In patients with hereditary transthyretin amyloidosis (hATTR) with polyneuropathy, the small interfering RNA agent vutrisiran appears to have greater efficacy on multiple measures of impairment and health-related quality of life (HRQOL) than the transthyretin tetramer stabilizer tafamidis, according to findings derived from phase 3, randomized controlled trials.

Results of the current study were published in the journal Expert Opinion on Pharmacotherapy.

Polyneuropathy is one of the most common sequelae observed in patients with hATTR. Abnormal protein deposits accumulate, which result in damage to multiple nerves (ie, polyneuropathy) and other organs. With disease progression, patients’ symptoms increase in severity, which is associated with loss of physical function, reduced HRQOL, and death. In fact, the median survival following diagnosis of hATTR is 4.7 years.

The researchers sought to perform an indirect treatment comparison (ITC) of vutrisiran and tafamidis in an effort to assist healthcare decision makers regarding the relative efficacy of each of the agents. With no head-to-head comparison of the 2 agents having been conducted to date, the ITC is a well-accepted technique used to evaluate the comparative efficacy of treatments for such rare diseases as hATTR.

Read more about experimental therapies for patients with hATTR

In September 2021, the authors conducted a systematic literature review of conference repositories, trial registries, and bibliographic databases to identify all relevant clinical/nonclinical evidence on the use of vutrisiran and tafamidis to treat adults with hATTR with polyneuropathy. They used Bucher methodology to evaluate differences in the treatment effects of vutrisiran vs tafamidis with respect to the following endpoints:

  • Neuropathy Impairment Score-Lower Limbs (NIS-LL)
  • Norfolk Quality of Life-Diabetic Neuropathy score
  • NIS-LL Response
  • Modified body mass index

Results of the study showed that at 18 months, greater treatment effects were seen with vutrisiran compared with tafamidis in all of the endpoints, with the following statistically significant improvements reported:

  • Polyneuropathy: relative mean change in NIS-LL: –5.3; 95% CI, –9.4 to –1.2; P =.011
  • HRQOL: relative mean change in Norfolk Quality of Life-Diabetic Neuropathy score: –18.3; 95% CI, –28.6 to –8.0; P <.001
  • Nutritional status: relative mean change in modified body mass index: 63.9; 95% CI, 10.1 to 117.7; P =.020
  • NIS-LL responder outcome at 18 months:
    • Odds ratio for NIS-LL response: 1.7; 95% CI, 0.6 to 4.6; P =.282
    • Risk difference, 13.9%; 95% CI, –16.3% to 44.0%; P =.368

It is critical for healthcare decision makers to weigh the safety and efficacy of each available option for the treatment of hATTR with polyneuropathy to optimize patients’ clinical outcomes. As this is frequently carried out with no available comparative evidence from head-to-head clinical trials, the current a priori ITC offers convincing evidence that vutrisiran provides greater treatment effects than tafamidis in multiple disease-relevant outcomes, such as HRQOL, sensorimotor neuropathy, and nutritional condition.

 “The statistical and clinical significance of these findings underscore the potential advantages of vutrisiran compared with tafamidis with regard to preservation of physical function and QOL when treating patients with hATTR with polyneuropathy,” the researchers concluded.


Merkel M, Danese D, Chen C, et al. Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy. Expert Opin Pharmacother. Published online May 26, 2023. doi:10.1080/14656566.2023.2215925