Givlaari (Givosiran)

Givlaari (givosiran) is an RNA-interference therapy, developed by Alnylam Pharmaceuticals, against the aminolevulinate synthase-1 (ALAS-1) enzyme for the treatment of acute hepatic porphyria (AHP).

Givlaari was approved by the U.S. Food and Drug Administration in November 2019 to treat adults with AHP. The EU approved Givlaari in March 2020 to treat patients 12 and above with AHP.

How does Givlaari work?

AHP is a group of four rare genetic diseases caused by mutations in genes responsible for the production of enzymes involved in the heme biosynthesis pathway. This pathway occurs in the liver and produces a compound called heme, which is an important constituent of the oxygen-carrying pigment hemoglobin in red blood cells. AHP can also be caused by mutations in genes that encode for metabolic enzymes.

For example, mutations in the ALAS1 gene result in the excess activity of the ALAS1 enzyme, resulting in the accumulation of compounds such as aminolevulinic acid (ALA) and porphobilinogen (PBG) which are normally converted to heme. When there is too much ALA and PBG, cells cannot convert them all to heme so these compounds accumulate inside cells and become toxic. Nerve cells are particularly vulnerable to ALA and PBG accumulation.

Givlaari is a small interfering RNA molecule that degrades the ALAS1 messenger RNA. Messenger RNA (mRNA) is an intermediary molecule generated from DNA during the production of proteins. The degradation of ALAS1 mRNA prevents further production of the ALAS1 enzyme and thereby reduces the levels of toxic ALA and PBG compounds accumulating inside cells.

Givlaari in clinical trials

A Phase 1 clinical trial (NCT02452372) to determine the safety and efficacy of Givlaari in patients with a type of AHP known as acute intermittent porphyria was completed in 2017. The results showed that Givlaari was well-tolerated, with six out of 40 patients showing serious adverse events. The study also showed that Givlaari reduced the need to use hemin by 48%. (Hemin is usually administered in the event of an acute porphyria attack).

Patients from the trial were given the opportunity to take part in a Phase 1/2 open-label extension trial (NCT02949830) studying the long-term safety and efficacy of Givlaari. Initial results showed that Givlaari could reduce the levels of ALAS1 mRNA by 60% to 70%, and ALA and PBG levels by 80% when administered monthly for up to 25 months. The use of hemin was also reduced by up to 88% in treated patients compared with those on placebo. The study is expected to be fully completed in October 2021.

Another Phase 1 clinical trial (NCT03505853) investigated the interaction between Givlaari and five other drugs commonly given to AHP patients including midazolam, caffeine, losartan, omeprazole, and dextromethorphan in an effort to see what affect Givlaari had on other enzymes. A total of 10 patients were monitored in the study and results of the study were presented at the 2019 International Congress on Porphyrins and Porphyrias. The study showed that Givlaari had a moderate impact on CYP1A2 (which modifies 0nly a small number of drugs such as theophylline) and CYP2D6 enzymes (which metabolizes such drugs as antipsychotics, antidepressants, and pain medications) so these medications should be more closely monitored in patients taking Givlaari.

A Phase 3 clinical trial (NCT03338816) called ENVISION is further studying the safety and efficacy of Givlaari. The trial enrolled 94 AHP patients across 18 countries and is expected to be completed in September 2021. Results available so far showed that monthly Givlaari administration reduced the mean annual rate of AHP attacks by 74% compared to a placebo. Researchers also observed a 92% decrease in the amount of ALA and an 89% reduction in PBG in the urine of patients.

Patients who chose to continue to take Givlaari for an additional 30 months in the study maintained lower annual AHP attack rates and ALA levels in the urine. Patients who switched from the placebo to Givlaari during the extension study also showed a rapid reduction in both AHP attack rates and ALA levels.

An ongoing observational trial (NCT02240784) called EXPLORE is studying the natural history and clinical management of AHP in 300 patients with recurring attacks. The trial is expected to be completed in December 2020. Initial findings from the study revealed that the annualized attack rate in these patients was 3.7, and each attack lasted for an average of 7.3 days. Patients also reported chronic pain between attacks even though they received hemin or opioid treatments.

Other information

Common side effects of Givlaari include nausea and injection site reactions such as rash, swelling, and pain. The treatment may also be toxic for the liver and kidneys. Less than 1% of patients in the clinical trials have experienced anaphylaxis (life-threatening allergic reaction) after Givlaari treatment.


Last updated: Mar. 16, 2020


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