Givlaari effective in AIP patients often excluded from clinical trials
Real-world study tested approved therapy in patients with sporadic attacks
In a real-world study in Germany, Givlaari (givosiran) was found to effectively prevent severe acute attacks and reduce chronic health burden in people with acute intermittent porphyria (AIP) — patients who are commonly excluded from porphyria studies and who would have been ineligible to participate in the clinical trial that backed the therapy’s approval.
The researchers noted that this study included patients with sporadic attacks and those with chronic symptoms but no attacks. Given either these individuals’ limited number of attacks or a lack of preventive treatment with hemin, the patients would not have been eligible for the Phase 3 clinical trial whose data was used for Givlaari’s approval.
Overall, 75% of these patients experienced clinical improvements with Givlaari treatment.
“Our study shows that [Givlaari] treatment has the potential to transform the lives of patients suffering from AIP with a range of symptoms, including those with chronic symptoms without attacks, with a generally satisfactory [adverse event] profile,” the researchers wrote.
According to the team, these findings are especially important given the therapy’s high price tag.
“[These results are] particularly relevant for [Givlaari] injections, where the estimated cost is [greater than] USD 400,000 per patient per year,” the researchers wrote.
The study, “German Real-World Experience of Patients with Diverse Features of Acute Intermittent Porphyria Treated with Givosiran,” was published in the Journal of Clinical Medicine.
Assessing Givlaari effective in AIP patients with acute, chronic disease
AIP — the most common form of acute porphyria — is caused by mutations in the HMBS gene, which disrupt the production of an enzyme called hydroxymethylbilane synthase, or HMBS. This enzyme is required for the production of heme, a molecule that enables red blood cells to transport oxygen.
As a result of HMBS mutations, porphobilinogen (PBG) and aminolevulinic acid (ALA) — intermediary molecules that are normally converted into heme — accumulate to toxic levels and drive the disease’s symptoms. Common symptoms of acute porphyrias include sudden and potentially severe attacks of acute abdominal pain, as well as chronic symptoms.
Givlaari is an approved treatment designed to reduce the production of aminolevulinate synthase 1 (ALAS1), an enzyme that’s overactive in people with acute porphyria and causes ALA and PBG levels to rise. The treatment is expected to stop intermediary molecules from reaching toxic levels, and consequently prevent porphyria attacks, particularly in patients experiencing them on a regular basis.
Now, a team led by researchers at the Porphyria Center at Chemnitz Hospital in Germany conducted a real-world study that included patients who had been treated with Givlaari at the center between 2018 and 2024. Their goal was to assess the therapy’s safety and efficacy in AIP patients with acute and chronic disease.
These individuals typically experience “difficult-to-manage chronic porphyria symptoms that are poorly controlled by conventional treatment,” the team wrote.
A total of 28 patients, mainly women (82.1%) and with a mean age of 42.7, were given Givlaari at a starting dose of 2.5 mg/kg for an average of 30 months, or 2.5 years.
The participants were classified into several groups, depending on the presence and frequency of attacks and other symptoms.
Those in the sporadic attack group — 13 patients or 46.4% — had three or fewer attacks within a 12-month period in the prior two years. Meanwhile, the five patients in the recurrent attack group (17.9%) had four or more attacks occurring within the same period. There were also two additional groups: one comprised of patients with chronic symptoms but no attacks in the prior two years (17.9%), and another with patients receiving regular hemin infusions to prevent attacks (also five patients or 17.9%).
Before treatment, the participants were found to have elevated levels of ALA and PBG in the urine, which significantly decreased after three months of treatment. That effect was sustained for up to six months, data showed.
A biochemical response, defined as a drop to below two times the upper limit of normal, occurred for ALA in all patients and for PBG in about two-thirds after six months of treatment.
Three-quarters of the patients saw their ALA levels normalize after six months, while 28% — eight patients — achieved normal PBG levels. These responses were not different between patient subgroups, the researchers noted.
[The findings suggest] that [Givlaari] can alleviate the recurrence of acute porphyria symptoms in patients with distinct AIP phenotypes [manifestations].
Altogether, clinical improvements were seen for 3 of every 4 patients in the study. In the overall patient population, the annualized attack ratio, or the number of attacks divided by time in months, decreased from 2.9 before treatment initiation to 0.45 after six months of treatment.
This reduction was seen across all groups of patients, suggesting “that [Givlaari] can alleviate the recurrence of acute porphyria symptoms in patients with distinct AIP phenotypes [manifestations],” the researchers wrote.
Improvements seen in all aspects of patient’s health-related quality of life
Patients also showed a sustained improvement across all aspects of health-related quality of life, as measured by the EQ-5D-5L questionnaire. The greatest benefit was seen in mental health, with a 38% improvement, and pain, where there was a 38% reduction. A 30% improvement was also seen in patients’ ability to perform everyday tasks.
These effects were seen across all patient groups, the researchers noted.
Six patients reported drug-induced side effects. Two withdrew from the study due to fatigue following three to four months of treatment. Many patients (41%) experienced moderate fatigue after three months of treatment, but for most, it was temporary and eased after six months. Among the patients with such fatigue, 66% reported none after six months.
Other adverse events included muscle cramps (36%) and nausea (29.1%). Three patients experienced unsatisfactory side effects that led to a dose reduction of 50% to 75%. No life-threatening adverse events were deemed related to treatment.
“Further research is required to evaluate whether patients receiving lower or less frequent doses of [Givlaari] are at a reduced risk of [adverse events] whilst continuing to be protected from acute episodes,” the researchers wrote.
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