Givosiran Reduces Porphyria Attacks Among Patients With Acute Intermittent Porphyria

Compared with placebo, treatment with the RNA interference therapy givosiran lowered the rate of porphyria attacks in patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria, according to results from the ENVISION trial.

According to the authors, led by Manisha Balwani, MD, of the Icahn School of Medicine in New York City, who published the study in the New England Journal of Medicine, givosiran represents a promising treatment option for patients who experience ongoing attacks, considering these individuals typically carry a heavy disease burden and treatment options to control attacks are limited. However, the improvements in efficacy were accompanied by a higher frequency of hepatic and renal adverse events (AEs).

The double-blind, placebo-controlled ENVISION trial enrolled 94 patients with acute hepatic porphyria (mean age = 38.8±11.4 years) – 89 of whom had acute intermittent porphyria – from 36 sites in 18 countries. Eligible patients had an elevated urinary delta-aminolevulinic acid (ALA) or porphobilinogen ≥4 times the upper limit of normal and had experienced at least two porphyria attacks that resulted in either hospitalization, urgent health care, or intravenous administration of hemin at home within 6 months of enrollment. The median historical annualized attack rate prior to trial enrollment was 8.

All patients discontinued prophylactic hemin during the trial.

Patients were randomized to receive 6 months of either:

  • monthly givosiran 2.5 mg/kg (n=48)
  • placebo (n=46)

The study’s primary endpoint was changes in the annualized rate of composite porphyria attacks throughout the 6-month treatment period. Secondary endpoints included ALA and porphobilinogen levels, hemin use, and scores for pain, fatigue, and nausea.

Coexisting illnesses or laboratory abnormalities among enrolled patients included increased aminotransferase levels (37%), iron overload (33%), liver disease (28%), hypertension (27%), and renal impairment (25%). Approximately 34% of patients in the study presented with an estimated glomerular filtration rate of <60 mL per minute per 1.73 m2 of body surface area at baseline. Roughly 40% of patients with acute hepatic and intermittent porphyria had previously received hemin prophylaxis.

Over the 6-month study period, the mean annualized rate of attacks in patients with acute intermittent porphyria who were treated with givosiran was 3.2, compared with 12.5 in the placebo-treated patients. This represented a 74% reduction (p<0.001). The results were similar among the entire study population of those with acute hepatic porphyria, with a 73% reduction, the authors reported.

Furthermore, one-half of patients treated with givosiran had no porphyria attacks during the treatment period, compared with 17% of patients treated with placebo.

“Such between-group differences were observed within the first month of treatment and were sustained throughout the intervention period, with 50% of patients having no porphyria attacks while they were receiving givosiran,” the authors wrote.

Treatment with givosiran also resulted in sustained reductions in levels of ALA and porphobilinogen, which dropped by 86% and 91%, respectively, from baseline to 6 months (p<0.001). Patients who received givosiran also had a lower mean annualized number of days of hemin use, compared with placebo, representing a 77% reduction (6.8 vs. 29.7, respectively; p<0.001). Patients with acute intermittent porphyria who received givosiran also reported better daily scores for pain than those who received placebo.

AEs were more frequent among givosiran-treated patients, compared with the placebo group (90% vs. 80%, respectively), as were serious AEs (21% vs. 9%). AEs that were reported more frequently in the givosiran group included injection-site reactions, nausea, chronic kidney disease, rash, increased alanine aminotransferase levels, and fatigue. No patients died during the study period.

While the difference in serious AEs was not driven by any particular event, the researchers noted, worsening of chronic kidney disease was more commonly reported in the givosiran-treated group. They also observed that hepatic AEs were more frequent in the givosiran group than in the placebo group (13% vs. 2%).

The study’s findings are limited by the relatively short duration of treatment; however, Dr. Balwani and coauthors pointed out, “[These] findings suggest that patients with all subtypes of acute hepatic porphyria would probably derive similar clinical benefits from givosiran, since the subtypes have common pathophysiological features and treatment.” Investigators are evaluating the long-term efficacy and safety of givosiran in the open-label extension period of the ENVISION trial, which is enrolling patients with all subtypes of acute hepatic porphyria.

Study authors report relationships with Alnylam Pharmaceuticals, which sponsored the trial.


Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382:2289-2301.