Nucresiran: Phase 1 Study

Nucresiran: Phase 1 Study

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The safety and efficacy of nucresiran 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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 Summary

INDEX

Study Design – Patient Demographics and Baseline Characteristics – Safety Results – Pharmacokinetic Results – Pharmacodynamic Results – Abbreviations – References

 Study design

The Phase 1 study of nucresiran (ALN‑TTRsc04) is a randomized, double-blind, placebo-controlled, single ascending dose study designed to evaluate the safety, tolerability, PK, and PD of nucresiran in healthy patients.1,2 Enrolled patients are randomized 3:1 per cohort to receive subcutaneous injections of 5, 25, 100, 300, 600, or 900 mg nucresiran (n=6 per cohort) or placebo (n=12) during the 12‑month double-blind evaluation period, followed by a minimum 6-month safety period for patients who have serum TTR levels that have not returned to ≥80% of pre-dose Day 1 level by the last post-dose follow‑up visit on Day 360.1

The primary endpoint is to assess the safety of nucresiran by the frequency of AEs. Secondary endpoints assess the change from baseline in serum TTR levels over time, urine PK through the fraction excreted in the urine until 24 hours, and plasma PK through the Cmax, Tmax, AUClast, and T1/2.1,2

Key study inclusion criteria are1:

      Healthy volunteers aged 18-65 years

      BMI ≥18.0 to ≤30 kg/m2

      eGFR ≥90 mL/min/1.73 m2

Key study exclusion criteria are1:

      Interfering medical conditions

      Prescription drugs within 14 days of nucresiran administration

 Patient Demographics & Baseline Characteristics

Patient demographics and baseline characteristics for 48 patients randomized to placebo or nucresiran by cohort are presented in Table 1.1

Table 1. Patient Demographics and Baseline Characteristics.1

 Safety results

The majority of AEs occurring among the nucresiran cohorts within 360 days of dosing were mild in severity, and none were considered related to treatment. There were no injection-site reactions or safety signals reported, including liver-related signals. No deaths were reported.1

Table 2. Adverse Events Within 360 Days of Dosing.1

 Pharmacokinetic Results

The mean concentration of nucresiran following a single subcutaneous dose was evaluated over time for the six dose cohorts; plasma levels of nucresiran declined below LLOQ within 72 hours (Figure 1). Mean (CV%) plasma half-life ranged from 4.5 (32.3) to 7.6 (41.3) hours across doses ranging from 25 to 900 mg. Nucresiran was minimally excreted by renal route (<21%) after 24 hours.1

Figure 1. Mean Concentration of Nucresiran Following a Single Subcutaneous Dose.1

 Pharmacodynamic Results

Serum TTR Levels

The mean percent change from baseline in serum TTR levels was evaluated over 360 days (Figure 2). In the 300 mg cohort, a 90.3% mean reduction in serum TTR levels was observed on Day 15, 96.5% on Day 29, and 92.6% on Day 180. In the 600 mg cohort, a 95.0% mean reduction in serum TTR levels was observed on Day 15, 97.8% on Day 29, and 96.0% on Day 180. On Day 29, there was low variability in the range for percent TTR reduction in both the 300 mg cohort (96.0‑96.7%) and 600 mg cohort (96.6‑98.6%).1

Figure 2. Mean Percent Change from Baseline in Serum TTR Levels Over Time.1

 Abbreviations

AE = adverse event; AUClast = area under the curve between time 0 and last observable concentration; BL = baseline; BMI = body mass index; Cmax = maximum observed plasma concentration; CV% = coefficient of variation; eGFR = estimated glomerular filtration rate; LLOQ = lower limit of quantitation; mRNA = messenger RNA; PD = pharmacodynamics; PK = pharmacokinetics; RNA = ribonucleic acid; RNAi = ribonucleic acid interference; SAE = serious adverse event; SD = standard deviation; SEM = standard error of the mean; T1/2 = half-life; Tmax = time to maximum observed plasma concentration; TTR = transthyretin; URTI = upper respiratory tract infection.

Updated 07 October 2025

 References

1.  Murad A, Lasko MJ, Badri P, et al. A phase 1, single ascending dose study to evaluate ALN-TTRsc04, a next-generation RNA interference therapeutic, in healthy participants for potential treatment of transthyretin amyloidosis. Presented at: American Heart Association (AHA) Scientific Sessions; November 16-18, 2024; Chicago, IL, USA.

2.  Alnylam Pharmaceuticals: A study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ALN‑TTRSC04 in healthy subjects. Available from: https://clinicaltrials.gov/study/NCT05661916. Accessed October 07, 2025.