By David Bautz, PhD
NASDAQ: ARWR
READ THE FULL ARWR RESEARCH REPORT
Business Update
Best Case Scenario for SHASTA-3 and SHASTA-4 Results
On July 22, 2026, Arrowhead Pharmaceuticals, Inc. (NASDAQ:ARWR) announced positive topline results for the SHASTA-3 and SHASTA-4 trials of plozasiran in patients with severe hypertriglyceridemia (sHTG). Both trials exceeded the best-case scenario for both triglyceride reduction and rate of acute pancreatitis (AP) compared to placebo. Arrowhead will be presenting detailed results from the study at the European Society of Cardiology (ESC) Congress on August 30, 2026 and will then hold a conference call and webcast to discuss the results on Aug 31, 2026.
The results showed median triglyceride reductions in the SHASTA-3 and SHASTA-4 trials of 79% and 81%, respectively, compared to a placebo reduction of approximately 27%. The trials included a pre-planned pooled analysis of AP events and the results showed a statistically significant reduction in both the event rate (any individual patient with at least one AP event, P<0.0221) and the total incidence rate of AP events (P<0.0077) in plozasiran-treated patients compared to placebo. For the broad sHTG population, which is defined as those with TG > 500 mg/dL with or without a prior history of AP, cumulative AP events were reduced by 78% in treated patients compared to placebo. For high-risk patients, defined as those with TG levels > 880 mg/dL and a prior history of AP, treatment with plozasiran resulted in a 100% reduction in AP events compared to placebo.
Importantly, plozasiran continued to have a favorable safety and tolerability profile with overall treatment emergent adverse events (TEAEs) and related TEAEs consistent with prior studies. There were no new safety signals and no clinically meaningful differences in routine laboratory measurements, including no statistically significant difference between plozasiran-treated and placebo-treated patients in mean liver fat content assessed by MRI-PDFF (in a prespecified subgroup) or clinically meaningful adverse changes in liver enzymes.
SHASTA-3 and SHASTA-4 are global, randomized, double blind, placebo controlled Phase 3 studies intended to evaluate plozasiran in adult subjects with sHTG and documented evidence of fasting triglyceride (TG) level > 500 mg/dL. Between the two studies, approximately 750 patients were treated once every three months with 25 mg plozasiran or placebo. The primary endpoint is percent change in fasting serum triglyceride level at month 12 from baseline compared to placebo. Patients who completed the trial through month 12 are offered the opportunity to continue in an open-label extension.
Conclusion
We believe these results substantially de-risk the commercial opportunity for plozasiran in sHTG. While the deep TG lowering was mostly expected based on the Phase 2 results, the statistically significant reduction in AP events supports the thesis that sustained APOC3 inhibition may translate into clinically meaningful outcomes beyond lipid lowering. Since prevention of recurrent pancreatitis is the primary treatment objective for sHTG patients, these data should strengthen physician confidence and payer acceptance while reinforcing plozasiran’s competitive profile.
The company is targeting to file an sNDA with the U.S. FDA by the end of 2026, with additional regulatory filings in multiple global geographies shortly thereafter. While Ionis has had first-mover advantage with Tryngolza, we believe plozasiran will ultimately take significant market share due to its once-quarterly dosing schedule, robust triglyceride lowering ability, and ability to reduce AP events, particularly in high-risk patients. Based on these results, we have increased our market share and peak sales estimates for plozasiran in sHTG, which has resulted in an increase in our valuation to $100 per share.
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