Wainua slows disease progression for adults with hATTR-PN, per trial analysis
Approved therapy also improves life quality for patients across mutations
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Use of the approved therapy Wainua (eplontersen) effectively slows disease progression and improves quality of life among adults with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) — characterized by damage to the peripheral nerves found outside the brain and spinal cord — across a range of disease-causing mutations.
These findings, which researchers called “suggestive of consistent benefits,” come from an exploratory analysis of NEURO-TTRansform (NCT04136184), a now-completed large clinical trial that supported the approval of Wainua as the first treatment for hATTR-PN that can be self-administered by patients via an autoinjector.
The global Phase 3 trial, sponsored by Ionis Pharmaceuticals, had tested the effectiveness of the injection therapy in people with hATTR-PN with a documented genetic mutation.
The results of the analysis were detailed in “Effect of Eplontersen in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy Across Genetic Variants: An Exploratory Analysis From the NEURO-TTRansform Trial,” a study published in the European Journal of Neurology. The work was funded by AstraZeneca, which markets Wainua outside the U.S. In the U.S., Wainua is marketed by both Ionis and AstraZeneca.
In hATTR-PN, also known as familial amyloid polyneuropathy, mutations in the TTR gene cause a protein of the same name to become unstable and break apart, forming toxic clumps that accumulate mainly in the nerves outside the brain and spinal cord.
Gradual damage to several of these peripheral nerves, known as polyneuropathy, causes neurological symptoms, and because the disease can affect multiple parts of the body, it often reduces quality of life.
Wainua contains a piece of genetic material that suppresses TTR production, preventing its formation and the accumulation of toxic clumps, or aggregates. This is expected to slow disease progression.
Wainua approvals based mainly on data from NEURO-TTRansform
The therapy is approved in the U.S., Canada, and the U.K. for adults with hATTR-PN, and in the European Union for those with Coutinho stages 1 or 2, reflecting mild to moderate hATTR-PN symptoms. It is also being tested for transthyretin amyloidosis with cardiomyopathy, a related disease in which toxic TTR aggregates mainly build up in the heart.
Wainua’s approvals were based mainly on data from the NEURO-TTRansform study, which showed that a little more than a year of treatment with Wainua dropped TTR levels by 81.7% relative to a placebo in adults with Coutinho stages 1 or 2. Further, the therapy was associated with reductions in polyneuropathy-related disability in 47% of patients and improvements in quality of life improvements in 58%.
Now, to better understand how Wainua works across hATTR-PN-causing mutations, a research team compared data from 144 Wainua-treated patients in NEURO-TTRansform with those from an external group of 60 patients given a placebo in a previous trial.
Data from that previous Phase 2/3 study (NCT01737398) supported the approval of Tegsedi (inotersen) for hATTR-PN, a therapy also developed by Ionis that has since been discontinued.
Patients in both groups were divided into three subgroups according to their disease-causing TTR mutation: early-onset Val30Met, with symptoms before age 50; late-onset Val30Met, with symptoms at age 50 or older; and non-Val30Met mutations. Val30Met is the most common mutation causing hATTR-PN.
Most patients were men. At the study’s start, or baseline, the participants’ average age ranged from about 39 to 40 in the early-onset group to about 58 to 69 in the late-onset and non-Val30Met groups.
Most patients could walk unaided, although 41.2% of those with late-onset Val30Met in the placebo group had more advanced disability, requiring one stick or crutch to walk, compared with patients in any of the other groups; in those groups, that proportion did not exceed 22.2%. Heart problems were present in as many as half of the patients in the late-onset Val30Met and non-Val30Met groups, and in none in the early-onset Val30Met group.
Life quality improved with therapy, worsened on the placebo
After about 1.2 years, blood TTR levels were reduced in all Wainua-treated patients compared with the external placebo group. This was by an average of 79.9% in early-onset Val30Met, by 85% in the late-onset Val30Met, and by 70.6% in non-Val30Met groups. In contrast, patients on the placebo showed little to no reduction, the researchers noted.
Neurological symptoms stayed stable or slightly eased with Wainua, especially in the early-onset Val30Met group, but worsened with the placebo, the data showed. Physical health also improved modestly.
Disability was measured using the Polyneuropathy Disability score. In the late-onset Val30Met group, fewer patients on Wainua worsened compared with those on the placebo (10.7% vs. 25%). Similar results were obtained in the non-Val30Met group (16.7% vs. 36.4%).
In the early-onset Val30Met group, worsening rates were similar (11.5% vs. 6.7%), but improvement occurred only in treated patients (5.8% vs. 0%). Across all groups, most patients (up to 93.3%) remained stable, the data showed.
[Wainua] demonstrated … consistent and significant benefits … in reducing [polyneuropathy] impairment, improving [quality of life], and in maintaining nutritional status in patients with [hATTR-PN] across TTR genetic [mutations].
Quality of life was measured using the Norfolk Quality of Life-Diabetic Neuropathy, where higher scores indicate worse quality of life. Patients treated with Wainua showed score reductions — which were greatest in the early-onset Val30Met group — while those on a placebo experienced score increases.
Nutritional status, assessed using the modified body mass index (which combines weight, height, and protein levels in blood) stayed stable with treatment but declined with the placebo, with the largest benefit seen in the early-onset Val30Met group, according to the data.
Wainua “has demonstrated numerically consistent and significant benefits versus [a] historical placebo in reducing [polyneuropathy] impairment, improving [quality of life], and in maintaining nutritional status in patients with [hATTR-PN] across TTR genetic [mutations],” the researchers wrote, noting that their findings “underscore the importance of early diagnosis and treatment” for people with hATTR-PN.
“These results … affirm the broad applicability of [Wainua] in a diverse patient population,” the team concluded.
