Diflunisal may be as effective as tafamidis free acid for treating FAP
Both therapies have been shown to stabilize TTR protein
Diflunisal is used off-label to treat familial amyloid polyneuropathy (FAP), but it may be as safe and effective as tafamidis free acid, which is approved in the U.S. under the brand name Vyndamax for treating a FAP-related condition, a study in Taiwan suggests.
Nearly all the evaluated FAP patients carried A97S, a common disease-causing mutation in Taiwan and East Asia that results in a clinical profile similar to Val30Met, the most common FAP-causing mutation.
“Diflunisal can effectively delay the progression of polyneuropathy [nerve damage] and cardiomyopathy [heart damage] with similar efficacy to [Vyndamax] and may become a cost-effective alternative treatment for late-onset [FAP],” the researchers wrote.
The study, “Diflunisal versus tafamidis on neuropathy and cardiomyopathy in hereditary transthyretin amyloidosis,” was published in the Annals of Clinical and Translational Neurology.
Hereditary transthyretin amyloidosis, or ATTRv, is caused by mutations in the TTR gene that lead to an unstable transthyretin (TTR) protein that forms toxic clumps called amyloid fibrils that deposit in tissues and cause damage. FAP is a type of ATTRv wherein amyloid fibrils accumulate in the nerves outside the brain and spinal cord, causing polyneuropathy. Some people with FAP may also have cardiomyopathy due to TTR clumps building up in heart tissue.
Tafamidis is a molecule that can stabilize TTR into its correct shape, preventing further clumping into toxic amyloid fibrils. It’s the active ingredient of Vyndamax (tafamidis free acid) and Vyndaqel (tafamidis meglumine), two Pfizer oral therapies approved in the U.S. for cardiomyopathy associated with both hereditary and nonhereditary forms of TTR amyloidosis. Vyndaqel is approved in the European Union, but not the U.S., for treating adults with FAP stage 1 or 2, reflecting early-stage disease.
Diflunisal, an oral anti-inflammatory medication, has also been shown to stabilize the TTR protein. It’s been investigated as a potential treatment for FAP with some promising results in a Phase 2/3 trial (NCT00294671). It’s not approved for the indication, but it’s often used off-label to slow its progression.
Diflunisal vs. tafamidis
No studies have compared diflunisal and tafamidis, especially in patients with mutations other than Val30Met, however.
Here, researchers in Taiwan looked at how well diflunisal and tafamidis bind to TTR when it harbors an A97S mutation, the main cause of ATTRv in Taiwan and East Asia, and found that both medications attached to two specific sites within the protein, stabilizing it and reducing the formation of amyloid fibrils.
The researchers followed 57 Taiwanese adults (41 men, 16 women) diagnosed with FAP stage 1 or stage 2 and treated with either diflunisal and tafamidis free acid. The disease was caused by the A97S mutation in all but three patients. Thirty-five patients were given diflunisal (250-500 mg per day) for an average of 31.6 months, or about 2.5 years, while the remaining 22 were given tafamidis free acid (61 mg per day) for an average of 35.3 months, or nearly three years.
To see if diflunisal slowed polyneuropathy progression, the researchers first analyzed the time it took for 21 diflunisal-treated patients and 85 onset age- and sex-matched untreated patients to progress from FAP stage 1 to stage 2. Those on diflunisal were 57% less likely to progress to stage 2 than the untreated patients.
For progression from stage 2 to stage 3, 21 patients on diflunisal were compared with 67 onset age- and sex-matched untreated patients. Diflunisal also slowed progression in this case, with diflunisal-treated patients being 82% less likely to progress to stage 3.
Nerve conduction studies, which measure how fast and how well electrical signals travel through nerves, showed diflunisal also preserved signal strength and slowed signal speed decline relative to no treatment.
There were no significant differences between diflunisal and tafamidis free acid in how fast patients progressed from FAP stage 1 to 2 or stage 2 to 3. Changes in nerve conduction studies were also similar.
Effects of cardiomyopathy
To evaluate the treatments’ effects on cardiomyopathy, the researchers first analyzed changes in heart levels of amyloid fibril, as assessed with heart imaging scans, from 15 diflunisal-treated patients and 20 taking tafamidis free acid. Both treatments equally reduced the levels of amyloid fibrils over time.
Moreover, there were no significant differences in heart wall thickness or blood pro-BNP levels, a marker of heart damage, before and after treatment in either group, suggesting both diflunisal and tafamidis free acid may delay cardiomyopathy progression.
Sharing the same mechanism of action with tafamidis, “diflunisal has been proven to delay the progression of both polyneuropathy and cardiomyopathy without discernible differences in the progression of biomarkers compared to [tafamidis free acid] in late-onset [FAP] patients,” wrote the researchers. They said the findings suggest “diflunisal may become an obtainable, cost-effective, and practical alternative treatment for ATTRv amyloidosis in selected patients,” even though the study included only Taiwanese patients, most of whom carried an A97S mutation.
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