Vutrisiran and patisiran treatment led to noticeable reductions in neurofilament light, indicating a potential biomarker of treatment response in hATTR amyloidosis patients.
Post-hoc data from the phase 3 APOLLO (NCT01960348) and HELIOS-A studies (NCT03759379) showed that as patients with hereditary transthyretin-mediated (hATTR) amyloidosis were treated with vutrisiran (Amvuttra; Alnylam Pharmaceuticals) or patisiran (Onpattro; Alnylam), noticeable decreases in neurofilament light (NfL), a biomarker of neuroaxonal damage, were observed.1
These findings were presented by lead author Emre Aldinc, MD, MA, senior director of Global Medical Affairs at Alnylam, at the 2023 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) annual meeting, held November 1-4, in Phoenix, Arizona. All told, investigators concluded that NfL may serve as a biomarker of treatment response as early as 4 months following initiation of either patisiran or vutrisiran.
APOLLO was a phase 3 study that randomly assigned patients with hATTR polyneuropathy 2:1 to either intravenous patisiran or placebo for a 3-week period. In HELIOS-A, patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks for 18 months. Between the 2 studies, NfL levels at baseline were slightly higher in APOLLO (69.4 pg/mL) than in HELIOS-A (58.2 pg/mL).
In APOLLO, placebo-treated patients demonstrated increased NfL plasma levels after 4 months (+19.0 pg/mL; P <.001) and 18 months (+36.3 pg/mL; P <.001) from baseline whereas those who were treated with patisiran showed decreased NfL levels at the same time points (4 months: –20 pg/mL; P <.001; 18 months: –23.2 pg/mL; P <.001). Similarly, in HELIOS-A, NfL in patisiran and vutrisiran groups decreased from baseline at 4 months (–9.7 and –11.0 pg/mL, respectively; P <.05) and these decreases were maintained at 18 months (–16.4 and –19.9 pg/mL, respectively; P <.001).
Vutrisiran, an investigational RNA interface therapeutic, was approved by the FDA as a treatment for ATTR amyloidosis in June 2022 based on positive 9-month data from HELIOS-A. Results from the study showed that the treatment met its primary end point of change in the modified Neuropathy Impairment Score (mNIS+7) at 9 months (P <.001). Additionally, vutrisian achieved statistically significant results (P <.001) on secondary measures such as the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN0 and timed 10-meter walk test (10-MWT) as compared with historical placebo results.2,3
Additional findings from HELIOS-A showed that at 18 months, treatment with vutrisiran resulted in a 0.46-point mean decrease (denoting improvement) in mNIS+7 from baseline, compared with 28.09-point mean increase for the external placebo group (n = 77). Furthermore, 48% of patients had improvement on mNIS+7 compared with just 4% of those on placebo. These patients also demonstrated a 1.2-point mean decrease (denoting improvement) in Norfolk QoL-DN score at that time point, whereas those on placebo had a 19.8-point mean increase (denoting worsening).
Patisirian, which has been on the market for several years as a therapy for polyneuropathy of ATTR amyloidosis, was rejected by the FDA as a potential treatment for patients with cardiomyopathy of ATTR amyloidosis. In the complete response letter (CRL), the FDA noted that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis was not confirmed. No issues with clinical safety, study conduct, drug quality or manufacturing were indicated in the CRL. As a result of the decision, Alnylam noted it no longer plans to pursue an expanded indication for patisirian in the United States.4