Analysis: RNA-targeted therapies are safe, effective for hATTR-PN
Treatments found to slow progression of patients' neurological symptoms
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RNA-targeted therapies — ones that zero in on molecules acting as messengers for genetic information in cells — are safe and effective at slowing the progression of neurological symptoms and improving quality of life among people with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).
Those are the findings of a systematic review and meta-analysis of clinical trials that evaluated the use of four approved RNA-based therapies in people with hATTR-PN, also known as familial amyloid polyneuropathy. The new analysis pooled safety and efficacy data from randomized, placebo-controlled studies that tested Amvuttra (vutrisiran), Onpattro (patisiran), Tegsedi (inotersen), and Wainua (eplontersen).
These results support “RNA-based treatments as a potentially safer, noninvasive option for hATTR management” and also “underscore the promise of RNA therapeutics as a targeted approach for treating this challenging condition,” the researchers wrote.
According to the team, this is the first large-scale analysis of the combined effectiveness of RNA-based therapies in people with hATTR-PN.
Their study, “Neurological efficacy and safety of RNA therapeutics in hereditary transthyretin amyloidosis: a systematic review and meta-analysis of randomized controlled trials,” was published in Therapeutic Advances in Cardiovascular Disease.
hATTR amyloidosis is caused by mutations in the TTR gene, which lead to the production of an abnormal protein of the same name. This TTR protein is prone to misfolding and forming clumps known as amyloid fibrils that accumulate in many tissues and organs.
In hATTR-PN, these fibrils primarily affect peripheral nerves — those outside the brain and spinal cord — resulting in progressive nerve damage, or polyneuropathy.
No analysis to date assessing RNA-based therapies in hATTR-PN
Several RNA-targeted therapies that reduce TTR production are approved for the treatment of hATTR-PN. These include the small interfering RNA (siRNA) therapies Amvuttra and Onpattro, developed by Alnylam Pharmaceuticals, and the antisense oligonucleotides (ASOs) Tegsedi and Wainua, developed by Ionis Pharmaceuticals.
siRNAs bind to TTR messenger RNA (mRNA) — the template molecule that is produced when the gene is read and is used to produce the TTR protein — and promote its degradation. ASOs, meanwhile, bind to mRNA and either block protein production or activate other mechanisms of mRNA degradation.
Both approaches reduce the amount of disease-causing TTR protein produced by the liver.
Multiple trials to date have tested these therapies in people with hATTR-PN. However, no meta-analysis has been conducted to assess the combined efficacy of RNA-based therapies in this patient population.
In the new study, a group of researchers in Pakistan conducted a systematic review and meta-analysis of four randomized controlled Phase 3 trials that all enrolled patients with hATTR-PN. These were APOLLO (NCT01960348) for Onpattro, HELIOS-A (NCT03759379) for Amvuttra and Onpattro, NEURO-TTR (NCT01737398) for Tegsedi, and NEURO-TTRansform (NCT04136184) for Wainua.
Together, the trials included more than 842 patients, most of whom were men (70%). All were followed for 15-18 months. A total of 568 participants received an RNA-based therapy, while 274 received a placebo. The HELIOS-A and NEURO-TTRansform studies used placebo groups from APOLLO and Neuro-TTR, respectively.
Impact of symptoms on daily activities far less for treated patients
Overall, the results showed that treatment with RNA therapeutics led to a significant reduction in the impact of neurological symptoms on daily activities, as measured by the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire.
Compared with the placebo group, in which Norfolk QoL-DN scores increased, most treated patients experienced a reduction in scores. Specifically, the average difference between groups was 18.79 points, indicating less severe impairment for those given RNA-targeted therapies. No significant differences were seen between siRNA and ASO therapies for this outcome.
The use of RNA therapies also significantly slowed the progression of polyneuropathy symptoms, as assessed by the modified Neuropathy Impairment Score (mNIS)+7. Patients on the placebo saw their scores increase by more than 25 points, indicating more severe polyneuropathy. Meanwhile, those who received one of the therapies experienced reductions or only slight increases in scores.
The mean difference between the treatment group and the placebo group was 26.9 points, and the benefits on this outcome were more pronounced with siRNA therapies than with ASOs, the data showed.
RNA therapeutics may effectively slow neurologic disease progression in hATTR patients while preserving nutritional status and enhancing quality of life.
Three trials also evaluated changes in nutritional status using the modified body mass index. Patients receiving RNA therapeutics experienced a significantly lower change in this measure, again indicating a slowing of disease progression compared with the placebo. The improvement was also greater with siRNAs than with ASOs, the researchers noted.
No significant differences were found between the treatment and placebo groups in the risk of side effects, serious side effects, and all-cause mortality. Safety outcomes were also similar between siRNA and ASO treatments.
Overall, the findings suggest that “RNA therapeutics may effectively slow neurologic disease progression in hATTR patients while preserving nutritional status and enhancing quality of life,” the researchers concluded.
