As described in a recent case report, high levels of the amino acid homocysteine, a potentially harmful side effect of Gibrari (gibosiran), may reduce vitamin B6 in women with hard-to-treat acute intermittent porphyria (AIP). They succeeded in normalizing the situation through resupply.
“Our results confirm the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria to improve management with appropriate vitamin supplementation. [Givlaari] treatment,” the researchers wrote.
The details of the incident were part of the research.”Prevention of hyperhomocysteinemia with vitamin B6 supplementation in acute intermittent porphyria treated with givosiran: highlights from a case report and brief literature review” was published. Molecular Genetics and Metabolism Report.
AIP is caused by mutations such as: HMBS A gene that interferes with the production of heme, a molecule involved in oxygen transport. Such destruction leads to toxic accumulation of intermediate molecules such as 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), leading to disease symptoms.
Givlaari is a subcutaneous (subcutaneous) injection therapy sold by Alnylam Pharmaceuticals that is approved in the United States for adults with acute hepatic porphyria (AHP), a group of porphyrias that also includes AIP. It is designed to inhibit the production of aminolevulinic acid synthase 1 (ALAS1), a liver enzyme that is overactive in patients with AHP and causes elevated ALA and PBG levels.
Patients treated with Gibrary may have increased levels of homocysteine in their bloodstream. Homocysteine is an amino acid or a building block of proteins. High levels of homocysteine are associated with cardiovascular disease.
Because vitamin B6 acts as an enzyme cofactor in the molecular cascade in which homocysteine is converted to other molecules, vitamin B6 supplements may be used to reduce homocysteine levels in AHP patients on Gibrary. .
Female case report
In this report, French researchers described how vitamin B6 was successful in reducing dangerously high levels of Gibralli-induced homocysteine in a 72-year-old woman with difficult-to-treat AIP. .
The woman had a history of high blood pressure, epilepsy, and a brain aneurysm. She was diagnosed with AIP at the age of 62 after having a severe acute attack with neurological involvement and was successfully treated with hemin. Through genetic analysis, HMBS mutation.
In the 8 years after diagnosis, she had four relapses of acute neurovisceral attacks. These attacks were characterized by abdominal pain, brain and spinal cord involvement, chronic hypertension, and a >10-fold increase in her urinary PBG levels. Infections were identified as the precipitating factor for two of her acute attacks.
Before starting Givlaari, she had persistently high levels of ALA and PBG in her urine and slightly compromised renal function. Her homocysteine level was also significantly elevated at 79 micromoles per liter (mcmol/L) compared to her normal range of less than 16 mcmol/L.
After one month of treatment, Givlaari significantly reduced the levels of ALA and PBG in the urine. But at the same time, her urinary homocysteine concentration increased dramatically to her 447 mcmol/L. The patient’s blood also contained 69 mcmol/L of homocysteine, a level that is normally undetectable. Her blood vitamin B6 levels were within normal limits.
Based on her urinary ALA and PBG levels, Gibrali doses were spaced approximately 2 to 3 months apart and were administered in combination with high-dose vitamin B6 (800 mg/day). In all, she received her 11 Gibrali injections over her 22 months (almost 2 years).
Although urinary ALA levels remained low, blood levels of homocysteine gradually returned to the normal range. However, urine levels of PBG remained relatively high, approximately 10 to 30 times higher than normal, and this level “has been reported in patients already receiving treatment.” [Givlaari] “started late in the course of the disease,” the authors wrote.
Despite a partial biological response, she has not experienced any new episodes of acute porphyria since starting Gibrari. Additionally, even though she reduced her vitamin B6 dose to 125 mg/day, her blood homocysteine level remained within normal limits even with repeated Gibrary injections. Gibrari was also well tolerated, with injection site reactions observed.
“Following studies with larger numbers of patients are needed to more precisely define the dosage of vitamin B6 that should be considered at the beginning of treatment and during long-term maintenance,” the researchers wrote. .
