- Company Expects to Initiate Phase 1 Trial in Patients with PH1 in Early 2016 -
- Ongoing Observational Study Measures Biomarkers Implicated in the Pathogenesis of PH1 -
- Company Identifies DsiRNA-EX-Conjugate Clinical Candidates
Targeting HAO1 Gene for
PH1 is a severe, rare, inherited liver disorder that has no approved therapies. Patients with PH1 over-produce 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. DCR-PH1 also increases the excretion of glycolate, a metabolite involved in oxalate production, providing further proof of inhibition of the GO enzyme, the target of DCR-PH1.
"Initiation of dosing in the first human trial with DCR-PH1 is an
important milestone in our robust clinical development program targeting
"PH1 is an aggressive cause of chronic kidney disease that affects
thousands of patients and has no approved therapy," noted
Normal Healthy Volunteer Study (DCR-PH1-102)
DCR-PH1-102 is a two-part, randomized, double-blind, placebo-controlled trial with the primary objective of determining the safety profile of DCR-PH1 in healthy adults following its intravenous (IV) infusion. Part 1 will assess single ascending doses (SAD) of DCR-PH1 and part 2 will examine multiple ascending doses (MAD) of the drug candidate. The study will also investigate the pharmacodynamics (PD) of DCR-PH1 by monitoring changes in plasma and urinary glycolate, the key PD marker of the activity of the oxalate-generating metabolic pathway that causes the pathology associated with PH1. Data from this trial are expected to be available in the second half of 2016.
"This study in healthy volunteers is an important milestone in the
development of desperately needed new therapies for patients with PH1, a
devastating disease that often causes early onset of renal failure,
which is treated today with highly invasive, combined kidney and liver
First Phase 1 Trial in Patients with PH1 (DCR-PH1-101)
In early 2016, Dicerna expects to initiate enrollment in this open-label study of DCR-PH1 in patients with PH1. The study will be conducted at multiple sites globally and will initially test single ascending doses of DCR-PH1 in patients as young as 12 years old. The DCR-PH1-101 trial will monitor 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.
"The two studies in normal healthy volunteers and patients could usher
in a new era of treatment for patients with PH1," said
Observational Study of PH1 Patients
Dicerna also announced initiation of the Primary HYperoxaluria Observational Study (PHYOS), an international, multicenter, observational study that is measuring changes in oxalate, glycolate, and other metabolites over a six-month period in patients with PH1. PHYOS investigators are also collecting data on the clinical manifestations of PH1, fluid intake, and quality of life. Although the study will not include investigational drugs or other interventions, its participants may be considered for enrollment in planned clinical trials of DCR-PH1.
"By collecting data on key biochemical parameters implicated in the
pathogenesis of PH1, PHYOS supports our efforts to understand the
baseline disease state and presentation of PH1 and will help us roll out
our Phase 1 trial," noted
Investigators are now enrolling PH1 patients for the PHYOS study, which will eventually include up to 50 patients at as many as 12 sites worldwide. Further details of the DCR-PH1-101, DCR-PH1-102, and PHYOS trials are available at www.dicerna.com.
Identification of DsiRNA-EX-Conjugates as Clinical Candidates for
Dicerna also reported that it has identified multiple DsiRNA-EX-Conjugates that meet key criteria the Company has established for selection of clinical candidates for the subcutaneous (SC) delivery of RNAi therapies to key cells in the liver (hepatocytes), targeting the HAO1 gene. Dicerna is developing DsiRNA-EX-Conjugates in parallel with DCR-PH1, with the goal of providing physicians and patients the option of either IV or SC therapy for their PH1 treatment. Preclinical data across multiple targets suggest that DsiRNA-EX-Conjugates can potently silence genes in the liver. A study presented at the recent EuroTIDES conference indicated an ED50 (a dose that produces a defined effect in 50% of a population) of 0.6 mg/kg in mice receiving DsiRNA-EX-Conjugate therapy with SC administration. Additionally, multiple DsiRNA-EX-Conjugates showing high potency in mice have been tested in non-human primates and have shown excellent translation of activity from mice to the non-human primate model, as expected.
"Based on our preclinical data, there are multiple DsiRNA-EX-Conjugate molecules that meet key criteria we have established for selection of a clinical candidate to follow our DCR-PH1 program, and we plan to take a conjugate to treat PH1 into clinical development in 2017," noted Bob D. Brown, Ph.D., chief scientific officer and senior vice president at Dicerna. "Thus we are well-positioned for clinical lead selection and development in other therapeutic areas as well."
"This is truly an exciting time for the PH1 community, as decades of
painstaking work are now yielding important research advances that may
bring us viable therapeutic options, which the community currently lacks
and urgently needs," said
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
About Primary Hyperoxaluria Type 1 (PH1)
PH1 is a severe, rare, inherited genetic liver disorder that causes excess oxalate production due to mutations in the AGXT gene, which encodes for the liver enzyme alanine:glyoxylate-aminotransferase (AGT).1 Kidneys are unable to eliminate the large amount of oxalate that is produced in PH1 patients, and its accumulation can result in severe damage to the kidneys and other organs. Currently, there are no approved therapies for the treatment of PH1 in the US.
Patients with PH1 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.
The estimated genetic prevalence of PH1 is 1 in 151,887, which suggests more than 5,000 patients in the US and EU.2 The median age at first symptoms is 5.8 years.3 The median age at diagnosis 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.4 Fifty percent of patients with PH1 reach end-stage renal disease (ESRD) by their mid-30s.5
Cautionary Note on Forward-Looking Statements
This press release includes forward-looking statements. Such
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. DCR-PH1 is in early clinical development,
and the process by which an early clinical therapeutic candidate could
potentially lead to an approved drug is long and subject to significant
risks and uncertainties. Applicable risks and uncertainties include
those relating to our preclinical and clinical research and other risks
identified under the heading "Risk Factors" included in our most recent
Form 10-K filing and in other future filings with the
Cochat, P, Rumsby, G. Primary hyperoxaluria.
Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype
correlations and estimated carrier frequencies of primary
|3.||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
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