Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1: Results from a Phase III Clinical Trial

Abstract

Introduction: Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx).

Methods: ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged ≥6 years with PH1 and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m². A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month 36.

Results: Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion ≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions.

Conclusion: In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract.

Keywords: RNA interference; lumasiran; oxalate; primary hyperoxaluria type 1; rare disease; renal.

Graphical abstract

Figure 1

Patient disposition. ^aParticipation stopped by the parent/guardian owing to the patient’s inability to comply with protocol-specific testing; the patient did not complete the 6-month DBP. ^bDiscontinued treatment for adverse events (unrelated to treatment) of fatigue and disturbance in attention; completed 6-month DBP but did not enter the EP. DBP, double-blind period; EP, extension period; M, month.

Figure 2

Mean (SEM) percent change in 24-hour UOx over time. ^aBaseline is the median of all valid 24-hour urine assessments collected prior to the first dose of the study drug (lumasiran or placebo). ^bAt month 36, the lumasiran/lumasiran group had received lumasiran treatment for 36 months, and the placebo/lumasiran group had received lumasiran treatment for 30 months. BL, baseline; BSA, body surface area; M, month; UOx, urinary oxalate.

Figure 3

Mean (SEM) 24-hour UOx over time. Dotted line represents the ULN of 0.514 mmol/24h per 1.73 m² for 24-hour UOx excretion. ^aBaseline is the median of all valid 24-hour urine assessments collected prior to the first dose of the study drug (lumasiran or placebo). ^bAt month 36, the lumasiran/lumasiran group had received lumasiran treatment for 36 months, and the placebo/lumasiran group had received lumasiran treatment for 30 months. BL, baseline; BSA, body surface area; M, month; UOx, urinary oxalate.

Figure 4

Mean SEM POx concentration over time. The dark gray horizontal dotted line represents the ULN of 12.11 μmol/l for POx. The light-gray horizontal dotted line represents the LLOQ of the POx assay at 5.55 μmol/l; values below the LLOQ were assigned a value of 5.55 μmol/l. ^aBaseline is the mean of all measurements prior to the first dose of the study drug (lumasiran or placebo). ^bAt month 36, the lumasiran/lumasiran group had received lumasiran treatment for 36 months, and the placebo/lumasiran group had received lumasiran treatment for 30 months. LLOQ, lower limit of quantitation; POx, plasma oxalate; ULN, upper limit of normal.

Figure 5

Mean (SEM) plasma glycolate concentration over time. ^aBaseline for plasma glycolate measurements during the extension period corresponded to the median of plasma glycolate measurements collected prior to the first dose of the study drug (lumasiran or placebo). ^bAt month 36, the lumasiran/lumasiran group had received lumasiran treatment for 36 months, and the placebo/lumasiran group had received lumasiran treatment for 30 months. BL, baseline, M, month.

Figure 6

Mean (SEM) eGFR over time. ^aBaseline is the last assessment prior to the first dose of the study drug (lumasiran or placebo). ^bAt month 36, the lumasiran/lumasiran group had received lumasiran treatment for 36 months, and the placebo/lumasiran group had received lumasiran treatment for 30 months. BL, baseline; eGFR, estimated glomerular filtration rate; M, month.

Figure 7

Kidney stone event rates^a in the (a) lumasiran/lumasiran group and (b) placebo/lumasiran group. ^aKidney stone event is defined as an event that includes at least 1 of the following: a visit to a health care provider because of a kidney stone, medication for renal colic, stone passage, or macroscopic hematuria due to a kidney stone. ^bPatient-reported history of kidney stone events. D, day; M, month; PY, person-year.

Figure 8

Change from baseline in medullary nephrocalcinosis in the (a) lumasiran/lumasiran group and (b) placebo/lumasiran group. ^aIncludes 2 patients whose status was “indeterminate.”