Acute porphyria is a group of uncommon diseases that can cause severe, potentially life-threatening attacks of abdominal pain, nausea, vomiting and paralysis. Acute hepatic porphyria (AHP) is the most common form of acute porphyria. Patients suffering from acute attacks are treated using an infusion containing a form of heme called hemin, which suppresses the formation of the toxic metabolites. Porphyria is caused by different inherited disorders in the synthesis of heme, the oxygen-binding component of red blood cells. Heme is also necessary for the metabolism of certain drugs and hormones by the liver through enzymes called P450 cytochromes. When the liver is unable to synthesize heme properly, toxic substances called porphyrin metabolites accumulate in the body, resulting in acute porphyria attacks. Among these, delta-aminolevulinic acid (ALA) is the main responsible for the neurological and painful symptoms. Porfobilinogen may contribute as well. A small group of porphyria patients suffer recurrent acute attacks, which cause them chronic debilitating symptoms requiring constant hospital care. Liver transplantation is currently the only effective treatment available for the most seriously afflicted patients. For patients with recurrent attacks, no other curative treatment is available than liver replacement.
However, a clinical trial conducted in collaboration with researchers at Karolinska Institutet in Sweden now shows that a new drug candidate can prevent attacks in these patients. The study has been conducted in close, long-standing collaboration with Porphyria Centre Sweden, which has also provided the majority of the patients.The study is published in The New England Journal of Medicine. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated as well.
The administration of givosiran reduced the number of acute attacks in the patients by up to 79%, and the need for hemin decreased by up to 83%. Most of the reported side effects were mild or moderate, and no clear link was observed between adverse reactions and dose. Severe adverse reactions were reported in six patients, including one death that was deemed unrelated to givosiran. In part C of the trial, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. Last August, Alnylam Inc. has achieved full patient accrual in its ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHPs). Enrollment was completed with 94 AHP patients randomized across 36 sites in 18 countries, surpassing the initial target of approximately 75 patients due to high patient demand. The drug candidate has been given PRIME and Breakthrough Designation by the European Medicines Agency and the FDA, which in speeding up the review process could mean that the drug may be available by early 2020.
The patients that took part in the phase I study will remain on givosiran in a combined phase I/II study, and complete results from a phase III study in 94 patients from around the world are expected in this next spring. The study’s lead author Eliane Sardh, researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and consultant at Karolinska University Hospital, explained: “Hemin, the iron-deprived form of heme, has saved the lives of many patients and will continue to be important, but it’s only for acute treatment. However, the new drug candidate givosiran, developed by Alnylam Pharmaceuticals, has shown promising results in a clinical phase I study in 40 patients. The drug candidate is based on a natural method of inhibiting gene expression called RNA interference (RNAi). Givosiran down-regulates ALAS1, the key enzyme of the hepatic heme synthesis pathway, which reduces the toxic metabolites without the use of hemin. It also has a lasting effect of at least one month, which gives us an effective means of preventing acute attacks in seriously afflicted porphyria patients who have limited treatment options”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Sardh E et al. N Engl J Med. 2019 Feb 7; 380(6):549-558.
Yasuda M et al. P.N.A.S. USA 2014 May 27; 111(21):7777.
Dott. Gianfrancesco Cormaci
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