Brezosiran: Phase 1b Study

Brezosiran: Phase 1b Study

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

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 Summary

Abbreviations

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CAG = cytosine‑adenine-guanine; CAP100 = CAG Age Product 100 score; CNS = central nervous system; CSF = cerebrospinal fluid; eGFR = estimated glomerular filtration rate; HD-ISS = Huntington's Disease Integrated Staging System; HTT = huntington; IT = intrathecal; LLoQ = lower limit of quantification; mHTT = mutant huntingtin; mRNA = messenger ribonucleic acid; NfL = neurofilament; NULISA = NUcleic acid Linked Immuno-Sandwich Assay; OLE = open-label extension; PD = pharmacodynamics; PK = pharmacokinetics; RNAi = ribonucleic acid interference; SAE = serious adverse event; SD = standard deviation; SE = standard error; SMC = single molecular counting immunoassay; ULN = upper limit of normal; WBC = white blood cell; wtHTT = wild-type huntingtin

 Index

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

 Study Design

The Phase 1b study is a randomized, double-blind, placebo-controlled, single ascending dose study designed to evaluate the safety, tolerability, PK, and PD of brezosiran (ALN‑HTT02) in adult patients with Huntington’s disease. Enrolled patients are randomized to receive IT injections of brezosiran or placebo in single ascending doses during the double-blind period (Figure 1).1

The decision for a patient to proceed to the next dosing cohort is determined by the Safety Review Committee. Each cohort is unblinded after all participants in a cohort have reached Month 6, and placebo-treated patients may receive a single open-label dose of brezosiran in the variable follow-up period. Participants from the Phase 1b study are able to receive brezosiran every 6 months in the OLE.1  

Figure 1. Phase 1b Study Design.1

The primary endpoint will assess the safety and tolerability of brezosiran through the frequency of AEs.1,2

PK and PD endpoints include1:

      PK: CSF and plasma profile of brezosiran

      PD: Change from baseline in mHTT levels in CSF

PK and PD are secondary endpoints for single-ascending doses and exploratory for repeat doses.1

Exploratory endpoints include1:

      Clinical, imaging, and biomarker measures of disease progression and safety

Select inclusion and exclusion criteria for the Phase 1b study are presented in Table 1.1,2

Table 1. Select Inclusion and Exclusion Criteria.1,2

 Patient Demographics & Baseline Characteristics

An interim analysis of the Phase 1b study included a total of 48 enrolled participants. The baseline demographics and characteristics across cohorts are presented in Table 2.1

Table 2. Interim Baseline Demographics and Patient Characteristics (Cohorts 1-5).1

 Pharmacodynamic Results

CSF mHTT

A dose-dependent reduction in CSF mHTT was observed using 2 independent assays. The changes from baseline in mHTT levels using the SMCxPRO and NULISA assays are shown in Figure 2. The mean maximum observed reduction in mHTT across cohorts is presented in Table 3.1

A total of 16 participants (33.3%) had a post-baseline measurement below the LLoQ using the SMCxPRO assay. No participants had a post-baseline measurement below the LLoQ using the NULISA assay.1

Figure 2. Change from Baseline in CSF mHTT with SMCxPRO and NULISA Assays.1

Table 3. Reduction in CSF mHTT by Dose Cohort at Month 3.1

 Safety Results

A summary of the blinded safety results are presented in Table 4. The active and placebo participants were pooled within each cohort owing to the ongoing blinded study.1

Table 4. Blinded Summary of Adverse Events (Dose Cohorts 1-5).1

CSF Neuroinflammatory Biomarkers

The mean CSF protein and CSF WBC count by dose cohorts are presented in Figure 3.1

Figure 3. CSF Total Protein and WBC Count.1,a

CSF Neuroaxonal Injury Biomarker

The mean absolute CSF NfL levels and mean fold change from baseline in CSF NfL by dose cohorts are presented in Figure 4.1

Figure 4. CSF NfL.1,a

Ventricle Size

The mean changes from baseline in lateral ventricle volume by dose cohorts as presented in Figure 5. There were no increases beyond the placebo range observed.1

Figure 5. Lateral Ventricle Volume.1,a

References

1.  Tabrizi S, Wild E, Leavitt B, et al. Interim data from a phase 1b study of ALN-HTT02, an investigational RNA interference therapeutic targeting exon 1 of Huntingtin for HTT-lowering in people with Huntington’s disease. Presented at: European Huntington’s Disease Network (EHDN) Clinical Research Congress; October 22-24, 2026; Krakow, Poland.

2.  Alnylam Pharmaceuticals: A Study to Evaluate ALN-HTT02 in Adult Patients With Huntington’s Disease. Available from: https://clinicaltrials.gov/study/NCT06585449. Accessed February 28, 2024.

Updated 30 October 2026