Sas, David J.

Abstract Background and Aims Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic oxalate overproduction. Excess oxalate is excreted by the kidneys, leading to recurrent kidney stones, nephrocalcinosis, and progressive kidney disease. Patients with PH1 generally experience a slow decline in kidney function over time that can be punctuated by abrupt worsening precipitated by infection, obstructing stones, or dehydration. Approximately half of patients with PH1 progress to kidney failure by early adulthood, and nearly all by 60 years of age. Lumasiran is an RNAi therapeutic indicated for the treatment of PH1 in all age groups. In clinical trials, treatment with lumasiran resulted in substantial reductions in urinary and plasma oxalate in pediatric and adult patients, with an acceptable safety profile. This analysis evaluates the change in kidney function of patients with PH1 with an eGFR of ≥30 mL/min/1.73m2 enrolled in clinical trials of lumasiran. Method We analyzed kidney function from 75 patients with PH1, age ≥12 months old, eGFR ≥30 mL/min/1.73m2, enrolled in 3 clinical trials of lumasiran (Phase 2 open-label extension, and Phase 3 ILLUMINATE-A and ILLUMINATE-B). In these trials, eGFR was calculated with the Modification of Diet in Renal Disease (MDRD) Study equation in adults or the bedside Schwartz equation in children. The effect of lumasiran on eGFR was assessed by baseline eGFR subgroup: ≥90, <90, 60 to <90, 45 to <60, and 30 to <45 mL/min/1.73m2. Results Of 75 patients available for analysis, 46 were treated with lumasiran from the start of the study through the Month 12 visit. eGFR remained stable in all eGFR subgroups. Patients with eGFR ≥90 mL/min/1.73m2 at baseline (N=16) demonstrated fluctuations in mean values by timepoint, with a mean change (95% CI) from baseline of -1 (-8, 6) mL/min/1.73m2 at Month 12. In patients with eGFR <90 mL/min/1.73m2 (N=30), no change in mean eGFR from baseline was observed at Month 12; the mean change (95% CI) was 0 (-3, 3). When evaluating subgroups with impaired kidney function, variations in the mean change were observed at Month 12 due to small sample sizes. For patients with eGFR 60 to <90 mL/min/1.73m2 (N=22), the mean change (95% CI) was -2 (-5, 1). For patients with eGFR 45 to <60 mL/min/1.73m2 (N=5), the mean change (95% CI) was 3 (-8, 14). For patients with eGFR 30 to <45 mL/min/1.73m2 (N=3), the mean change (95% CI) was 9 (7, 11). Conclusion Patients with PH1 had stable kidney function over time with lumasiran treatment, regardless of kidney function at baseline. Given the progressive kidney function decline that is characteristic of PH1, the eGFR stability observed during 12 months of treatment with lumasiran is encouraging. Kidney function will continue to be monitored for the duration of the lumasiran clinical trials.

Abstract Background: Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) is a rare condition of phosphate wasting due to variants in the SLC34A3 gene, encoding the sodium-phosphate cotransporter 2c (NaPi2c) at the brush border of proximal renal tubular cells (1). While labs are characterized by low serum phosphorus, high 1,25 dihydroxyvitamin D and inappropriately high levels of urine phosphate and calcium, the presenting symptoms can vary widely. Little remains known about specific phenotype-genotype correlations, especially in children. Clinical Cases: We report three new cases of HHRH in an unrelated 12 year-old male, 9 year-old female and 14 year-old male. All three patients were found to have low serum phosphorus for age (2.9-3.2 mg/dL), normocalcemia (9.4-9.9 mg/dL), low to low-normal parathyroid hormone (7-15 pg/mL), elevated 1,25 dihydroxyvitamin D (91-178 pg/mL), and hypercalciuria (4.5-7.6 mg/kg/day). Urine phosphorus was inappropriately elevated given the degree of their hypophosphatemia. Despite having similar lab findings, however, their clinical presentations were varied. The 12 year-old male presented with lower extremity pain, which was previously ascribed to patellofemoral pain syndrome. He had no history of renal symptoms, though a renal ultrasound later identified stones bilaterally. Conversely, the 9 year-old female and 14 year-old male presented with recurrent urinary stones and no bone symptoms. Genetic analyses identified 4 novel SLC34A3 gene mutations. Of interest, the 12 year-old male and 9 year-old female each shared a variant (c.575C-T (p.Ser192Leu)) despite having disparate symptoms. All three patients were treated with phosphorus supplementation and were advised to discontinue Vitamin D, if this had previously been prescribed. Conclusion: These three cases highlight the variability of presenting signs and symptoms among individuals with HHRH. Obtaining an accurate diagnosis is critical, as the addition of Vitamin D can seriously worsen symptoms in HHRH though it is a commonly used treatment for other disorders of phosphate wasting and bone demineralization. To aid in clinical decision making, we present a stepwise approach to the diagnosis of hypophosphatemic diseases. References: (1) Lorenz-Depiereux, B., Benet-Pages, A., Eckstein, G., Tenenbaum-Rakover, Y., Wagenstaller, J., Tiosano, D., Gershoni-Baruch, R., Albers, N., Lichtner, P., Schnabel, D., Hochberg, Z., Strom, T. Hereditary Hypophosphatemic Rickets with Hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am. J. Hum. Genetic. 2006;78:193-201.

Abstract Background Primary hyperoxaluria (PH) type 3 (PH3) is caused by mutations in the hydroxy-oxo-glutarate aldolase 1 gene. PH3 patients often present with recurrent urinary stone disease in the first decade of life, but prior reports suggested PH3 may have a milder phenotype in adults. This study characterized clinical manifestations of PH3 across the decades of life in comparison with PH1 and PH2. Methods Clinical information was obtained from the Rare Kidney Stone Consortium PH Registry (PH1, n = 384; PH2, n = 51; PH3, n = 62). Results PH3 patients presented with symptoms at a median of 2.7 years old compared with PH1 (4.9 years) and PH2 (5.7 years) (P = 0.14). Nephrocalcinosis was present at diagnosis in 4 (7%) PH3 patients, while 55 (89%) had stones. Median urine oxalate excretion was lowest in PH3 patients compared with PH1 and PH2 (1.1 versus 1.6 and 1.5 mmol/day/1.73 m2, respectively, P < 0.001) while urine calcium was highest in PH3 (112 versus 51 and 98 mg/day/1.73 m2 in PH1 and PH2, respectively, P < 0.001). Stone events per decade of life were similar across the age span and the three PH types. At 40 years of age, 97% of PH3 patients had not progressed to end-stage kidney disease compared with 36% PH1 and 66% PH2 patients. Conclusions Patients with all forms of PH experience lifelong stone events, often beginning in childhood. Kidney failure is common in PH1 but rare in PH3. Longer-term follow-up of larger cohorts will be important for a more complete understanding of the PH3 phenotype.

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.