Long-term Onpattro treatment prevents disease progression: Study

Real-world study supports APOLLO trial results

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Four years of treatment with Onpattro (patisiran) safely prevents disease progression for most familial amyloid polyneuropathy (FAP) patients, according to a retrospective real-world study in Italy.

“These data are not very different from those obtained in the APOLLO trial,” which supported the therapy’s approvals worldwide, the researchers wrote.

The study, “Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy,” was published in Neurological Sciences.

FAP is caused by mutations in the TTR gene, which result in the production of toxic clumps of the transthyretin protein that accumulate mostly in the nerves outside the brain and spinal cord, causing damage that leads to FAP symptoms.

While there is no cure for FAP, several treatments are available for reducing levels of toxic transthyretin clumps and slowing disease progression. One of these, Alnylam Pharmaceuticals’ Onpattro, was approved in 2018 for adults with FAP in the U.S. and for adults with FAP, or Coutinho, stage 1 or 2 in Europe.

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FAP stage 1 identifies patients with symptoms of polyneuropathy, or damage to several nerves, who are fully capable of walking, and FAP stage 2 refers to patients who need walking aids.

Prior to Onpattro’s European approval, patients in Italy were able to access it via a compassionate-use program. These programs are aimed at people with serious or life-threatening conditions that have few or no adequate treatments, and allow them access to investigational therapies outside of clinical trials.

To evaluate Onpattro’s long-term safety and efficacy, researchers in Italy retrospectively analyzed data from FAP stage 1 or 2 patients who received the therapy at 11 Italian centers via the compassionate use program and continued treatment after its approval.

Forty patients enrolled in the program were included in the analysis. Their median age was 70, and 75% of them were men. They received Onpattro treatment between May 2018 and December 2023, and were followed for a mean of 48 months, or about four years, with annual evaluations.

Most patients (75%) carried a FAP-causing mutation other than the most common, Val30Met. A total of 23 patients were classified as FAP stage 1, and the remaining 17 had FAP stage 2. Most patients (70%) also showed signs of heart involvement.

The majority (85%) were on other treatments at the time of Onpattro initiation, and these were stopped after enrollment in the program.

Onpattro efficacy was measured by assessing changes in several measures of disease progression. These included the four FAP stages, which are based mainly on how the disease affects walking ability, and the polyneuropathy disability (PND) system, which is divided into five stages based on neurologic health and walking skills. In general, higher stages in each scale are associated with more severe polyneuropathy-related disability.

Results from 31 patients with available Coutinho and PND staging scores after two years showed that the disease remained stable in most patients: 80.6% as assessed with the Coutinho system, and 70.9% based on the PND system. One patient scored lower with the PND system.

Additional efficacy measures included the Neuropathy Impairment Score (NIS), the Karnofsky Performance Status (KPS) scale, and the Compound Autonomic Dysfunction Test. The Norfolk Quality of Life-diabetic neuropathy (QoL-DN) questionnaire and the modified body mass index (mBMI), a modified ratio of height and weight, also were assessed.

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Disease status ‘largely maintained’ with treatment

There were “few significant differences from baseline [study’s start] to the four timepoints for the parameters analysed,” the team wrote.

Mean NIS scores dropped from 71.4 at the start of treatment to 68.2 at month 12 and 70.4 at month 24. But after that, mean NIS rose significantly, reaching 77.5 at month 48. This was mainly driven by “two cases who substantially worsened over the course of follow-up,” the researchers wrote.

After three years of treatment, the mean KPS score was significantly reduced, falling from 67.1 at baseline to 63.6 at month 36, indicating worse ability to perform daily activities. The mean score was even lower — 62.6 — at the end of the follow-up period.

The KPS score remained stable during the first two years in 51.6% of the patients, while “two patients improved over the 4 years of observation,” the researchers wrote.

The mean Norfolk QoL-DN score, which assesses patients’ perceptions of polyneuropathy-related symptoms, remained generally stable over the course of treatment. A statistically significant drop (improvement) was observed after one year and two years.

The mBMI showed no significant differences across all timepoints.

A total of nine patients (22.5%) experienced adverse events while on Onpattro. While most were serious, they were unrelated to the therapy. Onpattro-related adverse events were mild in intensity and included injection-site reactions.

In four patients, the therapy was discontinued due to adverse events. One patient resumed treatment following resolution of the adverse event.

Overall, “our data show that [Onpattro] largely maintained the disease status in Italian patients with [FAP],” the team wrote.