Abstract 67: Phase I Safety, Pharmacokinetic, and Pharmacodynamic Results for ALN-PCS, a Novel RNAi Therapeutic for the Treatment of Hypercholesterolemia
Bibliographic record
Abstract
Proprotein convertases subtilisin/kexin type 9 (PCSK9) is a member of the proprotein convertase (PC) family of subtilisin-like serine endoproteases that regulates low density lipoprotein receptor (LDLR) levels and function. Murine models and human genetic studies indicate that loss of PCSK9 protein increases LDLR levels while excess PCSK9 decreases LDLR levels. These changes in LDLR protein levels coincide with reciprocal changes in circulating levels of plasma LDL cholesterol (LDL-C). We have developed a highly potent RNA interference (RNAi) therapeutic, ALN-PCS, targeting both intra and extracellular PCSK9 for inhibition through an RNAi mechanism. Pre-clinical data in non-human primate models, indicate that a single intravenous dose of ALN-PCS results in rapid, dose dependent, and significant lowering of liver PCSK9 transcript, plasma PCSK9 protein and subsequently serum LDL-C and ApoB levels, without impacting serum HDL-C. Here we report on interim data from an ongoing Phase 1 trial of ALN-PCS being conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL) who are not on any lipid lowering therapy. The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with subjects being enrolled into sequential cohorts of increasing doses. Secondary objectives of the study include characterization of plasma and urine pharmacokinetics of ALN-PCS, assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels, and evaluation of clinical efficacy as measured by LDL-C levels. Data from 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg in a 3:1 randomization of drug to placebo will be presented. ALN-PCS was safe and well tolerated in this study and there have been no serious adverse events related to study drug administration to date. There have been no drug-related discontinuations from the study and no liver enzyme elevations. A mild, transient rash that resolved spontaneously was observed in three subjects that received ALN-PCS, and in two that received placebo. To date, administration of ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p<0.001). In addition, administration of ALN-PCS resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p<0.05) at the 0.250 mg/kg dose level. There was no significant decrease in high-density lipoprotein (HDL). Dosing of further cohorts at the current top dose (0.25 mg/kg) and at a higher dose is planned. Additional data will be presented as available.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".