Long-term diflunisal treatment may help slow hATTR progression
Real-world data support treatment’s benefits beyond clinical trial
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Long-term treatment with diflunisal may help slow disease progression in people with hereditary transthyretin amyloidosis (hATTR), according to a Swedish real-world study.
The therapy is approved in the European Union (EU), but not in the U.S. for this use, for adults with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), a form of hATTR marked by nerve damage. The EU approval covers adults with stage 1 or 2 polyneuropathy. It is sold by Purpose Pharma under the brand name Attrogy.
Real-world data aligned with the findings from a Phase 2/3 clinical trial (NCT00294671), whose results supported the treatment’s approval in the EU.
Real-world data support diflunisal benefits
“Our real-world registry data reinforce and extend the … trial findings, demonstrating that diflunisal provides durable stabilization of [nerve damage-related] and functional decline in [hATTR],” the researchers wrote. “Given its affordability and safety, when appropriately monitored, diflunisal represents a viable and more cost-effective treatment option, particularly relevant in resource-limited settings.”
The study, “Efficacy of diflunisal for hereditary transthyretin amyloidosis: the Swedish real-world experience,” was published in Amyloid, The Journal of Protein Folding Disorders.
Transthyretin amyloidosis (ATTR) is a group of conditions in which transthyretin (TTR) protein becomes unstable and misfolds, forming toxic clumps called amyloid fibrils. It can be caused by mutations in the TTR gene, as in hATTR, or by aging-related processes.
In hATTR, when TTR clumps mainly accumulate in the peripheral nerves, which are nerves outside the brain and spinal cord, the disease is called hATTR-PN. When these aggregates build up mainly in the heart, it is called hereditary transthyretin amyloid cardiomyopathy (hATTR-CM). Still, increasing evidence shows that many people with hATTR have a combination of heart and nerve problems, known as a mixed profile.
Diflunisal is an oral nonsteroidal anti-inflammatory medication that has been shown to stabilize the TTR protein, which may help prevent the formation of more toxic TTR clumps. It has historically been used off-label to treat hATTR-PN, and later, hATTR-CM.
Its approval in the EU for hATTR-PN was mainly based on results from a two-year pivotal randomized controlled trial, which tested the therapy against a placebo in 130 adults with hATTR-PN. Diflunisal was shown to significantly delay progression of neurological impairment and preserve quality of life compared with the placebo.
Swedish registry tracks long-term diflunisal use
Here, a team of researchers evaluated the long-term efficacy of diflunisal using data from the national Swedish TTR amyloidosis registry (SveATTR), which is open to people with hereditary and non-hereditary ATTR and people who carry TTR mutations but are not yet showing symptoms.
The analysis included 118 participants (mean age, 68.2 years; 75% men) who received diflunisal for a mean duration of 3.4 years. Most (92%) had peripheral neuropathy symptoms at disease onset, and 17% had heart symptoms at onset.
Most participants — 110 of 118, or 93% — carried a TTR gene variant. The most common was V30M, the most common hATTR-PN-causing mutation, which was found in 102 participants, or 86.4% of the full group. Another five patients developed ATTR amyloidosis after a domino liver transplant. Three patients with wild-type ATTR amyloidosis were excluded from the outcome analyses because most follow-up data were missing.
At the latest follow-up, 97% of patients had peripheral neuropathy symptoms. Among the 93 patients who underwent echocardiography, a test used to monitor heart structure and function, 38% had signs of hATTR-CM. TTR-specific scans, performed in 49 patients, showed signs of amyloid cardiomyopathy in 84% of that subgroup.
Validated outcome measures showed that, over time, patients experienced some disease progression, with mild worsening of nerve damage-related disability, functional impairment, and nutritional status, while physical impairment due to heart failure remained generally stable. The generally gradual progression observed in the registry was consistent with the idea that diflunisal may help slow disease progression over the long term.
Registry findings align with clinical trial results
Researchers then combined the registry data with results from the 64 hATTR-PN patients treated with diflunisal in the pivotal randomized controlled trial and compared them with data from the trial participants who were given a placebo. Available trial data allowed comparisons in terms of overall disease severity and nutritional status.
This larger analysis strengthened the evidence that people treated with diflunisal had better outcomes than those given placebo on the measures analyzed.
The Swedish registry adds to the clinical trial data, demonstrating that diflunisal benefits may persist in routine clinical practice, where patients were generally older and were followed for up to 10 years.
Future studies following patients over time “should evaluate long-term safety and conduct head-to-head comparisons with other approved TTR stabilizers to further define [diflunisal’s] therapeutic role,” the researchers wrote.
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