Safety study points to possible new side effect signals in AHP treatment

Givlaari (givosiran), an approved therapy for acute hepatic porphyria (AHP), was associated with several potentially new safety signals not included in the therapy’s prescribing information, according to a large real-world safety analysis.

By analyzing more than 1,200 reports of adverse events associated with Givlaari in a U.S. drug safety database, with supporting findings from more than 1,300 additional reports from a global drug safety database, researchers found signals consistent with several known safety concerns while also identifying potential new safety signals, including brain fog, excessive sleepiness, weight fluctuations, and abnormal weight loss.

Since reported adverse events sometimes emerged long after treatment began and the reporting risk did not appear to rise or fall substantially over time, the researchers emphasized “that continuous safety monitoring should be maintained throughout the entire treatment course” in people receiving Givlaari.

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Database study looks at Givlaari safety

The study, “Adverse events of givosiran in the treatment of acute hepatic porphyria: a pharmacovigilance study using the FAERS and VigiAccess databases,” was published in the Orphanet Journal of Rare Diseases.

Porphyrias are caused by mutations that disrupt the production of heme, a molecule needed for oxygen transport in the blood. When this process breaks down, heme precursors accumulate in the body’s tissues, triggering sudden, intense abdominal pain, often accompanied by vomiting, seizures, and psychiatric symptoms. AHP, in particular, is marked by the buildup in the liver of the heme precursors porphobilinogen (PBG) and aminolevulinic acid (ALA).

Givlaari, an RNA-based therapy developed by Alnylam Pharmaceuticals, was approved in the U.S. in 2019 for adults with AHP. The injectable therapy works by blocking aminolevulinic acid synthase 1 (ALAS1), an enzyme involved in producing the toxic compounds that drive AHP attacks. By reducing the production of these compounds, Givlaari can help reduce the frequency of AHP attacks and related AHP symptoms.

“Although [Givlaari] has demonstrated significant efficacy in reducing the frequency of acute attacks in patients with AHP, current knowledge regarding its safety profile is largely derived from clinical trials and limited observational studies,” the researchers wrote. “However, their relatively small sample sizes, strict inclusion criteria, and limited follow-up periods may restrict the detection of rare, delayed, or unexpected adverse events.”

To better understand the therapy’s safety in real-world clinical practice, a team of researchers in China analyzed reports from the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS), a database that collects reports of suspected side effects associated with approved medicines. The analysis included reports submitted from the database’s inception through the fourth quarter of 2025.

Analysis finds potential new safety signals

Among 1,286 reports associated with Givlaari, the researchers identified 22 significant adverse event signals, including nine that are not currently listed in the therapy’s prescribing information. These potential new safety signals included abdominal pain, seizures, stress, mental disorder, brain fog, excessive sleepiness, nerve pain, weight fluctuations, and abnormal weight loss.

Among the 22 significant adverse event signals identified, the five most frequently reported were abdominal pain, seizures, elevated blood homocysteine levels, stress, and increased blood creatinine levels, a sign of impaired kidney function.

When the researchers ranked adverse event signals according to their reporting frequency, clinical relevance, fatality rates, and signal stability, elevated homocysteine levels, pancreatitis (inflammation of the pancreas) and acute pancreatitis, seizures, abdominal pain, and kidney impairment emerged as the most clinically important safety concerns warranting closer monitoring in people receiving Givlaari.

Even after excluding events that could be attributed to AHP, including abdominal pain and seizures, several adverse event signals remained significantly associated with Givlaari. These included previously recognized safety concerns, such as elevated homocysteine levels and liver abnormalities, as well as pancreas-related complications and several potentially new safety signals, including brain fog, excessive sleepiness, stress, weight fluctuations, and abnormal weight loss.

Monitoring may be needed throughout treatment

Among reports that included information on when adverse events first emerged, slightly more than half (52.7%) occurred more than 365 days after treatment began. The researchers also found no evidence that the reporting risk increased or decreased substantially over time, indicating that ongoing monitoring may be important throughout treatment.

To strengthen their findings, the team then turned to VigiAccess, the World Health Organization’s global database of suspected drug-related adverse events. An analysis of 1,326 reports associated with Givlaari identified 35 significant adverse event signals, including 13 that were not listed in the therapy’s prescribing information. Notably, all of the potential new signals identified in the FAERS analysis, with the exception of brain fog, were also detected in the WHO database, providing additional support for the findings.

The researchers noted that FAERS and VigiAccess are spontaneous reporting systems and that this type of analysis identifies statistical associations rather than causal relationships.

“These findings highlight the importance of continued pharmacovigilance and long-term clinical monitoring of patients receiving [Givlaari], especially with respect to homocysteine levels, pancreatic function, [kidney] status, and neurological symptoms,” the researchers wrote. “Further prospective studies are warranted to clarify the underlying mechanisms and confirm these safety signals in clinical settings.”