Mivelsiran: Phase 1 Study

Mivelsiran: Phase 1 Study

The following information is provided in response to your unsolicited inquiry. It is intended to provide you with a review of the available scientific literature and to assist you in forming your own conclusions in order to make healthcare decisions. This document is not for further dissemination or publication without authorization.

The safety and efficacy of mivelsiran are currently being investigated in clinical studies and have not been evaluated by the FDA or any health authority.

If you are seeking additional scientific information related to Alnylam medicines, you may visit the Alnylam US Medical Affairs website at RNAiScience.com.

 Summary

Index

Study Design – Patient Demographics & Baseline Characteristics – Safety Results – Pharmacodynamic Results – Exploratory Results – Abbreviations – References

 Study Design

The Phase 1 study (NCT05231785) is an ongoing, global, randomized, double-blind, placebo-controlled, 2‑part study designed to evaluate the safety, tolerability, PD, and PK of mivelsiran in patients with EOAD. Part A of the study is a double-blind, single-ascending dose study, while Part B of the study is an open-label multi-dose study of mivelsiran.1,3

In Part A, study participants (N=36) were dosed with a single dose of mivelsiran or placebo via IT administration. Following completion of Part A, eligible patients were sequentially assigned to Part B cohorts (Figure 1).3

Figure 1. Phase 1 Study Design of Mivelsiran in EOAD.3

The primary endpoint assessed for each part separately is the safety and tolerability of mivelsiran as measured by the frequency of AEs. The secondary endpoints of the study are to assess the PK profile of mivelsiran in CSF and plasma and the PD of mivelsiran through change from baseline in CSF levels of sAPPα and sAPPβ. Exploratory endpoints assess biomarkers of disease progression through change from baseline in CSF levels of Aβ42, Aβ40, and NfL.1,3

 Patient Demographics & Baseline Characteristics

The patient demographics and baseline characteristics of patients enrolled in Part A and Part B are presented in Table 1.3

Table 1. Patient Demographics and Baseline Characteristics Across Cohorts in Parts A and B.3

 Safety Results

The safety and tolerability of mivelsiran was monitored throughout the study and in the follow-up period as a primary endpoint. A majority of the AEs were nonserious, mild or moderate, and considered not related to study drug. There were no serious or severe AEs that were considered related to study drug. The most common AEs were procedural pain and procedural headache. No drug-related ARIA events have occurred in the study as of a data cut-off of May 15, 2025, and no ARIA-E was observed. A safety summary of AEs across cohorts in Part A and Part B is shown in Table 2.3

Table 2. Safety Summary Across Cohorts in Parts A and B.3

Immune responses were not observed following single or multiple doses of mivelsiran, as assessed by routine CSF laboratory assessments (Figure 2).3

Figure 2. CSF Safety Laboratory Assessments of Mivelsiran.3

 Pharmacodynamic Results

CSF sAPPα and sAPPβ

In an interim analysis of Part A (25 mg, 35 mg, 50 mg, and 75 mg cohorts), there was a rapid reduction in CSF sAPPα and sAPPβ levels following a single dose of mivelsiran above 25 mg (Figure 2). At Month 1 following a single dose of mivelsiran 75 mg, peak mean reductions from baseline were 61.3% and 73.5% for sAPPα and sAPPβ, respectively. Dose-dependent reductions were sustained through Month 6, and reductions were observed through 12 months with the single 50 or 75 mg doses.1

Figure 3. Mean Percent Change from Baseline in CSF sAPPα and sAPPβ After Single Dose of Mivelsiran.1

Additional data on the mean percent change from baseline in CSF sAPPβ levels after single and multiple doses of mivelsiran are presented in Figures 4 and 5, respectively. Following a single dose of mivelsiran 150 mg, the peak mean reduction from baseline in sAPPβ was 85% and 75% at Month 1 and Month 6, respectively.3

Figure 4. Mean Percent Change from Baseline in CSF sAPPβ After Single Dose of Mivelsiran.3

Figure 5. Change from Baseline in CSF sAPPβ With Mivelsiran Q6M Dosing.3

 Exploratory Results

CSF Aβ42 and Aβ40

In Part A, reductions in CSF Aβ42 and Aβ40 were observed with all doses at Day 15. In the 150 mg cohort, the peak mean (SE) reductions from baseline in CSF Aβ42 and Aβ40 were 61% (8) and 79% (5), respectively, at Month 2. Following a single dose of mivelsiran over 25 mg, mean reductions in Aβ42 over 25% and in Aβ40 over 30% were sustained to Month 6.3

The change from baseline in CSF Aβ42 and Aβ40 observed with multiple doses of mivelsiran in Part B is presented in Figure 6.3

Figure 6. Mean Percent Change from Baseline in CSF Aβ42 and Aβ40 After Multiple Doses of Mivelsiran.3

 Abbreviations

Aβ = amyloid beta; Aβ40 = amyloid beta peptide length 40 amino acids; Aβ42 = amyloid beta peptide length 42 amino acids; AD = Alzheimer’s disease; AE = adverse event; ApoE = apolipoprotein E; APP = amyloid precursor protein; ARIA‑E = amyloid‑related imaging abnormality presenting as edema; BL = baseline; BMI = body mass index; CAA = cerebral amyloid angiopathy; CDR = Clinical Dementia Rating; CNS = central nervous system; CSF = cerebrospinal fluid; EOAD = early onset Alzheimer’s disease; IT = intrathecal; LP = lumbar puncture; M = month; MAD = multiple ascending dose; MCI = mild cognitive impairment; MMSE = Mini Mental State Examination; NfL = neurofilament light chain protein; PBO = placebo; PD = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; PY = patient-years; Q6M = every 6 months; RNAi = ribonucleic acid interference; SAD = single ascending dose; sAPP = soluble amyloid precursor protein; SD = standard deviation; SE = standard error; ULN = upper limit of normal.

Updated 05 August 2025

References

1.  Cohen S, Ducharme S, Brosch J, et al. Single ascending dose results from an ongoing phase 1 study of mivelsiran (ALN-APP), the first investigational RNA interference therapeutic targeting amyloid precursor protein for Alzheimer’s disease. Presented at: Alzheimer’s Association International Conference (AAIC); July 28-August 1, 2024; Philadelphia, PA, USA.

2.  Cohen S, Ducharme S, Brosch J, et al. Interim phase 1 part A results for ALN-APP, the first investigational RNAi therapeutic in development for Alzheimer’s disease. Presented at: Alzheimer’s Association International Conference (AAIC); July 16-20, 2023; Amsterdam, Netherlands.

3.  Cohen S, Ducharme S, Brosch J, et al. 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. Presented at: Alzheimer’s Association International Conference (AAIC); July 27-31, 2025; Toronto, Canada.