– Nedosiran Achieved Primary Endpoint
Demonstrating Statistically Significant Sustained Reduction in
Urinary Oxalate Excretion and Showed Robust Efficacy in PH1 –
– Real-World Healthcare Utilization Data Showed
Delayed Diagnosis in More Than 50% of Patients, High Rates of
Healthcare Use and Substantial Costs Following Start of Dialysis
–
Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA), a leading
developer of investigational ribonucleic acid interference (RNAi)
therapeutics, today announced results of the PHYOX™2 pivotal
clinical trial of nedosiran, an investigational GalXC™ RNAi
candidate for the treatment of primary hyperoxaluria (PH), in a
late-breaker poster presentation at the American Society of
Nephrology (ASN) Kidney Week 2021.
In the PHYOX2 pivotal trial, which included patients with PH
type 1 (PH1) and PH type 2 (PH2), nedosiran demonstrated a
statistically significant reduction from baseline in urinary
oxalate (Uox) excretion compared to placebo (p<0.0001).
Additionally, a significantly higher proportion of patients treated
with nedosiran achieved and sustained normal or near-normal Uox at
two or more consecutive visits after Day 90 compared to placebo
(p=0.0025). A post hoc subgroup analysis in participants with high
baseline Uox (at least one value ≥ 1.6 mmol) also showed
significantly greater Uox reduction in those treated with nedosiran
(p=0.0186). These robust and sustained Uox reduction results
observed in PHYOX2 were primarily driven by response to nedosiran
in the PH1 subgroup, which met both primary and key secondary
endpoints based on a post hoc analysis. There was no consistent
pattern of Uox reduction observed in participants with PH2.
“Our pivotal PHYOX2 data emphasize the potential of nedosiran to
be a safe and effective therapy option for people with PH1,” said
Shreeram Aradhye, M.D., Executive Vice President and Chief Medical
Officer at Dicerna. “Primary hyperoxaluria can lead to
life-threatening kidney damage, and there continues to be an urgent
need to provide the medical community with new therapeutic options
and build an understanding of disease biology across the PH
subtypes.”
“For people with primary hyperoxaluria, excessive oxalate
production compromises kidney function and can have severe
consequences,” said David Goldfarb, M.D., Clinical Chief of
Nephrology at NYU Langone Health and co-director of its Kidney
Stone Prevention Program. “More than 80% of people with PH1 taking
nedosiran achieved normal or near-normal urinary oxalate excretions
at Day 180 in the PHYOX2 trial. These data underscore the potential
of nedosiran to be a meaningful treatment option for those affected
by PH1, if approved.”
Separately, findings from a real-world study examining
de-identified electronic medical record (EMR) data, including
demographics, clinical characteristics and healthcare utilization
among 47 patients with PH pre- and post-dialysis treatment were
also presented at the conference. The study showed high rates of
costly healthcare utilization, including emergency and inpatient
visits, and confirmed that healthcare costs continued to be
substantial, exceeding $200,000, in the first year following
dialysis initiation. More than half of patients had no recorded PH
diagnosis until after initiating dialysis.
“These healthcare utilization findings confirm what many of us
know to be true – that people living with PH endure a high
frequency of doctor visits. Over the course of the study, more than
half of patients needed multiple emergency room visits and 70% had
one or more hospital stays, which are even more expensive and
disruptive to daily life,” Dr. Aradhye continued. “Of significant
concern was the high rate of delayed diagnosis. More than half of
patients did not receive a PH diagnosis until after their kidney
function declined to the point of dialysis, underscoring the need
for better education and understanding of the signs and symptoms of
PH.”
PHYOX2 Detailed Results
PHYOX2 (NCT03847909), a placebo-controlled, double-blind,
multicenter, pivotal study, was designed to evaluate the efficacy,
safety and tolerability of nedosiran over six months in
participants with PH1 or PH2 aged six years and older across 11
countries, including the U.S., Japan and Europe. Participants were
randomized 2:1 to a fixed dose of nedosiran or placebo administered
once monthly by subcutaneous injection.
The primary endpoint of the study was the percent change from
baseline in 24-hour Uox excretion, as assessed by area under the
curve (AUC) from Day 90 to Day 180. The key secondary endpoint was
percentage of patients (PH1 and PH2) achieving normalization
(defined as Uox level below 0.46 mmol adjusted per 1.73 m2 body
surface area in participants younger than 18 years when collected
over 24 hours) or near-normalization (defined as 1.3 times the
upper limit of normal; 0.60 mmol) on at least two consecutive
visits from Day 90 to Day 180.
Of the 35 patients randomized (23 nedosiran and 12 placebo; 29
with PH1 and 6 with PH2), 34 participants had at least one efficacy
assessment after Day 90 (modified intent-to-treat population;
mITT). Baseline mean estimated glomerular filtration rate (eGFR; a
measure of kidney function) was 89.5 mL/min/1.73 m2 (SD=37.5) for
participants given nedosiran and 82.0 mL/min/1.73 m2 (SD=30.0) for
participants given placebo. Baseline mean Uox values were 1.33
mmol/day (SD=0.47) and 1.96 mmol/day (SD=0.71) for the nedosiran
and placebo groups, respectively.
Nedosiran achieved the primary endpoint showing a statistically
significant reduction from baseline in Uox excretion compared to
placebo (p<0.0001). PHYOX2 also achieved its key secondary
endpoint, with a significantly higher proportion of patients
treated with nedosiran achieving and sustaining normal or
near-normal Uox at two or more consecutive visits after Day 90
compared to placebo (50% vs. 0%; p=0.0025). Of the participants
treated with nedosiran, 73% achieved normalization or
near-normalization at least once during the study.
The significant and sustained Uox reduction observed in PHYOX2
was primarily driven by response to nedosiran in participants with
PH1. There was no consistent pattern of Uox reduction observed in
participants with PH2. Based on further analysis of the data by PH
subtype, patients with PH1 treated with nedosiran achieved
statistically significant differences from placebo for both the
primary (p<0.0001) and the key secondary (p=0.0006) efficacy
endpoints of the trial.
Among study participants assessed for plasma oxalate (Pox),
where mean baseline Pox values were <10 µmol/L in both groups,
those treated with nedosiran showed a median decrease of 25% at Day
180 (p=0.0264; ns); based on a post hoc analysis, Pox reduction of
25% in nedosiran-treated participants with PH1 was statistically
significant compared to placebo (p=0.0168).
Nedosiran was generally well tolerated in the study with an
overall adverse event (AE) profile consistent with previously
reported data from PHYOX trials. The most common AEs in the trial
were mild, self-resolving injection-site reactions (two patients
given nedosiran and zero given placebo). There were three reported
kidney stone AEs in participants given nedosiran (13%) and five in
participants given placebo (42%).
Dicerna's posters for ASN will be made available on the
Company's website.
About Primary Hyperoxaluria (PH)
Primary hyperoxaluria (PH) is a family of ultra-rare,
life-threatening genetic disorders that initially manifest with
complications in the kidneys. There are three known subtypes of PH
(PH1, PH2 and PH3), each resulting from a mutation in one of three
different genes. These genetic mutations cause enzyme deficiencies
that result in the overproduction of oxalate, which is an
end-product of metabolism. Excess production and accumulation of
oxalate leads to recurrent kidney stones, nephrocalcinosis and
chronic kidney disease that may progress to end-stage renal disease
requiring intensive dialysis. Compromised renal function eventually
results in the accumulation of oxalate in a wide range of organs
including the skin, bones, eyes and heart. In the most severe
cases, symptoms start in the first year of life. A combined
liver-kidney transplant may be undertaken to resolve PH1 or PH2,
but it is an invasive solution with limited availability and high
morbidity that requires lifelong immune suppression to prevent
organ rejection. Genetic studies suggest approximately 8,500 people
in the U.S. are affected by PH, and researchers estimate that more
than 80% of patients remain undiagnosed.1 There is currently only
one approved therapy available that is limited to the treatment of
patients with PH1.
About Nedosiran
Nedosiran is in development for the treatment of primary
hyperoxaluria (PH) as part of the PHYOX clinical development
program and is Dicerna’s most advanced RNAi drug candidate
utilizing its proprietary GalXC RNAi technology. Nedosiran is
designed to inhibit production of the hepatic lactate dehydrogenase
(LDH) enzyme – an enzyme that catalyzes the final step in the
glyoxylate metabolism pathway that can lead to oxalate
overproduction in patients with PH.
About Dicerna Pharmaceuticals, Inc.
Dicerna Pharmaceuticals, Inc. (Nasdaq: DRNA) is a
biopharmaceutical company focused on discovering, developing and
commercializing medicines that are designed to leverage ribonucleic
acid interference (RNAi) to silence selectively genes that cause or
contribute to disease. Using our proprietary GalXC™ and GalXC-Plus™
RNAi technologies, Dicerna is committed to developing RNAi-based
therapies with the potential to treat both rare and more prevalent
diseases. By silencing disease-causing genes, Dicerna’s GalXC
platform has the potential to address conditions that are difficult
to treat with other modalities. Initially focused on
disease-causing genes in the liver, Dicerna has continued to
innovate and is exploring new applications of its RNAi technology
with GalXC-Plus, which expands on the functionality and application
of our flagship liver-targeted GalXC technology to tissues and cell
types outside the liver, and has the potential to treat diseases
across multiple therapeutic areas. In addition to our own pipeline
of core discovery and clinical candidates, Dicerna has established
collaborative relationships with some of the world’s leading
pharmaceutical companies, including Novo Nordisk A/S, Roche, Eli
Lilly and Company, Alexion Pharmaceuticals, Inc., Boehringer
Ingelheim International GmbH and Alnylam Pharmaceuticals, Inc.
Between Dicerna and our collaborative partners, we currently have
more than 20 active discovery, preclinical or clinical programs
focused on cardiometabolic, viral, chronic liver and
complement-mediated diseases, as well as neurodegenerative diseases
and pain. At Dicerna, our mission is to interfere – to silence
genes, to fight disease, to restore health. 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 our product candidates and the development thereof,
such as the Company’s PHYOX clinical development program for
nedosiran in PH; the impact of the results from the PHYOX2 trial of
nedosiran for the potential treatment of PH1; the therapeutic
potential of our product candidates, such as nedosiran; our belief
regarding the unmet need to provide new therapeutic options and to
build an understanding of disease biology across the PH subtypes;
the impact of data from the real-world healthcare; the Company’s
refined near-term nedosiran strategy to focus primarily on the
treatment of PH1; our business and operations, including the
discovery, development and commercialization of our product
candidates and technology platform, and the therapeutic potential
thereof; our collaboration with partners and any potential future
collaborations.
The process by which investigational therapies, such as
nedosiran, 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 filings on Forms 10-K and
10-Q 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 by us and our collaborative
partners and any potential future collaborations, including any
potential commercialization partner(s) for nedosiran; the potential
for additional or future data to alter initial, interim and
preliminary results of clinical trials; the impact of the ongoing
COVID-19 pandemic on our business operations and those of the third
parties and collaboration partners with whom we engage; the timing,
plans and reviews by regulatory authorities of our marketing
applications, such as for our planned submission to the FDA of an
NDA for nedosiran in PH1; the ability to secure, maintain and
realize the intended benefits of collaborations with partners,
including any commercialization partner(s) for nedosiran; market
acceptance for approved products and innovative therapeutic
treatments, such as nedosiran; competition; the possible impairment
of, inability to obtain, and costs to obtain intellectual property
rights; possible safety or efficacy concerns that could emerge as
new data are generated in R&D and following commercialization;
and 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.
1 Hopp K, et al. J Am Soc Nephrol. 2015;26(10):2559-2570 and
U.S. Census Bureau population on a date: February 20, 2020. United
States Census Bureau website, 2020.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20211104006090/en/
Media: Amy Trevvett +1 617-612-6253 atrevvett@dicerna.com
Investors: Kristen K. Sheppard, Esq. +1 617-514-2275
ksheppard@dicerna.com
Dicerna Pharmaceuticals (NASDAQ:DRNA)
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