Multiple‐Dose Results from an Ongoing Phase 1 Study of Mivelsiran, an Investigational RNA Interference Therapeutic Targeting Amyloid‐Beta Precursor Protein for Alzheimer’s Disease
Bibliographic record
Abstract
BACKGROUND: Single doses of mivelsiran, an investigational RNA interference (RNAi) therapeutic, have demonstrated robust amyloid-beta precursor protein (APP) lowering in the CNS. We report additional interim safety and pharmacodynamic data in patients with early-onset Alzheimer's disease (EOAD) who received single ascending doses (SAD) and, for the first time, multiple doses of mivelsiran in the ongoing Phase 1 study (NCT05231785). METHODS: Patients with EOAD (symptom onset <65 years of age, Clinical Dementia Rating global score 0.5 or 1.0, Mini-Mental State Examination score >20) were randomized to a single intrathecal dose of mivelsiran 25-100mg or placebo for 6 months (plus up to 6 months follow-up if needed for washout). After washout, patients could enter a separate multiple ascending dose (MAD) portion and receive open-label mivelsiran. Presented here are data from a SAD cohort of mivelsiran 100mg and a MAD cohort of mivelsiran 50mg every 6 months (Q6M). Frequency of adverse events (AEs) and pharmacodynamics were primary and secondary endpoints, respectively. RESULTS: Forty-five patients were enrolled in SAD cohorts (as of 11/20/2024). Of those, 9 patients were randomized to mivelsiran 100mg or placebo (mean [SD] age, 64.1 [3.7] years; 33.3% male; 100% white). Most AEs were mild or moderate. Peak mean (SE) change from baseline in cerebrospinal fluid (CSF) soluble APP beta (sAPPβ) at Month 1 (─84.5% [1.3]) was largely sustained through Month 10 (─61.1% [2.8]). After meeting washout criteria, 10 patients from SAD cohorts received mivelsiran 50mg Q6M (mean [SD] age, 59.9 [4.4] years; 70.0% male; 70.0% white). No serious or severe AEs were reported. At Day 15 after the first dose, mean (SE) change from baseline in CSF sAPPβ was ─63.7% (5.0); at Month 1 after the second dose, change was ─83.8% (2.3). Additional data will be presented. CONCLUSIONS: In this first report of multiple-dose clinical data for a CNS-targeting RNAi therapeutic, single and multiple doses of mivelsiran were generally well tolerated and continued to demonstrate robust, durable, dose-dependent CSF sAPPβ reductions. Further sAPPβ lowering was observed after a second dose of mivelsiran 50mg. These results support further evaluation of mivelsiran in patients with Alzheimer's disease or cerebral amyloid angiopathy.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".