Givlaari Effective at Diminishing AHP Symptom Burden: Study
The therapy helped reduce the use of painkillers both during and between attacks
Givlaari (givosiran) can effectively control symptoms of acute hepatic porphyria (AHP), reducing disease burden, even in patients with low attack rates.
That’s according to a post hoc analysis of the Phase 3 ENVISION trial (NCT03338816). As noted by researchers, these results support the long-term benefits of Givlaari as demonstrated in that trial.
The findings were reported in the study, “Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study,” published in Orphanet Journal of Rare Diseases.
AHP is a group of rare disorders marked by potentially life-threatening acute attacks. This is caused by the lack of specific enzymes involved in producing a molecule called heme, which is needed for oxygen transport in living cells. The condition results in toxic heme intermediates accumulating in several tissues and internal organs.
Givlaari is an RNA-based therapy designed to block the activity of the aminolevulinic acid synthase 1 (ALAS1) enzyme, preventing the accumulation of these heme intermediate compounds. RNA is a molecule derived from DNA used as a template for protein production in cells.
The treatment’s effectiveness at reducing the rates of porphyria attacks was evaluated in a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial and in its 30-month, open-label extension study.
In the main trial, 94 patients were randomized to receive either Givlaari (2.5 mg/kg) or a placebo once a month for six months. The treatment was given by subcutaneous (under-the-skin) injection.
All had active disease with at least two porphyria attacks occurring within the last six months. Upon completing the main trial, all but one patient entered the extension study and continued or started Givlaari.
Results have shown Givlaari reduced by 74% the mean annualized rate of composite porphyria attacks (AAR) in patients with acute intermittent porphyria (AIP), the most common form of AHP, compared with a placebo.
It also significantly decreased the levels of urinary heme intermediates and the use of hemin, a therapy given to ease symptoms of recurrent porphyria attacks. Pain reduction and improvements in patients’ quality of life were also observed.
Analyzing AHP’s symptom burden
Researchers analyzed this trial in order to evaluate the disease burden associated with AHP.
The analysis included patients who had a low number of acute attacks, those who had fewer than seven attacks in the previous 12 months and were given hemin at the study’s start, along with those who had up to 12 attacks in the same period of time and did not receive hemin at the study’s start.
Evaluated parameters included the occurrence of chronic symptoms, the presence of other health conditions, the use of other treatments (including hemin), and quality of life. The 12-Item Short-Form Health Survey, version 2 (SF-12), and the EuroQol-5 Dimension-5 Level Questionnaire were used to evaluate quality of life.
The study also assessed the association from the time since diagnosis to AAR, the number of working days lost due to AHP, and the need for personal care services.
Givlaari’s effectiveness according to previous preventive treatment with hemin was also evaluated, including patient-reported pain scores during and between attacks.
At the study’s start, or baseline, more than half (52%) of patients reported chronic symptoms, such as nausea, fatigue, and pain.
Low SF-12 and EuroQol scores were also found, illustrating patients’ poor quality of life at that point of the study. The decrease in quality of life was also demonstrated by the number of missed workdays. About one month before the study’s start, patients in the placebo group were losing a mean of six workdays, while those on Givlaari were missing three.
According to the researchers, “pain is one of the key factors associated with diminished [quality of life] among patients with AHP.”
The health disorders most frequently reported by patients at baseline included nerve damage, or neuropathy (38%), and psychiatric issues (47%), such as depression, anxiety, and insomnia. This was supported by the lower SF-12 mental health score in the study compared with the population average (40.9 vs. 50.0), and suggests that “AHP has a negative impact on mental health.”
Chronic opioids or painkillers were used either daily or on most days between attacks in 29% of the patients.
Hemin complications, benefits of Givlaari
Patients also reported complications related to using hemin, including blood clots (8%), infections (18%), and catheter obstruction (24%). The study also found that participants who had not previously received preventive hemin treatment showed a high disease burden (60%).
Results also showed there was a direct relationship from the time from diagnosis to AAR in the placebo group, suggesting AHP gradually worsens in the absence of effective treatment and “further highlighting the need to treat patients early with effective therapy.”
The study showed Givlaari lowered the number and severity of attacks, days with severe pain, and opioid use compared with a placebo, regardless of previous hemin treatment.
These results showed Givlaari “is effective in patients with recurrent AHP regardless of prior hemin use, and that it reduces analgesic use and pain both during and between porphyria attacks,” the researchers wrote.
“Given that long-term use of opioids is associated with tolerance, dependence, and addiction, a reduction in use of these medications is clinically relevant,” the team wrote.
Treatment with Givlaari was also related to higher SF-12 physical health scores, showing an improved quality of life.
“The current study highlights the severe disease burden associated with AHP, even in patients with a relatively low rate of attacks, and supports the effectiveness of givosiran for the management of certain acute and chronic porphyria symptoms,” the researchers wrote.
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