Market Overview

Dicerna Announces Proof of Concept for DCR-PHXC in the Treatment of Primary Hyperoxaluria


Initial 6-Week Data in PHYOX Phase 1 Trial Show Significant and
Sustained Reduction in Urinary Oxalate Levels Following Single-Dose
Administration in Adults with PH1 and PH2

A Detailed Data Readout of the PHYOX Trial is Anticipated in Q4 2018

Pharmaceuticals, Inc.
(NASDAQ:DRNA), a leading developer of
investigational ribonucleic acid interference (RNAi) therapeutics, today
announced preliminary proof-of-concept data from its ongoing PHYOX Phase
1 clinical trial. A single-dose administration of DCR-PHXC, the
Company's lead GalXC™ product candidate, brought urinary oxalate levels
into the normal range (defined as 24-hour excretion ≤0.46 mmol) or
near-normal range (defined as 24-hour excretion ≤0.6 mmol) in a majority
of the eight assessed patients with primary hyperoxaluria type 1 and
type 2 (PH1 and PH2). All of the assessed patients experienced
substantial and clinically significant reductions in urinary oxalate
(defined as >30% reduction compared to baseline). Assessed patients are
those patients for whom data are available through Week 6, or Day 43.
All assessed patients are adults and include seven patients with PH1 and
one patient with PH2.

The interim PHYOX data constitute preliminary clinical proof of concept
for DCR-PHXC. Moreover, the investigational agent was safe and
well-tolerated during the period of initial observation. The interim
data provide a promising indicator of DCR-PHXC's potential potency and
duration of action following administration of a single dose, and are
consistent with an anticipated once-quarterly administration. Dicerna
intends to present a detailed data readout from the PHYOX trial in the
fourth quarter of 2018, and plans to initiate a registration trial for
DCR-PHXC pending regulatory feedback in the first quarter of 2019.

"We are encouraged to see such an early demonstration of proof of
concept in the initial data readout from patients in the ongoing PHYOX
trial," said Ralf Rosskamp, M.D., chief medical officer of Dicerna. "The
magnitude of urinary oxalate reduction, coupled with the duration of
action, appear to validate therapeutic targeting of lactase
dehydrogenase, an enzyme involved in the ultimate step of hepatic
oxalate production. Based on this novel mechanism of action, DCR-PHXC
has the potential to work in all types of primary hyperoxaluria. We look
forward to sharing additional results from the PHYOX trial once data
from all patients become available."

"The substantial reductions in urinary oxalate appear to confirm that
our GalXC platform may effectively reduce target gene expression in
humans and suggest that our pioneering application of RNAi may treat all
genetic variants of primary hyperoxaluria," said Bob D. Brown, Ph.D.,
chief scientific officer of Dicerna. "Our results from preclinical GalXC
studies appear to have translated smoothly into patients with regards to
potency, durability, and tolerability. Looking beyond our DCR-PHXC
program, we are encouraged that our GalXC platform will continue to
perform in upcoming Dicerna clinical programs, including those in other
rare diseases, hepatitis B virus, and various cardiovascular and chronic
liver diseases."

Dicerna is investigating DCR-PHXC for the treatment of all forms of PH,
a family of severe, rare, inherited disorders of the liver that often
result in kidney failure. The Company initiated the PHYOX trial in
normal healthy volunteers (NHVs) in the fourth quarter of 2017 and dosed
the first patient with PH in May 2018.

The primary objective of the PHYOX trial (
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 a placebo-controlled, single-blind Phase 1 trial in 25 NHVs
    enrolled at a single site in the United Kingdom.
  • Group B is an open-label, multi-center trial of DCR-PHXC in 16
    patients with PH, including three cohorts of patients with PH1 dosed
    at 1.5, 3.0, and 6.0 mg/kg, and a fourth PH2-only cohort with flexible
    dosing. Group B patients are being enrolled at five sites in the
    European Union (EU) and one site in the United States.

Initial Results in PHYOX Phase 1 Trial Group B

In the first Group B cohort (1.5 mg/kg), preliminary results following a
single administration of DCR-PHXC show that three of four adult patients
had urinary oxalate levels in the near-normal range between Days 43 and
57, which are the latest observation days for those patients. The fourth
adult, whose baseline urinary oxalate level was 2.28 mmol/24hr, is
exhibiting substantial reductions, with the latest observation (Day 95)
showing the maximal reduction for that patient (urinary oxalate <1.0

In the second Group B cohort (3 mg/kg), two of four adult patients
reached normal urinary oxalate concentrations (<0.46 mmol/24hr) by Day
43. Both of the other patients also have substantial oxalate reductions
(one of which does not yet have Day 43 data).

The one adult patient with PH2 in the fourth Group B cohort has also
experienced a substantial reduction in 24-hour urinary oxalate excretion.

The PHYOX investigators have observed three mild-to-moderate injection
site reactions. All were transient and resolved without intervention.


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 GalXCTM 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 lactase dehydrogenase (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 might 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.

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 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 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 (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, subcutaneously delivered
RNAi-based therapeutics for the treatment of diseases involving the
liver, including rare diseases, viral infectious diseases, chronic liver
diseases, and cardiovascular 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. For more information, please visit

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 the GalXC™ platform, including DCR-PHXC;
(ii) research and development plans related to GalXC,™ including
DCR-PHXC; and (iii) the potential of our technology and drug candidates
in our research and development pipeline. The process by which an early
stage platform such as GalXC (including DCR-PHXC, our lead product
candidate) could potentially lead to an approved product is long and
subject to highly significant risks. In general, most earlier stage drug
candidates do not ultimately become approved drugs. Applicable risks and
uncertainties include those relating to Dicerna's clinical and
preclinical research and others identified under the heading "Risk
Factors" included in the Company's filings with the Securities and
Exchanges Commission (SEC). These risks and uncertainties include, among
others, the cost, timing and results of preclinical studies and clinical
trials and other development activities; the unpredictability of the
duration and results of regulatory review of New Drug Applications and
Investigational 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, 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





Oxalosis & Hyperoxaluria Foundation. Overview of hyperoxaluria.
2017. Available at:
Accessed July 6, 2017.


Rare Kidney Stone Consortium. Primary hyperoxaluria. 2010.
Available at:
Accessed July 6, 2017.

3. 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;
4. 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;
5. 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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