ESPN 53rd Annual Meeting

ESPN 2021


 
Compassionate use treatment with RNAi medication (Nedosiran) in two patients with primary hyperoxaluria type 1 and maintenance hemodialysis
CRISTINA MARTIN-HIGUERAS 1 GESA SCHALK 2 BERND HOPPE 3

1- GERMAN HYPEROXALURIA CENTER
2- KINDERNIERENZENTRUM BONN
3- DICERNA PHARMACEUTICALS, USA
 
Introduction:

The primary hyperoxalurias (PH) are three ultra-rare, autosomal recessive genetic disorders characterized by oxalate overproduction in the liver. Hyperoxaluria induces recurrent kidney stones, nephrocalcinosis, progressive renal impairment, and systemic oxalosis, especially in PH1. Nedosiran is an investigational RNAi therapeutic administered monthly by subcutaneous injection. It reduces hepatic LDHA protein thereby inhibiting the final step responsible of oxalate production in all PH.

Material and methods:

We report on two PH1 patients, a 40 year old woman (a) on hemodialysis (HD) 6 x 3 hours weekly, and a 6.5 year old boy (b) receiving 5 x 5 hours HD, both homozygous for AGXT c.508G>A and treated with pyridoxine. In patient (a), global longitudinal strain (GLS), an index of left ventricular contractibility, was impaired (-13 %; normal  ≤ -18%). Patient (b), had massive oxalate osteopathy, myocardial hypertrophy and cardiac insufficiency (GLS of – 9.98). They received Nedosiran as compassionate use medication for now 6 months. Monthly plasma oxalate (Pox in µmol/l, normal < 7.4) was measured, Speckle Echo and/or 3 Tesla MRI (left knee) were repeated.

Results:

Speckle Echo improved in both (a: GLS - 23; b: GLS -14.6, but month 6 result pending). Bone MRI ameliorated in patient (b) showing a nidus of normal trabecular structure.

 

Patient

Pox

Pre RNAi

Pox

Month 1

Pox

Month 2

Pox

Month 3

Pox

Month 4

Pox

Month 5

Pox

Month 6

(a)

64.2-71.6

40.9

60.2

52.8

37.67

23.2

32.4

(b)

73.1 – 101

96.5

40.6

56.9

48.08

69.7

51.3

Conclusions:

Clinics improved and Pox declined over the six months of treatment. Pox was influenced in (b) by severe oxalate osteopathy and therefore possibly dissolving oxalate and in (a) when dialysis regimen was reduced to 4 x 3 hours at month 6. We cautiously conclude, that liver transplantation may be avoidable in PH1 patients treated with Nedosiran.