Multicenter Long-Term Real World Data on Treatment With Lumasiran in Patients With Primary Hyperoxaluria Type 1

Abstract

Introduction: The RNA interference (RNAi) medication lumasiran reduces hepatic oxalate production in primary hyperoxaluria type 1 (PH1). Data outside clinical trials are scarce.

Methods: We report on retrospectively and observationally obtained data in 33 patients with PH1 (20 with preserved kidney function, 13 on dialysis) treated with lumasiran for a median of 18 months.

Results: Among those with preserved kidney function, mean urine oxalate (Uox) decreased from 1.88 (baseline) to 0.73 mmol/1.73 m² per 24h after 3 months, to 0.72 at 12 months, and to 0.65 at 18 months, but differed according to vitamin B6 (VB6) medication. The highest response was at month 4 (0.55, -70.8%). Plasma oxalate (Pox) remained stable over time. Glomerular filtration rate increased significantly by 10.5% at month 18. Nephrolithiasis continued active in 6 patients, nephrocalcinosis ameliorated or progressed in 1 patient each. At last follow-up, Uox remained above 1.5 upper limit of normal (>0.75 mmol/1.73 m² per 24h) in 6 patients. Urinary glycolate (Uglyc) and plasma glycolate (Pglyc) significantly increased in all, urine citrate decreased, and alkali medication needed adaptation. Among those on dialysis, mean Pox and Pglyc significantly decreased and increased, respectively after monthly dosing (Pox: 78-37.2, Pglyc: 216.4-337.4 μmol/l). At quarterly dosing, neither Pox nor Pglyc were significantly different from baseline levels. An acid state was buffered by an increased dialysis regimen. Systemic oxalosis remained unchanged.

Conclusion: Lumasiran treatment is safe and efficient. Dosage (interval) adjustment necessities need clarification. In dialysis, lack of Pox reduction may relate to dissolving systemic oxalate deposits. Pglyc increment may be a considerable acid load requiring careful consideration, which definitively needs further investigation.

Keywords: RNA interference; citrate; glycolate; oxalate; primary hyperoxaluria; treatment.

Graphical abstract

Figure 1

Urinary parameters in patients with preserved kidney function and treated with 3 mg/kg lumasiran monthly for the induction phase, and then quarterly: (a–e) Follow-up of urinary oxalate (Uox), glycolate (Uglyc), and citrate (Ucit), as well as percent reduction of Uox and percent increase in Uglyc, whole group and related to treatment or no treatment with vitamin B6 (VB6). Every point depicts mean (± SD) of n ≥ 3. (f) correlation of Uox/Ucit excretion.

Figure 2

Plasma parameters in patients with preserved kidney function and treated with 3 mg/kg lumasiran monthly for the induction phase, and then quarterly: Follow-up of plasma oxalate (Pox) (a) and plasma glycolate (Pglyc) (c), as well as percentage reduction of Pox (b) and percentage increase of Pglyc (d), whole group and related to treatment or no treatment with vitamin B6 (VB6). Every point depicts mean (± SD) of n ≥ 3. (e) Estimated glomerular filtration rate over time of lumasiran treatment, and according to VB6 medication; Δt depicts the eGFR change after 18 months of treatment, as compared to baseline. eGFR, estimated glomerular filtration rate.

Figure 3

Plasma parameters in patients with dialysis and treated with 3 mg/kg (or 6mg/kg according to age) lumasiran monthly for the induction phase, and then quarterly: Follow-up of plasma oxalate (Pox) (a) and plasma glycolate (Pglyc) (c), as well as percentage reduction of Pox (b) and percentage increase of Pglyc (d), whole group and related to treatment or no treatment with vitamin B6 (VB6, all of them treated with 3 mg/kg lumasiran). Every point depicts mean (± SD) of n ≥ 3. HD, hemodialysis.

Figure 4

Systemic oxalosis analysis in P21. MRI on bone (a–d) at 27 years old and eGFR 68.4 ml/min (a), at starting hemodialysis (b), and 6 months (c), and 12 months (d) after starting lumasiran treatment. Bone biopsy (e–h) stained with hematoxylin-eosin and analyzed under light microscope (e–g) and polarized light (h) revealed 50% fibrosis and a significant number or birefringent calcium-oxalate crystals at time of last MRI (d). eGFR, estimated glomerular filtration rate.

Figure 5

Systemic oxalosis analysis in P23. Bone MRI before starting (a), and after 5 months (b), 12 months (c), and 20 months (d) of lumasiran treatment.

Figure 6

Systemic oxalosis analysis in P31 (a) and P32 (b). Eye examination by fundoscopy revealed bilateral calcium oxalate deposits in both patients at diagnosis, shortly before starting lumasiran, and 6 months after starting the medication.