Acute hepatic porphyria, or AHP, is a group of rare genetic conditions that affect how the body makes a natural substance called heme. Heme is produced in the liver and is essential for many important functions, including carrying oxygen in the blood. In people with AHP, a key enzyme in the heme-making process called delta-aminolevulinic acid synthase (ALAS1) leads to harmful substances called aminolevulinic acid (ALA) and porphobilinogen (PBG) to build up in the liver and throughout your body.
In people with AHP, both ALA and PBG are linked to sudden, severe "attacks" of illness and other symptoms of the disease. During an attack, the most common symptom is intense stomach pain, but symptoms vary from person to person and may change over time.
Givlaari (givosiran) was approved by the FDA in 2019 for adults with AHP. The medicine works by preventing the overproduction of ALAS1, thereby lowering the risk of attacks and reducing the long-term problems that come with this disease.
How Does Givlaari Work?
Givlaari is a new kind of medicine called RNA interference (RNAi) therapy. RNAi is a natural process our cells use when making proteins. Givlaari uses this process, which lowers the amount of an enzyme called ALAS1. As a result, the amount of the harmful substances ALA and PBG is lowered. Givlaari may help prevent AHP attacks and reduce the need for emergency treatments.
How Do I Use Givlaari?
Givlaari is given once monthly as a shot under your skin. The dose of Givlaari is based on your weight. The Givlaari shot must be given by a health care professional.
How Was Givlaari Studied?
The ENVISION study was a clinical trial designed to see if Givlaari is safe and effective for people with AHP. To take part in the trial, people needed to be at least 12 years old and have a confirmed diagnosis of AHP. People were also required to have had at least two AHP attacks in the six months before starting the trial that led to hospitalization, an urgent health care visit, or the intravenous use of hemin at home. They also had to have high levels of ALA or PBG in their urine (pee). The use of preventive hemin was not allowed during the study.
People in the trial were randomly assigned to receive either Givlaari or a placebo shot (containing no medicine) once monthly under the skin. Neither the people in the trial nor the researchers knew which treatment was being given during the first six months of the trial. After six months, everyone had the option to continue in the trial and receive Givlaari for up to three years; this was referred to as the open-label extension (OLE) phase of the trial. People who had been receiving a placebo were switched over to Givlaari at that time.
The main goal of the trial was to find out whether Givlaari could lower the number of AHP attacks in people with acute intermittent porphyria (AIP), which is the most common type of AHP. An attack was counted if it led to hospitalization, an urgent health care visit, or treatment with hemin at home. The study also measured the following in people with AIP: changes in ALA and PBG levels in the urine, how often hemin was required, and changes in pain scores.
The ENVISION trial was done between 2017 and 2020 and enrolled 94 people with AHP. A total of 48 people received Givlaari and 46 people received a placebo. Of the 94 people who were enrolled, 89 of them (95%) had acute intermittent porphyria (AIP). A few of the people in the trial had other subtypes of AHP, including hereditary coproporphyria (one person), variegate porphyria (two people), and acute hepatic porphyria without identified mutation (two people). Among the people with AIP, 90% were women, 79% were White, and the average age was 39 years. Other races included were Asian (16%) and "other" (6%). At the time of enrollment, people with AIP had a median of eight attacks per year, and more than half (52%) reported chronic symptoms between attacks. Heme prophylaxis was previously used by 42% of enrolled people with AIP.
A total of 93 of 94 people from the ENVISION trial entered the OLE phase. In total, 89 patients were treated with Givlaari for at least six months, 87 for at least 12 months, 85 for at least 18 months, 84 for at least 24 months, and 41 for at least 30 months.
What Are the Main Benefits?
Results from the ENVISION trial show that people with AIP, the most common type of AHP, treated with Givlaari would have about three attacks per year that required hospitalization, an urgent health care visit, or treatment with hemin at home, compared with about 12 attacks in those receiving a placebo. This means that people who receive Givlaari instead of a placebo would have a 74% reduction in the average number of attacks each year. Also, half of the people in the Givlaari group had no attacks during the six-month treatment period, compared with only 17% in the placebo group.
In the 36-month OLE phase of the ENVISION trial, the benefits of Givlaari were sustained. By the end of the study, 86% to 92% of people were attack-free.
Your results may differ from what was seen in clinical studies.
Are There Other Potential Benefits Based on Studies?
The ENVISION trial also showed that people receiving Givlaari had reductions in urinary levels of ALA and PBG beginning within the first month of treatment. After six months of treatment with Givlaari, urinary ALA levels were reduced by 85% and PBG levels by 91%. A reduction in ALA and PBG reduces the risk of severe "attacks" of illness and other symptoms of the disease.
Hemin use was also substantially reduced with Givlaari. People treated with Givlaari needed hemin for about seven days per year, compared with nearly 30 days in the placebo group. This means that people who received Givlaari instead of a placebo would have a 77% reduction in the number of days they used hemin each year. Also, more than half of the people treated with Givlaari (54%) did not require hemin at all during the six-month treatment period, compared with less than a quarter (23%) in the placebo group. People in the Givlaari group also had significant reductions in pain, compared to those in the placebo group.
Your results may differ from what was seen in clinical studies.
How Strong Is the Evidence?
The ENVISION trial was the largest ever study of its kind done on people with AHP. Based on the results of this trial, Givlaari is safe and effective for adults with AHP, particularly those with the AIP subtype. Clinical treatment guidelines also support the use of Givlaari in adults with AHP who have four or more attacks per year.
What Do We Know About Long-Term Safety?
In the OLE phase of the ENVISION trial, people with AHP took Givlaari for up to three years. During this time, 97% of people reported some side effects, though most were mild to moderate. The most common were injection site reactions (39%), nausea (37%), tiredness (27%), headaches (21%), and infections such as colds or urinary tract infections (20%-27%). Serious side effects were reported in 39% of people. Four people stopped taking part in the study due to treatment-related side effects.
What Can I Do to Manage Side Effects?
Your health care provider will monitor you closely while you are receiving Givlaari. Before you start treatment, your health care provider will perform tests to see how well your liver is working. These tests will also be done monthly for the first six months. After that, the tests will be done when your health care provider feels they are needed. Tell your health care provider right away if you have stomach pain, vomiting, dark urine, or yellowing skin or eyes. If the tests show that your liver enzymes are high, your treatment with Givlaari may be paused. Once your liver tests return to normal, your health care provider may restart Givlaari at a lower dose. Your health care provider will also check how well your kidneys are working throughout your therapy with Givlaari. Keep all appointments to have your blood checked.
Before you start treatment with Givlaari, your health care provider will also check the levels of homocysteine in your blood. They will also check the levels of homocysteine in your blood at times during your therapy with Givlaari. Keep all appointments to have your blood checked. If the levels of homocysteine in your blood are high, your health care provider may also check the levels of vitamins. Your health care provider may have you start taking vitamins.
After you receive each shot of Givlaari, your health care provider will monitor you for signs and symptoms of an allergic reaction. Tell your health care provider if you have trouble breathing, feel itchy, or start to see a rash on your skin after you get your Givlaari shot. If you have a severe allergic reaction after receiving Givlaari, you will need to stop treatment with the medicine. You may also need to take other medicines to control the symptoms.