Targeted treatment lowers toxic protein in amyloidosis patients

Amvuttra (vutrisiran) rapidly and consistently reduces blood levels of transthyretin (TTR), the disease-causing protein in hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN), across a wide range of patients, according to clinical trial data.

Similar sustained reductions were seen in people with transthyretin amyloid cardiomyopathy (ATTR-CM), a related disease marked mainly by heart damage instead of neurological damage.

The treatment’s effect was generally consistent across age, sex, body weight, genetic background, disease severity, and other initial patient characteristics.

“These findings reflect reliable and consistent TTR knockdown across patient subgroups, supporting [Amvuttra] 25 mg [every three months] for patients with [hATTR-PN] and ATTR-CM without the need for dose adjustment, and are consistent with subgroup analyses of clinical and biomarker outcomes,” the researchers wrote.

The study, “Vutrisiran-Mediated Knockdown of Transthyretin in Patients with ATTR Amyloidosis,” was published in Clinical Pharmacokinetics.

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Transthyretin amyloidosis (ATTR) is a group of progressive conditions caused by the production of a misfolded TTR protein, which forms toxic clumps, called amyloid deposits, in the body’s tissues and organs.

hATTR-PN is caused by mutations in the TTR gene that cause toxic TTR aggregates to accumulate mainly in the peripheral nerves (those outside the brain and spinal cord). When these deposits mainly accumulate in the heart, the disease is called ATTR-CM. ATTR-CM can be caused by mutations or develop with aging without mutations.

Amvuttra, from Alnylam Pharmaceuticals, is designed to reduce the production of both abnormal and normal TTR protein in the liver, where most TTR is produced. By lowering circulating TTR, the therapy is expected to limit the formation of new amyloid deposits and slow disease progression.

Administered via under-the-skin injection once every three months at a dose of 25 mg, Amvuttra is approved for treating people with hATTR-PN based on findings from the Phase 3 HELIOS-A study (NCT03759379), and for ATTR-CM patients based on data from the Phase 3 HELIOS-B study (NCT04153149).

HELIOS-A involved 164 adults with hATTR-PN. Amvuttra was given to 122 of them every three months, while 42 received Onpattro (patisiran), an older TTR-reducing therapy by Alnylam, every three weeks, for 1.5 years. The Amvuttra group was also compared with an external placebo group from an earlier study.

HELIOS-B involved 654 adults with ATTR-CM who were randomly assigned to receive either Amvuttra or a placebo for up to three years.

In this analysis, researchers assessed how consistently Amvuttra lowered blood TTR levels across patient subgroups in HELIOS-A and HELIOS-B, including whether reductions differed according to demographic or disease-related characteristics.

In HELIOS-A, Amvuttra was associated with a median reduction in blood TTR levels of 64.2% at the earlier analysis (week 3) and 91% after 1.5 years. Median TTR lowering reached 91.6% at its peak and 86.2% just before the next dose.

The effect after 1.5 years was generally similar across hATTR-PN subgroups defined by characteristics including sex, age, body weight, race or ethnicity, TTR mutation, and starting blood TTR levels.

In HELIOS-B, median blood TTR levels were reduced by 69% at the earliest analysis (week 6) and by 86.8% after 2.5 years. The median reduction measured just before the next dose was 82.5%.

As in HELIOS-A, the treatment’s effect was consistent across ATTR-CM subgroups. Similar reductions were observed regardless of age, sex, body weight, presence of a hereditary disease, disease stage, heart failure class, walking ability, quality of life, heart-related biomarkers, or starting TTR levels.

Some people in HELIOS-B were taking Vyndamax (tafamidis), an older ATTR-CM-approved therapy that works by stabilizing TTR rather than reducing its production, at the study’s start.

After 2.5 years, this subgroup of patients showed a median TTR level reduction of 87.5%, while those on Amvuttra alone experienced an 84.8% reduction, suggesting that Amvuttra’s “impact on [blood] TTR is consistent, regardless of concomitant [Vyndamax] use or [initial] TTR concentrations,” the researchers wrote.

Antibodies against Amvuttra were detected during treatment in 4.1% of patients in HELIOS-A and 1.2% of those in HELIOS-B. They were generally low-level and temporary and did not appear to affect TTR lowering.

Mathematical modeling based on more than 10,000 blood samples from 843 participants predicted the same average TTR reduction — 86.7% — in the hATTR-PN and ATTR-CM populations at the latest timepoints of the respective trials.