Dicerna™ Announces the Presentation of Updated Data Demonstrating Utility of its Lead Compound DCR-PHXC in Treating Primary Hyperoxaluria Type 1 (PH1) and Type 2 (PH2)
Mar 29, 2019
—PHYOX™1 Investigators Reported Potent, Durable Response in Phase 1
Study in Patients with PH1 and PH2 at
—Company Announces Initiation of Participant Screening for PHYOX2 Pivotal Trial in PH1 and PH2—
“These latest results from PHYOX1 further support the potential potency
and duration of action of DCR-PHXC in treating all types of primary
hyperoxaluria,” stated lead investigator
Dr. Hoppe and colleagues reported that a single 3.0-mg/kg dose of DCR-PHXC was associated with a mean maximal reduction of 24-hour urinary oxalate of 71% (range: 62% to 80%). The 3.0-mg/kg dose also 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 four of five participants with PH1. The investigators also reported a mean maximal reduction in urinary oxalate of 51% (range: 28% to 72%) with a single 1.5-mg/kg dose, which led to near-normalization (defined as 24-hour excretion <0.6 and ≥0.46 mmol) in three of five participants with PH1. Additionally, among the three participants with PH1 dosed at 6.0-mg/kg, the mean maximal reduction in urinary oxalate was 76% (range: 58% to 100%); one participant in this cohort reached normalization at one or more post-dose time points; two are still in follow-up and may not yet have reached maximal 24-hour urinary oxalate reductions.
In their poster presentation, which is based on a data cut of
“DCR-PHXC is the only therapy being investigated in the RNAi space that
is designed for the treatment of patients with all forms of primary
The primary objective of the PHYOX1 Phase 1 trial (ClinicalTrials.gov: NCT03392896) 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 placebo-controlled, single-blind and includes 25 HVs
enrolled at a single site in the
United Kingdomwith five cohorts dosed at 0.3, 1.5, 3.0, 6.0 or 12.0 mg/kg of DCR-PHXC or placebo (3:2 randomization).
Group B is open-label and includes 18 participants with PH, including
three cohorts of participants with PH1 dosed at 1.5, 3.0 and 6.0 mg/kg
of DCR-PHXC, and a fourth cohort with flexible dosing. Group B
participants are enrolled among five sites in the
European Unionand one site in the United States.
The Company initiated the PHYOX1 Phase 1 trial in HVs in the fourth
quarter of 2017 and dosed the first participant with PH in
DCR-PHXC is an investigational drug in development for the treatment of all forms of primary hyperoxaluria (PH), 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.
About Primary Hyperoxaluria (PH)
Primary hyperoxaluria (PH) 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" (NMD) PH or idiopathic PH (IPH). 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: 1,2
- PH1, which is caused by a mutation in the AGXT gene, causing a deficiency of the enzyme alanine:glyoxylate-aminotransferase (AGT),
- 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 (HOGA).
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
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Forward-looking
statements are subject to risks and uncertainties that could cause
actual results to differ materially from those expressed or implied in
such statements. Examples of forward-looking statements include, among
others, statements we make regarding: (i) the therapeutic and commercial
potential of DCR-PHXC, DCR-HBVS and the GalXC™ platform; (ii) research
and development plans and timelines related to DCR-PHXC, DCR-HBVS, and
GalXC; and (iii) the potential of Dicerna™’s technology and drug
candidates in the Company’s research and development pipeline. The
process by which an early stage investigational therapy such as DCR-PHXC
and an early stage platform such as GalXC could potentially lead to an
approved product is long and subject to highly significant risks.
Applicable risks and uncertainties include those relating to Dicerna’s
clinical research and other risks identified under the heading "Risk
Factors" included in the Company’s most recent Form 10-K filing and in
other future filings with the
Dicerna™, GalXC™, and PHYOX™ are trademarks of
Oxalosis & Hyperoxaluria Foundation. Overview of hyperoxaluria. 2017. Available at: https://ohf.org/overview/. Accessed July 6, 2017.
Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. Available at: http://www.rarekidneystones.org/hyperoxaluria/physicians.html. Accessed July 6, 2017.
Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. Journal of the American Society of Nephrology 2015; 26(10):2559-2570.
van der Hoeven SM, van Woerden CS, Groothoff JW. Primary hyperoxaluria type 1, a too often missed diagnosis and potentially treatable cause of end-stage renal disease in adults: results of the Dutch cohort. Nephrology, Dialysis, Transplantation 2012; 27(10):3855-3862.
Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske JC. Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria. Kidney International 2015; 87:623-631.
Head of Corporate Communications
Dicerna Pharmaceuticals, Inc.