Abstract
Background and Aims
PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and ...multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1.
Method
Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6).
Results
Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions.
Conclusion
Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.
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).
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.
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.
In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.
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ILLUMINATE-A est un essai de phase 3 du lumasiran, ARNi thérapeutique réduisant la production hépatique d’oxalate.
L’essai a inclus 39 patients ≥ 6 ans atteints d’HP1 avec un DFGe≥30mL/min/1,73m2.
...L’essai comprenait une période de 6 mois en double aveugle versus placebo puis une période d’extension.
À 6 mois, la différence moyenne de traitement par la méthode des moindres carrés de l’excrétion urinaire d’oxalate sur 24h (UOx) pour le lumasiran vs placebo était de −53,5 % (p=1,7×10−14) et 84 % des patients sous lumasiran avaient atteint la normalisation ou quasi-normalisation de l’UOx (vs 0 % patients placebo). Dans l’extension, les patients initialement sous placebo ont été traités par lumasiran démontrant une évolution et ampleur similaires de la réduction d’UOx avec un pourcentage moyen de réduction de 57,3 % et une normalisation ou quasi-normalisation de l’UOx chez 77 % des patients à 6 mois. Chez les patients initialement randomisés sous lumasiran, la réduction de l’UOx a été maintenue à 12 mois.
Le taux d’événements de calculs rénaux (ECR) dans le groupe lumasiran a diminué, passant de 0,87 (0,70 ; 1,08) pendant les 12 mois pré-consentement à 0,30 (0,17 ; 0,51) après 6 mois en double aveugle puis 0,23 (0,13 ; 0,43) après 6 mois d’extension. Pour les patients initialement sous placebo, le taux d’ECR était de 0,15 (0,07 ; 0,31) pendant les 12 mois pré-consentement, de 0,18 (0,07 ; 0,48) pendant les 6 mois en double aveugle et de 0,05 (0,01 ; 0,32) pendant les 6 premiers mois sous lumasiran.
Comme pour la période en double aveugle, les événements indésirables les plus fréquents liés au lumasiran dans l’extension étaient des réactions légères et transitoires au site d’injection.
La réduction de l’UOx observée dans la période en double aveugle a été reproduite par des patients initialement sous placebo confirmant la robustesse du résultat. La baisse des taux d’ECR après 6 à 12 mois sous lumasiran est encourageante.
Wilms' tumor gene 1 (WT1) was recently found to play a role in solid and hematologic malignancies and serves as a marker of prognosis and minimal residual disease in acute leukemia. WT1 was also ...found to be involved in tumor angiogenesis. There are no data concerning the involvement of WT1 in angiogenesis in lymphoproliferative tumors. The aim of this study was to explore the involvement of WT1 in Hodgkin lymphoma.
The expression of WT1, neuropilin 1, and VEGF was tested by immunohistochemistry in lymph nodes biopsies of 20 Hodgkin patients and 7 reactive lymph nodes.
WT1 was expressed in endothelial cells, in 95% of the malignant lymph nodes. The average of WT1 expression scale was higher in the malignant lymph nodes than in reactive lymph nodes. We found a positive correlation between WT1 expression scale and the angiogenesis scale (0.53) that was statistically significant (P<0.05). As the number of vessels increases, the expression of WT1 is more intense.
We found, for the first time, that WT1 is expressed in endothelial cells in Hodgkin lymphoma. The clinical implications of these findings should be tested in a future study.
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