Centessa Pharmaceuticals plc (“Company”) (Nasdaq: CNTA), together
with subsidiary Palladio Biosciences, Inc. (“Palladio”), today
announced the initiation of active recruitment of the global ACTION
Study, a pivotal Phase 3 clinical trial evaluating lixivaptan as a
potential treatment for Autosomal Dominant Polycystic Kidney
Disease (ADPKD). Additionally, the Company reported initial safety
data from four subjects who participated in the ongoing open-label
ALERT Study of ADPKD subjects who previously discontinued JYNARQUE®
(tolvaptan) due to liver toxicity and announced the Notice of
Allowance for a U.S. Patent application covering use of lixivaptan
in ADPKD.
“Patients with ADPKD need alternative treatment options to the
currently approved therapy, which is associated with a Risk
Evaluation and Mitigation Strategies (REMS) program due to its side
effect profile. I have been encouraged by the pharmacodynamic and
tolerability data generated to date with lixivaptan and look
forward to seeing the benefit and safety data from the upcoming
pivotal ACTION Study,” said Vicente Torres, MD, PhD, Professor of
Medicine, Mayo Clinic and Chairman of the Steering Committee and
Principal Investigator of the ACTION Study.
“We are thrilled to begin the registrational ACTION Study so we
can further evaluate lixivaptan’s potential as a new treatment
option in the broader ADPKD patient population,” said Saurabh Saha,
MD, PhD, Chief Executive Officer of Centessa. “Furthermore, the
initial safety data from the ALERT Study in subjects who have
stopped JYNARQUE due to liver toxicity continues to support the
differentiated safety and tolerability profile of lixivaptan. In
addition, the allowed claims addressed in the recently issued
Notice of Allowance from the U.S. Patent & Trademark Office
should provide patent protection for the covered use of lixivaptan
in ADPKD treatment in the U.S. to at least 2038.”
“The initial safety data we shared
today from the ALERT Study is similar to the case study we
previously reported from the Mayo Clinic and provides additional
evidence of lixivaptan’s tolerability profile, especially in a
group of ADPKD subjects who had previous liver chemistry
abnormalities while taking tolvaptan,” said Neil Shusterman, MD,
Chief Medical Officer of Palladio. “We look forward to bringing
this potential new treatment option to ADPKD patients.”
ACTION Study Initiation
Recruitment has commenced in the global Phase 3 ACTION Study
which consists of a two-arm, double-blind, placebo-controlled,
randomized phase (Part 1) followed by a single-arm, open-label
phase (Part 2). The study will evaluate the benefit and safety of
lixivaptan that has been titrated to a maximum tolerated dose
between 100-200 mg BID in subjects with ADPKD and a Mayo Clinic MRI
imaging classification of 1C, 1D or 1E and an estimated glomerular
filtration rate (eGFR) ≥25 and ≤90 mL/min/1.73 m2.
The primary analysis of the ACTION Study will be performed at
the end of Part 1 of the trial, which will have a 2:1 randomization
(lixivaptan:placebo) and is designed to
assess lixivaptan in slowing the decline in renal
function as measured at 52 weeks by the difference in eGFR between
the lixivaptan-treated and placebo-treated subjects. Final
efficacy measurements at the end of the double-blind period will be
conducted while the subject is off study drug over three successive
clinic visits. The sample size of the study will be up to 1,350
subjects to provide 90% power to the primary analysis, aiming to
detect a 1.4 mL/min/1.73 m2 eGFR difference between
lixivaptan-treated and placebo-treated subjects. Thirteen clinical
sites have been initiated and the trial is ultimately expected to
enroll subjects across more than 200 sites in more than 20
countries. As previously disclosed, the Company expects to dose the
first subject in the ACTION Study by the first quarter of 2022.
All subjects successfully completing Part 1 are expected to
continue into Part 2 of the study and will be treated with
lixivaptan for an additional 54-56 weeks to further assess the
sustainability of the potential benefit on eGFR change over a
two-year period. Consistent with Part 1, updated efficacy
measurements will be conducted off study drug. Both parts of the
study will contribute to further establishing the safety profile
of lixivaptan. An independent data monitoring committee will
periodically review all safety data including the liver chemistry
data for all subjects throughout the study. The Company anticipates
completing enrollment in 2H 2023 and, pending positive data, plans
to submit a New Drug Application (NDA) after completion of the
one-year double-blind portion of the study (Part 1).
ALERT Study Update
The Company also reported initial safety data from the ongoing
open-label ALERT Study of ADPKD subjects who previously
discontinued JYNARQUE® (tolvaptan) due to liver toxicity. The ALERT
Study is designed to assess liver and non-liver safety in subjects
who previously experienced liver chemistry test abnormalities that
met the criteria for likely drug-induced liver injury (DILI) while
being treated with tolvaptan and who permanently discontinued the
drug. Subjects in the ALERT Study undergo up to 8 weeks of
screening followed by a three-week baseline measurement period and
then a three- to six-week titration phase with lixivaptan, with
weekly liver chemistry test monitoring during the baseline and
titration phases. During the maintenance phase, liver chemistry
tests are obtained every four weeks. The primary outcome measure in
the study is the proportion of subjects who develop alanine
aminotransferase (ALT) levels >3x ULN adjudicated to be related
to lixivaptan resulting in discontinuation of the study drug.
To date, ten subjects have entered screening, five failed
screening, and one failed the baseline measurement period. The
four subjects who enrolled in the study had cases of DILI while
being treated with tolvaptan for ADPKD and had ALT elevations that
peaked between 1.8x and 3.5x ULN and did not return to below ULN
until 23 to 140 days after tolvaptan use was
discontinued. Each of these subjects was successfully titrated
to a maintenance dose of lixivaptan of either 100 mg BID (one
subject) or 200 mg BID (three subjects) and entered the maintenance
phase of the study.
As of the most recent data cutoff (December 3, 2021), three out
of four subjects remain on lixivaptan with the longest treatment
duration being 366 days, and the remaining subjects at 174 days and
172 days on treatment. One subject successfully titrated to
200 mg BID lixivaptan but withdrew consent after 93 days of dosing.
No subjects have had clinically meaningful ALT elevations
attributed to lixivaptan and no subjects met the pre-specified
stopping criteria of an ALT level >3x ULN.
The ALERT Study remains open for enrollment of subjects who have
had a confirmed case of DILI while being treated with tolvaptan.
Most subjects who stop treatment with tolvaptan due to liver
toxicity are also eligible for enrollment in the ACTION Study,
which is now the primary focus of the Company’s recruitment
efforts.
Notice of Allowance for Key Lixivaptan U.S. Patent
Application
On December 3, 2021, the U.S. Patent and Trademark Office issued
a Notice of Allowance for Palladio’s patent application entitled
“Formulations of Lixivaptan for the Treatment of Polycystic
Disease,” which has claims drawn to using a divided dose regimen of
lixivaptan in treating ADPKD. The anticipated patent term
would expire June 8, 2038, before consideration of any applicable
patent term extensions or adjustments.
About Centessa PharmaceuticalsCentessa
Pharmaceuticals plc (“Centessa”) aims to bring impactful new
medicines to patients by combining the strengths of an
asset-centric model with the benefits of scale and diversification
typical of larger R&D organizations. The asset-centric model
refers to a highly specialized, singular-focused company that is
led by a team of well-recognized subject matter experts. Centessa’s
asset-centric companies’ programs range from discovery-stage to
late-stage development and include diverse therapeutic areas such
as oncology, hematology, immunology/inflammation, neuroscience,
hepatology, pulmonology and nephrology. For more information, visit
www.centessa.com.
About Palladio
BiosciencesPalladio Biosciences, Inc. (“Palladio”) was
created with the goal of developing transformative medicines for
rare diseases of the kidney. Palladio is actively investigating the
potential of its lead product candidate, lixivaptan, in patients
with autosomal dominant polycystic kidney disease (ADPKD).
About LixivaptanLixivaptan is an
investigational, oral, nonpeptide selective vasopressin V2 receptor
antagonist in development for the potential treatment of
ADPKD. The development program is designed to show that
lixivaptan can slow the decline in renal function that is typically
observed in ADPKD patients while avoiding the liver safety issues
associated with JYNARQUE®, a form of branded tolvaptan indicated
for ADPKD, which is the only drug currently approved for ADPKD.
Lixivaptan has been granted Orphan Drug Designation from the
FDA.
About the ACTION Study The ACTION Study is an
ongoing two-arm Phase 3 pivotal trial consisting of a double-blind,
placebo-controlled, randomized phase (Part 1) followed by a
single-arm open-label phase (Part 2) to assess the efficacy and
safety of lixivaptan in subjects with ADPKD.
In Part 1, all subjects will receive placebo and all subjects
will receive lixivaptan to establish dosing. Up to 1,350 subjects
will be randomized 2:1 to receive lixivaptan or placebo. After 52
weeks of randomized treatment, the administration of study drug
will be paused, and final eGFR assessments for Part 1 will be
obtained during three follow-up visits starting over a period of 28
days.
All subjects completing Part 1 are
expected to continue into Part 2 of the study and be treated with
the active drug, lixivaptan, for an additional 54-56 weeks. At the
end of that time, study drug will be discontinued, and final eGFR
assessments for Part 2 will be obtained during three follow-up
visits starting over a period of 28 days. Further information on
the study can be found at clinicaltrials.gov at the following
link:https://clinicaltrials.gov/ct2/show/NCT04064346
About the ALERT Study The ALERT Study is an
ongoing open-label, repeat-dose study designed to assess liver and
non-liver safety in subjects who previously experienced liver
chemistry test abnormalities while treated with tolvaptan and were
permanently discontinued from the drug for that reason. Subjects
will be enrolled and treated with lixivaptan for 52 weeks
following titration to an optimal dose. Further information on the
study can be found at clinicaltrials.gov at the following link:
https://clinicaltrials.gov/ct2/show/NCT04152837
About ADPKDADPKD is a
rare hereditary disorder characterized by the formation and
enlargement of cysts in the kidney, liver, and other organs. It is
the fourth leading cause of kidney failure in the U.S. and one of
the most common inherited genetic diseases in humans, occurring
equally in women and men, in all races, globally. There are an
estimated 140,000 diagnosed ADPKD patients in the U.S.
Forward Looking
Statements This press release contains
forward-looking statements. These statements may be identified by
words such as “aims,” “anticipates,” “believes,” “could,”
“estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,”
“plans,” “possible,” “potential,” “seeks,” “will,” and variations
of these words or similar expressions that are intended to identify
forward-looking statements. Any such statements in this press
release that are not statements of historical fact may be deemed to
be forward-looking statements, including statements related to the
Company’s ability to deliver impactful medicines to patients; the
ability of our key executives to drive execution of the Company’s
portfolio of programs; our asset-centric business model and the
intended advantages and benefits thereof; research and clinical
development plans; the scope, progress, results and costs of
developing our product candidates or any other future product
candidates; the design, scope and purpose of our ongoing ALERT and
ACTION studies; the development and therapeutic potential of our
product candidates, including lixivaptan; strategy; regulatory
matters, including the timing and likelihood of success of
obtaining approvals to initiate or continue clinical trials or
market any products; and market size and opportunity for our
product candidates.
Any forward-looking statements in this
press release are based on our current expectations, estimates and
projections only as of the date of this release and are subject to
a number of risks and uncertainties that could cause actual results
to differ materially and adversely from those set forth in or
implied by such forward-looking statements. These risks and
uncertainties include, but are not limited to, risks related to our
ability to protect and maintain our intellectual property position;
business, regulatory, economic and competitive risks,
uncertainties, contingencies and assumptions about the Company;
risks inherent in developing products and technologies; future
results from our ongoing and planned clinical trials; our ability
to obtain adequate financing, including through our financing
facility with Oberland, to fund our planned clinical trials and
other expenses; trends in the industry; the legal and regulatory
framework for the industry, including the receipt and maintenance
of clearances to conduct or continue clinical testing; future
expenditures risks related to our asset-centric corporate model;
the risk that any one or more of our product candidates will not be
successfully developed and commercialized; the risk that the
results of preclinical studies or clinical studies will not be
predictive of future results in connection with future studies; and
risks related to the COVID-19 pandemic including the effects of the
Delta, Omicron and any other variants. These and other risks
concerning our programs and operations are described in additional
detail in our most recent Form 10-Q, which is on file with the SEC.
We explicitly disclaim any obligation to update any forward-looking
statements except to the extent required by law.
Contacts:
Investors: |
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Jennifer Porcelli, Head of
Investor Relations |
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Centessa Pharmaceuticals |
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jennifer.porcelli@centessa.com |
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Media: |
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Dan Budwick, 1AB |
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dan@1abmedia.com |
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