Arrowhead Pharmaceuticals Presents New Pivotal Phase 3 Data at ESC 2024 from PALISADE Study of Plozasiran in Patients with Familial Chylomicronemia Syndrome

Rhea-AI Summary

Arrowhead Pharmaceuticals (NASDAQ: ARWR) announced positive results from its Phase 3 PALISADE study of plozasiran for treating familial chylomicronemia syndrome (FCS). The study met its primary endpoint, showing an 80% reduction in triglycerides from baseline and an 83% reduction in acute pancreatitis risk. Key findings include:

- Similar responses in genetically confirmed and clinically diagnosed FCS patients
- Plans to file a New Drug Application by year-end 2024
- Results published in The New England Journal of Medicine
- Median triglyceride reduction of 80% in the 25 mg group and 78% in the 50 mg group vs 17% for placebo
- APOC3 reductions of 93% and 96% in treatment groups vs 1% for placebo
- Favorable safety profile with common adverse events similar to placebo

Positive

• Phase 3 PALISADE study met primary endpoint with 80% reduction in triglycerides
• 83% reduction in risk of developing acute pancreatitis
• Plans to file New Drug Application by year-end 2024
• Results published in The New England Journal of Medicine
• Significant APOC3 reductions of 93% and 96% in treatment groups
• Favorable safety profile with adverse events similar to placebo

Negative

• None.

Medical Research Analyst

The PALISADE study results for plozasiran in FCS patients are highly promising. The 80% reduction in triglycerides and 83% reduction in acute pancreatitis risk are remarkable outcomes for a disease with no current FDA-approved treatments. The consistency of results across genetically confirmed and clinically diagnosed FCS patients expands the potential patient population. The 93-96% reduction in APOC3 levels further supports plozasiran's mechanism of action.

The safety profile appears favorable, with adverse events similar to placebo. However, the observed hyperglycemia in pre-diabetic and diabetic patients warrants further investigation. The planned NDA filing by year-end 2024 puts Arrowhead in a strong position to potentially bring the first targeted FCS treatment to market, addressing a significant unmet medical need.

Financial Analyst

Arrowhead's plozasiran data presents a compelling case for potential market success. The lack of approved FCS treatments in the U.S. creates a significant market opportunity. If approved, plozasiran could become a first-in-class therapy, potentially commanding premium pricing. The drug's efficacy in both genetically confirmed and clinically diagnosed FCS patients expands the addressable market.

The planned NDA filing by year-end 2024 suggests a possible launch in 2025-2026, subject to regulatory approval. This timeline could give Arrowhead a first-mover advantage in the FCS space. Additionally, the drug's potential in other triglyceride disorders, as hinted by management, could open up larger market opportunities in the future. Investors should monitor the regulatory progress and any partnership discussions, which could significantly impact Arrowhead's financial outlook.

Cardiovascular Specialist

The PALISADE results are groundbreaking for FCS management. The 80% triglyceride reduction is unprecedented and clinically significant, potentially reducing the risk of life-threatening pancreatitis. The 83% reduction in acute pancreatitis incidence is particularly noteworthy, as it directly addresses the most severe complication of FCS.

Plozasiran's ability to bring triglyceride levels below guideline-directed risk thresholds within one month is impressive, offering rapid relief for patients. The drug's efficacy in both genetically confirmed and clinically diagnosed FCS patients broadens its clinical utility. However, the hyperglycemia observed in pre-diabetic and diabetic patients requires careful consideration in patient selection and monitoring. Overall, plozasiran could revolutionize FCS treatment, significantly improving patient outcomes and quality of life.

- Plozasiran reduced triglycerides by 80% from baseline and reduced the risk of developing acute pancreatitis by 83%

- Similar responses were observed in patients with genetically confirmed and clinically diagnosed FCS

- Based on these findings, Arrowhead plans to file a New Drug Application by year-end 2024

- PALISADE results simultaneously published in The New England Journal of Medicine

- Company hosting a virtual analyst and investor event on September 3, 2024, at 8:00 am EDT to discuss results

PASADENA, Calif.--(BUSINESS WIRE)-- Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced results from the Phase 3 PALISADE study of investigational plozasiran in patients with familial chylomicronemia syndrome (FCS), a severe and rare genetic disease which currently has no approved treatments in the U.S. PALISADE successfully met its primary endpoint and all multiplicity-controlled key secondary endpoints, including statistically significant reductions in triglycerides (TGs), apolipoprotein C-III (APOC3), and the incidence of acute pancreatitis (AP). These data were presented today in a late-breaking oral presentation at the European Society of Cardiology (ESC) Congress 2024 and simultaneously published in The New England Journal of Medicine.

Based on these positive findings from the PALISADE study, Arrowhead intends to file a New Drug Application with the United States Food and Drug Administration (FDA) by year-end 2024 and plans to seek regulatory approval with additional global regulatory authorities thereafter.

“People living with extremely high triglyceride levels, like those in the PALISADE study, have a substantially higher risk of developing acute pancreatitis and associated long-term sequelae, including a poor quality of life. There are currently no approved therapies in the U.S. to specifically treat FCS, so as physicians we have very few options to help our patients other than various triglyceride-lowering medications which provide minimal benefit, and very strict diet restrictions that take a significant toll on patients and their families,” said Gerald F. Watts, D.Sc., M.D., Ph.D., Winthrop Professor of Cardio-metabolic Medicine at the University of Western Australia, Perth. “Plozasiran demonstrated very deep reductions in triglycerides in the PALISADE study and is the only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS in a controlled study. These results are encouraging and offer hope to people living with FCS and their physicians who are in desperate need of new safe and effective treatment options.”

Bruce Given, M.D., chief medical scientist at Arrowhead, added, “We continue to be impressed by the promising results from the SUMMIT program of clinical studies of plozasiran in various patient populations, including SHASTA in patients with severe hypertriglyceridemia, MUIR in patients with mixed hyperlipidemia, and now PALISADE in patients with FCS. Based on the data generated to date, we view plozasiran as potentially best-in-class and supportive of development across the spectrum of triglyceride disorders. Specifically, today we showed that in PALISADE a high proportion of patients receiving plozasiran achieved triglyceride levels below guideline-directed risk thresholds associated with the risk of acute pancreatitis, which is a critical treatment goal that physicians communicate to us frequently. Further, PALISADE included patients with an established genetic diagnosis of FCS and patients with symptomatic, persistent chylomicronemia suggestive of FCS. The consistency of results in PALISADE suggests that plozasiran response may be independent of the presence of known FCS-associated genetic variants. This is supportive of the potential value of plozasiran in patients with clinically diagnosed disease, regardless of genetic status.”

Select PALISADE Results

In PALISADE, 75 patients with persistent chylomicronemia, with or without a genetic diagnosis, were randomly assigned to receive subcutaneous plozasiran at 25 mg (n=26) or 50 mg (n=24) or placebo (n=25) every three months for 12 months. At baseline, the median triglyceride level was 2044 mg/dL. Forty-four patients (59%) had genetically confirmed FCS and 31 patients (41%) had clinically diagnosed persistent chylomicronemia suggestive of FCS.

At month ten, the median reduction from baseline in the fasting triglyceride level (the primary endpoint) was -80% in the 25 mg plozasiran group, -78% in the 50 mg plozasiran group, and -17% in the placebo group (p<0.001).

Marked reductions in the median triglyceride level below guideline-directed risk thresholds associated with acute pancreatitis occurred as early as one month after trial initiation and showed modest variation throughout the 12-month blinded treatment period. The mean percentage change in triglyceride level was similar to median values.

At month ten, APOC3 was significantly reduced with median reductions of -93% in the 25 mg plozasiran group, -96% in the 50 mg plozasiran group, and -1% in the placebo group (p<0.001).

The final alpha-controlled secondary efficacy end point compared the incidence of positively adjudicated acute pancreatitis in a pre-specified pooled analysis of the 25 mg and the 50 mg plozasiran groups versus the pooled placebo group. Among the 38 suspected cases of acute pancreatitis that were referred for adjudication, nine episodes in seven patients were positively adjudicated.

Plozasiran demonstrated statistical significance for this endpoint, with patients receiving plozasiran achieving an 83% reduction in the risk of developing acute pancreatitis versus placebo. A total of two cases occurred in two of 50 patients (4%) receiving plozasiran, and seven cases occurred in five of 25 patients (20%) receiving placebo (odds ratio, 0.17, p=0.03).

Safety and Tolerability

Plozasiran demonstrated a favorable safety profile in the PALISADE study. The most common adverse events were abdominal pain, COVID-19, nasopharyngitis, headache, nausea, back pain, upper respiratory tract infection, and diarrhea. Adverse events among the patients in the two plozasiran dose groups were generally similar to those in the placebo group. Severe and serious adverse events were more common in the placebo group. Hyperglycemia was observed in a limited number of patients in the treatment groups but was confined to patients with pre-diabetes and diabetes.

ESC 2024 Presentation Details

Title: A Randomised, Placebo-Controlled Phase 3 Study of Plozasiran in Patients with Familial Chylomicronemia Syndrome
Date/Time: September 2, 2024, 11:36 am BST
Presenter: Professor Gerald Watts, University of Western Australia
Session: Small trials, trial updates, and other studies on lipid therapy
Session Type: Late Breaking Science

Slides from the late-breaking oral presentation at ESC 2024 may be accessed on the Events and Presentations page in the Investors section of the Arrowhead website after the oral presentation concludes.

Virtual Analyst and Investor Event

The analyst and investor event on September 3, 2024, at 8:00 am EDT will feature an encore presentation of the ESC 2024 data by Professor Watts and will include discussion by Arrowhead management. To register for the event, please visit: https://lifescievents.com/event/arrowheadpharma/.

The live event and an archived webcast may also be accessed on the Events and Presentations page in the Investors section of the Arrowhead website.

About PALISADE Phase 3 Study

The PALISADE study (NCT05089084) is a Phase 3 placebo controlled study to evaluate the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS. The primary endpoint of the study is percent change from baseline in fasting TG versus placebo at Month 10. A total of 75 subjects distributed across 39 different sites in 18 countries were randomized to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every three months. Participants who completed the randomized period were eligible to continue in a 2-part extension period, where all participants receive plozasiran.

About Familial Chylomicronemia Syndrome

Familial chylomicronemia syndrome (FCS) is a severe and rare genetic disease often caused by various monogenic mutations. FCS leads to extremely high triglyceride (TG) levels, typically over 880 mg/dL. Such severe elevations can lead to various serious signs and symptoms including acute and potentially fatal pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues. Currently, the therapeutic options that can adequately treat FCS are limited.

About Plozasiran

Plozasiran, previously called ARO-APOC3, is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce production of apolipoprotein C-III (APOC3) which is a component of triglyceride rich lipoproteins (TRLs) and a key regulator of triglyceride metabolism. APOC3 increases triglyceride levels in the blood by inhibiting breakdown of TRLs by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver. The goal of treatment with plozasiran is to reduce the level of APOC3, thereby reducing triglycerides and restoring lipids to more normal levels.

In multiple clinical studies, investigational plozasiran demonstrated reductions in triglycerides and multiple atherogenic lipoproteins in patients with familial chylomicronemia syndrome (FCS), severe hypertriglyceridemia (SHTG), and mixed hyperlipidemia. Plozasiran has demonstrated a favorable safety profile to date with treatment emergent adverse events reported that generally reflect the comorbidities and underlying conditions of the study populations.

Plozasiran is being investigated in the SUMMIT program of clinical studies, including the PALISADE Phase 3 study in patients with FCS, which recently completed, the SHASTA studies in patients with SHTG, and the MUIR and CAPITAN studies in patients with mixed hyperlipidemia.

Plozasiran has been granted Orphan Drug Designation and Fast Track Designation by the U.S. Food and Drug Administration and Orphan Drug Designation by the European Medicines Agency. Arrowhead intends to file a New Drug Application with the FDA in 2024 and plans to seek regulatory approval with additional global regulatory authorities. Investigational plozasiran has not been reviewed or approved to treat any disease.

About Plozasiran EAP

Arrowhead is committed to bringing new investigational medicines to patients with serious diseases as quickly and efficiently as possible. The company has established an expanded access program (EAP) for some individuals living with FCS. As with any investigational medicine that has not been approved by regulatory authorities, investigational plozasiran may or may not be effective in treating your diagnosis or condition, and there may be risks associated with its use. If you are a patient or caregiver wishing to know more about this plozasiran EAP for FCS, please discuss this EAP and all treatment options with your treating physician. If you are a treating physician and are seeking information about the plozasiran EAP or would like to request access for a patient, please contact EAP@arrowheadpharma.com.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.

For more information, please visit www.arrowheadpharma.com, or follow us on X (formerly Twitter) at @ArrowheadPharma or on LinkedIn. To be added to the Company's email list and receive news directly, please visit http://ir.arrowheadpharma.com/email-alerts.

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Source: Arrowhead Pharmaceuticals, Inc.

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Arrowhead Pharmaceuticals, Inc.

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Source: Arrowhead Pharmaceuticals, Inc.

FAQ

What were the main results of Arrowhead's Phase 3 PALISADE study for plozasiran (ARWR)?

The PALISADE study showed an 80% reduction in triglycerides from baseline and an 83% reduction in acute pancreatitis risk for patients with familial chylomicronemia syndrome (FCS) treated with plozasiran.

When does Arrowhead Pharmaceuticals (ARWR) plan to file a New Drug Application for plozasiran?

Arrowhead Pharmaceuticals plans to file a New Drug Application for plozasiran with the FDA by year-end 2024, based on the positive PALISADE study results.

What were the triglyceride reductions observed in the PALISADE study for Arrowhead's plozasiran (ARWR)?

The PALISADE study showed median triglyceride reductions of 80% in the 25 mg plozasiran group and 78% in the 50 mg group, compared to 17% in the placebo group at month ten.

How did plozasiran (ARWR) affect APOC3 levels in the PALISADE study?

Plozasiran significantly reduced APOC3 levels, with median reductions of 93% in the 25 mg group and 96% in the 50 mg group, compared to 1% in the placebo group at month ten.