Vutrisiran
Trade names Amvuttra
Pregnancy category AU: D[1]
Routes of administration Subcutaneous
Drug class Small interfering RNA
Vutrisiran, sold under the brand name Amvuttra, is a medication used for the treatment of the polyneuropathy and cardiomyopathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults.
It is a double stranded small interfering RNA (siRNA) (also called RNA interference, or RNAi therapeutic) that interferes with the expression of the transthyretin (TTR) gene.
Transthyretin is a serum protein made in the liver whose major function is transport of vitamin A and thyroxine.
Rare mutations in the transthyretin gene result in accumulation of large amyloid deposits of misfolded transthyretin molecules most prominently in peripheral nerves and the heart.
Patients with hATTR typically present with polyneuropathy or autonomic dysfunction followed by cardiomyopathy which, if untreated, is fatal within 5 to 10 years.
Vutrisiran was approved for medical use in the United States in June 2022.
Vutrisiran is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Vutrisiran is generally well tolerated but side effects can include injection site reactions, fatigue, arthralgia, dyspnea, diarrhea and musculoskeletal pains.
Vutrisiran treatment leads to decreased Vitamin A levels and supplementation at the recommended daily allowance of vitamin A is advised.
Patients should be referred to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency associated night blindness.
Plasma concentration profiles of vutrisiran showed rapid absorption and elimination from systemic circulation.
Plasma concentrations of vutrisiran were detectable at 10 minutes after SC administration and peak plasma concentrations were seen at a median 4 h after SC administration of a 25 mg single dose in healthy volunteers.
Plasma half-life is 4.2–7.5 hours.
The apparent volume of distribution of vutrisiran is estimated to be 10.1 L.
Vutrisiran is 80% plasma protein bound; however, plasma protein binding is concentration dependent and decreases with increasing concentrations.
Vutrisiran distributes mainly to the liver after subcutaneous administration.
Vutrisiran is a subcutaneously administered RNA interference therapeutic agent that inhibits hepatic synthesis of both wild type and variant TTR messenger RNA at their source, resulting in rapid knockdown of the pathogenic protein before amyloid, causing monomers can form.
Modification of this drug allows for administration once every three months.
The plasma clearance of siRNA is primarily influenced by uptake into the liver where the siRNAs are gradually metabolized by endonucleases and exonucleases to short nucleotide fragments of varying sizes.
After a 25 mg single dose SC vutrisiran in healthy volunteers, the median elimination half-life was 5.2 h and the median apparent clearance was 21.4 L/h.
Its primary pathway for excretion is via the kidneys, although the fraction of renal clearance to total clearance was 15.5–27.5% after a single 5–300 mg subcutaneous dose in healthy volunteers, indicating that renal excretion is a minor route of elimination.
The percentage of vutrisiran dose excreted unchanged in urine through 24 hours ranged between 15 and 25% and increased slightly with increasing dose, with a majority excreted within the first 12 hours after administration.
Age, sex, bodyweight, race, and mild or moderate kidney impairment or mild hepatic impairment do not have clinically significant effects on vutrisiran pharmacokinetics.
Vutrisiran is neither a substrate nor inhibitor of cytochrome P450 enzymes and is not expected to cause drug- drug interaction by inducing CYP enzymes.
Mechanism of action reveals Vutrisiran is a gene silencing double-stranded siRNA-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through RNA interference by binding and silencing messenger RNA (mRNA) encoding for disease causing protein Transthyretin, which results in a reduction of serum TTR protein and TTRprotein.
A phase I clinical trial was completed in January 2018, in which vutrisiran was evaluated to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics in 80 healthy volunteers.
Vutrisiran was found to be well tolerated, established a good safety profile and elicited rapid robust and durable TTR reduction.
Vutrisiran achieved a dose-dependent TTR knockdown; a single 25 mg subcutaneous dose resulted in a maximum TTR reduction of 80%, which was sustained for 90 days.
Two phase III trials: HELIOS-A and HELIOS-B.
HELIOS-A was a phase III, global, open-label study comparing the efficacy and safety of vutrisiran to patisiran.
164 ATTRv amyloidosis patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or patisiran 0.3 mg/kg IV infusion every 3 weeks for 18 months’ treatment period to be followed by a lengthier extension period.
Vutrisiran treatment resulted in rapid (≤3 weeks) and sustained reduction in serum TTR levels over 18 months, similar to what was observed in the patisiran group.
Following 18 months of vutrisiran treatment, steady-state mean (SD) peak and trough serum TTR reductions from baseline were 87.6% and 81.0%, respectively.
Serum vitamin A levels were reduced in parallel with reductions in serum TTR levels in both treatment groups.
The extent of the reduction in TTR was not affected by TTR genotype or patient age, sex, body weight or race.
A subcutaneous dose of 25 mg vutrisiran every 3 months caused similar or greater efficacy than patisiran given as IV infusion three times a week.
Vutrisiran significantly improved multiple disease-relevant outcomes versus placebo, with an acceptable safety profile.
These findings from HELIOS-A resulted in FDA and EMA approval of vutrisiran for treatment of ATTRv-PN.
A study phase III HELIOS-B randomized, double-blind, placebo-controlled trial, in which patients with TTR-related amyloid heart disease, both wild-type and mutated forms, are enrolled to evaluate the possible effects of the drug in terms of cardiac involvement.
The estimated completion date is June 2025. Patients are randomized on a 1:1 basis to receive 25 mg of vutrisiran or placebo administered as a subcutaneous injection once every 3 months for up to 36 months.
Vutrisiran is well tolerated and has an acceptable safety profile. In contrast to patisiran, patients do not require premedication, although all patients require vitamin A supplementation.
The majority of adverse events in the phase I trial of vutrisiran were mild, and included nasopharyngitis, headache, diarrhea and nausea, and injection site reactions.
HELIOS-A trial also reported encouraging safety and tolerability, with the majority of adverse events being mild or moderate 10 and no drug- related discontinuations or deaths occurred.
Only two serious adverse events were attributed to vutrisiran—dyslipidemia and urinary tract infection.
AEs occurring in (≥ 10%) of patients receiving vutrisiran included falls, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness; all of which, except pain in extremity and arthralgia, occurred at a similar or lower rate than in the external placebo group.
There were no cardiac AEs related to vutrisiran in the safety population.
Five patients (4.1%) who received vutrisiran reported mild and transient injection site reactions (ISRs).
There were no safety signals regarding liver function tests, haematology, or renal function related to vutrisiran.
Four vutrisiran recipients (3.3%) developed antidrug antibodies (ADAs) that were low and transient with no evidence of an effect on clinical efficacy, safety, pharmacokinetics or pharmacodynamic parameters.
No clinically significant changes in laboratory measures, vital signs, physical examinations, or electrocardiogram were noted.