Onpattro may slow polyneuropathy where tafamidis meglumine didn’t
Real-world study analyzed data from 24 FAP patients who switched treatment
Onpattro (patisiran) may help familial amyloid polyneuropathy (FAP) patients who respond poorly to tafamidis meglumine stabilize or have reduced symptoms of nerve damage, called polyneuropathy.
The findings are part of of a real-world study in France that analyzed data from 24 patients on tafamidis meglumine, approved as Vyndaqel for FAP in Europe, but not the U.S., and for a year after switching to Onpattro.
“The results of this study confirmed what earlier real-world evidence has shown, that some patients experience substantial worsening on polyneuropathy measures with [Vyndaqel], requiring alternative therapeutic options,” the researchers wrote. “Timely switch … to [Onpattro] can be beneficial to avoid rapid disease progression.”
The study, “Effectiveness of patisiran after switching from tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy,” was published in the European Journal of Neurology. It was funded by Onpattro’s developer, Alnylam Pharmaceuticals, with which three of the study’s researchers are affiliated.
Tafamidis meglumine to Onpattro
In FAP, a misfolded version of the transthyretin protein forms toxic clumps that accumulate mostly in the nerves outside the brain and spinal cord, damaging them and leading to symptoms of polyneuropathy.
Pfizer’s tafamidis meglumine is an oral therapy that stabilizes transthyretin, preventing it from turning into the misfolded version in FAP. It was approved in the European Union (EU) for treating early-stage FAP patients, or with stage 1 polyneuropathy, in 2011, but isn’t cleared for that indication in the U.S.
Clinical trial results and real-word evidence show the treatment can slow FAP progression. Some data suggest tafamidis meglumine may be more effective in early-onset FAP patients who carry Val30Met, the most common FAP-causing mutation, and those with less disease severity at the start of treatment, however.
Onpattro, administered directly into the bloodstream, was approved in the EU in 2018 for adults with stage 1 or 2 polyneuropathy and in the U.S. for FAP around that same time. The therapy is designed to reduce abnormal transthyretin production by disrupting the genetic template molecule that guides it.
In Phase 3 trials of Onpattro, about a third of the enrolled patients had been treated with tafamidis meglumine, but stopped either due to disease progression or to participate in the Onpattro studies.
Effects of switching to Onpattro
Here, researchers reviewed medical records from 24 FAP patients seen at a center in France who switched from tafamidis meglumine to Onpattro by August 2019, within a year of its approval in the EU, to better understand the effects of switching in a real-world setting.
Half the patients carried the Val30Met mutation and started Onpattro at a mean age of 67.3. Tafamidis meglumine was used for a mean of around 2.5 years before the switch. For all, disease progression was cited as the main reason for starting Onpattro.
Polyneuropathy-associated disability worsened on tafamidis meglumine, reflected by a mean increase in scores on the total Neuropathy Impairment Score (NIS) from 36.9 at the start of treatment to 61.7 at the time it stopped. In contrast, NIS scores decreased to a mean of 59.1 after a year on Onpattro.
Mean NIS scores increased at a rate of 14.3 points per year during the last year on tafamidis meglumine, a rate the researchers noted was similar to the disease’s natural history. NIS scores increased by 2.9 points after a year on Onpattro.
When they started tafamidis meglumine, 29.2% of patients could still walk, but none had preserved walking abilities after discontinuing it. During the last year on tafamidis meglumine, no patients had improved walking, 68.8% saw no change and 31.3% worsened. In a year on Onpattro, 10.5% improved, 73.7% had no change, and 15.8% got worse.
Similar patterns favoring Onpattro were observed with diarrhea worsening and orthostatic intolerance, where a person’s blood pressure drops when they rise from sitting or lying down. These are common symptoms associated with dysfunction of the autonomic nervous system, which is involved in controlling involuntary body functions.
Slowing polyneuropathy progression and autonomic symptoms stabilizing with Onpattro have important implications for patient care, according to the researchers.
“The safety events reported were consistent with those that frequently occur in patients with [FAP], and no new safety concerns were observed,” the researchers wrote, noting the findings suggest “delaying the switch from tafamidis to [Onpattro] may place patients at heightened risk of progression on multiple measures of functioning.”
The researchers, who noted that “accumulating neuropathy impairment may not be entirely reversible,” wrote the data “emphasize the importance of monitoring disease progression and considering a timely switch to [Onpattro] in patients who experience worsening neuropathy with tafamidis to avoid unnecessary progression.”
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