Last updated Sept. 26, 2022, by Lindsey Shapiro, PhD
✅ Fact-checked by Joana Carvalho, PhD
What is Amvuttra for FAP?
Amvuttra (vutrisiran) is an approved treatment for adults with familial amyloid polyneuropathy (FAP), also known as polyneuropathy of hereditary transthyretin-mediated amyloidosis. It eases the symptoms of neuropathy, or those resulting from the nerve damage that marks the disease.
Previously known as ALN-TTRsc02, Amvuttra has shown the ability, in clinical trials, to improve quality of life, nutritional status, and heart function. It also was shown to ease disability in people with FAP.
The therapy is marketed by Alnylam Pharmaceuticals.
During clinical testing, in 2018, Amvuttra was granted orphan drug designation in the U.S. and Europe for the treatment of FAP. It also had been awarded fast-track designation in the U.S. in 2020.
How does Amvuttra work?
FAP is caused by mutations in the TTR gene that provides instructions for making a protein called transthyretin, which transports vitamin A and a hormone called thyroxine throughout the body. As a result of these mutations, an abnormal form of transthyretin is produced. It tends to form clumps, called amyloid fibrils, that build up in the body’s tissues, particularly in the nerves and heart.
To produce transthyretin, TTR’s genetic code is used to form an intermediate molecule called messenger RNA (mRNA). This mRNA is then used by the cells’ protein-making machinery, called ribosomes, as a template for making transthyretin.
Amvuttra is designed to bind to TTR mRNA, triggering a process called RNA interference that promotes mRNA destruction. Without a functional RNA template, the production of the faulty transthyretin protein that causes FAP is prevented.
The therapy’s mechanism is the same as the one used by Onpattro (patisiran), another FDA-approved treatment for FAP, also developed by Alnylam. Amvuttra was designed to have greater stability in the body, and thus is thought to have a more sustained and potent therapeutic effect than Onpattro.
Who can take Amvuttra?
The FDA approved Amvuttra for adults with FAP in June 2022. The European Commission gave its approval in September 2022 for FAP patients in the EU with stage 1 or stage 2 polyneuropathy. The therapy also is being considered for approval in Brazil and Japan.
Who should not take Amvuttra?
There are no known contraindications for Amvuttra’s use.
How is Amvuttra administered?
The recommended dose of Amvuttra is 25 mg, given once every three months as an under-the-skin (subcutaneous) injection by a healthcare professional. The therapy comes in single-dose, pre-filled syringes containing 25 mg of Amvuttra in 0.5 mL of a colorless-to-yellow solution.
A twice-yearly administration of Amvuttra at a dose of 50 mg is now being evaluated in clinical trials.
Amvuttra in clinical trials
Phase 1 safety study
The safety and tolerability of single increasing doses of Amvuttra were tested in a Phase 1 study (NCT02797847) launched in 2016.
This trial specifically investigated the therapy in doses of 5, 25, 50, 100, 200, or 300 mg against a placebo in 80 healthy volunteers. Secondary trial goals included the measurement of transthyretin levels in the blood and the therapy’s pharmacokinetics — its movement into, through, and out of the body. After the injection, participants were monitored for about a year, or until their transthyretin levels reached at least 80% of pre-treatment levels.
Results showed that Amvuttra was well-tolerated at all tested doses, with no serious adverse events reported and no treatment discontinuations due to side effects. Most reported adverse events were mild, and included temporary injection site reactions, itchy skin, cough, nausea, and fatigue.
Transthyretin levels were reduced in a dose-dependent manner, ranging from an 83% reduction in patients receiving 25 mg of Amvuttra to a 97% reduction in those receiving 300 mg. These reductions were sustained for at least 90 days (about three months).
The Phase 3 HELIOS-A trial (NCT03759379), initiated in 2019, is evaluating the efficacy of Amvuttra in 164 adults with FAP at more than 50 sites globally. Participants were randomly assigned to receive a 25 mg subcutaneous injection of Amvuttra once every three months, or an into-the-vein injection of Onpattro once every three weeks. Clinical data were compared with the placebo arm of a previously-completed Phase 3 study, called APOLLO (NCT01960348).
The trial’s main goal was to assess changes in neuropathy symptoms after nine months of treatment, measured using the Modified Neurologic Impairment Score +7 (mNIS+7). This goal was met, with participants who received Amvuttra experiencing a significant 2.24-point decline in mNIS+7 scores since the study’s start, reflecting an easing in neuropathy symptoms. By contrast, FAP patients in an external placebo group saw a marked 14.76-point increase in mNIS+7 scores over the same period of time.
An additional analysis after 18 months (1.5 years), showed Amvuttra’s continued effectiveness, with participants achieving a 0.46-point decrease in mNIS+7 scores compared with their baseline values. That was relative to a 28.09-point increase in the external placebo group.
Treatment with Amvuttra also led to improvements in walking speed, nutritional status, quality of life, and overall disability status. Sustained decreases in transthyretin levels also were seen up to 18 months, with levels dropping by a mean of 88% compared with pre-treatment — values comparable to those achieved with Onpattro.
Exploratory data from the trial at 18 months also suggested Amvuttra could lessen heart damage in patients with cardiac involvement, as reflected by a reduction in NT-proBNP, a biomarker of heart strain, and other heart function tests.
Following completion of the 18-month study, all participants were eligible to receive Amvuttra for an additional period of 18 months as part of the trial’s ongoing open-label extension period. Participants will receive either 25 mg of Amvuttra every three months or 50 mg every six months. Those who initially received Onpattro will switch to Amvuttra in the extension study.
A second Phase 3 trial, called HELIOS-B (NCT04153149), is evaluating Amvuttra in patients with transthyretin-mediated amyloidosis associated with cardiomyopathy — a disease of the heart’s muscles. That study enrolled 655 patients who were randomly elected to receive either 25 mg of Amvuttra, given by a subcutaneous injection, or a placebo every three months. HELIOS-B is double-blind, meaning that neither participants nor researchers know which patients are receiving the medication and which the placebo.
The trial’s primary goal is to determine the effects of treatment on all-cause mortality and on the number of cardiovascular events requiring hospitalizations or urgent heart failure visits. It will follow participants for up to three years. Other measures of heart function, functional assessments, and mortality also will be evaluated. Launched in 2019, HELIOS-B is expected to end in June 2025.
Common side effects of Amvuttra
The most common side effects reported when using Amvuttra include:
- joint pain (arthralgia)
- shortness of breath (dyspnea)
- decreased levels of vitamin A
Decreased vitamin A levels
Due to transthyretin’s role in transporting vitamin A throughout the body, most patients using Amvuttra experience a decrease in blood levels of vitamin A. In addition to antioxidant effects, this nutrient is important to vision, growth, cell division, reproduction, and immunity. Thus, daily vitamin A supplements are suggested for all patients using Amvuttra.
If patients experience eye-related symptoms, such as night blindness, that suggest a vitamin A deficiency, they should be referred to an ophthalmologist.
Pregnancy and breastfeeding
Pregnant women were not included in clinical trials of Amvuttra, so no information exists about whether the therapy is safe during pregnancy or breastfeeding. Further, vitamin A is essential for normal embryonic development, but the effects of low blood levels of vitamin A and the use of vitamin A supplementation on a developing fetus are unknown.
In animal studies, daily administration of Amvuttra to pregnant rats led to reduced fetal body weight and embryonic or fetal mortality at doses also associated with maternal toxicity. In rabbits, however, daily Amvuttra treatment was not associated with adverse effects on fetal development. In pregnant and lactating rats receiving Amvuttra once every six days, no toxicity to the developing offspring was observed.
Patients who are pregnant or wish to become pregnant or breastfeed while using Amvuttra should discuss this issue with their physician.
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