Zacks Small Cap Research – ARWR: Moving Plozasiran Forward in Phase 3 CVOT… – Technologist

By David Bautz, PhD

NASDAQ:ARWR

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Business Update

Moving Plozasiran Ahead in CVOT Trial

On June 25, 2024, Arrowhead Pharmaceuticals, Inc. (NASDAQ:ARWR) held a webinar (slides are available here) on the company’s cardiometabolic programs that included plans to move plozasiran forward into a cardiovascular outcomes trial (CVOT) and pause the development of zodasiran (will only move it forward into a Phase 3 trial with a partner). The details of the Phase 3 CAPITAN CVOT study are provided below. It will evaluate 25 mg plozasiran versus placebo in two cohorts: a secondary prevention cohort with triglyceride (TG) levels 200-800 mg/dl and non-HDL-cholesterol > 100 mg/dl and a primary prevention cohort with TG levels 250-800 mg/dl and non-HDL-cholesterol >130 mg/dl. The primary endpoint is the time from randomization to the first occurrence of any of the endpoints of the 5-point MACE (Major Adverse Coronary Event) consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, coronary revascularization, or major adverse limb events. The company will finalize the study design after receiving FDA feedback later this year.

The CAPITAN study is just one of five studies that Arrowhead is conducting with plozasiran in patients with elevated triglycerides.

SHASTA-3 and SHASTA-4 are the two pivotal studies in severe hypertriglyceridemia (sHTG; estimated U.S. population size of 2.7 million) that are designed to replicate what was seen in the SHASTA-2 trial but with a longer treatment duration (one year of treatment is required by both the FDA and EMA). MUIR-3 is designed to increase the safety database and the regulatory agencies agreed there was little difference between sHTG and mixed hyperlipidemia patient populations (HTG) thus the company will be able to draw from a much larger population of patients for that study. SHASTA-5 is not a requirement for the regulatory agencies but is being done for the payers, particularly those in Europe, as it will be the first study designed to test whether lowering TG levels can decrease the rate of acute pancreatitis. Details of the SHASTA-3, SHASTA-4, and MUIR studies are below.

Initial PALISADE Results

The company also provided topline data from the Phase 3 PALISADE study of plozasiran in patients with familial chylomicronemia syndrome (FCS). The full dataset will be shared at an upcoming medical conference. In the PALISADE study, patients were treated every three months with two different doses of plozasiran (25 mg or 50 mg) or placebo and the primary outcome was the placebo adjusted median change in triglycerides at month 10. The following figure shows deep reductions in both the level of APOC3 and triglycerides in patients treated with 25 mg or 50 mg plozasiran at months 10 and 12.

Plozasiran continued to be well tolerated as there were no new safety signals seen, the adverse events were comparable across treatment groups, and there were more severe/serious adverse events in the placebo group than in either treatment group.

While the full dataset will be presented at a medical conference later this year, we feel it is still worthwhile to do a quick comparison of the results of the PALISADE study with those for Ionis Pharmaceuticals’ olezarsen. Ionis recently reported that the NDA for olezarsen for the treatment of FCS was accepted for Priority Review with a PDUFA date of December 19, 2024. The results from the Phase 3 trial of olezarsen in FCS were recently published in The New England Journal of Medicine (Witztum et al., 2024). Since Arrowhead only released a limited amount of data it is difficult to do a full comparison of the results to those for olezarsen, however we believe that the following graphs showing the mean change over time in triglyceride levels for each study demonstrate what we believe to be is superior efficacy for plozasiran in decreasing triglycerides (with dosing just once every three months compared to olezarsen dosing once a month). Additional efficacy parameters will be announced with the full dataset.

Initial Preclinical Obesity Data for ARO-INHBE

Lastly, the company briefly touched on preclinical data for ARO-INHBE that was recently presented at the American Diabetes Association (ADA) 84th Scientific Sessions. A copy of the poster can be found here. Arrowhead reported that in a diet-induced obesity (DIO) model, mice administered ARO-INHBE had an approximately 95% reduction in INHBE mRNA expression, which led to a 19% suppression of body weight compared to saline controls. Body composition analysis by DEXA imaging showed a 26% loss of fat mass with preservation of lean mass. In addition, the combination of tirzepatide and ARO-INHBE allowed for the use of a lower tirzepatide treatment for a similar therapeutic effect. A full update on ARO-INHBE and a new adipose targeted program will be provided at Obesity/Metabolic R&D Webinar on August 15, 2024.

Conclusion

Arrowhead performed an exhaustive analysis in determining whether to move plozasiran, zodasiran, or both forward in development and with a finite amount of resources the company has decided that plozasiran is the best option to advance. This decision was not based solely on efficacy as both drugs produced great clinical results, and in fact we would not be surprised to see zodasiran get partnered. However, until that happens Arrowhead will pause development of zodasiran to devote its resources to plozasiran, which includes five ongoing/upcoming trials including the CAPITAN CVOT trial. We anticipate additional details on the CAPITAN study being released following FDA feedback and finalization of the study protocol. We are intrigued by the data recently presented at ADA on the new metabolic asset ARO-INHBE, and look forward to additional details being provided at the August 15 seminar on the company’s obesity/metabolic programs. With no changes to our model our valuation remains at $74 per share.

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