—PHYOX™1 Investigators Reported Potent, Durable Response in Phase 1
Study in Patients with PH1 and PH2 at German Society of Pediatric
Nephrology 50th Annual Meeting—
—Company Announces Initiation of Participant Screening for PHYOX2
Pivotal Trial in PH1 and PH2—
CAMBRIDGE, Mass.–(BUSINESS WIRE)–Dicerna™
Pharmaceuticals, Inc. (Nasdaq: DRNA), (the “Company” or “Dicerna”) a
leading developer of investigational ribonucleic acid interference
(RNAi) therapeutics, today announced the presentation of updated data
from its ongoing PHYOX™1 Phase 1 clinical trial evaluating DCR-PHXC, the
Company’s lead GalXC™ product candidate. The data showed post-dose
reductions in 24-hour urinary oxalate levels in adult and adolescent
study participants with primary hyperoxaluria type 1 (PH1) and type 2
(PH2). Investigators reported that a single dose of DCR-PHXC led to
normalization or near-normalization of urinary oxalate levels in a
majority of participants and was generally well-tolerated. The data were
presented in a poster on March 28 at the German Society of Pediatric
Nephrology 50th Annual Meeting in Cologne, Germany.
“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 Bernd Hoppe, M.D., head of the
Division of Pediatric Nephrology in the Department of Pediatrics at the
University of Bonn, Germany. “There is significant unmet medical need
among patients suffering from primary hyperoxaluria, as their
predisposition to the formation of stones in the urinary tract and
kidneys often results in renal damage. Having already established the
lactate dehydrogenase A enzyme, or LDHA, as a possibly ideal therapeutic
target, PHYOX1 continues to demonstrate the potential ability of
DCR-PHXC to improve clinical outcomes for these patients.”
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 March 14,
2019, the PHYOX1 investigators also reported that DCR-PHXC was generally
well-tolerated in this ongoing study, based on data from 18 participants
(15 adults and three adolescents [participants 12-17 years old]) with
PH1 (n=15) and PH2 (n=3) and 25 adult healthy volunteers (HVs). To date,
four serious adverse events (one mild, two moderate, and one severe)
have occurred in three participants, though none were deemed related to
the study drug. A total of nine participants (27%) dosed with DCR-PHXC
experienced mild or moderate injection site reactions, all of which
resolved without intervention within 96 hours.
“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
hyperoxaluria,” said Ralf Rosskamp, M.D., chief medical officer of
Dicerna. “By demonstrating marked 24-hour reductions in urinary oxalate,
along with favorable tolerability, the latest data from PHYOX1
strengthen the rationale for a multi-dose regimen of DCR-PHXC, which we
expect will show more pronounced and sustained reductions in the urinary
oxalate burden. We are pleased to announce the start of participant
screening in the pivotal PHYOX2 trial, which will evaluate a multi-dose
regimen of DCR-PHXC in individuals with PH1 and PH2.”
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 Kingdom with 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 Union and
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 May 2018.
About DCR-PHXC
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 United States and European Union
have the disease.3 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.4 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.2
About Dicerna™ Pharmaceuticals, Inc.
Dicerna™ Pharmaceuticals, Inc., 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. Dicerna is leveraging its
proprietary GalXC™ RNAi technology platform to build a broad pipeline in
these core therapeutic areas, focusing on target genes where connections
between target gene and diseases are well understood and documented.
Dicerna intends to discover, develop and commercialize novel
therapeutics either on its own or in collaboration with pharmaceutical
partners. Dicerna has strategic collaborations with Eli Lilly and
Company, Alexion Pharmaceuticals, Inc. and Boehringer Ingelheim
International GmbH. For more information, please visit www.dicerna.com.
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 Securities and Exchange Commission. These
risks and uncertainties include, among others, the cost, timing and
results of preclinical studies and clinical trials and other development
activities; the likelihood of Dicerna’s clinical programs being executed
within timelines provided and reliance on the Company’s contract
research organizations and predictability of timely enrollment of
subjects and patients to advance Dicerna’s clinical trials; the
potential for future data to alter initial and preliminary results of
early stage clinical trials; the unpredictability of the duration and
results of the regulatory review of Investigational New Drug
Applications (NDAs) and Clinical Trial Applications that are necessary
to continue to advance and progress the Company’s clinical programs and
the regulatory review of NDAs; market acceptance for approved products
and innovative therapeutic treatments; competition; the possible
impairment of, inability to obtain and costs of obtaining intellectual
property rights; and possible safety or efficacy concerns that could
emerge as new data are generated in research and development, general
business, financial and accounting risks and litigation. The
forward-looking statements contained in this press release reflect
Dicerna’s current views with respect to future events, and Dicerna does
not undertake and specifically disclaims any obligation to update any
forward-looking statements.
Dicerna™, GalXC™, and PHYOX™ are trademarks of Dicerna Pharmaceuticals,
Inc.
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References |
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1. |
Oxalosis & Hyperoxaluria Foundation. Overview of hyperoxaluria. |
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2. |
Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010. |
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3. |
Hopp, K, Cogal, A, Bergstralh, E, et al. Phenotype-genotype |
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4. |
van der Hoeven SM, van Woerden CS, Groothoff JW. Primary |
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5. |
Tang X, Bergstrath EJ, Mehta RA, Vrtiska TJ, Milliner DS, Lieske |
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Contacts
Rebecca Peterson
Head of Corporate Communications
Dicerna
Pharmaceuticals, Inc.
PH: 617-642-6235
rpeterson@dicerna.com