Amvuttra RNAi Therapeutic Wins FDA Approval for Rare Genetic Protein Disorder

Amvuttra RNAi Therapeutic Wins FDA Approval for Rare Genetic Protein Disorder

Amvuttra is an RNAi therapeutic that targets a defective gene that underlies the pathophysiology of the rare hereditary condition transthyretin-mediated (ATTR) amyloidosis. (Photo: Business Wire)

Alnylam Pharmaceuticals, a leading RNA interference (RNAi) therapeutics biopharmaceutical company, announced it received approval from the US Food and Drug Administration (FDA) for its RNAi therapeutic Amvuttra (vutrisiran) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (ATTR) amyloidosis in adults.

Hereditary ATTR amyloidosis is a rare, rapidly progressive condition that causes serious nerve damage, affecting approximately 50,000 people worldwide. It is characterized by debilitating polyneuropathy manifestations and cardiomyopathy in a small portion of cases. The condition has very limited treatment options.

Amvuttra is administered via subcutaneous injection four times a year or once every three months (quarterly).

Amvuttra’s FDA approval is based on positive data from the global, randomized, open-label, multicenter HELIOS-A Phase III study from a period of nine months. Results of the study show that the RNAi therapeutic significantly improved the signs and symptoms of polyneuropathy and 50 percent of patients achieved a cease or reversal of their disease manifestations.

Alnylam’s Onpattro was its first licensed and approved RNAi therapy for ATTR polyneuropathy. However, unlike Onpattro, which is given via intravenous infusion once every three weeks, Amvuttra can be administered less frequently and under the skin once every three months due to having high metabolic stability and increased potency.

Related: Alnylam Files Lawsuits Against Pfizer and Moderna Over Patent Infringement of RNA Delivery Technology

In the HELIOS-A study, Amvuttra was found to help ATTR polyneuropathy patients achieve an average improvement of 2.2 points on a modified neuropathy impairment score after nine months, compared to a worsening of an average of 17.7 points in an external placebo group. Overall, half of the patients had some level of improvement. In the same study, those who received Onpattro scored an improvement of 1.4 points.

Hereditary transthyretin-mediated amyloidosis (ATTR)

Hereditary ATTR has an autosomal dominant pattern of inheritance and is caused by point mutations in the transthyretin (TTR) gene that codes for the transthyretin transport protein found in the plasma and cerebrospinal fluid. TTR is made in the liver and is involved in carrying the thyroid hormone thyroxine (T4) and retinol (vitamin A) to the liver.

Defects in the TTR transporter leads to a buildup of amyloid protein (amyloidosis) in tissues and organs, occurring mainly in the nerves in the peripheral nervous system. This leads to loss of sensation in the extremities (peripheral neuropathy) and the autonomic nervous system can also be affected.

Some of the signs and symptoms of hereditary ATTR can include swelling of the ankles and legs; major fatigue and weakness; shortness of breath with minimal exertion; unable to lie down flat due to shortness of breath; numbness, tingling or pain in the hands or feet; and wrist pain (carpal tunnel syndrome). Individuals with the cardiac form of ATTR can have an abnormal heartbeat (arrhythmia), an enlarged heart (cardiomegaly) or orthostatic hypertension. These abnormalities can lead to progressive heart failure and death.

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Amvuttra is an RNAi therapeutic that targets mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA). Alnylam designed it to have increased potency and high metabolic stability using its proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, allowing for injection once every three months.

In addition to inherited ATTR, there is also a non-inherited form of the condition, which is mainly cardiomyopathy. According to estimates, ATTR cardiomyopathy affects 200,000 to 300,000 people globally, but the prevalence is likely higher because it is underdiagnosed. Therefore, more people are affected by ATTR cardiomyopathy than hereditary ATTR.

Alnylam is currently conducting the HELIOS-B study to evaluate Amvuttra for ATTR cardiomyopathy and expects patient survival data in 2024. At the same time, investors’ eyes are on the company’s Phase III APOLLO-B trial for Onpattro in this heart disease indication.

Evaluate Vantage speculates that given Amvuttra’s potential for ATTR cardiomyopathy, the drug could reach $1.8 billion in global sales by 2026.

However, Alynylm will be going head-to-head against Pfizer in the ATTR cardiomyopathy arena. Pfizer has not one but two approved ATTR cardiomyopathy therapies, Vyndaqel and Vyndamax, which secured $2 billion in sales last year. Other big names like AstraZeneca and Novo Nordisk are also making their way into the playing field, striking partnerships and buying ATTR programs from other companies (Ionis and Prothena, respectively).

Alnylam has also been in the news recently over claims that it holds the patent for the lipid nanoparticle technology Pfizer and Moderna used in their COVID-19 vaccines. Alnylam filed lawsuits against both companies in March this year over the alleged patent infringements.