By Eleanor McDermid, Senior MedWire Reporter
The results of a randomized trial suggest that tafamidis treatment may slow the progression of early-stage V30M transthyretin familial amyloid polyneuropathy.
During 18 months of treatment, 45.3% of the 65 patients given tafamidis 20 mg/day worsened by less than 2 points on the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The rate among 63 placebo-treated patients was 29.5%, which was a nonsignificant difference.
The Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) worsened by 2.0 points in the tafamidis group, compared with 7.2 points in the placebo group - also a nonsignificant difference.
But this analysis was based on the intent-to-treat population. A higher than anticipated dropout rate, caused by patients requiring liver transplantation, meant that just 87 of the original 125 patients actually completed the treatment.
In this group, 60.0% versus 38.1% of those treated with tafamidis and placebo had a less than 2-point deterioration on the NIS-LL, and TQOL scores worsened by a corresponding 0.1 versus 8.9. These differences were statistically significant, report Teresa Coelho (Hospital de Santo António, Porto, Portugal) and colleagues in Neurology.
Editorialist Colin Chalk (McGill University, Montréal, Canada) writes: "In essence, because of the high attrition rate, this otherwise meticulously conducted study proved to be underpowered."
Tafamidis stabilizes tetrameric transthyretin, inhibiting its dissociation and thus the production of amyloid and neurodegeneration. This offers an alternative to liver transplantation, which removes the source of mutant transthyretin, but can itself have serious consequences. Two patients in the tafamidis group and three in the placebo group died of complications related to liver transplantation.
Adverse events occurred in similar proportions of the tafamidis and placebo groups, with serious adverse events occurring in 9.2% and 7.9%, respectively.
But Chalk notes that this is restricted to 18 months of treatment, with longer-term effects as yet unknown. "Most importantly, what is the drug's effect on cardiac and autonomic function, impairment of which is the major cause of morbidity and mortality in most patients?"
He concludes: "Tafamidis is an important therapeutic advance, although transthyretin amyloidosis is a rare disease, and few neurologists will have direct experience with affected patients. In a broader sense, however, the tafamidis story nicely illustrates how an understanding of polyneuropathy pathophysiology at a molecular level can lead to disease-specific therapies. More examples are sorely needed."
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