Intellia Therapeutics, a leading clinical-stage gene editing company focused on revolutionising medicine with CRISPR-based therapies, has announced positive follow-up data from the ongoing phase 1 clinical trial of its investigational product nexiguran ziclumeran (nex-z) in patients with transthyretin (ATTR) amyloidosis with cardiomyopathy.
‘These longer-term data showed a consistent and durable reduction in TTR and stability or improvement in multiple markers of cardiomyopathy following a single dose of nex-z,’ said Intellia President and Chief Executive Officer John Leonard, M.D. ‘It’s remarkable that even in patients with advanced heart failure, a population that declines rapidly, disease stabilization or improvement was observed out to 24 months in a majority of participants. We look forward to seeing how these data mature in longer-term follow up. In addition, we are working diligently to address the ongoing clinical hold the FDA placed on our Magnitude and Magnitude -2 phase 3 clinical trials.’
The phase 1 clinical trial is an open-label, two-part trial evaluating the safety and efficacy of nex-z in patients with ATTR amyloidosis with cardiomyopathy (ATTR-CM). The trial enrolled 36 patients, a high proportion of whom had advanced disease at baseline (50% classified as New York Heart Association (NYHA) Class III and 31% with variant ATTR-CM).
Continuation of Deep and Durable Serum TTR Reduction in phase 1
Across all patients, a one-time treatment of nex-z led to consistently rapid, deep and sustained serum TTR reduction, regardless of baseline levels, through the latest follow-up. All patients continued to show a sustained response with no evidence of a waning effect over time. Among the nine patients who reached 36 months of follow-up, the mean serum TTR reduction was 87% (mean absolute serum TTR level of 22.9 µg/mL [mean 95% CI, 16.0 to 29.8]), consistent with the overall cohort at month 24. Based on multiple studies in ATTR amyloidosis, low levels of serum TTR have been shown to lead to a meaningful clinical benefit.
Evidence of Stability or Improvement on Clinical and Biomarker Measures in phase 1
Patients dosed with nex-z continued to show evidence of disease stabilization or improvement at month 24 compared to baseline. Evaluation was based on multiple markers of cardiomyopathy, including N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity Troponin T (hs-Troponin T), six-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ) and echocardiographic measures.
At 24 months, NT-proBNP and hs-Troponin T, which are markers known to be associated with disease progression, showed stability or improvement in 70% and 85% of patients, respectively. Preservation of functional status, as measured by 6MWT, was observed with 69% of patients either showing stability or improvement. Notably, 81% of patients were stable or improved in their NYHA classification at 24 months, including improvement in 83% of patients with NYHA Class III. There also was evidence of benefit in quality of life, regardless of NYHA Class at baseline as assessed by KCCQ. Assessment of cardiac structure with echocardiography showed a similar pattern of stability with limited progression of cardiac remodelling at 24 months.
Post-Hoc Mortality Assessment of phase 1 Data
Additionally, findings from a mortality assessment were presented. This post-hoc analysis was conducted on a cohort of 1,792 ATTR-CM patients from the National Amyloidosis Center (NAC) whose baseline characteristics were matched to those of the Phase 1 nex-z population. The analysis showed patients receiving a one-time treatment with nex-z had an all-cause mortality rate of 3.9 per 100 patient-years, while the matched cohort had an all-cause mortality rate of 12.7 per 100 patient-years (HR 0.27, p=0.009).
Phase 1 safety
Nex-z was generally well tolerated across all patients in the phase 1 clinical trial. The most commonly reported treatment-related adverse events were infusion-related reactions (IRRs) and transaminase elevations. In this phase 1 population, liver enzyme elevations did not exceed Grade 2. Through the long-term follow-up evaluation, including patients who reached 44 months, any event leading to death (n=4) was related to the progression of the patients’ underlying cardiovascular disease, consistent with what is expected for this patient population.
