In patients with Cushing’s syndrome maintained
on Recorlev, a lower baseline mUFC was associated with higher
cortisol normalization rate.
Lower mUFC at baseline was also associated with
lower maintenance dose requirements and lower rates of potentially
clinically important liver-related adverse events and liver test
abnormalities.
The SONICS study previously showed that
Recorlev treatment was effective at normalizing cortisol across the
spectrum of Cushing’s syndrome severity.
Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), a growth-oriented
biopharmaceutical company committed to improving patients’ lives by
developing and commercializing innovative products across a range
of therapies, today announced it presented a post-hoc analysis from
its previously published SONICS study on the effects of
levoketoconazole (Recorlev®) in adults with Cushing’s syndrome at
ENDO 2024 in Boston, June 1-4, 2024.
“The results of this analysis suggest that patients with
Cushing’s syndrome/disease with lower mUFC(s) normalize at a higher
rate than those with more severe disease and may require lower
doses of Recorlev and experience lower rates of liver-related
adverse events. This exploratory analysis brings further
perspective to the importance of individualizing and tailoring
medical management,” said James Meyer, PharmD, Xeris’ Senior
Director, Publications and Medical Communications.
Title: Effects of Levoketoconazole on
24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline
mUFC in Adults with Cushing’s Syndrome: A Post-hoc Analysis
(SAT-085)
This post-hoc exploration included all enrolled patients in
SONICS who were treated and had a post-baseline mUFC, aiming to
further elucidate relationships between baseline biochemical
disease severity, drug dose, and intermediate-term mUFC response.
For the current analyses, 92 patients treated with levoketoconazole
and with baseline mUFC measurement (modified ITT) were stratified
into 3 baseline mUFC subgroups: Group 1 (≤ 2.5x upper limit of
normal (ULN)); Group 2 (>2.5x to ≤ 5x ULN); or Group 3 (>5x
ULN) and analyzed in respect to mUFC response, average daily dose,
and adverse events following 6 months of maintenance therapy.
Groups 1 and 2 were similar in baseline characteristics; whereas
Group 3 differed with younger age, fewer female participants, more
recently diagnosed, and more frequently on prior therapy.
Group 2 (Baseline mUFC 267.9 nmol/D) had the highest apparent
mUFC response rate (12/33 [36.4%]), 95% CI 0.20, 0.54) as compared
with Group 1 (Baseline mUFC 498.7 nmol/D) (12/38 [31.6%], 95% CI
0.16, 0.47) or Group 3 (Baseline mUFC 1672.8 nmol/D) (5/21 [23.8%];
95% CI 0.01, 0.55); Group 3 having a notably lower response.
Daily doses of levoketoconazole were related to baseline mUFC.
Thus, Group 3 used a nominally higher average daily dose (631 mg
and 741 mg) during maintenance therapy and at the last dose in the
6-month maintenance phase (regardless of completion status) than
Group 1 (475 mg and 545 mg) or Group 2 (548 mg and 611 mg).
Group 3 had more liver-related AEs of special interest than
Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to
discontinuation (24% vs 12% or 16%). Group 3 had a higher incidence
of liver test (ALT, AST, GGT) abnormalities compared to Group 1 and
Group 2.
This post hoc analysis demonstrated:
- Normalization of mUFC with levoketoconazole in Cushing’s
syndrome patients maintained on levoketoconazole in the SONICS
study for up to 6 months appeared to vary inversely with baseline
mUFC.
- Lower mUFC at baseline was also associated with lower
maintenance dose requirements and lower rates of potentially
clinically important liver-related AEs and liver test
abnormalities.
- Whether observed baseline characteristic differences between
the highest tertile of baseline mUFC and the 2 lower tertiles were
simply coincidental to or confounders or mediators of the described
relationships with mUFC remains to be explored.
About Cushing’s Syndrome
Endogenous Cushing’s syndrome is a rare, serious, and
potentially fatal endocrine disease caused by chronic elevated
cortisol exposure–often the result of a benign tumor of the
pituitary gland. This benign tumor tells the body to overproduce
high levels of cortisol for a sustained period of time, which often
results in characteristic physical signs and symptoms that are
distressing to patients. The disease is most common among adults
between the ages of 30–50, and it affects women three times more
often than men. Women with Cushing's syndrome may experience a
variety of health issues including menstrual problems, difficulty
becoming pregnant, excess male hormones (androgens), primarily
testosterone, which can cause hirsutism (growth of coarse body hair
in a male pattern), oily skin, and acne.3
Additionally, the multisystem complications of the disease are
potentially life threatening. These include metabolic changes such
as high blood sugar or diabetes, high blood pressure, high
cholesterol, fragility of various tissues including blood vessels,
skin, muscle, and bone, and psychological disturbances such as
depression, anxiety, and insomnia.3 Untreated, the five-year
survival rate is only approximately 50%.4
About Recorlev®
Recorlev® (levoketoconazole) is a cortisol synthesis inhibitor
for the treatment of endogenous hypercortisolemia in adult patients
with Cushing’s syndrome for whom surgery is not an option or has
not been curative.1 Endogenous Cushing’s syndrome is a rare but
serious and potentially lethal endocrine disease caused by chronic
elevated cortisol exposure.2 Recorlev is the pure 2S,4R enantiomer
of ketoconazole, a steroidogenesis inhibitor.1 Recorlev has
demonstrated in two successful Phase 3 studies to significantly
reduce mean urine free cortisol.1
The Phase 3 program for Recorlev included SONICS and LOGICS, two
multinational studies designed to evaluate the safety and efficacy
of Recorlev when used to treat endogenous Cushing’s syndrome. The
SONICS study met its primary and secondary endpoints, significantly
reducing and normalizing mean urinary free cortisol concentrations
without a dose increase.1,2 The LOGICS study, which met its primary
endpoint and key secondary endpoint, was a double-blind,
placebo-controlled randomized-withdrawal study of Recorlev that was
designed to supplement the efficacy and safety information provided
by SONICS.1 The ongoing open-label OPTICS study will gather further
useful information related to the long-term use of Recorlev.
Recorlev was approved by the US FDA in December 2021 and
received orphan drug designation from the FDA and the European
Medicines Agency for the treatment of endogenous Cushing's
syndrome.
Indication & Important Safety Information for
Recorlev®
BOXED WARNING: HEPATOTOXICITY AND QT PROLONGATION
HEPATOTOXICITY
Cases of hepatotoxicity with fatal outcome or requiring liver
transplantation have been reported with oral ketoconazole. Some
patients had no obvious risk factors for liver disease. Recorlev is
associated with serious hepatotoxicity. Evaluate liver enzymes
prior to and during treatment.
QT PROLONGATION
Recorlev is associated with dose-related QT interval
prolongation. QT interval prolongation may result in
life-threatening ventricular dysrhythmias such as torsades de
pointes. Perform ECG and correct hypokalemia and hypomagnesemia
prior to and during treatment.
INDICATION
Recorlev is a cortisol synthesis inhibitor indicated for the
treatment of endogenous hypercortisolemia in adult patients with
Cushing’s syndrome for whom surgery is not an option or has not
been curative.
Limitations of Use
Recorlev is not approved for the treatment of fungal
infections.
CONTRAINDICATIONS
- Cirrhosis, acute liver disease or poorly controlled chronic
liver disease, baseline AST or ALT > 3 times the upper limit of
normal, recurrent symptomatic cholelithiasis, a prior history of
drug induced liver injury due to ketoconazole or any azole
antifungal therapy that required discontinuation of treatment, or
extensive metastatic liver disease.
- Taking drugs that cause QT prolongation associated with
ventricular arrythmias, including torsades de pointes.
- Prolonged QTcF interval > 470 msec at baseline, history of
torsades de pointes, ventricular tachycardia, ventricular
fibrillation, or prolonged QT syndrome.
- Known hypersensitivity to levoketoconazole, ketoconazole or any
excipient in Recorlev.
- Taking certain drugs that are sensitive substrates of CYP3A4 or
CYP3A4 and P-gp.
WARNINGS AND PRECAUTIONS
Hepatotoxicity
Serious hepatotoxicity has been reported in patients receiving
Recorlev, irrespective of the dosages used or the treatment
duration. Drug-induced liver injury (peak ALT or AST greater than 3
times upper limit of normal) occurred in patients using Recorlev.
Avoid concomitant use of Recorlev with hepatotoxic drugs. Advise
patient to avoid excessive alcohol consumption while on treatment
with Recorlev. Routinely monitor liver enzymes and bilirubin during
treatment.
QT Prolongation
Use Recorlev with caution in patients with other risk factors
for QT prolongation, such as congestive heart failure,
bradyarrythmias, and uncorrected electrolyte abnormalities, with
more frequent ECG monitoring considered. Routinely monitor ECG and
blood potassium and magnesium levels during treatment.
Hypocortisolism
Recorlev lowers cortisol levels and may lead to hypocortisolism
with a potential for life-threatening adrenal insufficiency.
Lowering of cortisol levels can cause nausea, vomiting, fatigue,
abdominal pain, loss of appetite, and dizziness. Significant
lowering of serum cortisol levels may result in adrenal
insufficiency that can be manifested by hypotension, abnormal
electrolyte levels, and hypoglycemia. Routinely monitor 24-hour
urine free cortisol, morning serum or plasma cortisol, and
patient’s signs and symptoms for hypocortisolism during
treatment.
Hypersensitivity Reactions
Hypersensitivity to Recorlev has been reported. Anaphylaxis and
other hypersensitivity reactions including urticaria have been
reported with oral ketoconazole.
Risks Related to Decreased
Testosterone
Recorlev may lower serum testosterone in men and women.
Potential clinical manifestations of decreased testosterone
concentrations in men may include gynecomastia, impotence and
oligospermia. Potential clinical manifestations of decreased
testosterone concentrations in women include decreased libido and
mood changes.
ADVERSE REACTIONS
Most common adverse reactions (incidence > 20%) are
nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic
hypertension, headache, hepatic injury, abnormal uterine bleeding,
erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper
respiratory infection, myalgia, arrhythmia, back pain,
insomnia/sleep disturbances, and peripheral edema.
DRUG INTERACTIONS
- Consult approved product labeling for drugs that are substrates
of CYP3A4, P-gp, OCT2, and MATE prior to initiating Recorlev.
- Sensitive CYP3A4 or CYP3A4 and P-gp
Substrates: Concomitant use of Recorlev with these
substrates is contraindicated or not recommended.
- Atorvastatin: Use lowest
atorvastatin dose possible and monitor for adverse reactions for
dosages exceeding 20 mg daily.
- Metformin: Monitor glycemia,
kidney function, and vitamin B12 and adjust metformin dosage as
needed.
- Strong CYP3A4 Inhibitors or
Inducers: Avoid use of these drugs 2 weeks before and during
Recorlev treatment.
- Gastric Acid Modulators: See Full
Prescribing Information for recommendations regarding concomitant
use with Recorlev.
USE IN SPECIFIC POPULATIONS
Lactation: Advise not to breastfeed
during treatment and for one day after final dose.
To report SUSPECTED ADVERSE REACTIONS, contact Xeris
Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
Please see Full Prescribing Information
including Boxed Warning.
About Xeris
Xeris (Nasdaq: XERS) is a growth-oriented biopharmaceutical
company committed to improving patient lives by developing and
commercializing innovative products across a range of therapies.
Xeris has three commercially available products; Gvoke®, a
ready-to-use liquid glucagon for the treatment of severe
hypoglycemia, Keveyis®, a proven therapy for primary periodic
paralysis, and Recorlev® for the treatment of endogenous Cushing’s
syndrome. Xeris also has a robust pipeline of development programs
to extend the current marketed products into important new
indications and uses and bring new products forward using its
proprietary formulation technology platforms, XeriSol™ and
XeriJect®, supporting long-term product development and commercial
success.
Xeris Biopharma Holdings is headquartered in Chicago, IL. For
more information, visit www.xerispharma.com, or follow us on X,
LinkedIn, or Instagram.
Forward-looking Statement
Any statements in this press release other than statements of
historical fact are forward-looking statements. Forward-looking
statements include, but are not limited to, statements about future
expectations, plans and prospects for Xeris Biopharma Holdings,
Inc. including statements regarding expectations for the release of
clinical data, post hoc analyses or results from clinical trials,
including the SONICS study, the market and therapeutic potential of
its products and product candidates, including the levoketoconazole
(Recorlev®), the potential utility of its formulation platforms and
other statements containing the words “will,” “would,” “continue,”
“expect,” “should,” “anticipate” and similar expressions,
constitute forward-looking statements within the meaning of The
Private Securities Litigation Reform Act of 1995. These
forward-looking statements are based on numerous assumptions and
assessments made in light of Xeris’ experience and perception of
historical trends, current conditions, business strategies,
operating environment, future developments, geopolitical factors,
and other factors it believes appropriate. By their nature,
forward-looking statements involve known and unknown risks and
uncertainties because they relate to events and depend on
circumstances that will occur in the future. The various factors
that could cause Xeris’ actual results, performance or
achievements, industry results and developments to differ
materially from those expressed in or implied by such
forward-looking statements, include, but are not limited to, its
financial position and need for financing, including to fund its
product development programs or commercialization efforts, whether
its products will achieve and maintain market acceptance in a
competitive business environment, its reliance on third-party
suppliers, including single-source suppliers, its reliance on third
parties to conduct clinical trials, the ability of its product
candidates to compete successfully with existing and new drugs, and
its and collaborators’ ability to protect its intellectual property
and proprietary technology. No assurance can be given that such
expectations will be realized and persons reading this
communication are, therefore, cautioned not to place undue reliance
on these forward-looking statements. Additional risks and
information about potential impacts of financial, operational,
economic, competitive, regulatory, governmental, technological, and
other factors that may affect Xeris can be found in Xeris’ filings,
including its most recently filed Annual Report on Form 10-K filed
with the Securities and Exchange Commission, the contents of which
are not incorporated by reference into, nor do they form part of,
this communication. Forward-looking statements in this
communication are based on information available to us, as of the
date of this communication and, while we believe our assumptions
are reasonable, actual results may differ materially. Subject to
any obligations under applicable law, we do not undertake any
obligation to update any forward-looking statement whether as a
result of new information, future developments or otherwise, or to
conform any forward-looking statement to actual results, future
events, or to changes in expectations.
1. Recorlev [prescribing information]. Chicago, IL: Xeris
Pharmaceuticals, Inc.; 2021. 2. Fleseriu M, et al. Lancet Diabetes
Endocrinol. 2019;7(11):855-865. 3. Pivonello R et al. Lancet
Diabetes Endocrinol. 2016; 4: 611-29. 4. Plotz CM, et al. Am J Med.
1952 November;13(5):597-614.
Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM,
Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to
Xeris Pharmaceuticals, Inc. PANTHERx Rare Pharmacy is a service
mark of PANTHERx Rare, LLC. All other trademarks referenced herein
are the property of their respective owners. All rights reserved.
US-PR-22-00001 1/22
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version on businesswire.com: https://www.businesswire.com/news/home/20240603311134/en/
Investor Contact Allison Wey Senior Vice President,
Investor Relations and Corporate Communications
awey@xerispharma.com
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