Dicerna Pharmaceuticals presented updated data from its ongoing PHYOX1 Phase 1 clinical trial evaluating DCR-PHXC, the Company’s lead GalXC product candidate. The data was presented in a poster at the German Society of Pediatric Nephrology 50th Annual Meeting in Cologne, Germany.
The primary objective of the PHYOX1 Phase 1 trial is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-ascending doses of DCR-PHXC. Secondary endpoints include the change in 24-hour urinary oxalate excretion from baseline, defined as the mean of two 24-hour collections during screening. The trial is divided into two groups:
- Group A is placebo-controlled, single-blind and includes 25 healthy volunteers (HVs) enrolled at a single site in the United Kingdom with five cohorts dosed at 0.3, 1.5, 3.0, 6.0 or 12.0 mg/kg of DCR-PHXC or placebo (3:2 randomization).
- Group B is open-label and includes 18 patients with primary hyperoxaluria (PH), including three cohorts of patients with PH1 dosed at 1.5, 3.0 and 6.0 mg/kg of DCR-PHXC, and a fourth cohort with flexible dosing. Group B patients are enrolled among five sites in the European Union and one site in the United States.
Presented data showed that a single 3.0-mg/kg dose of DCR-PHXC was associated with a mean maximal reduction of 24-hour urinary oxalate of 71%. The 3.0-mg/kg dose also brought urinary oxalate levels into the normal range (defined as 24-hour excretion <0.46 mmol) at one or more post-dose time points in four of five patients with PH1. The investigators also reported a mean maximal reduction in urinary oxalate of 51% with a single 1.5-mg/kg dose, which led to near-normalization (defined as 24-hour excretion <0.6 and ≥0.46 mmol) in three of five patients with PH1. Additionally, among the three patients with PH1 dosed at 6.0-mg/kg, the mean maximal reduction in urinary oxalate was 76%; one participant in this cohort reached normalization at one or more post-dose time points; two are still in follow-up and may not yet have reached maximal 24-hour urinary oxalate reductions. DCR-PHXC was generally well-tolerated.
Based on this data, patient screening in the pivotal PHYOX2 trial is underway. PHYOX2 will evaluate a multi-dose regimen of DCR-PHXC in patients with PH1 and PH2.
About Primary hyperoxaluria
Primary hyperoxaluria (PH) is a family of severe, rare, genetic liver disorders characterized by overproduction of oxalate, a natural chemical in the body that is normally eliminated as waste through the kidneys. In patients with PH, the kidneys are unable to eliminate the large amount of oxalate that is produced, and the accumulation of oxalate can result in severe damage to the kidneys and other organs. Currently, there are no approved therapies for the treatment of PH. There are three known types of PH, each of which results from a mutation in a specific gene. PH1, which is caused by a mutation in the AGXT gene, causing a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT). PH2, which is caused by a mutation in the GRHPR gene, causing a deficiency of the enzyme glyoxylate/hydroxypyruvate reductase (GR/HPR), and PH3, which is caused by a mutation in the HOGA1 gene, causing a deficiency of the enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA).
DCR-PHXC is the most advanced product candidate utilizing Dicerna’s GalXC™technology. GalXC is a proprietary platform invented by Dicerna scientists to discover and develop next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. In animal models of PH, DCR-PHXC selectively silences lactate dehydrogenase A enzyme, or LDHA, in the liver, blocking the excess production of oxalate, a hallmark of the disease. In preclinical studies of DCR-PHXC, the compound was well tolerated with no adverse effects in the liver. Studies have shown that people who are completely deficient in LDHA show no liver dysfunction and can lead normal lives. LDHA deficiency in the liver may be beneficial for patients with PH, as the LDHA enzyme is implicated in the abnormal production of oxalate in PH, which in turn is responsible for the severe damage to kidneys and other organs in patients with PH.