Treatment switch slows neuropathy progression in hATTR-PN study
Adults who didn’t respond to tafamidis meglumine fared better on Onpattro
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Onpattro (patisiran) slows neuropathy (nerve damage) progression in people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) who respond poorly to tafamidis meglumine, a real-world study in Europe showed.
After switching to Onpattro, patients had a significantly slower annual increase in a measure of nerve damage, while most tests of nerve function showed little further deterioration. Tafamidis meglumine is approved in the EU and many other regions outside the U.S. under the brand name Vyndaqel to treat adults with early-stage hATTR-PN.
“While tafamidis remains a valuable option for selected … patients with very mild neuropathy [nerve damage], particularly due to its lower cost and wider accessibility, early recognition of disease progression and timely treatment escalation are needed to prevent irreversible disability,” the researchers wrote.
The study, “Neuropathy Progression in Variant Transthyretin Amyloidosis: Comparison Between TTR Stabilizers and Gene Silencer Therapies,” was published in Muscle & Nerve.
hATTR-PN is caused by mutations in the TTR gene. The condition, also known as familial amyloid polyneuropathy (FAP), is a progressive disease in which these mutations cause the protein transthyretin (TTR) to misfold and form toxic clumps that accumulate in and damage peripheral nerves (those outside the brain and spinal cord).
Treatments include TTR stabilizers
Several hATTR-PN treatments are available, including TTR stabilizers such as tafamidis meglumine and gene-silencing therapies that reduce TTR production, such as Onpattro.
Tafamidis meglumine, given orally once daily, is commonly used in the EU as an initial treatment, particularly for people with early-stage disease who are able to walk without assistance. However, some patients continue to experience disease progression despite treatment. In these cases, switching to Onpattro — which is available for patients who can walk without or with assistance — may be considered. Onpattro is administered directly into the bloodstream once every three weeks.
Evidence of Onpattro’s effectiveness in people who switch from tafamidis meglumine because of worsening disease remains limited. To learn more, a team of researchers retrospectively analyzed data from 32 adults with hATTR-PN who switched from tafamidis meglumine to Onpattro due to disease progression. All participants carried Val30Met, the most common hATTR-PN-causing mutation, and were followed at one of two European centers, one in Portugal and another in Spain.
The patients received each treatment for at least one year; tafamidis meglumine was given for a mean of 4.5 years and Onpattro for a mean of 2.3 years. The 13 patients (41%) who received tafamidis meglumine for at least five years experienced disease progression after a mean of nearly 7.5 years on the therapy.
Before tafamidis meglumine, six people (18.8%) also showed heart involvement.
All 32 participants had mild/early-stage hATTR-PN disease and were able to walk without assistance, placing them as Coutinho FAP stage 1. Most (69%) also had a Polyneuropathy Disability (PND) score of 1, the mildest symptomatic level on a scale that mainly reflects how nerve damage affects walking and mobility. Their mean Neuropathy Impairment Score (NIS), which measures nerve damage, was 14.6, compatible with early disease.
During tafamidis meglumine treatment, some patients showed FAP stage and PND score worsening, and total NIS and lower-limb NIS scores had significantly increased (worsened) by the time they switched treatment.
After switching to Onpattro, total NIS and scores assessing the legs and feet remained largely stable. One patient experienced a FAP stage worsening and five had PND score worsening. Overall, the annual rate of NIS increase was significantly lower during Onpattro treatment than during tafamidis meglumine (0.7 vs. 3.9 points per year).
Similar findings were seen in tests measuring nerve function. These measures worsened significantly during tafamidis meglumine treatment, but most showed no significant further deterioration after the switch to Onpattro. The exception was sensory nerve action potential, a measure of the electrical response of sensory nerves, which continued to decline after Onpattro.
Blood tests showed that TTR levels increased significantly during tafamidis meglumine treatment and fell significantly after Onpattro, consistent with the therapies’ mechanisms of action.
Kidney function declined during tafamidis meglumine treatment but did not change significantly after the switch. The annual rate of kidney-function change did not differ significantly between the two treatment periods.
Markers of heart damage remained stable, as did patients’ nutritional status.
Quality of life gradually worsened during both treatment periods. Autonomic symptoms, or those affecting involuntary bodily functions, worsened during tafamidis meglumine treatment and appeared to ease after Onpattro, although the difference failed to reach statistical significance.
Onpattro “effectively attenuated neuropathy progression in [hATTR-PN] patients who had demonstrated clinical decline despite prior treatment with Tafamidis,” the researchers wrote. “The observed stabilization during [Onpattro] treatment [is] particularly meaningful, as it suggests that gene-silencing therapies can still provide clinical benefit even beyond the early disease phase.”
The findings also emphasize the importance of ongoing monitoring to identify hATTR-PN progression and guide personalized treatment decisions, the team concluded.
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