Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria

Abstract

BACKGROUNDUp-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODSIn this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTSA total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONSAmong patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events.

Cost savings with hemin versus givosiran for the treatment of patients with acute intermittent porphyria (AIP)

“…Data from 2017 was chosen to avoid the exclusion of patients that enrolled in the Phase III clinical trial for givosiran, which began recruiting in November 2017 17,25 . Treatment patterns for hemin are not expected to have changed between 2017 and 2019, so the year of data acquisition is not expected to impact the conclusions of this research.…”

“…Givosiran prophylaxis dosing was based on the label, 2.5 mg/kg body weight once monthly by subcutaneous injection. An average of 1.2 vials per dose was based on the distribution of patient weight from data reported from the Phase III trial 17,25 .…”

“…Givosiran is administered as an in-office monthly subcutaneous injection. According to FDA-approved labelling, givosiran, when given to patients who had been experiencing frequent recurrent acute attacks, reduced further attacks by 70% compared to monthly subcutaneous injections of placebo, based upon results of recent clinical trials 16,17 .…”

Ckj consolidation among Q1 Urology and Nephrology journals

“…Topics addressed include genetic causes of focal segmental glomerulosclerosis in adults [ 20 ], Bartter and Gitelman syndromes [ 18 ] and kidney diseases in porphyria [ 27 ]. A successful clinical trial of the RNAi therapeutic givosiran for acute intermittent porphyria was recently reported [ 46 ]. Kidney disease was one of the main themes in the trial, as givosiran may be associated with kidney disease deterioration despite improving porphyria symptoms.…”

Tyrosine-Modification of Polypropylenimine (PPI) and Polyethylenimine (PEI) Strongly Improves Efficacy of siRNA-Mediated Gene Knockdown

“…The second siRNA therapeutic, Givosiran (GIVLAARI ® ), was approved one year later for targeting aminolevulinic acid synthase 1 (ALAS1) in the treatment of acute hepatic porphyrias (AHPs). Givosiran is an siRNA bearing extensive chemical modifications and it is coupled to GalNAc for the targeted delivery to hepatocytes [16,17]. Despite these impressive advances, most siRNA delivery systems are unable to efficiently deliver siRNAs into target sites other than the liver, thus showing serious limitations, for example, in anti-tumor therapies [18,19].…”