Arcturus Therapeutics Holdings Inc. Common Stock Status update

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Good afternoon and welcome to Arcturus Therapeutics presentation. Today's call will be led by Joe Payne, our President and CEO, Dr. Alan Cohen, our Chief Medical Officer, Dr. Marshall Summar, a recognized expert in rare diseases and OTC deficiency, and Dr. Pad Chivukula, our Chief Scientific Officer. Before we begin, please note that today's call may contain forward-looking statements. Such statements are based on current expectations and assumptions, and actual results may differ. Please refer to our filings made with the SEC, including the risk factors contained therein for more information. We undertake no obligation to update any forward-looking statement. With that, I will now turn the call over to Joe.

Thank you, Neda. Before we turn to the data, I want to frame the four key messages you will hear today. First, ARCT-810, our mRNA therapeutic candidate to treat OTC deficiency, has generated preliminary phase II clinical evidence that supports our core therapeutic hypothesis that with generally safe and well-tolerated repeat dosing, we can produce biomarker changes consistent with improved urea cycle function. Second, we introduce LUNAR 2.0, a new standard in mRNA delivery, producing greater than 30-fold higher protein expression in non-human primates across two different studies with two different mRNA payloads. Third, the LUNAR 2.0 delivery platform has been incorporated into our OTC deficiency program. We call this mRNA therapeutic candidate ARCT-2601. As advised by the FDA during our Type C meeting in June, we plan to integrate ARCT-2601 into the ongoing ARCT-810 phase II study this year.

LUNAR 2.0 is expected to help us achieve lower, less frequent dosing, and shorter infusion times. Fourth, our mRNA therapeutics platform, together with engineered mRNA and proprietary AI-enabled computational design capabilities, creates opportunities to expand our liver franchise into PKU, gout, and additional indications. Today's message is straightforward. Clinical validation today, a compellingly more powerful delivery platform going forward, and multiple new opportunities made possible with this new platform to create substantial value. Alan, I will turn the presentation over to you.

Thanks, Joe. Good afternoon, and thank you for joining. Today, I will walk you through ARCT-810, our LUNAR-OTC mRNA therapeutic candidate for ornithine transcarbamylase deficiency. The arc is simple. First, the disease and why current standards of care and clinical management options fall short. Then I will review Arcturus' clinical program to date, including the preliminary findings from our U.S. phase II study, summarizing safety, biomarkers, protein intake, and what this means for urea cycle function. Let's begin with the disease and the biology that makes mRNA a rational approach to consider and develop as a next-generation therapeutic option. Protein metabolism constantly generates ammonia, which is toxic to the brain even at modest levels. But through the urea cycle in the liver, ammonia is converted to urea, preventing ammonia buildup in the blood.

Ornithine transcarbamylase deficiency, or OTC deficiency, is the most common urea cycle disorder, affecting roughly 10,000 people across the United States and Europe. With deficient OTC enzyme expression or activity, if individuals consume a normal protein-containing diet, ammonia will accumulate in the blood, leading to potentially irreversible neurological damage and even coma or death. Today's standard of care asks people suffering with OTC deficiency to adhere to a strict low-protein, high-fluid diet and use ammonia scavenger medications to keep ammonia levels low. That regimen is demanding, and it still does not reliably prevent life-threatening ammonia spikes. For severe patients, liver transplantation unfortunately remains the only cure. That is the unmet medical need that LUNAR-OTC is designed to address.

To deliver mRNA to the liver, restore expression of the OTC enzyme, and reactivate urea cycle activity so ammonia is detoxified in the bloodstream before it causes harm, while potentially mitigating or forestalling the need for a liver transplant. With that in mind, let's look at ARCT-810's clinical trial journey. Here's a summary of the clinical development program for ARCT-810 thus far, from first in human studies through phase II. Phase I was first initiated in 24 healthy adult volunteers, where ARCT-810 was observed to be safe and generally well-tolerated. We then moved into a phase I-B single ascending dose study in 16 adults with OTC deficiency, testing doses from 0.2 to 0.5 milligrams per kilo, again with a clean safety and tolerability profile. Phase II moved to repeat dosing.

Our placebo-controlled study in the U.K. and Europe enrolled adolescents and adults at 0.3 milligrams per kilo with a total of six intravenous infusions every two weeks. We observed that ARCT-810 continued to be safe and generally well-tolerated across multiple repeated administrations. Limited glutamine measures suggested an early clinical signal via a reduction in the treated group versus placebo, an early signal of potential efficacy. With this supportive early clinical data, we then initiated a phase II study to evaluate two doses, 0.3 and 0.5 milligram per kilo over five intravenous infusions every two weeks. I will now share with you the preliminary data from this recently concluded phase II study. The phase II program was an open-label, U.S.-based study investigating the safety, PK, and efficacy of ARCT-810 at 0.3 and 0.5 milligrams per kilo over 10 weeks with a four-week observation follow-up period after discontinuation of study drug.

Eight adolescents and adults with confirmed OTC deficiency were enrolled, four individuals per dosing cohort. For four weeks prior to dosing, participants were required to be on a stable protein-restricted diet as well as continue their standard of care medical management, including all of their typical medications. In this phase II study, we observed that ARCT-810 continued to be safe and well-tolerated across repeated dosing at both the 0.3 and 0.5 milligram per kilogram doses. There were no serious adverse events and no adverse events of special interest, and most importantly, no hyperammonemia events observed in either dosing cohort. Every study participant had at least one treatment-emergent adverse event, but the large majority were mild to moderate, and the most common were headache, transaminitis, and infusion-related reactions, each in two of eight participants.

Two grade 3 events occurred, both asymptomatic transaminitis, and both resolved without intervention after study drug was stopped. One discontinuation was the result of an intravenous infiltration and a subsequent injection site reaction, a procedural event rather than a systemic drug effect. Based on these safety and tolerability findings, we are overall pleased with the safety profile of ARCT-810. Regarding the phase II study measures of efficacy at both the 0.3 and 0.5 milligram per kilo doses, we measured several relevant biomarkers and clinically meaningful functional measures for people with OTC deficiency. Effects in the urea cycle impact protein metabolism and lead to a buildup of ammonia in the bloodstream, which also unfortunately can cross the blood-brain barrier and cause transient and more permanent injury to the brain and central nervous system. When the nitrogen load increases, glutamine levels also increase.

These two biomarkers of urea cycle function are routinely used in the clinical care of those with OTC deficiency to assess urea cycle activity and serve to direct clinical decision-making and management. As such, we measured both ammonia and glutamine levels in the blood. We also measured OTC activity by looking at the formation of urea cycle byproducts in a metric called relative urea function. Since these biomarkers are influenced by the consumption of protein, referred to as the protein load, we additionally examined how dietary protein intake compared in study subjects pre- and post-ARCT-810 administration. The table on the right shows the baseline characteristics of seven individuals who received more than one dose of ARCT-810. The current phase II study focused on adolescents and adults with OTC deficiency, and given the X-linked recessive genetics pattern of the disease, all of these adult subjects were not unexpectedly female.

Nearly all participants were also on nitrogen scavenger medications at baseline, which is typical of most individuals with OTC deficiency. We had all study subjects remain on their usual standards of care, including all of their dietary restrictions and medications. The first biomarker we will examine is ammonia. As mentioned, it is imperative to keep ammonia levels low to prevent neurological damage. To achieve this, many individuals with OTC deficiency are on ammonia scavenger medications, and not unexpectedly, most of our study participants were on these medications as well. At all reported ammonia measurements illustrated here, participants in both the 0.3 and 0.5 milligram per kilogram cohorts were on the same amount of ammonia scavenger medications. Thus, we would anticipate stability or a flat line in ammonia levels across the study period.

At 0.3 and 0.5 milligrams per kilo, we observed that mean first-morning fasting ammonia levels were generally similar or lower than baseline values. Of clinical importance, after either the 0.3 or 0.5 milligram per kilogram dose of ARCT-810, all individuals were able to achieve and maintain normal plasma ammonia levels. Glutamine is a physiologic repository of excess nitrogen. But like ammonia, too much glutamine can be toxic. Like ammonia, glutamine is an important measurement of urea cycle activity, often being used in clinical practice to direct diet and medication adjustments. In OTC deficiency, plasma glutamine can be elevated even when ammonia levels are normal, indicating persistent nitrogen excess and impaired urea cycle activity. Thus, glutamine can be a very useful and highly sensitive indicator of nitrogen burden and urea cycle activity. All study participants had elevated glutamine levels at baseline, even though most had normal ammonia levels.