Personalized Givlaari regimen found effective for AIP in case series
Dosing altered 'without diminishing treatment effectiveness,' researchers say
The dosing of Givlaari (givosiran) may be personalized for people with acute intermittent porphyria (AIP), who are in stable condition after one year of treatment.
That’s according to a recent study that described the cases of three women for whom treatment normalized the levels of delta-aminolevulinic acid (ALA), which are typically higher in AIP patients. Dose adjustments were made considering ALA levels, as well as the levels of the amino acid homocysteine, which tend to be elevated in patients receiving Givlaari, a known and potentially harmful side effect of the therapy.
“The sustained efficacy of [Givlaari] in the majority of patients allowed us to personalize the dosing frequency without diminishing treatment effectiveness,” researchers wrote.
The study was published as a scientific letter, titled “Personalized dosage of Givosiran in acute intermittent porphyria,” in the journal Medicina Clínica.
Acute intermittent porphyria caused by mutations in HMBS gene
AIP, the most common form of acute porphyria, is caused by mutations in the HMBS gene, which disrupt the production of heme, a molecule essential for the transport of oxygen in the body. As a result, heme precursors, including ALA and porphobilinogen (PBG), accumulate to toxic levels, leading to sudden and potentially severe attacks characterized by abdominal pain and, in some cases, neurological symptoms.
In the letter, researchers in Spain described the cases of three AIP patients treated with Givlaari, a medication approved for acute hepatic porphyrias, a disease group that includes AIP. The therapy works by reducing the production of aminolevulinate synthase 1, a liver enzyme that increases the levels of ALA and PBG.
The levels of homocysteine, a type of amino acid, or protein building block, were monitored in all patients. Treatment with Givlaari may increase the levels of homocysteine in the bloodstream, which has been associated with a higher risk of cardiovascular diseases. The levels of homocysteine, along with those of ALA, allowed doctors to adjust and personalize Givlaari dosing by temporarily suspending the medication, using it solely as a rescue therapy, or spacing its doses.
The first patient, a 38-year-old woman, experienced a severe AIP attack marked by a series of neurological symptoms and dysfunction of the autonomic nervous system, which is the part of the nervous system that controls involuntary bodily processes, such as heart rate and breathing.
After one year of treatment with Givlaari given once monthly, the patient’s disease crisis ended with the normalization of ALA levels, which dropped from 64.3 mg/24 hours before treatment to 5.53 mg/24 hours after treatment.
Homocysteine levels reached an average value of 4.47 mg/L, corresponding to a moderate increase. The treatment was adjusted to be given as needed, with the patient receiving it for nearly three years.
Another patient had experienced disease episodes during her menstrual period
The second patient, a 36-year-old woman, experienced AIP episodes during menstrual periods that caused axonal neuropathy, which is a condition marked by damage to axons, a specific part of nerves that is responsible for transmitting nerve impulses.
After 21 months (nearly two years) of monthly treatment with Givlaari, her ALA levels decreased from 18.03 mg/24 hours to 1.79 mg/24 hours. The treatment also caused a moderate increase in her blood homocysteine levels, which subsequently returned to normal without any change in dosage. At the last evaluation, the patient was receiving Givlaari once every two months for four months.
The third patient, a 24-year-old woman, was admitted to the intensive care unit due to severe AIP episodes that included abdominal pain, neurological alterations, liver disease, and cardiovascular issues.
She was on monthly treatment with Givlaari for nearly four years. During that period, ALA levels dropped from an average of 24.86 mg/24 hours to 5.4 mg/24 hours. Her blood homocysteine levels severely increased during that time, although without affecting her general health.
After adjusting dosing to once every two months, her homocysteine levels normalized, and her clinical symptoms went into remission.
“According to our clinical experience, [Givlaari] has demonstrated being helpful in reducing ALA levels, as it was evidenced by analyses conducted in all our patients. Moreover, while receiving this treatment, none of them experiences disease relapses,” the researchers wrote.
The team noted, however, “the impact of [Givlaari] on [kidney] and [liver] function remains limited, especially in patients with previous [kidney and liver] diseases, underscoring the need for further studies.”
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