Real-world study compares 2 options for amyloidosis treatment
Better nerve function helps predict success of hATTR-PN infusion therapy
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A real-world study in Spain comparing two similar medications for hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) showed greater benefits with the infusion therapy Onpattro (patisiran) versus the injection treatment Tegsedi (inotersen) among adults with the rare genetic disease, which is marked by damage to the body’s peripheral nerves.
Use of Onpattro was associated with higher response rates and slower progression of nerve damage, as well as lower discontinuation rates, than Tegsedi, according to the researchers.
The two treatments have a comparable mechanism of action and belong to a therapy class called TTR silencers. Tegsedi was approved for hATTR-PN in the U.S, but discontinued in 2024 due to limited utilization. It is also scheduled for withdrawal from the European market in December as part of a commercial decision by its manufacturer. It remains available in Europe until then, and in other parts of the world. Onpattro, meanwhile, is available for certain patients in the U.S., the European Union, Switzerland, Japan, and Brazil.
According to researchers, the new study also showed that better preserved nerve function among people with amyloidosis before starting treatment was linked to a greater likelihood of patients responding to therapy. Better function of the small nerve fibers appeared to be the strongest potential predictor of treatment response among those receiving Onpattro, the scientists found.
As such, the team noted that their study provides real-world evidence on how the two therapies compare while identifying clinical features that “may help identify patients more likely to benefit from treatment.”
Still, the researchers cautioned that the “findings should be interpreted with caution due to the limited sample size and the observational nature of the study.”
The study, “Real-world effectiveness and clinical predictors of response to first-generation TTR silencers in variant ATTR amyloidosis with polyneuropathy,” was published in the journal Scientific Reports.
hATTR-PN is caused by mutations in the TTR gene that ultimately result in the production of an abnormal transthyretin (TTR) protein. This protein tends to misfold, forming toxic clumps called amyloid deposits that accumulate and damage nerves and other tissues and organs, causing hATTR-PN symptoms.
Onpattro and Tegsedi are gene-silencing treatments designed to suppress TTR production, thereby slowing the formation of toxic amyloid deposits. Both were approved in the U.S. and the EU in 2018 as a treatment for TTR-PN.
Developed by Alnylam Pharmaceuticals, Onpattro is given by intravenous, or into-the-vein, infusions once every three weeks. Ionis Pharmaceuticals’ Tegsedi is administered once weekly by a subcutaneous, or under-the-skin, injection.
Investigating Onpattro vs. Tegsedi
Data from clinical trials showed that both therapies could slow disease progression compared with a placebo. Yet, “real-world treatment responses remain [variable] and difficult to predict,” the researchers wrote.
Thus, “there is a clear need for clinically deployable predictors to support therapy selection, prognostication, and optimization of treatment timing in routine practice, particularly in settings constrained by access, monitoring capacity, and patient frailty,” the researchers wrote.
To learn more about the real-world benefits of these two treatments, a team led by a pair of researchers from the Hospital Universitario Son Llàtzer in Palma reviewed the medical records of 98 adults with hATTR-PN. Each had received Onpattro or Tegsedi for at least six months between 2015 and 2024 at 10 referral hospitals across the country.
Participants started treatment — 81 with Onpattro and 17 with Tegsedi — at a mean age of 64.3. Nearly two-thirds were men. The most common clinical profile, seen for slightly more than half of patients, was late-onset neurological disease, indicating the condition started after age 50. This was followed by mixed, seen for about one-third, and early-onset neurological disease, meaning before age 50, in slightly fewer than 15%. A mixed profile is one characterized by both nerve and heart damage.
Based on changes in their symptoms and the Neuropathy Impairment Score (NIS), patients were classified as complete responders, partial responders, or nonresponders. The NIS is a measure of nerve damage in which higher scores indicate greater neurological impairment.
The researchers also assessed whether patient and clinical characteristics could help predict treatment response.
Response rates higher with Onpattro as hATTR-PN treatment
Overall, about 60% of people treated with Onpattro were classified as complete responders, compared with nearly 25% of those on Tegsedi. Patients receiving Onpattro also tended to experience slower neurological decline, with a median annual increase in NIS of 0.31 points versus four points with Tegsedi,though this difference was not statistically significant.
Onpattro was also associated with better treatment persistence. None of the patients receiving this medication discontinued treatment because of adverse events, whereas 41% of those treated with Tegsedi did so, most commonly because of intolerance. Overall, patients receiving Onpattro remained on treatment significantly longer, the researchers found.
Further statistical analyses showed that age, sex, clinical profile, disease stage, and most laboratory biomarkers were not significantly associated with treatment response.
In routine practice, [Onpattro] was associated with more favourable effectiveness and tolerability compared to [Tegsedi.
However, people who achieved a complete response generally had better preserved nerve function before starting therapy, the researchers found. Specifically, these patients had stronger motor nerve signals, measured by compound muscle action potential (CMAP), and better function of the small nerve fibers, assessed using electrochemical skin conductance (ESC).
Among the measures evaluated, ESC showed the strongest ability to distinguish complete responders from nonresponders, particularly among patients receiving Onpattro, the data showed.
The researchers noted, overall, that “gene-silencing therapies have transformed outcomes” for people with hATTR-PM, but concluded that “in routine practice, [Onpattro] was associated with more favourable effectiveness and tolerability compared to [Tegsedi].”
The scientists also noted that “[initial] neurological preservation, particularly motor and small-fiber measures, may help identify patients more likely to benefit from treatment.”
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