Arrowhead Pharmaceuticals Presents New Data at AHA24 from PALISADE Phase 3 Study and Open-Label Extension from MUIR and SHASTA-2 Studies of Plozasiran
Arrowhead Pharmaceuticals presented new data from Phase 3 PALISADE study and open-label extension (OLE) of MUIR and SHASTA-2 studies for plozasiran at AHA24. The PALISADE study showed plozasiran induced significant triglyceride reductions of approximately -80% at 25mg dose, with similar efficacy in both genetically confirmed and clinically diagnosed FCS patients. In the OLE studies, extended treatment with 25mg plozasiran demonstrated mean triglyceride reductions up to -73% in MUIR and -86% in SHASTA-2 patients through 15 months. The drug was generally well-tolerated across studies.
Arrowhead Pharmaceuticals ha presentato nuovi dati dallo studio di Fase 3 PALISADE e dall'estensione open-label (OLE) degli studi MUIR e SHASTA-2 per plozasiran durante l'AHA24. Lo studio PALISADE ha mostrato che plozasiran induce riduzioni significative dei trigliceridi di circa -80% alla dose di 25 mg, con un'efficacia simile sia nei pazienti FCS confermati geneticamente sia in quelli clinicamente diagnosticati. Negli studi OLE, il trattamento prolungato con plozasiran a 25 mg ha dimostrato riduzioni medie dei trigliceridi fino a -73% nei pazienti MUIR e -86% nei pazienti SHASTA-2 per un periodo di 15 mesi. Il farmaco è stato generalmente ben tollerato in tutti gli studi.
Arrowhead Pharmaceuticals presentó nuevos datos del estudio de Fase 3 PALISADE y de la extensión de etiqueta abierta (OLE) de los estudios MUIR y SHASTA-2 para plozasiran en AHA24. El estudio PALISADE mostró que plozasiran induce reducciones significativas de triglicéridos de aproximadamente -80% con una dosis de 25 mg, con una eficacia similar en pacientes FCS confirmados genéticamente y clínicamente diagnosticados. En los estudios OLE, el tratamiento prolongado con plozasiran de 25 mg demostró reducciones medias de triglicéridos de hasta -73% en pacientes MUIR y -86% en pacientes SHASTA-2 a lo largo de 15 meses. El fármaco fue generalmente bien tolerado en todos los estudios.
Arrowhead Pharmaceuticals는 AHA24에서 plozasiran에 대한 3상 PALISADE 연구 및 MUIR, SHASTA-2 연구의 오픈 라벨 확장(OLE)에서 새로운 데이터를 발표했습니다. PALISADE 연구에서는 plozasiran이 25mg 용량에서 약 -80%의 유의미한 중성지방 감소를 유도했으며, 유전적으로 확인된 FCS 환자와 임상적으로 진단된 FCS 환자 모두에서 유사한 효능을 보였습니다. OLE 연구에서는 25mg plozasiran으로 15개월 동안 MUIR에서 -73%, SHASTA-2에서 -86%에 이르는 평균 중성지방 감소가 나타났습니다. 이 약물은 모든 연구에서 일반적으로 잘 견디는 것으로 나타났습니다.
Arrowhead Pharmaceuticals a présenté de nouvelles données de l'étude de Phase 3 PALISADE et de l'extension à étiquette ouverte (OLE) des études MUIR et SHASTA-2 pour plozasiran lors de l'AHA24. L'étude PALISADE a montré que plozasiran induisait des réductions significatives des triglycérides d'environ -80% à une dose de 25 mg, avec une efficacité similaire chez les patients FCS confirmés génétiquement et cliniquement diagnostiqués. Dans les études OLE, le traitement prolongé avec plozasiran à 25 mg a démontré des réductions moyennes des triglycérides allant jusqu'à -73% chez les patients MUIR et -86% chez les patients SHASTA-2 pendant 15 mois. Le médicament a généralement été bien toléré dans toutes les études.
Arrowhead Pharmaceuticals hat neue Daten aus der Phase-3-Studie PALISADE und der offenen Verlängerung (OLE) der Studien MUIR und SHASTA-2 für plozasiran auf der AHA24 präsentiert. Die PALISADE-Studie zeigte, dass plozasiran signifikante Triglyceridreduktionen von etwa -80% bei einer Dosis von 25 mg induzierte, mit ähnlicher Wirksamkeit bei genetisch bestätigten und klinisch diagnostizierten FCS-Patienten. In den OLE-Studien zeigte die verlängerte Behandlung mit 25 mg plozasiran mittlere Triglyceridreduktionen von bis zu -73% bei MUIR- und -86% bei SHASTA-2-Patienten über einen Zeitraum von 15 Monaten. Das Medikament wurde in allen Studien allgemein gut vertragen.
- Deep triglyceride reductions of approximately -80% in PALISADE study
- Sustained efficacy with -73% to -86% triglyceride reductions in OLE studies through 15 months
- Over 50% of patients maintained triglycerides below 500 mg/dL threshold
- Favorable safety profile across clinical studies
- Increased LDL-C levels observed in PALISADE study
Insights
The Phase 3 PALISADE study results demonstrate significant clinical efficacy for plozasiran in treating FCS patients. The drug achieved
The long-term data from MUIR and SHASTA-2 studies show impressive durability, with triglyceride reductions maintained up to
These robust clinical results significantly de-risk Arrowhead's plozasiran program and position it well for potential FDA approval. The drug's efficacy in both genetic and clinical FCS patients expands the addressable market beyond just genetically confirmed cases. The sustained efficacy in the open-label extension studies suggests strong potential for recurring revenue through long-term patient retention.
The multiple potential indications - from rare FCS to broader hypertriglyceridemia - create a tiered market opportunity. The safety profile and quarterly dosing schedule offer competitive advantages over existing treatments. This could translate to meaningful market share in a growing cardiovascular therapeutics space, particularly given the unmet need in FCS treatment.
- Plozasiran induced deep and sustained reductions in triglycerides and impacted a wide spectrum of lipoproteins that may be involved with atherosclerotic cardiovascular disease
- Similar responses were observed in patients with genetically confirmed and clinically diagnosed FCS
- Mean reductions in triglycerides of up to -
“In the Phase 3 PALISADE study in patients with and without a genetic confirmation of familial chylomicronemia syndrome (FCS), plozasiran induced deep and sustained reductions in triglycerides and impacted a wider spectrum of lipoproteins that may be involved with atherosclerotic cardiovascular disease. Importantly, responses were independent of specific known gene variants causing FCS,” said Bruce Given, M.D., chief medical scientist at Arrowhead. “In the open-label extension (OLE) from the Phase 2 MUIR and
AHA24 Presentation Details
Title: PALISADE: A Phase 3 Study to Assess the Efficacy and Safety of Plozasiran in Adults with Genetically or Clinically-Defined Familial Chylomicronemia Syndrome (FCS) at High Risk of Acute Pancreatitis (AP)
Date/Time: November 16, 2024, 2:04 pm CST
Presenter: Gerald Watts
Session: Featured Science: Novel Approaches to Managing Lipid Risk
Title: Plozasiran and Triglyceride Levels in Hypertriglyceridemia: Long-Term Efficacy and Safety Data from Subjects in an Open-Label Extension Trial (MUIR and
Date/Time: November 18, 2024, 10:45 am CST
Presenter: Christie Ballantyne
Session: New Insights in Lipids and lipid lowering therapies
Slides from the AHA24 presentations may be accessed on the Events and Presentations page in the Investors section of the Arrowhead website after the oral presentation concludes.
Select PALISADE Results
In PALISADE, 75 patients with FCS, 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 (
Plozasiran, at the 25 mg dose being proposed for marketing approval, induced rapid, deep, and sustained reductions in apolipoprotein C-III (APOC3), of greater than -
Plozasiran decreased total cholesterol (TC) with least square (LS) mean reductions of -
Select MUIR and
In the OLE, a total of 418 subjects from the Phase 2 MUIR study in patients with mixed hyperlipidemia and the
10, 25, or 50 mg of plozasiran in the blinded portion of the studies produced mean reductions in TGs up to -
Favorable sustained reductions in TGs and APOC3, decreases in remnant cholesterol, non-HDL-C, favorable changes in apoB, and increases in HDL-C were observed, with no changes in LDL-C or Lp(a) and remained durable over the duration of the open-label extension. No worsening of HbA1c and no new onset diabetes mellitus were observed, providing further evidence that long-term safety appears favorable with repeated dosing and longer observation periods.
Safety and Tolerability
Overall, plozasiran has been generally well-tolerated to date. In the PALISADE study, the most frequently reported treatment emergent adverse events for the 25 mg dose were abdominal pain, COVID-19, nasopharyngitis, and nausea. Across clinical studies and study populations, the most frequently reported treatment emergent adverse events for the 25 mg dose were COVID-19, upper respiratory tract infection, headache, Type 2 diabetes mellitus, and abdominal pain.
About Familial Chylomicronemia Syndrome
Familial chylomicronemia syndrome (FCS) is a severe and rare 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, there are no therapeutic options that can adequately treat FCS in the US.
About Severe Hypertriglyceridemia
Severe hypertriglyceridemia (SHTG) is characterized by triglyceride (TG) levels greater than 500 mg/dL. Very severe forms (TG greater than 880 mg/dL) include familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS). SHTG significantly increases the risk of atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP), often with recurrent attacks requiring repeat hospital admissions and worsening outcomes. AP risk is proportional to number, characteristics, and concentration of triglyceride rich lipoproteins (TRLs), particularly chylomicrons, and increases as TGs rise. Limited treatment options exist to sustainably reduce TGs below the pancreatitis risk threshold.
About Mixed Hyperlipidemia
Mixed hyperlipidemia, also called mixed dyslipidemia, is a highly prevalent disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels. Despite the efficacy of LDL-C-lowering therapies in reducing atherosclerotic cardiovascular disease (ASCVD) risk in mixed hyperlipidemia, there remains substantial residual risk attributed to elevated non-HDL driven by remnant cholesterol in triglyceride-rich lipoproteins. Genome-wide association and Mendelian randomization studies also support a causal role for triglyceride rich lipoproteins in ASCVD.
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 has demonstrated reductions in triglycerides and multiple atherogenic lipoproteins in patients with familial chylomicronemia syndrome (FCS), severe hypertriglyceridemia (SHTG), and mixed hyperlipidemia. Plozasiran has been generally well tolerated to date with treatment emergent adverse events reported that generally reflect the comorbidities and underlying conditions of the study populations. Across clinical studies and study populations, the most frequently reported treatment emergent adverse events for the 25 mg dose were COVID-19, upper respiratory tract infection, headache, Type 2 diabetes mellitus, and abdominal pain.
Plozasiran is being investigated in the SUMMIT program of clinical studies, including the PALISADE Phase 3 study in patients with FCS, the
Plozasiran in the treatment of patients with FCS has been granted Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation by the
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 MUIR Phase 2 Study
MUIR (NCT04998201) is a double-blind, placebo-controlled Phase 2b clinical study in adults with mixed hyperlipidemia. Plozasiran was evaluated against placebo in 353 participants who had fasting triglycerides between 150-499 mg/dL and either LDL-cholesterol greater than 70 mg/dL or non-HDL-cholesterol greater 100 mg/dL. Participants were randomly assigned in a 3:1 ratio to receive 10, 25, or 50 mg plozasiran or placebo by subcutaneous injections on day 1 and week 12, or 50 mg plozasiran or placebo on day 1 and week 24. The primary objective of the study was to evaluate the safety and efficacy of plozasiran in adults with mixed hyperlipidemia.
About
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.
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FAQ
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