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 is on track to file a clinical trial application (CTA) in Europe for DCR-PHXC in late 2017 and to commence human clinical trials in the first quarter of 2018.

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.

Dicerna is on track to file a clinical trial application (CTA) in Europe for DCR-PHXC in late 2017 and to commence human clinical trials in the first quarter of 2018. During the workshop, Dicerna disclosed that the DCR-PHXC clinical trial will be conducted at multiple sites in Europe and will include both healthy volunteer and patient cohorts. The Company anticipates that study participants will receive a single ascending dose of DCR-PHXC via subcutaneous injection, transitioning, as appropriate, to multiple ascending doses. The primary endpoints will include safety and tolerability, urine and plasma biomarkers, and pharmacokinetics.

DCR-PHXC Overview

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