Gesa Schalk

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of primary hyperoxaluria. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% participants in Group A and 27.8% participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.

Introduction L’hyperoxalurie primaire de type I (HP1) est une maladie genetique rare, caracterisee par une production hepatique excessive d’oxalate, une excretion urinaire elevee d’oxalate, des calculs renaux recurrents et une nephrocalcinose, la progression vers l’insuffisance renale chronique et l’accumulation systemique d’oxalate dans tous les organes. Il n’existe aucun traitement pharmacologique approuve. Le lumasiran, un ARNi therapeutique experimental administre par voie sous-cutanee, cible la glycolate-oxydase et reduit la production hepatique d’oxalate. Description Nous presentons ici les resultats a 6 mois de l’essai ILLUMINATE-A, une etude controlee de phase 3, randomisee en double aveugle contre placebo. Methodes Les criteres d’inclusion etaient : âge ≥ 6 ans, diagnostic d’HP1 confirme par genotypage, excretion urinaire spontanee d’oxalate (UOx) ≥ 0,70 mmoL/24 h/1,73 m2, debit de filtration glomerulaire calcule ≥ 30 mL/min/1,73 m2. La randomisation a permis une attribution du lumasiran a 26 malades et d’un placebo a 13 malades. Le lumasiran a ete donne a la dose de 3 mg/kg par mois pendant trois mois puis tous les trimestres. Resultats Le traitement par lumasiran est associe a une reduction significative d’UOx sur 24 heures dans le groupe traite par rapport au placebo : −65,4 % vs 11,8 %, respectivement (difference de 53,5 % [p = 1,7 × 10−14], par la methode des moindres carres). Quatre-vingt-quatre pour cent des malades traites par lumasiran ont atteint un niveau d’UOx sur 24 heures ≤ 1,5 × limite superieure normale a M6 (contre 0 % de ceux traites par placebo, p = 8,3 × 10−7), et une reduction de 39,5 % de l’oxalemie a M6 par rapport a la valeur initiale a ete observee (p = 2,9 × 10−8). Les evenements indesirables les plus frequents lies au lumasiran etaient des reactions legeres et transitoires au site d’injection. Il n’y a pas eu d’evenements indesirables graves ou severes. Conclusion Le traitement par lumasiran est associe a une diminution significative, rapide et soutenue de l’oxalurie avec un profil de tolerance favorable.

PURPOSE Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. METHODS This single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. RESULTS All patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. CONCLUSION Lumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.

Nedosiran is an N-acetyl-D-galactosamine (GalNAc)–conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate  ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concer...

Background IgA vasculitis (IgAV) is the most common form of systemic vasculitis in childhood and frequently involves the kidney. A minority of patients with IgA vasculitis nephritis (IgAVN), especially those presenting with heavy proteinuria and/or kidney failure at onset, are at risk of chronic end-stage kidney disease. For deciding upon treatment intensity, knowledge of the short-term clinical course of IgAVN is needed to improve treatment algorithms. Methods For this retrospective multicenter study, the medical records of 66 children with biopsy-proven IgAVN were reviewed. Age, gender, medical history and therapeutic interventions were recorded. Laboratory data included serum creatinine, albumin, urinary protein excretion (UPE) and glomerular filtration rate (eGFR). Threshold values were determined for each parameter, full remission was defined as no proteinuria and eGFR > 90 ml/min/1.73m2. Results Median age at onset of IgAVN was 8.9 years. 14.1% of the children presented wit...

In vielen Studien wird der Einfluss der Ejakulatqualität auf die assistierte Reproduktion untersucht. Die Bedeutung sowohl der klass. als auch der funktionellen Sperm.parameter wird durch den mehrfachen Nachweis signifikanter Zusammenhänge verschiedener Forschungsgruppen unterstrichen. Um Zusammenhänge zu erkennen, wird in den meisten Studien allerdings dasjenige Ejakulat herangezogen, das auch für die assistierte Reproduktionstechnik Verwendung findet. Wird der Zusammenhang aber, wie es für diagnostische Zwecke erforderlich ist, auf ein zeitlich anderes Ereignis bezogen, gibt es Probleme bei der Vorhersage von Fertilisation/Schwangerschaft. In der Arbeit sollte untersucht werden, inwiefern der Faktor Zeit einen Einfluss für die Prädiktion von Fertilisation/Schwangerschaft darstellt od. ob trotz Zeitabstand Korrelationen beschrieben werden können. Sämtliche Untersuchungen bzgl. des Zusammenhangs zwischen Sperm.parametern und Ergebnissen der assist. Reproduktion wurden anhand von Bef...

Introduction L’hyperoxalurie primaire de type I (HP1) est une maladie genetique rare, caracterisee par une production hepatique excessive d’oxalate, une excretion urinaire elevee d’oxalate, des calculs renaux recurrents et une nephrocalcinose, la progression vers l’insuffisance renale chronique et l’accumulation systemique d’oxalate dans tous les organes. Il n’existe aucun traitement pharmacologique approuve. Le lumasiran, un ARNi therapeutique experimental administre par voie sous-cutanee, cible la glycolate-oxydase et reduit la production hepatique d’oxalate. Description Nous presentons ici les resultats a 6 mois de l’essai ILLUMINATE-A, une etude controlee de phase 3, randomisee en double aveugle contre placebo. Methodes Les criteres d’inclusion etaient : âge ≥ 6 ans, diagnostic d’HP1 confirme par genotypage, excretion urinaire spontanee d’oxalate (UOx) ≥ 0,70 mmoL/24 h/1,73 m2, debit de filtration glomerulaire calcule ≥ 30 mL/min/1,73 m2. La randomisation a permis une attribution du lumasiran a 26 malades et d’un placebo a 13 malades. Le lumasiran a ete donne a la dose de 3 mg/kg par mois pendant trois mois puis tous les trimestres. Resultats Le traitement par lumasiran est associe a une reduction significative d’UOx sur 24 heures dans le groupe traite par rapport au placebo : −65,4 % vs 11,8 %, respectivement (difference de 53,5 % [p = 1,7 × 10−14], par la methode des moindres carres). Quatre-vingt-quatre pour cent des malades traites par lumasiran ont atteint un niveau d’UOx sur 24 heures ≤ 1,5 × limite superieure normale a M6 (contre 0 % de ceux traites par placebo, p = 8,3 × 10−7), et une reduction de 39,5 % de l’oxalemie a M6 par rapport a la valeur initiale a ete observee (p = 2,9 × 10−8). Les evenements indesirables les plus frequents lies au lumasiran etaient des reactions legeres et transitoires au site d’injection. Il n’y a pas eu d’evenements indesirables graves ou severes. Conclusion Le traitement par lumasiran est associe a une diminution significative, rapide et soutenue de l’oxalurie avec un profil de tolerance favorable.

mance in drug-naive mild AD patients (MMSE 20-26) (Scheltens, 2010) and secondary analysis suggested a possible beneficial effect on cognition in patients with worse baseline cognitive performance (ADAS-cog) (Kamphuis, 2011).Methods: To confirm and extend these results, additional randomized controlled double-blind studies with Souvenaid were designed as part of the Souvenaid Clinical Trial Program, including: 1) S-Connect: 24-week study, aimed to assess the effects on cognitive performance (ADAS-cog) in mild-to-moderate AD patients (MMSE 14-24) using AD medication; 2) Souvenir II: 24-week study, aimed to assess the effects on memory performance (memory domain of Neuropsychological Test Battery (NTB)) in drug-naive mild AD patients (MMSE 20); 3) Souvenir II openlabel-extension (OLE): 24-week open-label study, aiming to collect longterm safety and compliance data in patients completing Souvenir II; 4) LipiDiDiet 2: 24-month study, aiming to assess the effects on memory performance (modified NTB) in 300 prodromal AD patients (Dubois, 2007); 5) Mode of Action of Souvenaid: studies exploring electroencephalography and magnetoencephalography in the Souvenir II study and magnetic resonance spectroscopy and FDG-positron emission tomography in future studies. Results: In Souvenir II, Souvenaid significantly improved memory performance (NTB memory domain) during 24 weeks in drug-naive mild AD patients (Scheltens, CtAD 2011), thereby confirming and extending the Souvenir I results, whereas the S-Connect study did not show an effect on cognition in more severely impaired patients using AD medication (Shah, CtAD 2011). Other studies in drug-naive mild AD and prodromal AD are ongoing.Conclusions: Souvenaid’s efficacy and mechanisms of action during different stages of AD continues to be evaluated in the Souvenaid Clinical Trial program.

Background Primary hyperoxalurias (PHs) are rare genetic diseases that increase the endogenous level of oxalate, a waste metabolite excreted predominantly by the kidneys and also the gut. Treatments aim to improve oxalate excretion, or reduce oxalate generation, to prevent kidney function deterioration. Oxalobacter formigenes is an oxalate metabolizing bacterium. This Phase III, double-blind, placebo-controlled randomized trial investigated the effectiveness of orally administered Oxabact™, a lyophilized O. formigenes formulation, at reducing plasma oxalate levels in patients suffering from PH. Methods Subjects (≥ 2 years of age) with a diagnosis of PH and maintained but suboptimal kidney function (mean estimated glomerular filtration rate at baseline < 90 mL/min/1.73 m2) were eligible to participate. Subjects were randomized to receive Oxabact or placebo twice daily for 52 weeks. Change from baseline in plasma oxalate concentration at Week 52 was the primary study endpoint. Resu...

Summary Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab. Complement activation was assessed by analysing the haemolytic complement function of the classical (CH50) and the alternative pathway (APH50), C3 and the activation products C3d, C5a and sC5b-9 prior to, 3 and 6 months after eculizumab treatment. Eculizumab concentrations were determined by a newly established specific enzyme-linked immunosorbent assay (ELISA). Serum eculizumab concentrations up to 1082...

Figure S1. Comparison of MFI Peak de novo DSA. Table S1. Average Mismatches. Table S2. Peak dnDSA Specifity for the individual patients. Table S3. Immunosuppression. Table S4. Individual characteristics of the pediatric recipients developing de novo DSA. (DOCX 35 kb)

To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4–15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological com...

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 pe...

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. Not every patient with aHUS...