CAMBRIDGE, Mass.—Dicerna Pharmaceuticals announced today the presentation of late-breaking data from its ongoing PHYOX Phase 1 trial, in which single-dose administration of DCR-PHXC, the company’s lead GalXC product candidate, was associated with normalization or near-normalization of urinary oxalate levels in a majority of adult patients with primary hyperoxaluria types 1 and 2 (PH1 and PH2).
DCR-PHXC is an investigational drug in development for the treatment of all forms of primary hyperoxaluria. In animal models of PH, DCR-PHXC selectively silences lactase dehydrogenase (LDHA) in the liver, blocking the excess production of oxalate, a hallmark of the disease. Studies have shown that people who are completely deficient in LDHA show no liver dysfunction and can lead normal lives.
In a poster presented at the American Society of Nephrology (ASN) Annual Kidney Week 2018 in San Diego, investigators reported that a single 3.0-mg/kg dose of DCR-PHXC 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 three of four participants, including a mean maximal reduction in 24-hour urinary oxalate of 65%. Investigators also reported that a single 1.5-mg/kg dose led to near-normalization (defined as 24-hour excretion <0.6 and ≥0.46 mmol) in three of four PH1 participants and led to a mean maximal reduction in urinary oxalate of 50% in the five patients dosed at that level, including one PH2 patient. All patients demonstrated a clinically significant reduction in urinary oxalate (defined as >30% reduction compared to baseline).
In their poster presentation, based on a data cut of October 1, 2018, the PHYOX investigators reported that DCR-PHXC is safe and well-tolerated in this ongoing study, based on data from 12 adult participants with PH1 (n=11) and PH2 (n=1) and 25 adult normal healthy volunteers (NHVs). The ASN presentation follows Dicerna’s announcement last month of preliminary proof-of-concept for DCR-PHXC, based on interim PHYOX data demonstrating substantial and clinically significant reductions in urinary oxalate in all assessed patients with PH.
“The observed reduction in 24-hour urinary oxalate following a single dose of DCR-PHXC in both PH1 and PH2 participants is a promising sign of this compound’s potential potency and duration of action,” said Ralf Rosskamp, MD, chief medical officer of Dicerna. “Based on accumulated experience in animals and humans, we see a strong scientific rationale for a multi-dose regimen of DCR-PHXC, which we anticipate will show even more pronounced and sustained 24-hour urinary oxalate reductions, with potential utility in all types of primary hyperoxaluria. The encouraging findings from PHYOX thus lay the groundwork for Dicerna’s planned Phase 2/3 registration trial for DCR-PHXC, which we aim to initiate in the first quarter of 2019, pending regulatory feedback.”
Dicerna is investigating DCR-PHXC for the treatment of all forms of PH, a family of severe, rare, inherited disorders of the liver that often result in kidney failure. The company initiated the PHYOX trial in NHVs in the fourth quarter of 2017, and dosed the first patient with PH in May 2018. The primary objective of the PHYOX 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 a placebo-controlled, single-blind Phase 1 trial in 25 NHVs enrolled at a single site in the United Kingdom; and group B is an open-label, multi-center trial of DCR-PHXC in 16 patients with PH, including three cohorts of patients with PH1 dosed at 1.5, 3.0, and 6.0 mg/kg, and a fourth PH2-only cohort with flexible dosing. Group B patients are enrolled at five sites in the European Union (EU) and one site in the United States.
In terms of safety, no severe or serious adverse events have occurred as of the October 1 data cut, and there have been no clinically significant changes in electrocardiography (ECG), vital signs, laboratory or hematology values. Among the 27 participants dosed with DCR-PHXC in both Group A and B, the investigators observed a total of five participants with mild-to-moderate injection site reactions (19%), all of which were transient and resolved without intervention within 24 to 72 hours.
“The PHYOX trial continues to generate meaningful and highly encouraging data on urinary oxalate reduction, and we look forward to gaining a more complete view of the magnitude of this effect as the trial progresses,” added PHYOX investigator Bernd Hoppe, MD, head of the Division of Pediatric Nephrology in the Department of Pediatrics at the University of Bonn, Germany. “We are optimistic about attaining normalization or near-normalization of urinary oxalate in an even greater percentage of patients than we have seen thus far. Such an achievement would be a welcome development for the primary hyperoxaluria community, within which there is a significant unmet medical need.”