Dicerna doses first patient in phase 1 trial of DCR-PH1 in patients with primary hyperoxaluria type 1

A severe, rare, inherited disorder of the liver, PH1 often results in kidney failure, and there are no approved therapies for the disease.

The U.S. Food and Drug Administration (FDA) designated DCR-PH1, an investigational Dicer substrate short interfering RNA (DsiRNA) therapeutic, as an Orphan Drug in April 2015. In August 2015, the European Medicines Agency (EMA) granted Orphan Drug Designation to DCR-PH1 in the European Union (EU). More recently, in December 2015, Dicerna initiated dosing in a Phase 1 trial of DCR-PH1 in healthy volunteers.

"Dosing of our first patient with PH1 is an important milestone for DCR-PH1, as it brings us a step closer to offering a potentially meaningful therapeutic option to this underserved patient population," said Pankaj Bhargava, M.D., chief medical officer of Dicerna.

"We eagerly await the first clinical readout from this study, as well as from the normal healthy volunteer study, and we look forward to sharing the results with the PH1 community."

In patients with PH1, the liver over-produces oxalate, a metabolite that can accumulate throughout the body and particularly in the kidneys, often resulting in end-stage renal disease (ESRD) and the need for both kidney and liver transplants. DCR-PH1, the lead investigational product candidate in Dicerna’s pipeline of therapies targeting rare diseases of the liver, is based on the Company’s proprietary DsiRNA-EX technology.

In a genetic mouse model of PH1, DCR-PH1 markedly knocked down HAO1, the gene transcript that encodes for the enzyme glycolate oxidase (GO), causing near normalization of oxalate levels. In preclinical models, DCR-PH1 also increased the excretion of glycolate, a metabolite that is the substrate of the GO enzyme, and as a result, a pharmacodynamic marker of effective knockdown.

"There is a significant unmet medical need for a treatment option for patients with primary hyperoxaluria type 1, a devastating disease that often causes early-onset renal failure," said Bernd Hoppe, M.D., Head of the Division of Pediatric Nephrology in the Department of Pediatrics at the University of Bonn, Germany.

"Currently, patients with PH1 must resort to combined transplantation of the kidney and liver, a highly invasive and burdensome procedure. Given the encouraging inhibitory activity of DCR-PH1 in animal studies, we are excited to begin dosing in humans, as we hope this clinical trial will produce similarly positive results."

The DCR-PH1-101 clinical trial is testing single ascending doses of DCR-PH1 in patients who have a genetically confirmed diagnosis of PH1, 24-hour urine oxalate excretion = 0.7 mmol per 1.73 m2 body surface area (BSA), and an estimated glomerular filtration rate (eGFR) of = 40 mL/min/1.73 m2 BSA. Investigators will monitor patients for changes in urinary and plasma glycolate and oxalate, key efficacy markers in PH1. Once safety has been demonstrated with single doses, the trial will transition to a multi-dose study that will include a pharmacokinetic analysis to identify an appropriate dose for future studies of DCR-PH1.

"The successful dosing of the first patient in the DCR-PH1-101 trial is a major event in the clinical development program for this promising product candidate," commented Douglas Fambrough, Ph.D., president and chief executive officer of Dicerna. "If successful, the trial will validate our DsiRNA-EX technology platform as a vehicle for inducing RNA interference, and it will provide important justification for our innovative approach to treating rare and debilitating diseases."

About DCR-PH1

DCR-PH1 is being developed by Dicerna for the treatment of PH1 by addressing its pathology through the targeting and destruction of the messenger RNA (mRNA) produced by the HAO1 gene. HAO1 encodes glycolate oxidase (GO), an upstream enzyme involved in the production of oxalate, the mediator of pathogenesis and progression of PH1.

Preclinical studies have shown that DCR PH1 inhibited HAO1 and significantly increased levels of glycolate and reduced levels of urinary oxalate.

DCR-PH1 incorporates small interfering RNA (siRNA) formulated in a proprietary lipid nanoparticle (LNP) technology that is being investigated as a system for efficient delivery to the liver after intravenous (IV) administration. Dicerna obtained rights to this delivery technology through a licensing agreement with Arbutus Biopharma Corporation, formerly known as Tekmira Pharmaceuticals Corporation.