No 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.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% is efficacious and well-tolerated in people with hemophilia A (PwHA). As some may benefit from higher FVIII troughs, the PROPEL trial compared safety and efficacy of 2 target FVIII trough levels in PwHA with severe disease, aged 12-65 years, annualized bleeding rate ≥2, and previous FVIII treatment. They were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1-3% (reference arm) or 8-12% (elevated arm). Treatment-adjustment period was in the first 6 months. Primary endpoint: proportion of PwHA (full analysis set [FAS]) with zero total bleeds (all bleeds) during second 6 months. Overall, 115 male PwHA were randomized (N=115, FAS; N=95, per-protocol analysis set [PPAS]). In the 1-3% and 8-12% arms, respectively, point estimates (95% CI) of proportions of PwHA with zero total bleeds were 42% (29-55%) and 62% (49-75%) in FAS (P=0.055) and 40% (27-55%) and 67% (52-81%) in PPAS (P=0.015). Dosing frequency and consumption varied widely in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA. Serious AEs occurred in 7/115 (6%) PwHA, including 1 treatment-related serious AE in 8-12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms, with no new safety signal in the 8-12% arm vs previous studies. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and also emphasize the importance of personalized treatment. Trial registration: www.ClinicalTrials.gov (#NCT02585960).

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in hTTP patients is largely lacking. This study reports prospective data of 87 patients from the Hereditary TTP Registry (ClinicalTrials.gov NCT01257269) for survival, frequency and severity of acute episodes from enrollment until December 2019. The 87 patients, followed for median 4.2 years (range 0.01-15), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and of 18 years (range 0.0-70 for both), respectively. Forty-three patients received regular plasma prophylaxis, while 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes of which 91 (69%) occurred in patients on regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95%CI 0.29-0.44) with and of 0.41 (95%CI 0.30-0.56) without regular plasma treatment. More than one third of acute episodes (n=51) were documented in children &lt;10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients &gt;40 years of age (1.18 [95% CI 0.88-1.55] vs. 0.14 [95% CI 0.08-0.23]). Prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, caregivers, patients and their guardians are reluctant to start regular plasma infusions, from which particularly children would benefit.

No abstract