Real-world Amvuttra safety signals mostly match known profile
Study found possible night blindness and cardiac-related signals
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Many adverse-event reports and safety signals linked to Amvuttra (vutrisiran) treatment for hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in real-world databases were consistent with the therapy’s reported safety profile in clinical trials, a study showed.
However, the analysis also detected potential safety signals not listed in the prescribing information, including vision-related signals and cardiac-related signals, in hATTR-PN patients on the therapy. While a cause-and-effect relationship remains to be determined, some of these signals “are more likely to represent indicators of underlying disease severity, … complications of transthyretin-mediated amyloidosis, or downstream clinical management decisions, rather than direct adverse drug reactions attributable to [Amvuttra],” the researchers wrote.
Still, the scientists said these reports highlight a need for continued study into the safety profile of this drug, stressing a particular need for further research into Amvuttra’s potential effects on vision.
Researchers call for continued Amvuttra safety monitoring
The study, “Assessing the real-world safety of vutrisiran for transthyretin-mediated amyloidosis with polyneuropathy: Based on WHO-VigiAccess and FAERS databases,” was published in PLOS One. The work was funded by the National Natural Science Foundation of China and other research-focused organizations in China.
hATTR-PN is a genetic disease in which mutations in the TTR gene lead to abnormal transthyretin protein that can misfold and form toxic clumps, called amyloid deposits. These deposits can damage nerves outside the brain and spinal cord, causing symptoms such as abnormal sensations and muscle weakness.
Amvuttra, sold by Alnylam Pharmaceuticals, is an approved hATTR-PN treatment that works by reducing transthyretin levels, which is expected to help slow the disease’s progression.
Given by injection under the skin every three months, Amvuttra is also approved for adults with transthyretin-mediated amyloidosis with cardiomyopathy (ATTR-CM), a related condition in which transthyretin clumps mainly damage the heart.
Amvuttra has been shown in clinical trials to slow the progression of neurological problems in people with hATTR-PN. But like any medication, Amvuttra can cause side effects.
According to its label in the U.S., the most commonly reported adverse reactions in Amvuttra trials include pain in the arms or legs, joint pain, and shortness of breath. The therapy can also lead to decreased levels of vitamin A in the blood, which can affect eye health, and patients taking the drug should receive vitamin A supplements. Injection-site reactions also have been reported in real-world safety data and prior studies.
Study reviewed more than 1,400 adverse-event reports
The World Health Organization’s (WHO) VigiAccess database provides public access to adverse-event reports submitted by healthcare professionals and patients. The U.S. Food and Drug Administration (FDA) maintains a similar database, called FAERS.
In this study, a team of scientists in China reviewed more than 1,400 adverse-event reports in these two safety databases in which Amvuttra was listed as the main suspected drug. The researchers looked for safety signals associated with the hATTR-PN treatment.
“These research and analysis results provide doctors with more safety information to consider the adverse reactions of this drug,” the scientists wrote.
Many reported events and safety signals were consistent with the known safety profile of Amvuttra — for example, there were many reports related to pain, fatigue, or decreased vitamin A levels. There also were reports of injection-site reactions, such as redness, swelling, and pain.
But in addition to known adverse reactions, the analysis detected some less-expected safety signals. In particular, there were reports of vision problems, most notably night blindness, or difficulty seeing in dim light, which is a common symptom of vitamin A deficiency.
Vision-related signals need more study
Although this type of analysis cannot prove a cause-and-effect relationship between the therapy and an adverse event, “the correlation appears noteworthy and clinically relevant,” the team wrote.
“The development of night blindness in patients treated with [Amvuttra] may result from vitamin A deficiency,” the researchers wrote. “Therefore, in clinical practice, patients receiving [Amvuttra] should be informed of this potential risk, and preventive strategies—such as concurrent vitamin A supplementation—may be considered.”
The team also highlighted a need for more research into how Amvuttra treatment may impact vision.
The analysis also detected signals involving cardiac procedures or disorders, kidney-related procedures, and fractures, including pacemaker insertion, renal transplantation, and pelvic fractures. The researchers said these signals should be interpreted cautiously because they may reflect advanced hATTR-PN, co-occurring diseases, or clinical management decisions rather than direct effects of Amvuttra.
“Signals related to advanced [heart] or [kidney] interventions were observed but likely reflect underlying disease severity rather than direct drug effects,” the team wrote.
“Well-designed clinical trials and post-marketing surveillance studies are warranted to further substantiate and validate the real-world safety profile of [Amvuttra],” the researchers concluded.
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