Vutrisiran (Amvuttra®)

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Safety

There are currently no known contraindications to vutrisiran. The phase I trial showed no severe reactions, drug-related discontinuations, or treatment-related death3. There were no clinically significant changes in laboratory measures, vital signs, or physical examination. In the phase III HELIOS-A trial comparing patisiran and vutrisiran, injection site reactions including symptoms of pain, redness, or burning were reported in 6.7% of patients receiving vutrisiran and were all mild in severity 4. Authors note that patisiran had significantly more infusion-related reactions in comparison to vutrisiran. There are no dose adjustments recommended by the manufacturer for patients with altered renal or hepatic function3

Tolerability

Vutrisiran is well tolerated by patients. The most common adverse effects observed with vutrisiran use included arthralgias and dyspnea, both of which are common complications of the disease state itself. In the HELIOS-A trial, 11% of patients experienced arthralgia symptoms and 7% experienced dyspnea compared to placebo4. In some cases, vutrisiran has been shown to decrease serum vitamin A levels (occurred in approximately 7% of patients studied), which could result in ocular complications such as night blindness. The manufacturer recommends patients consume the daily recommended amount of vitamin A via diet or supplementation3

Effectiveness

During the phase I clinical trial conducted in healthy patients, a single 25 mg dose of vutrisiran resulted in a maximum TTR protein reduction of 94% and an average TTR protein reduction of 80%, which was sustained for approximately 90 days3. During the 18-month phase III clinical trial of vutrisiran (HELIOS-A), a single subcutaneous dose demonstrated an 87% decrease in serum levels of TTR protein, which was sustained over 18 months. In addition, serum TTR decreased significantly within three weeks of treatment. Results showed that 48% of patients experienced a reversal of neuropathy symptoms using the modified neuropathy impairment score (mNIS+7) from baseline compared to only 4% in the placebo group. In addition, 57% of patients experienced improvement in quality of life from baseline compared to only 10% in the placebo group4. Compared to patisiran (Onpattro®), a medication approved in 2018 with the same mechanism of action, vutrisiran has been shown to be just as effective with less adverse effects and easier administration.

Price

Vutrisiran is priced per subcutaneous dose (25 mg/0.5 mL) which is given once every three months. One injection of vutrisiran (0.5 mL) is priced at $139,050.00, which would make the total annual cost of the medication $556,200.00. However, through the Alnylam Pharmaceuticals manufacturer site, patients can find an assistance program that helps uninsured patients to receive the medication at no cost and patients with commercial insurance to receive each dose at decreased cost5 Patisiran costs approximately $7,000 per dose for a patient weighing greater than or equal to

Materia Medica

one hundred kilograms. Since this medication is given once every three weeks, the total annual cost is approximately $121,333.33. Although the cost is lower, the time of administration is significantly longer than that of vutrisiran, which could result in more indirect and intangible health care costs, such as the patient’s time spent in the office, increased stress, or discomfort of a prolonged infusion6.

Simplicity

Vutrisiran is 25 mg/0.5 mL subcutaneous injection which is administered by a healthcare provider in the office once every three months5 This medication can be injected into the subcutaneous tissue around abdomen, upper thigh, or upper arm and is relatively painless. In comparison, patisiran is an intravenous infusion given every three weeks that takes approximately eighty minutes to infuse. There is no premedication or lab monitoring required for vutrisiran and no observation period required post-injection, as there is with patisiran5,6. Due to the known decrease in vitamin A levels, it is recommended that all patients take a vitamin A supplement as needed to maintain the daily recommended dose3.

Bottom Line

Hereditary transthyretin amyloidosis presents with many debilitating complications, including polyneuropathy, a result of mutated TTR proteins2. Vutrisiran is a small interfering RNA therapeutic that targets the synthesis of the transthyretin protein by silencing the TTR gene in the liver. Vutrisiran showed a clinically significant decrease in serum levels of TTR protein, which was sustained for 90 days. The overall decrease in serum TTR proteins has been proven to improve symptoms of polyneuropathy and overall quality of life3. Vutrisiran can be prescribed in patients with varying degrees of polyneuropathy in haTTR and is given once every three months with no premedication or lab monitoring required. Due to the debilitating nature of the disease, the