Genetic Liver-Targeted Diseases

Novel Investigational Drug for PH: DCR-PHXC

DCR-PHXC: Dicerna's most advanced GalXC product candidate

DCR-PHXC utilizes Dicerna’s GalXC technology, a proprietary platform that advances the development of next-generation RNAi-based therapies designed to silence disease-driving genes in the liver. Dicerna filed a clinical trial application in the UK in the fourth quarter of 2017 and initiated human dosing in a Phase 1 clinical trial of DCR-PHXC in December of 2017.

GalXC enables subcutaneous delivery of RNAi therapies to hepatocytes in the liver and offers several distinct potential benefits, as extensively demonstrated in various animal models. Such benefits could include potent silencing of the lactate dehydrogenase A (LDHA) gene and other genes; highly specific targeting to hepatocytes, sparing other cell types in the body; a long duration of action; and a simple, infrequent dosing regimen.

In patients with PH, 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.

At the 12th International Workshop, Dicerna presented research findings on LDHA inhibition, which was shown in animal models to reduce oxalate to normal or near-normal levels in PH types 1, 2, and idiopathic PH (IPH). Research from multiple animal models of PH demonstrated how DCR-PHXC inhibits LDHA, which the Company has identified as potentially being a superior therapeutic target in patients with the disease. The data highlights included:

  • LDHA inhibition reduces oxalate to normal or near-normal levels in PH types 1, 2, and ethylene glycol-induced hyperoxaluria (a model for IPH).
  • LDHA reduction has a near-linear correlation with oxalate reduction and offers a minimal metabolic intervention. These benefits of LDHA inhibition may translate into consistent therapeutic activity even in the event of a missed dose. There are numerous case reports of LDHA deficiency naturally occurring in healthy humans, with no reported adverse effects due to deficiency in the liver.
  • DCR-PHXC appeared to be well tolerated in these animal studies, with no adverse effects in the liver. Formal animal toxicology studies are ongoing.

DCR-PHXC-101: Phase 1 Clinical Development Program

In order to speed the drug development process, Dicerna developed a novel clinical trial design: DCR-PHXC-101 is a single ascending-dose study in normal healthy volunteers (NHVs) and patients with PH. This clinical trial design was selected to rapidly advance DCR-PHXC as Dicerna works to develop a therapy for this devastating disease.

The study is divided into two groups: Group A is a placebo-controlled, single-blind, single-center Phase 1 study in NHVs; Group B is an open-label, multi-center study in patients with PH types 1 (PH1) and 2 (PH2). Dicerna expects to dose the first patient with PH in the first quarter of 2018.

The primary objective for the trial is to evaluate the safety and tolerability of single doses of DCR-PHXC in both groups. Secondary objectives are to characterize the pharmacokinetics of single doses of DCR-PHXC in NHVs and patients with PH, and to evaluate the pharmacodynamic effects of single doses of DCR-PHXC on biochemical markers including, but not limited to, changes in urine oxalate concentrations.

DCR-PHXC Overview

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