#AANAM – Onpattro Reduced Nervous System Damage in Trial

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 more stories from the conference.

Treatment with Onpattro (patisiran) lessened signs of nervous system damage in people with familial amyloid polyneuropathy (FAP), new clinical trial data suggests.

Findings from a separate analysis also indicated the safety and efficacy of Onpattro are not affected by concurrent or prior treatment with transthyretin stabilizers, a different class of medications sometimes used to treat FAP.

Developed and marketed by Alnylam Pharmaceuticals, Onpattro is a widely-approved treatment for FAP that works by reducing levels of misfolded transthyretin (TTR) protein, which causes the disease.

The medication’s safety and efficacy have been demonstrated in several clinical trials, including the Phase 3 APOLLO study (NCT01960348) and a Phase 2 extension trial (NCT01961921). Individuals who completed these trials had the option to enroll in another global open-label extension (OLE) trial (NCT02510261), which is still underway.

Two-year data from this global OLE study, also presented at this year’s American Academy of Neurology (AAN) 2021 Virtual Annual Meeting, showed that treatment with Onpattro eased polyneuropathy and improved patients’ quality of life.

At other presentations at the meeting, researchers from Alnylam and other institutions presented additional analyses of data from the global OLE trial, as well as from previous studies of Onpattro. The intent was to better understand the therapy’s biological effects and safety when used in combination with other medications.

In one poster, “Neurofilament Light Chain (NfL) as a Potential Biomarker of Treatment Response in Hereditary Transthyretin-Mediated Amyloidosis: Data from the Patisiran Global OLE Study,” researchers examined the effects of Onpattro on the levels of neurofilament light chain in the blood.

Neurofilament light chain, or NfL, is a structural protein in neurons (nerve cells). When neurons become damaged — for example, due to the buildup of abnormal protein deposits that are known to cause FAP — this protein is released into bodily fluids. As such, measuring NfL levels in the blood may be used to indirectly assess nerve damage.

Among patients who had been on placebo during APOLLO, blood NfL levels continually increased. By the end of the 18-month trial, average NfL levels were 36.3 picograms per milliliter (pg/mL) higher than they had been at the study’s start (baseline). This suggests that, in the absence of an active treatment, nerve damage continually progressed during the trial.

Participants given a placebo in APOLLO who enrolled in the global OLE after completing the main trial, started treatment with Onpattro upon entering the global OLE. After two years of Onpattro treatment in the global OLE, blood NfL levels in these patients were on average 19.0 pg/mL lower than they had been at the start of APOLLO, suggesting a reduction in nerve damage.

Among participants who had been assigned originally to receive Onpattro in APOLLO, blood NfL levels continued to drop until reaching a minimum value of 44.0 pg/mL after two years of treatment in the global OLE (and nearly four years of total treatment).

In addition to suggesting that Onpattro can reduce nerve damage, these findings indicate that measuring blood NfL levels may be a useful way to assess disease progression and treatment responses in these patients.

In another poster, researchers analyzed data from APOLLO and the Phase 2 extension study to assess the safety, efficacy, and pharmacological properties of Onpattro in people who were also being treated with transthyretin stabilizers, or who had been receiving these medications prior to starting treatment with Onpattro. The poster was titled “Evaluation of Patisiran With Concomitant or Prior Use of Transthyretin Stabilizers.”

Although transthyretin stabilizers also are meant to treat FAP, they have a distinct mechanism of action different from Onpattro. While Onpattro works by reducing the production of misfolded TTR protein, stabilizers, as the name suggests, help stabilize the protein so that it does not form the toxic clumps that trigger the disease.

Among the 27 patients who participated in the Phase 2 extension trial, seven were treated with Onpattro alone, while the remaining 20 also received transthyretin stabilizers (either tafamidis or diflunisal). Over the course of 24 months of treatment in this trial, TTR protein levels decreased by similar amounts — about 80% — in all groups.

Safety findings across the different treatment groups also were similar. While almost all trial participants reported at least one adverse event, most were not serious or severe.

At the start of APOLLO, 74 participants reported to have been treated previously with tafamidis and 45 with diflunisal. Safety analyses found no significant difference in the rates of adverse events, serious adverse events, or severe adverse events, in individuals who had or had not been treated with transthyretin stabilizers.

Efficacy analyses also demonstrated that patients treated wtih Onpattro experienced similar easing of polyneuropathy symptoms and improvements to quality of life, regardless of prior treatment with transthyretin stabilizers.

Collectively, these findings “indicate that patients with [FAP] benefit from patisiran [Onpattro] treatment regardless of contaminant or prior use of a TTR stabilizer,” the researchers concluded.