Last updated April 19, 2023, by Marisa Wexler, MS
 Fact-checked by Joana Carvalho, PhD
What is Givlaari for porphyria?
Givlaari (givosiran) is an injectable therapy approved in the U.S. for adults with acute hepatic porphyria (AHP). It is marketed by Alnylam Pharmaceuticals.
How does Givlaari work?
AHP refers to a group of rare genetic diseases caused by mutations that disrupt the production of heme, a molecule required for oxygen transport in the body. As a result, intermediary molecules, such as aminolevulinic acid (ALA) and porphobilinogen (PBG) that are normally converted into heme, build up to toxic levels. It’s the toxic accumulation of intermediary molecules like ALA and PBG that ultimately drives AHP symptoms.
Givlaari is designed to reduce the production of aminolevulinate synthase 1 (ALAS1), an enzyme that’s overactive in AHP and causes ALA and PBG levels to rise. By lowering ALAS1 levels and activity, Givlaari should keep ALA and PBG from reaching toxic levels, thereby preventing AHP attacks and other disease manifestations.
Givlaari can lower the production of ALAS1 because it contains a small interfering RNA molecule that specifically targets and degrades its messenger RNA — an intermediary molecule that’s made when the ALAS1 gene that provides instructions for making the enzyme is used by cells to produce ALAS1.
Who can take Givlaari?
Givlaari is approved in the U.S. to treat adults with AHP, including those with acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALAD-deficiency porphyria (ADP).
It’s also approved in Europe to treat AHP in patients ages 12 and older.
Who should not take Givlaari?
Givlaari should not be taken by anyone with a known allergy to its active ingredient, givosiran.
Givlaari may also cause liver and/or kidney toxicity, and increase the levels of homocysteine, a risk factor for heart disease. For this reason, homocysteine levels and liver and kidney function should be closely monitored in patients on Givlaari.
Givlaari shouldn’t be given alongside therapies that are metabolized, or processed, by the liver enzymes CYP1A2 or CYP2D6 if small changes in the levels of those therapies could lead to serious or life-threatening toxicities. This is because drug interaction studies have shown Givlaari can impact the activity of these liver enzymes. In cases where the simultaneous use of Givlaari and these medicines is unavoidable, it’s recommended that patients are given a lower dosage of those therapies, in accordance with the instructions on their label.
How is Givlaari administered?
Givlaari is administered by subcutaneous (under-the-skin) injection once a month at a recommended dose of 2.5 milligrams per kilogram of body weight (mg/kg).
The injection should be administered by a healthcare professional in a setting where medical support is available if an adverse reaction to the medication occurs. The injection may be given in the abdomen, upper arms, or thighs. The injection site should be rotated so the injection isn’t given in the same place two months in a row and should never be administered where the skin is scarred, red, swollen, or inflamed.
If a scheduled dose of Givlaari is missed, that dose should be given as soon as possible, with the next dose being given one month after the missed dose is administered.
Givlaari in clinical trials
Givlaari’s approval for treating AHP was supported by data from a Phase 3 trial called ENVISION (NCT03338816).
ENVISION trial
ENVISION enrolled 94 people with AHP, including 89 with AIP, two with VP, one with HCP, and two with an unknown disease type.
Participants ranged in age from 19 to 65; most were female (89%) and white (78%). In the six months before entering the trial, all the participants had experienced at least two serious porphyria attacks requiring medical treatment.
For the first six months of the trial, participants were randomly assigned to receive subcutaneous injections of Givlaari (2.5 mg/kg) or a placebo once a month.
Results showed patients on Givlaari had about 70% fewer porphyria attacks than those on a placebo. On average, patients on a placebo had more than six attacks over the six-month study, while those on Givlaari had less than two. Consistently, patients on Givlaari required significantly fewer days of treatment with hemin, a therapy given to control acute porphyria attacks. Givlaari also markedly lowered the levels of ALA and PBG in the urine of treated patients.
After the initial placebo-controlled portion of ENVISION, all but one participant continued into the study’s open-label extension phase, wherein all were treated with Givlaari and monitored for long-term outcomes.
Two-year data showed that long-term treatment led to a consistent reduction in porphyria attacks. In the first three months of treatment, about 60% of patients remained attack-free. By comparison, in months 21 to 24, the latest three-month period in that analysis, more than 80% of patients who’d been consistently on Givlaari were attack-free. Similar rates were seen in months 33-36.
The most common treatment-related side effects reported with Givlaari were injection site reactions, nausea, and fatigue. One patient discontinued treatment due to side effects in the first six months of ENVISION, while three others discontinued treatment for the same reason after the first six months.
Ongoing trials
Alnylam is currently sponsoring a study called ELEVATE (NCT04883905) that’s tracking real-world outcomes for people with AHP who are treated according to standard clinical practice. The study aims to collect more information about how AHP impacts patients’ lives and to further characterize the effectiveness and safety of Givlaari and other approved treatments.
The study intends to recruit about 150 people with AHP, ages 12 and older. Recruitment is ongoing in the U.S., France, Germany, Italy, and the U.K.
Common side effects of Givlaari
The most common side effects of Givlaari reported in clinical trials of porphyria include:
- nausea
- injection site reactions, including redness, pain, itching, discoloration, or swelling
Allergic reactions
Serious allergic reactions, referred to as anaphylaxis, have occurred with Givlaari. Medical support should always be available when it is administered in case an allergic reaction occurs.
If an allergic reaction happens, the therapy should immediately be stopped and appropriate supportive treatment started at once.
Liver and kidney toxicity
Givlaari may cause damage to the liver and/or kidneys. For this reason, markers of liver and kidney health should be routinely evaluated in patients on the therapy and treatment should be paused or discontinued if major issues occur.
If the therapy is paused, it should be initially restarted at a lower dose of 1.25 mg/kg per month. It may then be increased to the normal recommended therapeutic dose of 2.5 mg/kg per month if problems don’t reoccur.
Elevated homocysteine
Patients treated with Givlaari may see an increase in levels of homocysteine in the blood. High levels of this molecule have been linked to an increased risk of heart and circulatory problems in the general population, though the clinical relevance of increased homocysteine in AHP patients on Givlaari isn’t known.
It’s recommended that homocysteine levels be measured before and during treatment with Givlaari
Since taking vitamin B6 supplements can help reduce homocysteine levels, these supplements may be recommended for patients who have increased homocysteine levels while on Givlaari.
Use in pregnancy and breastfeeding
There are no available data on using Givlaari in people who are pregnant or breastfeeding. In some animal experiments, using Givlaari during pregnancy has resulted in toxic effects for both the mother and the developing offspring.
At the same time, AHP attacks in pregnancy are common and can cause substantial complications for the mother and fetus.
The decision to use Givlaari during pregnancy or while breastfeeding should be made on a case-by-case basis by patients and their healthcare providers, taking into account the potential risks associated with taking or foregoing treatment.
Porphyria News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare providers with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.