#AANAM – Onpattro Continues Improving Quality of Life in Ongoing Study

Editor’s note: The FAP News Today team is providing in-depth coverage of the 2021 Virtual AAN Annual Meeting, April 17–22. Go here to read the latest stories from the conference.

Onpattro (patisiran) over two years continues to ease symptoms of polyneuropathy and to improve quality of life among people with familial amyloid polyneuropathy (FAP), according to data from an ongoing global extension study.

Findings from the study were presented by Michael Polydefkis, MD, a professor at Johns Hopkins University, in Maryland, at this year’s American Academy of Neurology (AAN) Virtual Annual Meeting, held online April 17-22. The presentation was titled “Global Open-label Extension: 24-month Data in Patients with hATTR Amyloidosis,”

Developed and marketed by Alnylam Pharmaceuticals, Onpattro is a treatment for FAP that has been approved in the U.S., Europe, and elsewhere. It works by lowering levels of misfolded transthyretin protein, which causes FAP.

The medication is given by an infusion directly into the bloodstream (intravenously) every three weeks, at doses depending on the patient’s body weight.

Regulatory approvals of Onpattro were supported by positive results from a global Phase 3 trial, called APOLLO (NCT01960348), in which FAP patients were given either Onpattro or a placebo for 18 months.

Individuals who completed APOLLO had the option to enroll in an ongoing, open-label extension (OLE) study (NCT02510261), in which all participants are being treated with Onpattro. This global OLE trial also enrolled some patients who participated in a prior Phase 2 extension study (NCT01961921).

One-year data from the OLE trial, published late last year, showed that Onpattro was able to ease symptoms and improve patients’ quality of life. At the AAN meeting, Polydefkis presented data from 178 participants who had been in the global OLE for two years.

In the trial, polyneuropathy symptoms were assessed with the modified Neuropathy Impairment Score +7 (mNIS+7), in which higher mNIS+7 scores indicate worse symptoms.

Among trial participants who had been on Onpattro prior to enrolling in the global OLE, mNIS+7 scores showed sustained improvements, compared with scores observed at the start of each original trial.

Specifically, among participants who were originally in the APOLLO trial, mean mNIS+7 scores were 4.9 points lower after two years in the OLE, compared with the start of that trial. For participants who were originally in the previous Phase 2 extension study, mNIS+7 scores were 5.9 points lower after two years in the global OLE, compared with the start of the original extension study.

The data also showed that, among participants who had been on the placebo in APOLLO, mNIS+7 scores after two years in the global OLE were on average 26.3 points higher compared with those at the start of APOLLO. However, this increase was mainly reflective of the disease progressing while patients had been on a placebo in the original trial. Over the course of the global OLE itself, when participants were being treated with Onpattro, mNIS+7 scores increased by a mean of 0.1 points.

Patients’ quality of life, assessed with the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire, followed a similar trend. Of note, higher Norfolk QOL-DN scores indicate a worse quality of life.

Participants who had been on Onpattro prior to enrolling in the global OLE study showed sustained improvements during the OLE, with Norfolk QOL-DN scores dropping 2.4 points after two years in the OLE compared with the start of APOLLO.

Those who switched over from a placebo experienced worsening while they were on the placebo, and then their Norfolk QOL-DN scores stabilized or improved after starting treatment with Onpattro in the OLE. During the OLE, these patients had a mean reduction of 4.1 points. Notably, however, these individuals had substantially worse Norfolk QOL-DN scores after being in the OLE for two years, compared with those at the start of APOLLO — a mean increase of 15.8 points. This was due to continual worsening during the time they were treated with a placebo in APOLLO.

The same trend was seen for modified body mass index, a measure of overall nutritional status.

“An additional 24 months of treatment in the [Onpattro] treatment arm [led to] persistent reversal of neuropathy from the parent study baseline, and this was paralleled by a sustained and durable treatment effect on quality of life and maintained nutritional status,” Polydefkis said during the presentation.

“The patients who were initially on placebo progressed during the APOLLO study, but once started on treatment in the global open-label extension, saw a halting of neuropathy progression and an improvement in their quality of life and nutritional status. However, they did not recapture the original APOLLO baseline, so what was lost remained largely lost,” Polydefkis added.

Polydefkis also added that this finding “underscores the importance for early treatment.”

Global OLE data revealed no new safety-related concerns for Onpattro.

“The majority of adverse events were mild to moderate [in severity],” Polydefkis said, noting that most recorded adverse events were infusion-related reactions that primarily occurred early on in the treatment course and improved with time.

There were 29 on-study deaths, none of which were deemed to be related to treatment with Onpattro.

Statistical analyses also demonstrated that the overall exposure-adjusted mortality rate for individuals given at least one dose of Onpattro (4.3 deaths per 100 patient-years) was generally lower than what is seen in untreated FAP patients (6.3–29 deaths per 100 patient-years). Of note, patient-years is a measure of the number of people participating in a study and the amount of time they were followed. For example, 100 person-years pertains to data gathered by following 100 people for one year.

Polydefkis noted that the death rate was highest among individuals who had been on placebo in the APOLLO study and, consequently, had been treated with Onpattro for the least amount of time.