Arrowhead Pharmaceuticals Presents New Phase 2 Data of Plozasiran in Patients with Mixed Hyperlipidemia
Arrowhead Pharmaceuticals presented Phase 2 data for its investigational drug plozasiran at the European Atherosclerosis Society 92nd Congress. The drug significantly reduced triglyceride levels in patients with mixed hyperlipidemia, showing reductions in APOC3, non-HDL-C, and remnant cholesterol. These results were also published in the New England Journal of Medicine. In the MUIR study, plozasiran achieved -50% to -62% reductions in triglycerides and normalization in up to 92% of patients. Significant reductions in other atherogenic lipoproteins were also observed. Plozasiran demonstrated a favorable safety profile with comparable treatment-emergent adverse events (TEAEs) to placebo. Arrowhead will continue to investigate the drug in Phase 3 studies.
- Plozasiran achieved significant triglyceride reductions of -50%, -56%, and -62% at 10, 25, and 50 mg doses respectively.
- Fasting triglyceride levels were normalized in 79-92% of patients treated with plozasiran.
- Significant reductions observed in APOC3 (-57%, -73%, -79%), non-HDL-C (-17%, -18%, -24%), apoB (-10%, -13%, -19%), and remnant cholesterol (-43%, -49%, -48%).
- Plozasiran demonstrated a favorable safety profile with TEAEs rates comparable to placebo.
- Data simultaneously presented at EAS Congress and published in the New England Journal of Medicine, indicating strong clinical relevance and visibility.
- None of the adverse events listed, including COVID-19, worsening glycemic control, and upper respiratory tract infections were linked to the treatment itself but were observed in over 5 patients.
- The MUIR study is a Phase 2 trial; efficacy and safety must be confirmed in larger Phase 3 trials before market approval.
Insights
The Phase 2b MUIR study data for plozasiran, as presented, underscores its efficacy in reducing triglyceride levels and other atherogenic lipoproteins, such as APOC3, non-HDL-C and remnant cholesterol. These reductions are not just statistically significant but also clinically meaningful, given their strong correlation with lower cardiovascular risk. For context, high triglycerides and related lipoproteins are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD). Plozasiran’s ability to normalize fasting triglyceride levels in 79-92% of patients within 24 weeks is impressive. Such a high rate of efficacy suggests a robust potential for plozasiran to address unmet needs in lipid management, particularly for patients with genetic predispositions or those who are refractory to conventional therapies.
One term to understand here is APOC3, which is a protein that inhibits lipoprotein lipase and hepatic lipase, enzymes involved in the metabolism of triglycerides. By silencing APOC3, plozasiran significantly impacts lipid metabolism, resulting in the observed reductions. This mechanism is innovative and differs from traditional lipid-lowering agents. However, further studies, particularly Phase 3 trials, will be necessary to confirm these findings and assess long-term safety and effectiveness.
From a financial standpoint, the positive results from the Phase 2b MUIR study could be a catalyst for Arrowhead Pharmaceuticals. A successful Phase 2b study often leads to increased investor confidence and can be an indicator of future potential approval and commercialization. The publication in a high-impact journal like the New England Journal of Medicine and presentation at the European Atherosclerosis Society Congress further bolster the credibility of these findings. This dual recognition can generate significant interest and potentially drive the stock price higher in the short-term as investors react to the news.
However, it’s important to consider the financial risks and the costs associated with advancing plozasiran to Phase 3 trials. Investors should remain aware of the R&D expenditures and the company's ability to fund these without diluting shareholder value. Moreover, competition in the lipid-lowering drug market is intense, with several established players and new entrants constantly emerging. Thus, while these results are promising, they need to be viewed in the context of the broader market dynamics and the company's financial health. Investors should watch for updates on Phase 3 trial designs, timelines and any partnerships Arrowhead might secure to offset development costs.
Considering the market potential, plozasiran targets a significant unmet need in patients with mixed hyperlipidemia and other related conditions like familial chylomicronemia syndrome and severe hypertriglyceridemia. The global market for hyperlipidemia therapeutics is substantial, with a growing need for new treatments due to the high prevalence of cardiovascular diseases. Plozasiran's novel mechanism of action and the substantial reductions in triglycerides and other lipoproteins position it uniquely against existing therapies.
Additionally, the Phase 2b results align with current market trends favoring biotechnological innovations over traditional pharmaceuticals. Investors should note the emphasis on precision medicine, where treatments are tailored based on genetic and phenotypic information, which plozasiran supports by targeting APOC3.
Looking long-term, if plozasiran progresses successfully through Phase 3 and gains regulatory approval, it could capture a significant market share, provided it demonstrates superior efficacy and safety compared to existing treatments. This success could lead to strategic partnerships or acquisition opportunities, further enhancing shareholder value.
- Plozasiran significantly lowered triglyceride levels with commensurate reductions in APOC3, non-HDL-C, and remnant cholesterol
- Data presented at European Atherosclerosis Society 92nd Congress and simultaneously published in the New England Journal of Medicine
“Plozasiran demonstrated potent and durable reductions of atherogenic lipoproteins, such as non-HDL-C, ApoB, and remnant cholesterol in the Phase 2 MUIR study that supports its further development in Phase 3 studies for patients with increased risk for ASCVD,” said Christie M. Ballantyne, M.D., Baylor College of Medicine, and Principal Investigator for the MUIR study. “Despite advances in treatment, patients with mixed hyperlipidemia have elevated and persistent ASCVD risk due in part to high levels of atherogenic triglyceride rich lipoproteins. The promising results from treatment with plozasiran in the MUIR study help to lay the groundwork for a more extensive study to potentially test whether plozasiran reduces ASCVD risk.”
Bruce Given, M.D., interim chief medical scientist at Arrowhead added, “Results from the MUIR study of plozasiran in patients with mixed hyperlipidemia are encouraging and we are excited to present data at EAS and publish the results today in the New England Journal of Medicine. We believe plozasiran shows promise in multiple diseases with substantial unmet need, including familial chylomicronemia syndrome, severe hypertriglyceridemia, and mixed hyperlipidemia, and we are eager to further investigate plozasiran in additional clinical studies.”
Select MUIR Results
By silencing Apolipoprotein C-III (APOC3), plozasiran significantly reduced triglycerides and atherogenic triglyceride rich lipoproteins and increased HDL, across all dose levels at Week 24 in patients with mixed dyslipidemia.
At week 24, representing trough effect after 2 quarterly doses, plozasiran treatment was associated with placebo adjusted reductions in triglycerides of -
Changes in other atherogenic lipoprotein parameters were also observed. At week 24, for the quarterly doses of 10, 25, and 50 mg, the following placebo adjusted changes were observed: non-HDL-C levels -
Safety and Tolerability
Plozasiran demonstrated a favorable safety profile in the MUIR study. The overall rates of occurrence of treatment-emergent adverse events (TEAEs) and discontinuations were similar for plozasiran and placebo throughout the 48 weeks of observation. Observed adverse events generally reflected the comorbidities and underlying conditions of the study population. TEAEs occurring in 5 or more patients were COVID-19, worsening glycemic control, upper respiratory tract infection, urinary tract infection, headache, and bronchitis.
Arrowhead is also presenting data from the SHASTA-2 study of plozasiran and the ARCHES-2 study of zodasiran (formerly ARO-ANG3) at EAS. Details about the EAS presentations are listed below.
European Atherosclerosis Society (EAS) 92nd Congress – May 26-29, 2024
Title: PLOZASIRAN (ARO-APOC3), DECREASES APOC3 AND TRIGLYCERIDES (TG) IN PATIENTS WITH MIXED DYSLIPIDEMIA: MUIR FINAL RESULTS
Date/Time: May 28, 2024, 12:04 p.m. CEST
Presenter: Christie M Ballantyne, M.D.
Session: New Therapeutics
Title: PLOZASIRAN (ARO-APOC3), AN INVESTIGATIONAL RNAI THERAPEUTIC, DEMONSTRATES PROFOUND AND DURABLE REDUCTIONS IN APOC-3 AND TRIGLYCERIDES (TG) IN PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA (SHTG), SHASTA-2 FINAL RESULTS
Date/Time: May 28, 2024, 2:49 p.m. CEST
Presenter: Daniel Gaudet, M.D., Ph.D.
Session: SaaG Session: The Enigmas of TG-rich Lipoproteins
Title: ZODASIRAN SILENCES HEPATIC ANGPTL3 LEADING TO DEEP AND DURABLE REDUCTIONS IN ATHEROGENIC LIPIDS AND LIPOPROTEINS IN MIXED DYSLIPIDEMIA PATIENTS: FINAL RESULTS FROM ARCHES-2, DOUBLE-BLIND PERIOD
Date/Time: May 29, 2024, 11:30 a.m. CEST
Presenter: Robert Rosenson, M.D.
Session: Late Breaker Session 2: New Therapeutic Agents
Presentation material may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website after each presentation concludes.
About MUIR
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 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 plozaisran 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 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 lipoproteins3-6. Genome-wide association and Mendelian randomization studies also support a causal role for triglyceride rich lipoproteins in ASCVD7-10.
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 reflect the comorbidities and underlying conditions of the study populations. Plozasiran is currently being investigated in the PALISADE Phase 3 clinical study in patients with FCS, which recently completed, and the Phase 3 SHASTA-3 and SHASTA-4 studies in patients with SHTG.
Plozasiran has been granted Orphan Drug Designation and Fast Track Designation by the
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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Source: Arrowhead Pharmaceuticals, Inc.
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1. Bharadiya VM. Curr Cardiovasc Risk Rep. 2022;16:131–144. |
2. Baratta, F. et al. Int J Mol Sci. 2023;24:4268. |
3. Gugliucci A. J Clin Med. 2023;12:4399. |
4. Silverman MG, et al. JAMA. 2016;316(12):1289-1297 |
5. Langsted A, et al. J Int Med. 2020;288:116–127. |
6. Fu L, et al. Diabetes Care. 2022;45(9):2136-2143. |
7. Bjornson E, et al. Eur Heart J. 2023;44:4186-4195 |
8. Nordestgaard BG. Circ Res. 2016;118:547-563. |
9. Virani SS, et al. J Am Coll Cardiol. 2021;78(9):960-993 |
10. Hussain A, et al. Curr Atheroscler Rep. 2020;22:25. |
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Source: Arrowhead Pharmaceuticals, Inc.
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