No recurring AIP attacks with Givlaari, small real-life study reports

Almost all people with severe and recurrent acute intermittent porphyria (AIP) were free of symptomatic attacks after treatment with Givlaari (givosiran), a small real-world study has shown.

Givlaari “significantly reduced the attack rate in our cohort, as 96% were attack-free at the time of the study,” the researchers wrote.

Early treatment resulted in significantly better responses, allowing dosage reduction in some patients.

However, the study also confirmed the high prevalence of adverse events,”most of which are benign but can affect the patient’s quality of life, such as feveroften reported fatigue and nausea,” the team wrote.

Thus, they suggested that the The impact of Givlaari on urinary heme metabolites should be monitored monthly to allow for dose adjustments and an individual approach to treatment.

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The study, “Givosiran in acute intermittent porphyria: a personalized medicine approachwas published in the journal Molecular genetics and metabolism.

AIP is caused by a genetically inherited deficiency in HMBS, an enzyme that helps produce heme, a molecule essential for transporting oxygen in the body.

Although most people with HMBS mutations do not develop symptoms, acute attacks can occur due to activation of a related enzyme called ALAS1. It can be triggered by hormonal changes, infections, alcohol consumption, smoking, reduced calorie intake, and stress.

Activated ALAS1 leads to the accumulation of two heme precursors – delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) – in the liver, triggering symptoms such as abdominal pain with nausea and vomiting. and, in severe cases, convulsions, states of confusion and hallucinations.

Most patients will experience one or a few attacks in their lifetime, but less than 10% will develop recurrent symptoms. AIP patients and mutation carriers are also known to be at increased risk of developing high blood pressure and kidney and liver disease.

Givlaari, a therapy developed by Alnylam Pharmaceuticals and designed to suppress ALAS1, was recently approved for porphyrias that affect the liver, including AIP. In clinical trials, patients treated with monthly subcutaneous (under the skin) injections had significantly fewer acute attacks and lower levels of ALA and PBG in urine.

In this report, researchers from the University of Paris, together with collaborators from various sites across France, described the impact of Givlaari in 24 AIP patients, in whom the dosing frequency was adjusted according to the levels individual ALAs throughout their treatment.

“We decided to evaluate a personalized medicine approach based on each patient’s ALA level and follow up individually,” the team wrote.

Patients eligible for AIP experienced four or more attacks per year and/or were treated with heme arginate, a drug that suppresses porphyrin production, as a preventive measure. They initially received 2.5 mg/kg of Givlaari every month, regardless of early response, and were treated and followed for a median of 16 months (one year, three months).

At the time of analysis, Givlaari produced a sustained overall reduction in urinary ALA levels, which fell by a median of 89.9%. Notably, 23 of the 24 participants (95.8%) did not experience an acute attack.

Prior to treatment, urinary ALA levels ranged from 7.9 to 51.4 micromoles per millimole (mcmol/mmol) of creatinine, well above the normal maximum of 3 mcmol/mmol of creatinine. It should be noted that ALA values ​​are normalized to creatinine concentrations to account for differences in urine volume.

After treatment with Givlaari, 20 patients (83%) consistently had creatinine below 5 mcmol/mmol, and of these some measurements were below 3 mcmol/mmol creatinine. The other four individuals showed a moderate decrease in ALA levels.

One participant (patient 9) showed a limited (78.1%) and variable decrease in ALA, which never fell below 5 mcmol/mmol creatinine. She had regular attacks requiring heme arginate every four or six weeks and was given opioids to manage her daily abdominal pain. Three other patients with a partial response – a 51.5% to 76.9% drop in ALA levels – no longer had acute attacks.

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Givlaari |  News Porphyria |  illustration of a graph

Statistical analysis showed a significant positive association between the year of AIP onset and the reduction in ALA percentage, demonstrating that “treatment efficacy was better in patients whose disease course was the shortest,” the researchers wrote.

Clinicians adjusted the frequency of Givlaari administration based on monthly ALA measurements, which led to two distinct groups of patients: 14 (58%), who required Givlaari every three months or more frequently , due to moderate or unstable declines in ALA levels; and 10 (42%) who were treated less frequently and maintained low ALA levels.

“The heterogeneity [variability] individual responses over time strongly supports that personalized therapeutic adaptation is necessary,” the researchers wrote.

Among those who required more frequent treatment, there was either a moderate decrease in ALA or a rapid increase after starting Givlaari. There was an overall 82.8% drop in ALA levels on treatment in this group, with an average ALA level of 5.6 mcmol/mmol. Six of these patients were treated every two to three months, while eight received treatment every four to six weeks.

Patients treated less frequently had an overall reduction of 95.6% in ALA levels, which remained at an average of 1.4 mcmol/mmol. Dosing frequency ranged from four to 14 months (median 7.5 months), which was only expected when ALA levels increased. These people did not experience acute symptoms on Givlaari.

A higher injection frequency was more likely in those who had acute symptoms for a longer period. Consistently, there was a significant difference in the mean number of years since disease onset between patients requiring less or more frequent treatments (6.7 vs 19.6 years).

All participants reported at least one adverse event. Elevated ALT levels, a sign of liver damage, were documented in eight patients (32%), occurring within the first six months of treatment in all but one case. Fatigue was felt in 17 (68%), nausea in 10 (40%), and six (24%) had increased hair loss and/or spontaneous nail loss.

A moderate and short-lasting increase in blood creatinine levels, a sign of impaired renal function, was observed in 91% of patients. High levels of homocysteine, which can damage blood vessels, were present in all 23 patients with measurements. Homocysteine ​​levels tended to increase with treatment (median increase 305%).

One patient experienced a serious adverse event leading to study discontinuation after four months due to acute pancreatitis, a sudden inflammation of the pancreas. Another patient was interrupted for 2.5 months due to a marked increase in pancreatitis markers and then resumed at a lower dose without relapse. Other serious adverse events included elevated liver enzyme levels, pulmonary embolism and decline in kidney function.

“In our cohort under [Givlaari] treatment, all but one (95.8%) severe AIP patients, defined as 4 or more acute attacks per year or requiring heme arginate prophylaxis, were acute attack free,” the authors wrote. . “The long-lasting treatment effect in some patients allowed us to reduce the frequency of administration under close monitoring of heme precursor levels without reduction in biological or clinical efficacy.”

“Early treatment with [Givlaari] was associated with a better biological response and allowed us to decrease dosing frequency,” they wrote.

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