these healthy volunteers.[5]

6.1.2. ARCT-810-02: Single Ascending Dose Study in Adults with Stable OTC Deficiency

Following the healthy volunteer study, a Phase 1b SAD study (ARCT-810-02) was conducted in Europe, enrolling 16 adult participants (age range 22-68 years) with a documented diagnosis of mild, stable OTC deficiency. This study, which was recently completed, randomized participants 3:1 to receive a single IV dose of ARCT-810 or placebo.[5] Dose cohorts evaluated were 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, and 0.5 mg/kg. Infusions were administered using either a 90-minute 2-step protocol or a 3-hour 3-step protocol, with premedication consisting of ibuprofen and H1/H2 blockers.[5]

The primary objective remained the assessment of safety and tolerability, with PK as a secondary objective. Exploratory PD objectives included the evaluation of changes in key biomarkers of urea cycle function, such as plasma ammonia, plasma amino acids (glutamine, citrulline, arginine), urine orotic acid, plasma OTC enzyme activity, and ureagenesis as measured by a 13C-acetate breath test.[5]

ARCT-810 was generally found to be safe and well-tolerated in this patient population. No serious or severe AEs, and no dose-limiting toxicities were reported. Vital signs, physical examinations, ECGs, and safety laboratory parameters did not reveal any significant safety concerns. IRRs occurred in 3 of the 11 participants who received ARCT-810 (one mild IRR at 0.2 mg/kg; two moderate IRRs at 0.3 mg/kg and 0.5 mg/kg). One participant in the 0.3 mg/kg cohort withdrew from the study due to an IRR. These IRRs were reported to be associated with transient changes in complement activation markers, high-sensitivity C-reactive protein (hsCRP), and cytokine levels. Observations suggested that slower infusion rates might reduce the frequency and severity of IRRs.[5]

The PK profile of ARCT-810 in OTCD patients was similar to that observed in healthy volunteers. Maximum plasma concentrations (Cmax) of the mRNA were typically observed at the end of the infusion. The terminal half-life (t½) of the mRNA was estimated to be approximately 52-62 hours, with mRNA detectable in plasma for 2-4 weeks post-dose. Consistent with the healthy volunteer data, the ionizable lipid component was not detected in plasma beyond 48 hours post-infusion.[5]

In terms of exploratory PD endpoints, no clear trends or significant changes from baseline were identified for any of the measured urea cycle biomarkers after a single dose of ARCT-810. This outcome was attributed by the investigators to several factors: the study's primary focus on safety with a single dose administration, the generally mild nature of OTC deficiency in the enrolled participants (many of whom were stable on existing dietary management and/or nitrogen-scavenging therapies), and the possibility that the ureagenesis assay, performed 24 hours post-dose, was conducted too early to detect a significant change in enzyme activity. The company concluded that demonstrating proof of activity would likely necessitate multiple-dose studies in patients with more severe OTC deficiency.[5]

6.2. Phase 2 Studies

The clinical development of ARCT-810 has progressed to Phase 2, with multiple-dose studies designed to further evaluate safety, tolerability, and pharmacodynamic effects, including potential efficacy signals.

6.2.1. ARCT-810-03 (EUCTR2021-001081-38): European Multicenter Study

This Phase 2 study is a randomized, double-blind, placebo-controlled, nested single and multiple ascending dose trial conducted in Europe and the UK.[7] It is designed to evaluate the safety, tolerability, and pharmacokinetics of ARCT-810 in adolescent (≥12 years) and adult participants with OTC deficiency.[8] Participants are randomized on a 3:1 basis to receive either ARCT-810 or placebo. The multiple-dose regimen involves up to six IV infusions administered at 14-day intervals.[8]

Arcturus Therapeutics has reported the completion of the dosing phase for an initial cohort of eight participants who received 0.3 mg/kg of ARCT-810 or placebo.[3] While the EU Clinical Trials Register indicates the trial status as "Completed" for several national sites (Belgium, Spain, France, Sweden, Italy) with a start date of December 23, 2021 [9], company communications in 2024 suggest the study is ongoing in the UK and EU.[6] This may reflect the completion of specific cohorts or national components, with the overall program or long-term follow-up continuing. The primary objectives focus on the safety and tolerability of multiple doses, with PK and exploratory PD markers as secondary and tertiary aims.[8] An update on this study was anticipated by July 1, 2024, though more recent communications point to broader Phase 2 interim data in Q2 2025.[6]

6.2.2. ARCT-810-04 (NCT06488313): US Open-Label Study

Initiated as an expansion of the Phase 2 program into the United States, ARCT-810-04 is a Phase 2a, open-label, multiple ascending dose study.[7] The study is designed to enroll up to nine adolescent (≥12 years of age) and adult participants with a confirmed clinical diagnosis of OTC deficiency.[10] Key inclusion criteria include a history of symptomatic hyperammonemia or documented elevations in plasma ammonia or glutamine, and participants must be clinically stable on their current OTC deficiency management (protein-restricted diet, dietary supplements, and/or ammonia scavenger regimen, if applicable) for at least 28 days prior to enrollment.[10] Exclusion criteria are comprehensive, ruling out patients with recent OTC gene therapy, liver-derived stem cell therapy within the past 2-3 years, organ transplants, severe allergic reactions to LNP components, or other significant uncontrolled medical conditions.[11]

Participants in ARCT-810-04 receive five intravenous infusions of ARCT-810, administered every two weeks. The study evaluates one of three ascending dose levels, and there is no placebo arm.[1] The first participant was dosed in December 2024, starting at the 0.5 mg/kg dose level.[1] The total study duration for each participant is approximately 16 weeks, which includes a screening period (with at least 4 weeks of diet stabilization) and around 13 study visits. Participants continue their existing clinical management for OTC deficiency throughout the study.[10]

The primary objectives of ARCT-810-04 are to evaluate the safety and tolerability of multiple doses of ARCT-810. Secondary and exploratory objectives focus on assessing the drug's efficacy in restoring urea cycle function, as measured by changes in clinical biomarkers such as plasma ammonia, plasma amino acid profiles (glutamine, citrulline, arginine), urine orotic acid levels, plasma OTC enzyme activity, and ureagenesis assays.[10] The study is actively recruiting and is being conducted at Uncommon Cures in Chevy Chase, Maryland, USA.[3]

The strategic shift from a placebo-controlled design in the European Phase 2 study to an open-label design for the US Phase 2a study is noteworthy. This change likely reflects an accumulation of safety data from the Phase 1 program and initial cohorts of the European Phase 2 study, potentially de-risking the compound sufficiently to proceed without a concurrent placebo group in the US. In rare diseases with high unmet medical needs, such as OTC deficiency, an open-label design can facilitate faster recruitment and allows all participants to receive the investigational therapy, thereby maximizing the data collected on pharmacodynamic responses and dose-effect relationships for key biomarkers. This approach is critical for informing dose selection for subsequent pivotal studies.

6.3. Anticipated Data Readouts and Milestones

Arcturus Therapeutics has guided that interim data from the ongoing Phase 2 program for ARCT-810 are expected in the second quarter of 2025.[12] These data will be crucial in assessing the multi-dose safety profile and the potential for ARCT-810 to achieve clinically meaningful pharmacodynamic effects on urea cycle biomarkers.

The consistent inclusion of adolescents (≥12 years) in the Phase 2 studies, coupled with an EMA-approved Pediatric Investigation Plan (PIP) [1] and FDA Rare Pediatric Disease Designation [1], underscores a clear regulatory and clinical strategy to develop ARCT-810 for younger patient populations. Given that OTC deficiency often manifests with severe consequences early in life, establishing efficacy and safety in pediatric patients will be a critical long-term goal for the program, aimed at preventing irreversible neurological damage.

7. Safety and Tolerability Profile

The safety and tolerability of ARCT-810 have been evaluated in single ascending dose studies in both healthy adult volunteers (ARCT-810-01) and adult patients with stable, mild OTC deficiency (ARCT-810-02).

Table 3: Summary of Key Safety Findings for ARCT-810 (Phase 1/1b SAD Studies)

Feature	ARCT-810-01 (Healthy Volunteers) 5	ARCT-810-02 (OTCD Adults) 5
Most Common Adverse Events	Mild, non-serious AEs typical for Phase 1 studies.	Treatment-related TEAEs in 6/11 (54.5%) ARCT-810 subjects (mostly mild; 2 moderate). Symptoms included nausea, abdominal cramps, flushing, leg pain. No TEAEs in placebo group (N=5).
Serious Adverse Events (SAEs)	None reported.	None reported.
Dose-Limiting Toxicities (DLTs)	None reported.	None reported.
Infusion-Related Reactions (IRRs)	One moderate IRR at 0.4 mg/kg (flat 90-min infusion), resolved with protocol modification (2-step infusion).	3 IRRs in 11 ARCT-810 subjects (27.3%): 1 mild (0.2 mg/kg), 2 moderate (0.3 mg/kg, 0.5 mg/kg). One withdrawal (0.3 mg/kg) due to IRR. Symptoms: chest pain, tachycardia, nausea, flushing. Associated with transient complement/cytokine changes.
Other Safety Observations	No safety concerns for vitals, ECGs, labs.	No safety concerns for vitals, ECGs, labs.

In the ARCT-810-01 study with healthy volunteers, ARCT-810 was generally well-tolerated. Adverse events were mild and non-serious. A single moderate IRR was observed in a subject receiving 0.4 mg/kg via a flat 90-minute infusion. This led to a protocol amendment to a 2-step, 90-minute infusion, after which no further IRRs were noted in that cohort.[5]

In the ARCT-810-02 study involving adults with mild OTC deficiency, ARCT-810 was also generally safe and well-tolerated. No SAEs or DLTs occurred. Treatment-related TEAEs were reported in 6 of 11 (54.5%) participants receiving ARCT-810, mostly mild in severity, with two cases being moderate. In contrast, no treatment-related TEAEs were reported in the five placebo recipients. IRRs were observed in three ARCT-810-treated participants: one mild IRR at the 0.2 mg/kg dose, and two moderate IRRs, one at 0.3 mg/kg (leading to study withdrawal) and one at 0.5 mg/kg. Symptoms associated with these IRRs included chest pain, tachycardia, mild oxygen desaturation (particularly when infusion was started via a central IV port in one case), nausea, abdominal cramps, flushing, leg pain, and transient bradycardia. These reactions were associated with transient elevations in complement activation markers, hsCRP, and cytokines. Investigators noted that slower infusion rates appeared to reduce the frequency and severity of IRRs, and a 3-step, 3-hour infusion protocol was explored.[5]

The ongoing Phase 2 studies (ARCT-810-03 and ARCT-810-04) are further assessing the safety and tolerability of multiple doses of ARCT-810.[8] Management strategies for IRRs, including premedication (ibuprofen, H1/H2 blockers) and optimized infusion protocols, are integral to these studies.[5] The company has acknowledged the need to further optimize premedication regimens for OTCD patients, potentially considering alternatives to corticosteroids due to contraindications in this patient population.[5]

The occurrence of IRRs is a known class effect for LNP-delivered nucleic acid therapeutics, often attributed to the activation of the complement system or other innate immune responses. The proactive approach by Arcturus in modifying infusion protocols and premedication regimens indicates an adaptive strategy to manage these AEs. The long-term success of ARCT-810 will depend, in part, on the ability to establish a well-tolerated dosing regimen that minimizes the frequency and severity of IRRs, ensuring patient compliance and a favorable risk-benefit profile for chronic administration.

8. Pharmacodynamic and Potential Efficacy Data

The primary pharmacodynamic goal of ARCT-810 is to restore or enhance urea cycle function in patients with OTC deficiency. This is assessed through a panel of biomarkers.

8.1. Biomarkers of Urea Cycle Function

Key biomarkers monitored in the clinical development program include [5]:

• Plasma Ammonia (NH4): A direct indicator of urea cycle dysfunction; reduction is a primary therapeutic goal.
• Plasma Amino Acids:
• Glutamine and Alanine: Often elevated as they serve as alternative nitrogen carriers when ammonia detoxification is impaired.
• Citrulline and Arginine: May be low as they are downstream products of OTC activity.
• Urine Orotic Acid: Elevated due to shunting of carbamoyl phosphate into pyrimidine synthesis when the urea cycle is blocked at the OTC step.
• Plasma OTC Enzyme Activity: Direct measurement of the target enzyme, if feasible and reflective of intrahepatic activity.
• Ureagenesis Assays: Functional tests, such as those using 13C-labelled acetate or 15N-labelled ammonium chloride as tracers, to measure the liver's capacity to synthesize urea.

8.2. Findings from Phase 1b Study (ARCT-810-02)

In the Phase 1b SAD study involving adults with mild, stable OTC deficiency, no clear trends or significant changes from baseline were observed in any of the exploratory PD biomarkers after a single dose of ARCT-810.[5] This outcome was attributed to several factors:

• The study's primary objective was safety, and a single dose was not necessarily expected to elicit robust PD effects in this specific population.
• Most participants had mild OTC deficiency and were already well-managed with protein-restricted diets and/or nitrogen-scavenging therapies, potentially masking subtle improvements.
• The ureagenesis assay, performed 24 hours post-dose, might have been conducted too early to capture the peak effect of newly synthesized OTC enzyme.[5]

The investigators concluded that demonstrating proof of activity and clinical benefit would likely require multiple-dose studies, particularly in patients with more significant OTC deficiency or less optimized baseline management.[5]

8.3. Potential for Clinical Benefit and Phase 2 Objectives

The ultimate therapeutic goal for ARCT-810 is to restore sufficient functional OTC enzyme activity in the liver to significantly reduce blood ammonia levels, thereby eliminating or reducing the frequency and severity of hyperammonemic crises. This, in turn, could prevent or mitigate progressive neurocognitive impairment and improve the overall quality of life for individuals with OTC deficiency.[1]

The ongoing Phase 2 studies (ARCT-810-03 and ARCT-810-04) are designed to assess these pharmacodynamic effects with multiple doses of ARCT-810. The open-label design of ARCT-810-04, in particular, will allow for the evaluation of dose-response relationships for these biomarkers across all participants.[11] The insights from the Phase 1b study regarding biomarker assessment, such as the potential need for 24-hour ammonia profiling (as opposed to single fasting ammonia levels) and optimization of stable isotope labels for ureagenesis assays, are likely informing the PD evaluation strategy in these multi-dose trials.[5] The interim data from these Phase 2 studies, expected in Q2 2025, will be critical for demonstrating whether ARCT-810 can achieve clinically meaningful modulation of urea cycle function.[12]

9. Regulatory Landscape

ARCT-810 has received several important regulatory designations from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), reflecting the significant unmet medical need in OTC deficiency and the potential of this novel therapeutic approach.

Table 4: Regulatory Designations for ARCT-810

Regulatory Agency	Designation Type	Date Granted (if available)	Indication Covered	Key Snippets
FDA	Orphan Drug Designation	Prior to Feb 2019 (reaffirmed)	Ornithine Transcarbamylase Deficiency	1
FDA	Rare Pediatric Disease Designation	Prior to Dec 2024	Ornithine Transcarbamylase Deficiency	1
FDA	Fast Track Designation	April 2025	Ornithine Transcarbamylase Deficiency	12
EMA	Orphan Medicinal Product Designation	Granted	Ornithine Transcarbamylase Deficiency	1
EMA	Approved Pediatric Investigation Plan (PIP)	Approved	Ornithine Transcarbamylase Deficiency	1

9.1. U.S. Food and Drug Administration (FDA)

• Orphan Drug Designation: ARCT-810 has received Orphan Drug Designation from the FDA for the treatment of OTC deficiency. This status is granted to drugs intended for rare diseases or conditions affecting fewer than 200,000 people in the U.S. and provides incentives such as tax credits for clinical trials, exemption from user fees, and potential for seven years of market exclusivity upon approval.[1]
• Rare Pediatric Disease Designation: The FDA has also granted ARCT-810 Rare Pediatric Disease Designation for OTC deficiency. This designation is for serious or life-threatening diseases primarily affecting individuals aged from birth to 18 years. If ARCT-810 is approved for this indication, Arcturus Therapeutics may be eligible to receive a Priority Review Voucher (PRV). A PRV can be redeemed to obtain priority review for a subsequent marketing application for a different product or can be sold to another company.[1]
• Fast Track Designation: In April 2025, the FDA granted Fast Track Designation to ARCT-810 for the treatment of OTC deficiency. This designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. Benefits include more frequent meetings with the FDA, eligibility for Accelerated Approval and Priority Review if relevant criteria are met, and the option for a Rolling Review of the marketing application.[12]

9.2. European Medicines Agency (EMA)

• Orphan Medicinal Product Designation: ARCT-810 has received Orphan Medicinal Product Designation from the EMA for the treatment of OTC deficiency. Similar to the FDA's designation, this status is for drugs intended for life-threatening or chronically debilitating rare conditions (affecting not more than 5 in 10,000 people in the EU) and provides benefits such as protocol assistance, fee reductions, and ten years of market exclusivity in the EU upon marketing authorization.[1]
• Approved Pediatric Investigation Plan (PIP): The EMA has approved a PIP for ARCT-810. A PIP is a mandatory development plan aimed at ensuring that the necessary data are obtained through studies in children to support the authorization of a medicine for pediatric use. Agreement on a PIP is a prerequisite for filing a Marketing Authorisation Application for any new medicine in Europe.[1]

The combination of these regulatory designations provides Arcturus Therapeutics with significant strategic advantages. They facilitate more frequent interactions with regulatory agencies, offer financial incentives, and can lead to expedited review processes and extended market exclusivity if ARCT-810 successfully demonstrates safety and efficacy. This comprehensive regulatory support underscores the recognition of OTC deficiency as a serious condition with a high unmet medical need and acknowledges the potential of ARCT-810 as an innovative therapeutic solution.

10. Manufacturing and Formulation

ARCT-810 is an mRNA-based therapeutic, and its manufacturing involves specialized processes for both the mRNA drug substance and the LUNAR® LNP drug product. Arcturus Therapeutics leverages its proprietary mRNA design constructs and manufacturing processes for ARCT-810.[1] The company highlights its mRNA drug substance and drug product manufacturing expertise, which is also a component of its collaborations with other entities, such as CSL Seqirus for vaccine development.[2]

The LUNAR® lipid nanoparticle technology is central to the formulation of ARCT-810. This system is designed to encapsulate the OTC mRNA, protect it from degradation, and facilitate its delivery to hepatocytes following intravenous administration.[1] The specific composition of the lipids within the LNP, particularly the proprietary ionizable lipid, is critical for the formulation's stability, delivery efficiency, and endosomal escape characteristics.[5]

The ability to control and optimize these manufacturing and formulation processes is a significant aspect of developing mRNA therapeutics. Arcturus's in-house expertise in these areas provides a degree of control over product quality and scalability, which is crucial for advancing ARCT-810 through clinical trials and, potentially, towards commercialization. This vertical integration can be particularly advantageous in managing the complexities of producing consistent LNP-mRNA formulations.

11. Developer Profile: Arcturus Therapeutics

11.1. Company Overview and Focus

Arcturus Therapeutics Holdings Inc. (NASDAQ: ARCT) is a global, commercial-stage messenger RNA (mRNA) medicines company. Its strategic focus encompasses the development of infectious disease vaccines and therapeutic opportunities within rare liver and respiratory diseases.[1] The company's pipeline prominently features ARCT-810 (LUNAR-OTC) for Ornithine Transcarbamylase deficiency and ARCT-032 (LUNAR-CF) for Cystic Fibrosis, alongside partnered vaccine programs, notably with CSL Seqirus for COVID-19 (KOSTAIVE®) and influenza.[1]

11.2. Historical Collaborations Relevant to ARCT-810

The development of ARCT-810 initially involved a 50/50 collaboration with CureVac AG. However, in February 2019, Arcturus Therapeutics announced that it had reassumed 100% global rights to ARCT-810 after CureVac elected not to continue its obligations for the preclinical development of this specific asset. At the time, CureVac remained committed to developing other assets within the broader collaboration, utilizing CureVac's mRNA technology and Arcturus's LUNAR® delivery platform.[4] This decision by Arcturus to fully internalize the ARCT-810 program signaled a strong belief in its potential.

11.3. Financial Position

As of the first quarter of 2025, Arcturus Therapeutics reported that its cash runway is expected to extend into 2028. This financial guidance is based on the company's current pipeline and programs, reflecting a strategic prioritization of its mRNA therapeutics pipeline, including ARCT-810 and ARCT-032.[12] This financial stability is crucial for sustaining the resource-intensive clinical development of its lead rare disease candidates. The company's strategic focus on its core rare disease assets, such as ARCT-810, while leveraging partnerships for broader vaccine applications, appears to be a key element of its operational and financial planning.

12. Scientific Dissemination and Future Directions

12.1. Key Presentations and Publications

Arcturus Therapeutics has actively disseminated preclinical and early clinical data on ARCT-810 at relevant scientific conferences. A significant presentation occurred at the 45th Annual Society for Inherited Metabolic Disorders (SIMD) meeting in April 2024. Dr. Markey McNutt from UT Southwestern Medical Center presented an update titled "It translates: an update on the ARCT-810 mRNA therapy for OTC deficiency".[5] This presentation included safety and pharmacokinetic data from the completed Phase 1 SAD study in healthy volunteers (ARCT-810-01) and the Phase 1b SAD study in adults with mild OTC deficiency (ARCT-810-02).[5] Earlier, in May 2019, the company had also planned to present updates on ARCT-810 at the TIDES: Oligonucleotide & Peptide Therapeutics conference, indicating early efforts to engage with the scientific community.[4]

12.2. Future Clinical Development

The primary focus for ARCT-810 is the continued advancement and completion of its Phase 2 clinical studies: ARCT-810-03 in Europe/UK and ARCT-810-04 in the US.[12] A key upcoming milestone is the anticipated release of interim data from these Phase 2 studies in the second quarter of 2025.[12]

Based on the learnings from the Phase 1b study, which did not show clear pharmacodynamic biomarker changes after a single dose in mildly affected, well-managed patients, the multi-dose design of the Phase 2 trials is critical. These studies will be essential for determining if repeated dosing of ARCT-810 can lead to sustained and clinically meaningful improvements in urea cycle biomarkers and, ultimately, clinical outcomes. The company has acknowledged that further studies in patients with more severe OTC deficiency and in younger pediatric populations are warranted.[5] The validation of specific pharmacodynamic biomarkers, such as 24-hour ammonia profiles (as opposed to single fasting ammonia measurements) and the optimization of stable isotope labels (e.g., 13C vs. 15N) for ureagenesis assays, will also be important components of future clinical assessments.[5] This iterative learning process, refining biomarker strategies and trial designs based on emerging data, is characteristic of efficient drug development for complex rare diseases.

12.3. Potential Impact

If the ongoing and future clinical trials demonstrate robust efficacy and a favorable long-term safety profile, ARCT-810 has the potential to be a transformational, disease-modifying therapy for individuals with OTC deficiency.[1] By addressing the root enzymatic defect, ARCT-810 could significantly reduce the burden of current management strategies, prevent life-threatening hyperammonemic crises, and mitigate the progressive neurocognitive damage associated with the disorder. The success of ARCT-810 would also provide significant validation for Arcturus's LUNAR® LNP platform for systemic mRNA delivery to the liver, potentially de-risking its application for other liver-targeted mRNA therapeutics in the company's pipeline and bolstering confidence in the broader field of mRNA-based medicines for genetic disorders.

13. Conclusion

ARCT-810 (LUNAR-OTC) represents a pioneering application of mRNA replacement therapy aimed at addressing the fundamental cause of Ornithine Transcarbamylase (OTC) deficiency. By utilizing the LUNAR® lipid nanoparticle platform to deliver functional OTC mRNA to hepatocytes, ARCT-810 seeks to enable patients to produce their own OTC enzyme, thereby restoring urea cycle function and mitigating the severe consequences of ammonia accumulation.

Preclinical studies have provided a strong rationale for its development, demonstrating efficacy in animal models of OTC deficiency. Early-phase clinical trials (Phase 1 and 1b) have established an initial safety and tolerability profile for single ascending doses, with infusion-related reactions being identified as manageable adverse events. Pharmacokinetic data from these studies support the feasibility of repeat dosing.

The program is now in Phase 2, with multiple-dose studies (ARCT-810-03 in Europe/UK and ARCT-810-04 in the US) underway in adolescent and adult patients. These trials are critical for evaluating the safety of repeated administrations and, importantly, for assessing whether ARCT-810 can produce clinically meaningful and sustained improvements in biomarkers of urea cycle function. Interim data from these Phase 2 studies, expected in Q2 2025, will be a key inflection point for the program.

Supported by multiple orphan drug and expedited pathway designations from both the FDA and EMA, ARCT-810 holds the promise of becoming a transformative, disease-modifying treatment for a patient population with significant unmet medical needs. Its success would not only offer a novel therapeutic option for OTC deficiency but also provide broader validation for LNP-mediated mRNA delivery to the liver for other genetic and metabolic disorders. The continued careful evaluation of multi-dose safety, the demonstration of robust and durable pharmacodynamic effects, and ultimately, positive clinical outcomes will determine the future trajectory of this innovative therapeutic candidate.

References

(Note: In a final report, this section would list all cited sources in a consistent citation style. For this exercise, the in-text citations suffice as per instructions.)

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