Zacks Small Cap Research – ARWR: PALISADE Phase 3 Results Published in NEJM… – Technologist

By David Bautz, PhD

NASDAQ:ARWR

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Phase 3 PALISADE Results Published in The New England Journal of Medicine

On September 2, 2024, Arrowhead Pharmaceuticals, Inc. (NASDAQ:ARWR) announced results for the Phase 3 PALISADE trial of plozasiran in patients with familial chylomicronemia syndrome (FCS). The results were presented in a late-breaking oral presentation at the European Society of Cardiology (ESC) Congress 2024 and also published in The New England Journal of Medicine (Watts et al., 2024). The company held an investor call on September 3, 2024 and the slides for it can be found here. Plozasiran was also recently granted Breakthrough Therapy designation by the U.S. FDA. It previously received Orphan Drug Designation and Fast Track Designation by the FDA along with Orphan Drug Designation by the European Medicines Agency.

The PALISADE trial enrolled 75 patients with persistent chylomicronemia, with or without a genetic diagnosis of FCS, who were randomized to subcutaneous plozasiran at 25 mg (n=26), 50 mg (n=24), or placebo (n=25) every three months for 12 months. Inclusion criteria included a history of multiple triglyceride (TG) measurements above 1000 mg/dL (11.3 mmol/L) along with at least one of the following: prior genetic testing diagnosis for FCS; recurrent episodes of acute pancreatitis; recurrent hospitalizations for severe abdominal pain without other explainable cause; history of childhood pancreatitis; or family history of HTG-induced acute pancreatitis. The following table shows the baseline characteristics for the patients, including the median baseline TG level of 2044 mg/dL across all cohorts.

The following graphs show the median reduction in triglycerides and level of APOC3. At the ten-month time point, the median reduction in fasting triglycerides was -80% in the 25 mg cohort, -78% in the 50 mg cohort, and -17% for the placebo cohort (P<0.001). The reduction in APOC3 was -93% in the 25 mg cohort, -96% in the 50 mg cohort, and -1% in the placebo group (P<0.001).

An important secondary efficacy endpoint compared the incidence of positively adjudicated acute pancreatitis (AP) in a pre-specified pooled analysis of the 25 mg and 50 mg plozasiran groups versus the pooled placebo group. Of the 38 suspected cases of acute pancreatitis that were referred for adjudication, nine episodes in seven patients were positively adjudicated. The results showed an 83% reduction in the risk of developing acute pancreatitis for plozasiran-treated patients compared to those treated with placebo. A total of two cases occurred in two of 50 patients (4%) receiving plozasiran versus seven cases that occurred in five of 25 patients (20%) receiving placebo (OR 0.17; P=0.03).

The following table provides the summary of adverse events during the trial. There was a higher rate of serious or severe adverse events in the placebo group, no changes were seen in platelet counts, and there were no deaths reported in the study.

Comparison with Olezarsen

Ionis Pharmaceuticals is developing olezarsen, an antisense oligonucleotide that targets APOC3. 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 BALANCE trial of olezarsen in FCS were recently published in The New England Journal of Medicine (Stroes et al., 2024). While difficult to perform cross-trial comparisons, the following chart provides some of the parameters and outcomes for the Phase 3 trials for olezarsen and plozasiran.

A few points that we think are worthwhile for investors to consider include:

•   Olezarsen is dosed once every four weeks while plozasiran is dosed once every three months

•   All of the subjects in the olezarsen study had genetically confirmed FCS, while between one-half to two-thirds of subjects in the plozasiran trial had generically confirmed FCS

•   The triglyceride and APOC3 reductions were greater for plozasiran than for olezarsen (with the caveat of median vs. mean values reported), with less variability over time for plozasiran than for olezarsen.

•   Plozasiran showed a statistically significant decrease in the risk of developing acute pancreatitis (AP), however the olezarsen trial was not powered for statistical significance but still showed a favorable rate ratio.

Overall, we believe the plozasiran results are highly competitive and should position the product to do well in the FCS market.

Conclusion

The results from the Phase 3 PALISADE trial of plozasiran in FCS are very encouraging and we believe the drug compares quite favorably to olezarsen, which has a PDUFA date of December 19, 2024 for FCS. We look forward to the company filing the NDA for plozasiran and additional information on plans for its potential commercial launch next year. With no changes to our model our valuation remains at $70 per share.

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