6 May 2019 - - US-based investigational ribonucleic acid interference therapeutics developer Dicerna Pharmaceuticals, Inc. (NASDAQ: DRNA) has submitted an updated investigational new drug application to the US Food and Drug Administration for DCR-PHXC, the company's lead GalXC product candidate for the treatment of all forms of primary hyperoxaluria, the company said.

The update reflects agreement on the primary endpoint for the PHYOX2 pivotal clinical trial, which is enrolling patients with PH type 1 and PH type 2, and alignment with the FDA regarding the path to full approval for the treatment of patients with PH1, as conveyed during a recent FDA Type A meeting.

The company will continue its ongoing dialogue with the FDA regarding endpoints for studies involving patients with PH2 and PH3, as part of the PHYOX clinical development program for DCR-PHXC.

For the forthcoming pivotal PHYOX2 study, Dicerna reached agreement with the FDA on a primary endpoint of 24-hour urinary oxalate burden, expressed as the time-weighted standardized area under the curve from Day 90 to 180, based on percent change from baseline.

Dicerna recently announced initiation of participant screening in the PHYOX2 trial, which will evaluate a multi-dose regimen of DCR-PHXC in individuals with PH1 and PH2.

The company expects to begin enrolling patients to the PHYOX2 trial in the second quarter of 2019.

Dicerna recently presented updated data from the ongoing PHYOX1 Phase 1 clinical trial of DCR-PHXC, which showed post-dose reductions in 24-hour urinary oxalate levels in adult and adolescent study participants with PH1 and PH2.

The PHYOX1 data also showed that a single dose of DCR-PHXC led to normalization or near-normalisation of urinary oxalate levels in a majority of patients and was generally well-tolerated.

DCR-PHXC is an investigational drug in development for the treatment of all forms of primary hyperoxaluria, and 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.

Primary hyperoxaluria 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, as well as PH for which the molecular basis remains unknown, often referred to as "no mutation detected" PH or idiopathic PH.

The known PH mutations cause a decrease in the activity of a specific enzyme in the liver, triggering an increase in oxalate production. In each case the decreased enzyme activity changes the balance of intermediary metabolites, resulting in overproduction of oxalate.

The three genetically known types of PH are PH1, which is caused by a mutation in the AGXT gene, causing a deficiency of the enzyme alanine: glyoxylate-aminotransferase, 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.

Patients with severe PH often undergo both liver and kidney transplants, which are major surgical procedures, and subsequently must take immunosuppressant drugs for the rest of their lives. Patients with decreased renal function may also experience oxalosis, which involves a build-up of oxalate in other organs such as the bone, skin, heart, and retina, possibly causing other concomitant, debilitating complications.

PH occurs in an estimated 1 in 120,000 live births around the world.3 The estimated genetic prevalence of PH1 is 1 in 151,887 births, which implies more than 5,000 patients in the United States and European Union have the disease.

The estimated genetic prevalence of PH2 is 1 in 310,055 and that of PH3 is 1 in 135,866.3 The median age at the first appearance of PH1 symptoms is 5.8 years.

The median age at diagnosis of PH1 is between 4.2 and 11.5 years, depending on whether nephrocalcinosis (calcification in the renal parenchyma, the functional part of the kidney) is present.5 Fifty percent of patients with PH1 reach end-stage renal disease by their mid-30s.

Dicerna Pharmaceuticals is a biopharmaceutical company focused on the discovery and development of innovative, subcutaneously delivered RNAi-based therapeutics for the treatment of diseases involving the liver, including rare diseases, chronic liver diseases, cardiovascular diseases and viral infectious diseases.