ARWR: Encouraging Data Presented for Both ARO-APOC3 and ARO-ANG3…

By David Bautz, PhD

NASDAQ:ARWR

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Positive Data for ARO-APOC3 and ARO-ANG3 Presented at ESC 2020

On August 31, 2020, Arrowhead Pharmaceuticals, Inc. (NASDAQ:ARWR) announced the presentation of data from ongoing Phase 1/2 clinical trials of ARO-APOC3 and ARO-ANG3 at the European Society of Cardiology (ESC) Congress 2020. Below we present some of the highlights from each presentation.

ARO-APOC3

In a presentation titled “RNA Interference Targeting Apolipoprotein C-3 with ARO-APOC3 in Healthy Volunteers Mimics Lipid and Lipoprotein Findings Seen in Subjects with Inherited Apolipoprotein C-3 Deficiency” the company presented data from repeat doses of ARO-APOC3 in healthy volunteers. A copy of the presentation can be found here.

ARO-APOC3 is targeted to apolipoprotein C-III (APOC3), a component of very low density lipoprotein (VLDL) and an inhibitor of lipoprotein lipase. This program is currently focused on treating patients with severe hypertriglyceridemia and a history or high risk of pancreatitis. In support of targeting APOC3, an APOC3 loss-of-function mutation results in lower triglyceride (TG) levels (Jørgensen et al., 2014). Approximately 80-90% of APOC3 is produced in hepatocytes, thus making it an ideal target for the TRiM™ platform.

The following slide gives an overview of the ongoing Phase 1/2 clinical trial. The company had previously presented results from the single dose portion of the study in healthy volunteers at AHA 2019. For this portion of the study, ARO-APOC3 was administered on Days 1 and 29 at 10 mg, 25 mg, or 50 mg per dose. The primary objective of the study is evaluating the safety and tolerability of multiple doses of ARO-APOC3 with secondary objectives exploring the pharmacokinetics of the drug and exploratory endpoints evaluating fasting lipids along with fasting and 2-hr postpandrial triglycerides.

Baseline characteristics for each of the dosing cohorts are shown in the following table. Inclusion criteria included a triglyceride level of >0.903 mmol/L (80 mg/dL) and not currently on statins or other lipid-lowering medications.

To demonstrate target engagement, the following graph shows a substantial decrease in APOC3 ranging from a peak decrease of 73% at the lowest dose to a peak decrease of 94% at the highest dose. In addition, the reduction in APOC3 is sustained out through 16 weeks following a dose at time 0 and 4 weeks. This suggests that dosing two or three times per year may be feasible.

The sustained reduction in APOC3 levels translates to substantial, sustained reductions in triglyceride levels with maximal reductions of 58% at the lowest dose to a maximal reduction of 75% at the highest dose.

In addition to substantial decreases in triglyceride levels, decreases in low-density lipoprotein cholesterol (LDL-C) and increases in high-density lipoprotein cholesterol (HDL-C) were also noted.

Lastly, ARO-APOC3 was generally well tolerated as shown in the following table. The reported adverse events (AEs) were generally mild (including all injection site AEs) and there were no reported serious adverse events (SAEs). In addition, there were no significant adverse changes in platelets, total bilirubin, creatinine, and transaminases.

ARO-ANG3

In a presentation titled “RNAi Inhibition of Angiopoietin-like Protein 3 (ANGPTL3) with ARO-ANG3 Mimics the Lipid and Lipoprotein Profile of Familial Combined Hypolipidemia” the company presented data from repeat doses of ARO-ANG3 in healthy volunteers. A copy of the presentation can be found here.

ARO-ANG3 is focused on treating patients with mixed dyslipidemia and potentially metabolic diseases through targeting 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). Just like APOC3, the majority of ANGPTL3 is produced in hepatocytes, also making it an ideal target for the TRiM™ platform.

The following slide gives an overview of the ongoing Phase 1/2 clinical trial. The company had previously presented results from the single dose portion of the study in healthy volunteers at AHA 2019. For this portion of the study, ARO-ANG3 was administered on Days 1 and 29 at 100 mg, 200 mg, or 300 mg per dose. The primary objective of the study is evaluating the safety and tolerability of multiple doses of ARO-ANG3 with secondary objectives exploring the pharmacokinetics of the drug and exploratory endpoints evaluating fasting lipids along with fasting and 2-hr postpandrial triglycerides.

Baseline characteristics for each of the dosing cohorts are shown in the following table. Inclusion criteria included a triglyceride level of >1.13 mmol/L (100 mg/dL), LDL >1.81 mmol/L (70 mg/dL), and not currently on statins or other lipid-lowering medications.

To demonstrate target engagement, the following graph shows a substantial decrease in ANGPTL3 ranging from a maximum of 81% at the lowest dose to a maximum of 96% at the highest dose. In addition, the reduction in ANGPTL3 is sustained out through 16 weeks following a dose at time 0 and 4 weeks. This suggests that dosing two or three times per year may be feasible.

The sustained reduction in ANGPTL3 levels translates to substantial, sustained reductions in triglyceride levels with maximal reductions of 62% for the 100 mg dose, 72% for the 200 mg dose, and 67% for the 300 mg dose.

In addition to substantial decreases in triglyceride levels, substantial decreases in LDL-C, ranging from 37% to 50%, and HDL-C, ranging from 22% to 47%, were also noted.

Lastly, ARO-ANG3 was generally well tolerated as shown in the following table. The reported adverse events (AEs) were generally mild (the most commonly reported was headache) and there were no reported serious adverse events (SAEs). In addition, there were no significant adverse changes in platelets, total bilirubin, creatinine, and transaminases.

Conclusion

The data for both ARO-APOC3 and ARO-ANG3 are very impressive and show substantial reductions in triglycerides and other lipoproteins in addition to exhibiting strong on-target effects. Despite advancements in LDL and triglyceride management, there exists a significant population of patients that are not responsive to currently available therapies (e.g., statins, PCSK9s, etc.). In addition, the decrease in triglycerides of 50-75% puts these compounds in a ‘league of their own’ when compared to currently available therapies such as Vascepa®, which results in average decreases in triglycerides of 25-30% (Vascepa prescribing information).

At this point the company has many different regulatory pathways it could pursue with both drugs. For example, ARO-APOC3 could be used in patient populations ranging from those with an ultra-rare, genetically defined disease such as familial chylomicronemia syndrome (FCS), with a prevalence of approximately 1 in 1 million, all the way to those with simply mildly elevated triglycerides > 150 mg/dL, which has a population measured in the tens of millions. The same holds true for ARO-ANG3, which may be appropriate for patients with both elevated triglycerides and LDL cholesterol. We look forward to updates on these two programs over the next several months, including additional data and the planned regulatory pathway for each. With no changes to our model, our valuation remains at $58.

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