The Company Expects to Initiate Clinical Dosing
in Q1 2018
Dicerna Pharmaceuticals, Inc. (NASDAQ: DRNA), a leading
developer of investigational RNA interference (RNAi) therapeutics,
today announced the first submission of a clinical trial
application (CTA) to the Medicines and Healthcare products
Regulatory Agency (MHRA) in the United Kingdom to initiate a Phase
1 clinical trial of DCR-PHXC, the company’s most advanced GalXCTM
product candidate, for the potential treatment of primary
hyperoxaluria (PH). PH is a group of severe, rare, inherited
disorders of the liver that often result in kidney failure. Once
the CTA is authorized by the MHRA and local ethics committees,
Dicerna plans to begin its Phase 1 clinical study in healthy
volunteers and in patients with PH types 1 and 2 at trial sites in
the United Kingdom. The company plans to submit additional CTAs in
other European countries later this year.
“The filing of this CTA marks an important milestone for
Dicerna, for our GalXC technology platform, and most importantly,
for our pipeline of GalXC product candidates,” said Douglas
Fambrough, Ph.D., president and chief executive officer of Dicerna.
“Specifically, the filing signals our readiness to begin
GalXC-based clinical efforts as we further investigate a needed
pharmaceutical treatment option for patients with PH, a family of
severe disorders with a high unmet medical need. I want to thank
the many Dicerna employees, external collaborators and the primary
hyperoxaluria community, who have been instrumental in advancing
our GalXC-based program for PH to this point. Pending CTA approval,
we look forward to dosing the first person with DCR-PHXC and moving
this program through clinical trials. We expect to present initial
data from our Phase 1 proof-of-concept study in 2018.”
Once the CTA is authorized by the MHRA, Dicerna plans to conduct
the Phase 1 trial as a randomized, single-blind,
placebo-controlled, single-ascending dose study, enrolling up to 25
healthy volunteer subjects and up to 16 patients with PH. The
primary objective of the study is to evaluate the safety and
tolerability of single doses of DCR-PHXC, with participants being
enrolled into as many as five sequential cohorts of increasing
doses. Patients with PH will be dosed after safety has been
established at the same dose level in normal healthy volunteers.
Secondary endpoints include the pharmacokinetics of DCR-PHXC and
its pharmacodynamic effects on oxalate biomarkers in plasma and
urine.
DCR-PHXC is the most advanced product candidate utilizing
Dicerna's GalXC technology, 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. DCR-PHXC targets the lactate dehydrogenase A (LDHA)
gene, a non-essential gene that Dicerna has identified as being a
potentially optimal therapeutic target in patients with PH.
In animal models of PH, DCR-PHXC selectively silences 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 should 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
organ systems in patients with PH.
“Based on pre-clinical data, LDHA has the potential to be an
ideal therapeutic target in patients with PH and we hope to
replicate the inhibitory effect on oxalate production in human
clinical studies,” said Ralf Rosskamp, M.D., chief medical officer
of Dicerna Pharmaceuticals. “Our research findings to date, along
with the findings from our PHYOS observational study, have been
instrumental in our understanding of PH and informing our clinical
development plan. Preclinical studies have shown that DCR-PHXC
results in the potent, durable, and consistent knockdown of LDHA
and reduces oxalate in multiple animal models of PH. We are
committed to investigating a treatment option for patients with all
forms of PH and are excited to begin the Phase 1 trial.”
“With this CTA filing, and the expected initiation of a
first-in-human, proof-of-concept Phase 1 trial of DCR-PHXC once the
MHRA authorizes the CTA, Dicerna is pursuing an exciting and
important approach that may address a high unmet medical need in
primary hyperoxaluria,” noted Craig B. Langman, M.D., The Isaac A
Abt MD Professor of Kidney Diseases at the Feinberg School of
Medicine at Northwestern University. “Given the lack of curative
treatment options for individuals with this devastating family of
diseases, a medication that suppressed oxalate production would be
a welcome therapeutic solution for these patients.”
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 in the US or the EU.
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 idiopathic PH (IPH) or
"no mutation detected" (NMD) 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: 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)
- 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 affects an estimated 1 in 58,000 individuals around the
world. PH1 is the most common form of the disease, accounting for
approximately 80% of cases, whereas PH2 and PH3 each account for
roughly 10% of cases.3 The estimated genetic incidence of PH1 is 1
in 151,887 births, which implies more than 5,000 patients in the US
and EU have the disease.4 The median age at the first appearance of
PH1 symptoms is 5.8 years.5 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.6 Fifty percent of patients with PH1 reach
end-stage renal disease (ESRD) by their mid-30s.2
About Dicerna Pharmaceuticals, Inc.
Dicerna Pharmaceuticals, Inc., is a biopharmaceutical company
focused on the discovery and development of innovative RNAi-based
therapeutics for diseases involving the liver, including rare
diseases, chronic liver diseases, cardiovascular diseases, and
viral infectious diseases. The Company 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. The Company intends to discover, develop
and commercialize novel therapeutics either on its own or in
collaboration with pharmaceutical partners. For more information,
please visit www.dicerna.com.
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. Examples of
forward-looking statements include, among others, statements we
make regarding: (i) the therapeutic and commercial potential of
GalXC™; (ii) research and development plans related to GalXC; and
(iii) the potential of our technology and drug candidates in our
research and development pipeline. The process by which early
clinical technology and product candidates such as DCR-PHXC could
potentially lead to an approved product is long and subject to
highly significant risks. Applicable risks and uncertainties
include those relating to our preclinical research and other risks
identified under the heading "Risk Factors" included in our most
recent Form 10-Q filing and in other future filings with the SEC.
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.
References
1. Oxalosis & Hyperoxaluria
Foundation. Overview of hyperoxaluria. 2017. Available at:
https://ohf.org/overview/. Accessed July 6, 2017.
2. Rare Kidney Stone Consortium. Primary
hyperoxaluria. 2010. Available at:
http://www.rarekidneystones.org/hyperoxaluria/physicians.html.
Accessed July 6, 2017.
3. Genetics Home Reference. Primary
hyperoxaluria. U.S. Department of Health & Human Services,
National Institutes of Health, National Library of Medicine; 2017.
Available at:
https://ghr.nlm.nih.gov/condition/primary-hyperoxaluria#statistics.
Accessed October 9, 2017.
4. 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. 5. 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. 6. 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20171016005219/en/
Investors:Rx Communications GroupMelody Carey,
917-322-2571mcarey@rxir.comorMedia:SmithSolveAlex Van Rees,
973-442-1555 ext. 111alex.vanrees@smithsolve.com
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