ALN-HTT02: Phase 1b Study

ALN-HTT02: Phase 1b Study

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The safety and efficacy of ALN-HTT02 are currently being investigated in clinical studies and have not been evaluated by US Food and Drug Administration or any health authority.

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Index

Study Design – Abbreviations – References

 Study design

The phase 1b study of ALN-HTT02 is an ongoing, randomized, double-blind, placebo-controlled, single ascending dose study designed to evaluate the safety, tolerability, PK, and PD of ALN-HTT02 in adult patients with Huntington’s disease.1,2 Enrolled patients will be randomized to receive IT injections of ALN-HTT02 or placebo in single ascending doses during a double-blind period of up to 12 months (Figure 1). The decision for a patient to proceed to the next dosing cohort will be determined by the Safety Review Committee. After all patients in the double-blind cohort have reached Month 6, the cohort will be unblinded and placebo-treated patients may receive a single open-label dose of ALN-HTT02. The open-label dose observation period for patients initially randomized to placebo will last up to 12 months.2

Figure 1. ALN-HTT02 Phase 1b Study Design.2

The primary endpoint will assess the safety of ALN-HTT02 through the frequency of adverse events.1,2

Secondary endpoints include1:

• Change from baseline in levels of mHTT in CSF
• Concentrations of ALN-HTT02 in plasma
• Concentrations of ALN-HTT02 in CSF
• Concentrations of ALN-HTT02 in urine

Exploratory endpoints include2:

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

Key study inclusion criteria are2:

• Age 25-70 years with >39 CAG repeats
• HD-ISS Stage 2 or early Stage 3

Key study exclusion criteria are1:

• Significant structural or degenerative neurologic disease other than Huntington's disease at screening
• Primary or secondary immune compromise at screening due to infections, medical conditions, or chronic therapies
• ALT or AST >2× ULN
• eGFR <45 mL/min/1.73m2 at screening
• Received an investigational agent within the last 1 year or 5 half-lives (if known)

The trial is listed as recruiting as of February 28, 2025.1

 Abbreviations

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CAG = cytosine-adenine-guanine; CNS = central nervous system; CSF = cerebrospinal fluid; eGFR = estimated glomerular filtration rate; HD-ISS = Huntington's Disease Integrated Staging System; HTT = huntington; IT = intrathecal; mHTT = mutant huntingtin; mRNA = messenger ribonucleic acid; PD = pharmacodynamics; PK = pharmacokinetics; ULN = upper limit of normal; wtHTT = wild-type huntingtin.

Updated 20 October 2025

 References

1.  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.

2.  Sloan K. ALN-HTT02, a novel C16-siRNA conjugate for HTT-lowering in the CNS. Presented at: European Huntington’s Disease Network (EHDN) and Enroll-HD Congress; September 12-14, 2024; Strasbourg, France.

3.  Sloan, K. ALN-HTT02, an investigational RNAi therapeutic targeting Exon 1 of HTT in Phase 1 development for Huntington’s disease. Presented at: CHDI Huntington’s Disease Therapeutics Conference; February 24-27, 2025; Palm Springs, CA, USA.