On November 16, at the American Heart Association (AHA) Annual Scientific Sessions, Rona Therapeutics announced positive results from the Phase I clinical trial of its novel GalNAc-conjugated PCSK9 siRNA drug RN0191. The drug aims to significantly reduce low-density lipoprotein cholesterol (LDL-C) and other lipid indicators.

This Phase I study is a randomized, single-dose escalation, placebo-controlled trial designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects with elevated LDL-C levels. The trial subjects are aged between 18 and 60 years, with a Body Mass Index (BMI) ranging from 19 to 30 kg/m².²Between. The data cutoff date was October 14, 2024. A total of 32 subjects were randomly assigned to receive treatments of 60mg, 200mg, 400mg, and 600mg. The average baseline LDL-C level was between 110-130 mg/dL.

After a single subcutaneous injection, RN0191 demonstrated good safety, with no serious adverse events reported. Only mild and transient adverse events were reported across all dose groups. Meanwhile, dose-dependent, significant, and sustained changes in PCSK9, LDL-C, and other lipid parameters were observed (see table below). Among them,

• Achieve an average maximum reduction of over 85% in PCSK9AndMore than 55% average maximum reduction in LDL-C; On Day 180, the reduction in LDL-C remained as high as 42%,This result supports the subsequent development of RN0191 with a dosing regimen administered once every six months.

• Significant reductions in ApoB, Lp(a), non-HDL-C, and total cholesterol levels

• AboveThe reduction effects on PCSK9, LDL-C, and other lipid parameters can be maintained for up to 6 months.(Until the end of the trial follow-up)

According to the company news,RN0191 as a novel PCSK9 siRNA therapy,Demonstrates the best potential in the same category, supporting its development as a monotherapy or in combination with other therapies to further reduce the risk of atherosclerotic cardiovascular disease.

November 17,AlnylamOral Presentation at the 2024 American Heart Association Scientific SessionsRona Therapeutics' Next-Generation siRNA Therapy for the Treatment of Transthyretin Amyloidosis (ATTR)Nucresiran（ALN-TTRsc04）Latest Results of Phase I Clinical Trial。

The Phase 1 study disclosed herein is a randomized, double-blind, placebo-controlled, single ascending dose trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of nucresiran in healthy adult subjects. The study enrolled 48 healthy adult subjects who were randomly assigned in a 3:1 ratio to receive single ascending doses of nucresiran or placebo at doses of 5, 25, 100, 300, 600, or 900 mg.

The primary endpoint of the study is safety, and secondary endpoints include serumTransthyretin (TTR)Changes over time and plasma and urine pharmacokinetic (PK) characteristics after the use of nucresiran.

Results:

• AdoptSingle doses of 300 mg or higher of nucresiran rapidly reduced serum TTR with minimal interpatient variability; mean reductions exceeded 90% from baseline by Day 15 and were sustained to at least Day 180.

• At these doses, the peak reduction in average TTR levels on day 29 exceeded 96% 。

• InSerum TTR Levels Still Significantly Reduced on Day 360; among which, the average reduction exceeds 70% after a single dose of 300 mg.

• Patients showed good tolerance at all test doses; most adverse events between doses were mild and none were considered treatment-related. No injection site reactions were found, and no safety signals, including liver-related ones, were observed.

Plozasiran (ARO-APOC3) is a liver-targeted small interfering RNA drug that efficiently and persistently silencesApolipoprotein C-III (APOC3)The mRNA level is targeted to reduce the expression of the APOC3 protein, thereby effectively lowering serum triglycerides and triglyceride-rich lipoprotein levels through both lipoprotein lipase-dependent and -independent pathways.The drug has been granted Orphan Drug Designation and Fast Track Designation by the FDA, as well as Orphan Drug Designation by the EMA. Currently, plozasiran has generated compelling clinical data in three indications under research, including hypertriglyceridemia, dyslipidemia, and FCS.

At the 2024 AHA conference, Arrowhead announced positive results from the PALISADE study, a randomized, double-blind, placebo-controlled Phase III clinical trial in which participants were randomly assigned to receiveSubcutaneous injection of 25mg or 50mg plozasiran or placebo every three months, lasting for 12 months. Subjects who complete the randomized period are eligible to continue participating in the extension period study. The primary endpoint is the change in median triglyceride (TG) levels at the 10th month, adjusted by placebo. The results showed:

• Patients treated with 25mg or 50mg of plozasiran achieved median TG level reductions of 80% and 78%, respectively.

• Plozasiran also achieved all key secondary endpoints, including the percentage change in fasting triglycerides from baseline at Month 10 and Month 12 (average); the percentage change in fasting APOC3 from baseline at Month 10; the percentage change in fasting APOC3 from baseline at Month 12; and the incidence of acute pancreatitis events during the randomized controlled trial period.

• Plozasiran administered once every three months consistently reduced triglyceride levels throughout the study period with low variability.

• In terms of safety, the number of participants reporting adverse events (AEs) during treatment was similar between the plozasiran and placebo groups. Severe and serious adverse events were less common in the plozasiran group compared to the placebo group. The most frequently reported adverse events were abdominal pain, COVID-19, nasopharyngitis, headache, and nausea.

Based on the aforementioned results, Arrowhead submitted to the FDA on the same dayplozasiranRegarding the marketing application for FCS.

• The published results show,Within 36 weeks,Zerlasiran（300 mg/16 weeks group、300 mg/24 weeks groupOr450 mg/24-week group) ofLp(a) Levels Adjusted by Placebo GroupDecreased by more than 80% from baseline.

• It is worth mentioning that,This is the first report on time average.Lp(a)Analytical research that can more accurately assess the effects of treatment over time (including dose intervals).Lp(a)The maximum reduction exceeds 90%.
• At the last examination 60 weeks after the initial dosing,Lp(a)The decline is still ongoing.；Moreover, infrequent medication use has not led to any safety issues.

Ionis：Olezarsen Completes OneSystematic Review and Meta-Analysis

• After 6 months of Olezarsen treatment, patients' TG levels were significantly reduced.（SMD -52.04，95%CI：-64.55~-39.52；P<0.00001）；
• The levels of apo-C3, apo-B48, and non-HDL-C were all significantly reduced.
• In terms of safety, olezarsen did not show significant side effects. This finding provides a new treatment option for patients with hypertriglyceridemia.

Source:

1. International Circulation: AHA2024: A Century-Breakthrough in the Lipid Field Witnessed by AHA's 100 Years

2. Official Websites of Various Companies

3、POCKET IN：AHA 2024丨LBS 08：ALPACAR、KRAKEN、BROOKLYN and other research highlights!

4. Asymchem Pharma News