ARWR: Interim Data for Phase 1/2 Trial of ARO-RAGE Shows Potential for Pulmonary TRiM™ Platform…
NASDAQ:ARWR
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Business Update
Interim Data for Phase 1/2 Trial of ARO-RAGE Shows Potential for Pulmonary Program
On April 25, 2023, Arrowhead Pharmaceuticals Inc (NASDAQ:ARWR) announced interim results from the ongoing Phase 1/2 clinical trial of ARO-RAGE, which is being developed to reduce production of the receptor for advanced glycation end products (RAGE) as a potential treatment for inflammatory diseases such as asthma. It is a two-part trial: Part 1 is a randomized, double blind, placebo controlled study in normal healthy volunteers; Part 2 is the same design but in patients with mild-to-moderate asthma.
The interim results from Part 1 of the study in normal healthy volunteers showed that following two doses of 92 mg on Day 1 and Day 29, reductions in soluble RAGE (sRAGE) as measured in the serum were as follows:
• The mean maximum reduction was 80% with a maximum reduction of 90%
• Mean maximum reductions at 10 mg to 44 mg dose levels showed a dose response ranging from 31% to 59%
• The duration of pharmacological effect persisted for at least six weeks following the second dose at the 92 mg level
Following a single dose, reductions in sRAGE in bronchoalveolar lavage fluid (BALF) on Day 31 showed:
• A mean reduction at 92 mg dose of 75% with a maximum reduction of 92%
• Mean reductions at 10 mg to 44 mg doses ranged from 44% to 52%
Following a single dose, reductions in serum sRAGE showed:
• A mean maximum reduction at 92 mg dose of 56% with a maximum reduction of 68%
• Mean maximum reductions at 10 mg to 44 mg dose levels showed a dose response that ranged from 23% to 53%
In contrast to patients treated with ARO-RAGE, pooled placebo groups had a mean sRAGE increase of 8% in BALF and a mean decrease of 1% in serum.
In regards to safety, there were no patterns of adverse changes in any clinical safety parameters, there were no reported serious or severe adverse events, and there were no discontinuations due to study drug or adverse events.
The duration of the pharmacologic effect persisted for at least six weeks following the second administration of the 92 mg dose. This is important as it suggests that monthly, bi-monthly, or even less frequent dosing may be possible with ARO-RAGE. In addition, the above results serve not only as a validation of ARO-RAGE as a potential therapy to treat inflammatory lung diseases but also as a validation for the pulmonary TRiM platform.
The data shown above includes results from 4 of 5 escalating dose levels, and data from the single and multiple dose cohorts at 184 mg will be reported later this year.
Update on Early Development Programs
ARO-MUC5AC: This product targets expression of mucin 5AC (MUC5AC) in bronchial epithelium. MUC5AC is a mucin protein that is upregulated in the airway of asthmatic patients (Bonser et al., 2017). As shown in MUC5AC knockout mice, it is not required for normal mucociliary transport or anti-bacterial defense (Roy et al., 2014). The protein plays a role in asthma pathogenesis based on results from ovalbumin sensitization and challenge studies (Evans et al., 2015). Arrowhead is currently conducting a Phase 1/2 trial similar in design to the ARO-RAGE trial and enrollment of the asthma patient cohort has commenced.
ARO-MMP7: Matrix metalloproteinase 7 (MMP7) is a secreted endopeptidase that is highly overexpressed in patients with idiopathic pulmonary fibrosis (IPF) (Bauer et al., 2017). It is useful as a biomarker due to its increased expression being correlated with disease progression. In addition, MMP7 knockout mice are protected from pulmonary fibrosis induced by intratracheal bleomycin (Zuo et al., 2002). Unfortunately, MMP7 is a difficult target for drug development as there is substantial domain homology with other MMPs, thus making gene silencing a potentially useful mechanism for downregulating MMP7 expression. Arrowhead recently initiated a Phase 1/2 single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-MMP7 in healthy volunteers and patients with IPF.
ARO-C3: This program is targeting complement component 3 (C3). The complement pathway is a part of the innate immune system and C3 activation is required for the classical complement pathway, the alternative complement pathway, and the lectin pathway. The company is conducting a Phase 1/2, placebo controlled, dose-escalating trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in up to 24 healthy volunteers (Part 1) and up to 14 adult patients with complement-mediated renal disease (Part 2).
The company recently reported interim topline data for Part 1 of the study. ARO-C3 demonstrated a dose-dependent mean reduction of 88% after two doses at the highest dose tested. In addition, a dose-dependent reduction in AH50, a marker of alternative complement pathway hemolytic activity, was seen with a 91% mean reduction at the highest dose tested. Due to its long duration of pharmacologic effect, it may be possible to dose quarterly or even less frequently.
Update on Cardiometabolic Candidates
The company’s two cardiometabolic candidates, ARO-APOC3 and ARO-ANG3, are currently being studied in multiple ongoing clinical trials. The U.S. FDA recently granted Fast Track designation to ARO-APOC3 for reducing triglycerides in adult patients with familial chylomicronemia syndrome (FCS) after previously being granted Orphan Drug designation by both the FDA and the EMA. ARO-APOC3 is currently being studied in the following trials:
PALISADE: This is a Phase 3, double blind, placebo controlled trial in patients with FCS. These patients have fasting triglyceride levels >880 mg/dL. Target enrollment of 72 patients has completed and patients are being assigned to one of four dose cohorts in a 2:1:2:1 manner (ARO-APOC3 25 mg, volume-matching placebo, ARO-APOC3 50 mg, volume-matching placebo). The primary endpoint of the trial is the percent change from baseline at month 10 in fasting triglycerides. Secondary and exploratory endpoints will include the change in lipid parameters, incidence of acute pancreatitis, and other measures. We anticipate study completion in the second quarter of 2024, a data readout shortly thereafter, and then preparation for a new drug application (NDA).
SHASTA-2: This is a Phase 2b, double blind, placebo controlled trial in patients with severe hypertriglyceridemia (SHTG; TG > 500 mg/dL). The primary endpoint of the trial is the safety and efficacy of ARO-APOC3 and to select a dosing regimen for later-stage patients in this population. The trial is fully enrolled with 216 subjects. We anticipate topline results being reported in the second half of 2023.
MUIR: This is a Phase 2b, double blind, placebo controlled trial in adults with mixed dyslipidemia, which is defined as having TG between 150 and 500 mg/dL and non-HDL cholesterol > 100 mg/dL or LDL cholesterol >70 mg/dL. The primary objective is to evaluate the safety and efficacy of ARO-APOC3 and to select a dosing regimen for later stage trials in this patient population. Enrollment of 353 patients has been reached. We anticipate topline results in the second half of 2023.
ARO-ANG3 targets the angiopoietin like protein 3 (ANGPTL3). ANGPTL3 loss-of-function mutations lead to low levels of LDL, VLDL, HDL, and TG (Musunuru et al., 2010), with one study showing an ANGPTL3 loss of function associated with a 34% reduction in odds of coronary artery disease (CAD) (Stitziel et al., 2017). Arrowhead is currently testing ARO-APOC3 in the following clinical trials under the VISTA program:
ARCHES-2: This is a Phase 2b, double blind, placebo controlled trial in adults with mixed dyslipidemia (patients are defined just as those in the MUIR trial). The primary objective is to evaluate the safety and efficacy of ARO-ANG3 and to select a dosing regimen for later stage trials in this patient population. Three dose levels of ARO-ANG3 (50 mg, 100 mg, 200 mg) were tested. Patients received a subcutaneous injection on day 1 and week 12. The trial completed with a total of 204 patients and the company is currently in the process of generating and analyzing study data, which we anticipate being reported later this year.
GATEWAY: This is a Phase 2, open-label trial in 18 patients with homozygous familial hypercholesterolemia (HoFH). Patients were randomized 1:1 to receive two doses of 200 or 300 mg ARO-ANG3 on Day 1 and Day 84 and evaluated over a 36-week period. The study is fully enrolled and interim data will be presented at the 91st European Atherosclerosis Society Congress on May 23. During the 2QFY23 conference call, management indicated that the LDL-C reduction seen appears to be competitive to evinacumab, a monoclonal antibody that targets ANGPTL3 and is currently approved to treat HoFH patients.
We anticipate additional details regarding the future plans for the cardiometabolic programs and the commercial strategy at the Analyst Day on June 1, 2023.
Targeting Central Nervous System Diseases
Arrowhead announced it is expanding into treating central nervous system (CNS) diseases and now has a construct optimized for intrathecal administration with good distribution throughout the brain and in all relevant brain cell types. The first program from the CNS platform is ARO-SOD1, which is designed to reduce expression of superoxide dismutase 1 (SOD1) as a potential treatment for patients with amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations. In preclinical studies, a single intrathecal dose of ARO-SOD1 resulted in 95% mRNA knockdown in spinal cord tissue in SOD1 transgenic rats. In non-human primates, ARO-SOD1 maintained >80% spinal cord mRNA knockdown three months after a single intrathecal dose. We anticipate the company filing a CTA in the third quarter of 2023 and to provide additional information on the program at the Analyst Day on June 1, 2023.
Financial Update
On May 2, 2023, Arrowhead announced financial results for the second quarter of fiscal year 2023 that ended March 31, 2023. The company reported revenue of approximately $146.3 million for the second quarter of fiscal year 2023 compared to approximately $151.8 million for the second quarter of fiscal year 2022. The revenue in the current period relates primarily to the collaboration agreements with Takeda and GlaxoSmithKline (GSK). R&D expenses for the quarter ending March 31, 2023 were approximately $74.9 million compared to $76.0 million for the quarter ending March 31, 2022. The decrease was primarily due to decreased candidate costs due to a reduction in outsourced manufacturing and toxicity study costs. G&A expenses for the second quarter of fiscal year 2023 were $23.2 million compared to $34.2 million for the second quarter of fiscal year 2022. The decrease was primarily due to lower non-cash, stock-based compensation.
Arrowhead exited the second quarter of fiscal year 2023 with approximately $559.8 million in cash, cash equivalents, and investments. As of April 24, 2023, Arrowhead had approximately 106.9 million shares outstanding and, when factoring in stock options and restricted stock units, a fully diluted share count of approximately 113.8 million.
Conclusion
We believe the interim data for ARO-RAGE is an important step forward for the company as it validates the use of the TRiM platform for pulmonary conditions and shows that it is possible to effectively dose patients in the lungs, which will greatly expand the potential therapeutic applications for the TRiM technology. We look forward to the Analyst Day on June 1, 2023 as the company will likely share additional data regarding ARO-RAGE and the potential to expand the pulmonary pipeline. We are also looking forward to additional information on the potential for the TRiM platform to be utilized for CNS indications. With no adjustments to our model our valuation remains at $80 per share.
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