AMVUTTRA® (vutrisiran) was approved by the FDA in March 2025 for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.
The approval expands the indication for AMVUTTRA, which now becomes the first and only therapeutic approved by the FDA for the treatment of ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.
“AMVUTTRA is an RNAi therapeutic that works upstream to deliver rapid knockdown of TTR, addressing the disease at its source, with only four convenient subcutaneous doses per year. By rapidly knocking down TTR production, AMVUTTRA substantially decreases deposition of TTR fibrils, which form amyloid and cause irreversible cardiovascular damage and premature death in patients with ATTR-CM.” according to Alnylam’s press release.
The Use of RNA Interference Science in the Treatment of Hereditary Amyloidosis
Hereditary transthyretin amyloidosis (hATTR) is a severe, adult-onset inherited systemic disease which can affect the peripheral and autonomic nervous system, heart, kidney and the eyes. (1)
TTR (transthyretin) is a protein found in blood plasma and blood serum as well as in the cerebrospinal fluid (CSF). The protein is mainly synthesized (assembled) by the liver and the choroid plexus (CP). The name transthyretin is derived from the protein’s function of transporting the hormone thyroxin as well as retinol. The protein is created by a process called biosynthesis. Biosynthesis is carried out in accordance with genetic instructions encoded from ones DNA. The DNA instructions create messenger RNA (mRNA), which in turn biosynthesize transthyretin proteins in the form of a tetramer. (2)
In the case of hereditary amyloidosis, a DNA mutation causes an errant mRNA signal, which results in destabilization of the tetramer and misfolding of the protein. The misfolded TTR proteins aggregate into amyloid fibrils as shown in the figure below.(3) The Amyloid then deposits throughout the body, eventually causing symptoms that may be cardiac, neuropathic, gastro-intestinal, etc. in nature.
RNA interference (RNAi) is a natural process that controls gene “expression” to messenger RNAs (mRNA), thus blocking the RNA instruction for creating a protein.
The figure shown below illustrates this process. (4)In basic terms, the interfering process begins with a long double-stranded RNA (dsRNA) being “diced” into small fragments by an enzyme called a “Dicer”. These fragments, referred to as small interfering RNAs (siRNA), bind to proteins called argonaute proteins. After binding to an argonaute protein, one strand of the double-stranded RNA is removed. The remaining strand then binds to the targeted messenger RNA. The argonaute protein then cleaves the messenger RNA, destroying it.
RNA interfering therapeutic medicines mimic this natural process, utilizing designed small interfering RNAs (siRNA) that ultimately bind to and destroy disease-causing RNA. As a result, the cell is no longer able to produce the misfolded Amyloid protein. One such therapeutic is the drug Vutisiran, used to treat hereditary amyloidosis with polyneuropathy. The figure shown below shows how Vutisiran carries out the same silencing process. (5)
For additional information on ATTR Treatments such as stabilizers and silencers, please view the short Expert Insights video below by Dr. Brett W. Sperry from our Amyloidosis Lecture Series.
Sources —————————————–
Carroll, A., Dyck, P. J., Carvalho, M. de, Kennerson, M., Reilly, M. M., Kiernan, M. C., & Vucic, S. (2022, June 1). Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. Journal of Neurology, Neurosurgery & Psychiatry. https://jnnp.bmj.com/content/93/6/668
“RNAi Therapeutics: How RNA Interference Works: Alnylam® Pharmaceuticals.” RNAi Therapeutics | How RNA Interference Works | Alnylam® Pharmaceuticals, alnylam.com/our-science/the-science-of-rnai
Breaking News – FDA approves WAINUA for ATTRv-PN
The U.S. FDA has approved a new treatment for adults living with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN).
WAINUA™ (eplontersen) granted regulatory approval in the U.S. for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis.
U.S. FDA approval based on Phase 3 NEURO-TTRansform results showing WAINUA demonstrated consistent and sustained benefit halting neuropathy disease progression and improving neuropathy impairment and quality of life
Additional regulatory reviews for WAINUA underway in rest of world
WAINUA will be available in the U.S. in January 2024
“Many people living with hereditary transthyretin-mediated amyloid polyneuropathy are unable to fully enjoy their lives because of the relentless, progressive and debilitating effects of the disease,” said Michael J. Polydefkis, M.D., professor of neurology at Johns Hopkins University School of Medicine and an investigator in the NEURO-TTRansform study. “Approval of WAINUA represents a meaningful advancement in treatment, one that gives those who are living with transthyretin-mediated amyloid polyneuropathy help managing the disease.”
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