-
CAHtalyst™ Pediatric Study Met Primary and Key Secondary Endpoints,
with Crinecerfont Treatment Decreasing Androstenedione Levels and
Enabling Glucocorticoid Dose Reduction While Maintaining
Androstenedione Control
- 30%
of Crinecerfont Participants Achieved a Physiologic Glucocorticoid
Dose at Week 28 while Maintaining Androgen Control versus 0% of
Placebo Participants
-
Favorable Trends in Endpoints Reflecting Supraphysiologic
Glucocorticoid Dosing and Androgen Excess
-
Crinecerfont was Generally Well Tolerated
SAN
DIEGO, June 3, 2024 /PRNewswire/
-- Neurocrine Biosciences, Inc. (Nasdaq: NBIX) today announced
that the primary study results from its CAHtalyst™ Pediatric Phase
3 study investigating crinecerfont for the treatment of congenital
adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have
been published in The New England Journal of Medicine online
edition and will appear in a future print issue of the journal. The
CAHtalyst Pediatric Phase 3 study met the primary and key secondary
endpoints related to androgen reduction (during an initial
glucocorticoid-stable period) and glucocorticoid (GC) dose
reduction while maintaining androgen control. Favorable trends were
observed with endpoints that reflect the consequences of long-term
supraphysiologic glucocorticoid therapy and androgen excess. In
addition to appearing in The New England Journal of
Medicine, CAHtalyst Pediatric Phase 3 data were presented at
ENDO 2024 (Poster #SUN-441).
"In treating children with CAH, from the moment they are
diagnosed we are challenged with finding a balance between
supraphysiologic glucocorticoid dosing and the need to prevent
androgen excess. Tipping the scale too far one way or the other can
adversely impact growth and pubertal development," said Kyriakie
Sarafoglou, M.D., Professor, Department of
Pediatrics and Department of Experimental and Clinical
Pharmacology, Divisions of Endocrinology and Genetics &
Metabolism, at the University of
Minnesota. "Based on the CAHtalyst Pediatric study results,
crinecerfont represents a potential non-glucocorticoid therapeutic
approach to meet this challenge. In addition to meeting primary and
key secondary endpoints related to reducing elevated
androstenedione and supraphysiologic glucocorticoid dosing during
the 28-week study, treatment with crinecerfont also showed
favorable trends in ameliorating the consequences of the current
treatment paradigm, with reductions in body weight, improved
insulin resistance, and reduced hirsutism in females."
Crinecerfont is an investigational, oral, selective
corticotropin-releasing factor type 1 receptor (CRF1)
antagonist being developed to reduce and control excess
adrenocorticotropic hormone (ACTH) and adrenal androgens through a
GC-independent mechanism for the treatment of CAH.
"The outstanding results achieved in the CAHtalyst Pediatric
Phase 3 study demonstrate the ability of crinecerfont to reduce
elevated androstenedione levels while also enabling reduction in
supraphysiologic glucocorticoid doses to more physiologic level
dosing while maintaining androgen control in pediatric participants
with CAH," said Eiry W. Roberts, M.D., Chief Medical Officer at
Neurocrine Biosciences. "This could potentially enable
physicians to fundamentally change their approach to the important
task of controlling androgens in pediatric patients with
crinecerfont, without the need for long-term supraphysiologic
steroid dosing, thus removing the burden that long-term excess
glucocorticoid use places on development and outcome for these
patients."
The CAHtalyst Pediatric Phase 3 global registrational study was
conducted in 103 participants and designed to evaluate the safety,
efficacy, and tolerability of crinecerfont in children and
adolescents ages 2 to 17 years with CAH due to 21-hydroxylase
deficiency. Over 95% of participants completed the 28-week
double-blind, placebo-controlled treatment period of the study with
minimal missing data.
The Phase 3 Pediatric study met the primary endpoint of change
from baseline in androstenedione (key adrenal androgen) following
the initial 4-week GC-stable period.
- Crinecerfont treatment led to a significantly greater reduction
in androstenedione compared to an increase with placebo at Week 4
(least squares mean [LSM] change from baseline of -196.8 ng/dL
versus +71.0 ng/dL, with least squares mean difference [LSMD] of
-268 ng/dL, P < 0.001). Actual value is P < 0.0001. (Figure
A)
After Week 4 and through Week 28, mean androstenedione remained
below baseline in the context of reduced GC dose with crinecerfont
but increased above baseline in the placebo group despite increased
GC dose, highlighting the challenge of maintaining androgen control
even with supraphysiologic GC doses in pediatric patients enrolled
in this trial.
The Phase 3 Pediatric study also met the key secondary endpoint
of percent change from baseline in GC dose (while maintaining
androstenedione control) and the secondary endpoint of achievement
of reduction to a physiologic GC dose (while maintaining
androstenedione control) at Week 28:
- Crinecerfont treatment led to a significantly greater GC dose
reduction at Week 28 while maintaining androstenedione control
compared to placebo (LSM change from baseline of -18% versus +5.6%,
with LSMD of -23.5%; P < 0.001). Actual value is P < 0.0001.
(Figure C)
- Importantly, 30% of crinecerfont-treated participants achieved
a physiologic GC dose (≤ 11 mg/m2/day hydrocortisone
equivalents) at Week 28 while maintaining androstenedione control,
compared to zero participants in the placebo group (nominal P-value
= 0.0009). (Figure D)
Despite the short-term duration of this Phase 3 study, favorable
trends were observed for endpoints associated with long-term
supraphysiologic GC therapy such as body mass index standard
deviation score and insulin resistance that were encouraging
considering the relatively short time frame of reduced GC dose. In
addition, there was reduction in hirsutism (excessive hair growth)
in female participants and improvement in the androstenedione to
testosterone ratio in male participants.
Crinecerfont was generally well tolerated, with the most common
adverse events being headache, fever and vomiting. There were no
adrenal crises in either group. Few serious adverse events
occurred, with none assessed as related to crinecerfont, and there
were few discontinuations due to adverse events. No events of
adrenal crisis were reported during the double-blind period, and
the incidence of adverse events leading to glucocorticoid stress
dosing was similar in the crinecerfont and placebo groups.
Note: P-values in the text and figures reflect the Journal's
convention of calculating to two significant figures. Actual
P-values to three significant figures are also provided. Figures
reflect observed means rather than the LSM and LSMD described in
the text.
Figures are from The New England Journal of Medicine,
Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal
Hyperplasia, Sarafoglou K, Kim M, Lodish M, et.al. This article was
published online on June 2, 2024.
Copyright © 2024 Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
About Congenital Adrenal Hyperplasia
Congenital
adrenal hyperplasia (CAH) is a rare genetic condition that results
in an enzyme deficiency that alters the production of adrenal
hormones which are essential for life. Approximately 95% of CAH
cases are caused by a mutation that leads to deficiency of the
enzyme 21-hydroxylase (21-OHD). Severe deficiency of this enzyme
leads to an inability of the adrenal glands to produce cortisol
and, in approximately 75% of cases, aldosterone. If left untreated,
CAH can result in salt wasting, dehydration, and even death.
Glucocorticoids (GCs) are currently used not only to correct the
endogenous cortisol deficiency, but doses used are higher than
cortisol replacement needed (supraphysiologic) to lower the levels
of adrenocorticotropic hormone (ACTH) and adrenal androgens.
However, glucocorticoid treatment at supraphysiologic doses has
been associated with serious and significant complications of
steroid excess, including metabolic issues such as weight gain and
diabetes, cardiovascular disease, and osteoporosis. Additionally,
long-term treatment with supraphysiologic GC doses may have
psychological and cognitive impact, such as changes in mood and
memory. Adrenal androgen excess has been associated with abnormal
bone growth and development in pediatric patients, female health
problems such as acne, excess hair growth and menstrual
irregularities, testicular rest tumors in males, and fertility
issues in both sexes.
To learn more about CAH, click here.
About Crinecerfont and the CAHtalyst™
Studies
Crinecerfont is an investigational, oral,
selective corticotropin-releasing factor type 1 receptor
(CRF1) antagonist being developed to reduce and control
excess adrenocorticotropic hormone (ACTH) and adrenal androgens
through a glucocorticoid-independent mechanism for the treatment of
congenital adrenal hyperplasia (CAH) due to 21-hydroxylase
deficiency. Antagonism of CRF1 receptors in the
pituitary has been shown to decrease ACTH levels, which in turn
decreases the production of adrenal androgens and potentially the
symptoms associated with CAH. Our data demonstrate that lowering
adrenal androgen levels enables lower, more physiologic dosing of
glucocorticoids and thus could potentially reduce the complications
associated with exposure to greater than normal glucocorticoid
doses in patients with CAH.
The CAHtalyst™ Pediatric and Adult Phase 3 global registrational
studies are designed to evaluate the safety, efficacy, and
tolerability of crinecerfont in children and adolescents, and
adults respectively, with congenital adrenal hyperplasia due to
21-hydroxylase deficiency. The primary portions of the CAHtalyst
Phase 3 studies have completed and enrollment is closed, while
the open-label extension treatment portions of both studies
are ongoing. Data from the CAHtalyst Pediatric and CAHtalyst Adult
Phase 3 studies supported two New Drug Application submissions to
the U.S. Food and Drug Administration in April 2024.
To learn more about crinecerfont and the CAHtalyst studies,
click here.
About Neurocrine Biosciences, Inc.
Neurocrine Biosciences is a leading neuroscience-focused,
biopharmaceutical company with a simple purpose: to relieve
suffering for people with great needs, but few options. We are
dedicated to discovering and developing life-changing treatments
for patients with under-addressed neurological, neuroendocrine and
neuropsychiatric disorders. The company's diverse portfolio
includes FDA-approved treatments for tardive dyskinesia, chorea
associated with Huntington's disease, endometriosis* and uterine
fibroids*, as well as a robust pipeline including multiple
compounds in mid- to late-phase clinical development across our
core therapeutic areas. For three decades, we have applied our
unique insight into neuroscience and the interconnections between
brain and body systems to treat complex conditions. We relentlessly
pursue medicines to ease the burden of debilitating diseases and
disorders, because you deserve brave science. For more information,
visit neurocrine.com, and follow the company on LinkedIn, X
(formerly Twitter), and Facebook.
(*in collaboration with AbbVie)
The NEUROCRINE BIOSCIENCES Logo Lockup and YOU DESERVE BRAVE
SCIENCE are registered trademarks of Neurocrine Biosciences, Inc.
CAHtalyst is a trademark of Neurocrine Biosciences, Inc.
Forward-Looking Statements
In addition to historical
facts, this press release contains forward-looking statements that
involve a number of risks and uncertainties. These statements
include, but are not limited to, statements regarding the potential
benefits to be derived from crinecerfont. Among the factors that
could cause actual results to differ materially from those
indicated in the forward-looking statements include: the
crinecerfont NDAs may not be accepted for filing by the FDA or may
not obtain regulatory approval or such approval may be delayed;
additional regulatory submissions may not occur or be submitted in
a timely manner; the FDA may make adverse decisions regarding
crinecerfont; crinecerfont may not be found to be safe and/or
effective or may not prove to be beneficial to patients;
development activities for crinecerfont may not be completed on
time or at all; clinical development activities may be delayed for
regulatory or other reasons, may not be successful or replicate
previous and/or interim clinical trial results, or may not be
predictive of real-world results or of results in subsequent
clinical trials; competitive products and technological changes
that may limit demand for our products; uncertainties relating to
patent protection and intellectual property rights of third
parties; our dependence on third parties for development and
manufacturing activities related to crinecerfont, and our ability
to manage these third parties; our future financial and operating
performance; risks and uncertainties associated with the
commercialization of our products; and other risks described in the
Company's periodic reports filed with the Securities and Exchange
Commission, including without limitation the Company's quarterly
report on Form 10-Q for the quarter ended March 31, 2024. Neurocrine Biosciences disclaims
any obligation to update the statements contained in this press
release after the date hereof.
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