First prospective long-term levoketoconazole
study demonstrating a sustained effect on cortisol levels, as well
as improvements in biomarkers of Cushing’s syndrome (CS)
comorbidity, clinical signs and symptoms of CS and quality of life
(QoL).
With a median treatment duration of 15 months,
levoketoconazole was well tolerated and no new drug-related safety
signals were observed.
Further supports a role for levoketoconazole in
long-term therapy for patients with endogenous Cushing’s syndrome
(CS).
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 that the European Journal of
Endocrinology (EJE) published the extended evaluation (EE) results
of the SONICS study (NCT01838551) evaluating longer-term effects of
levoketoconazole on cortisol levels, biomarkers of Cushing’s
syndrome (CS) comorbidities, clinical signs and symptoms of CS, and
quality of life.1 The manuscript also reports findings from
pituitary adenoma imaging in the SONICS study.
For the first time, the longer-term effects of levoketoconazole
are reported from the EE phase of the previously published SONICS
study1,2. EE study participants (N=60) received maintenance
treatment with levoketoconazole (median exposure for entire study
of 15 months, range 7.9-22 months) with assessments scheduled at
Month 9 and Month 12. The majority (39/60 [65%]) received
levoketoconazole doses of 600 mg/day or less at the start of the EE
period. Forty-six (77%) patients completed the study (Month
12).
Key Study Findings:
- Sixty patients entered EE at Month 6; 61% (33/54 with data)
exhibited normal mean urinary free cortisol (mUFC). At Months 9 and
12, respectively, 55% (27/49) and 41% (18/44) of patients with data
had normal mUFC. In addition, reductions in late-night salivary
cortisol (LNSC) and random serum cortisol were observed at Month 6,
9, and 12.
- Mean fasting glucose, total and LDL-cholesterol, body weight,
body mass index, abdominal girth, Cushing QoL, and BDI-II scores
improved from study baseline at Months 9 and 12.
- Female patients reported significant mean decreases in
hirsutism score at all assessments; mean testosterone levels
decreased significantly at Month 6 and were maintained throughout
EE period
- Of 31 patients with tumor measurements at baseline and Month 12
or follow-up, largest tumor diameter was stable in 27 (87%)
patients, decreased in 1, and increased in 3 (largest increase 4
mm).
- Forty-six patients completed Month 12; 4 (6.7%) discontinued
during EE due to adverse events. The most common adverse events in
EE were arthralgia, headache, hypokalemia, and QT prolongation
(6.7% each)
- No patient experienced ALT or AST >3x ULN, QTcF interval
>460 msec, or adrenal insufficiency during EE.
"The results from this extended evaluation of the SONICS study
provide important new evidence in support of Recorlev and will help
inform clinicians’ decisions and individualization of medical
therapy for patients with endogenous CS,” said Dr. Ken Johnson,
Senior Vice President, Global Development and Medical Affairs at
Xeris. "I would like to extend our gratitude to all the
investigators, study coordinators and patients who participated in
the SONICS trial program. Their contributions are integral in our
mission to improve outcomes for patients with this rare,
debilitating, and life-threatening condition.”
Recorlev received Food and Drug Administration marketing
approval in December 2021. The initial approval was based upon
safety and efficacy data from two positive Phase 3 studies that
evaluated a combined study population of 166 patients, which was
representative of the adult drug-treated U.S. population with
Cushing’s syndrome.2 The SONICS study met its primary and key
secondary endpoints, significantly reducing and normalizing mean
urinary free cortisol concentrations without a dose increase
(detailed results here).2,3
LOGICS, a double-blind, placebo-controlled randomized-withdrawal
study that met its primary and key secondary endpoints, confirmed
the efficacy and safety of Recorlev in normalizing and maintaining
therapeutic response compared with placebo (detailed results
here).2
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.4
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.4 Untreated, the five-year
survival rate is only approximately 50%.5
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.2 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.2 Recorlev has
demonstrated in two successful Phase 3 studies to significantly
reduce mean urine free cortisol.2
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.2,3 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.2 The ongoing open-label OPTICS study will gather further
useful information related to the long-term use of Recorlev.
Recorlev 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.
INDICATIONS AND USAGE
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.
- 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 13% of 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. 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 patients’ 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®, the first and only FDA-approved 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
Twitter, LinkedIn, or Instagram.
Forward-Looking Statements
Any statements in this press release about future expectations,
plans and prospects for Xeris Biopharma Holdings, Inc., including
statements regarding the market and therapeutic potential of
Recorlev, results of the SONICS study, the market and therapeutic
potential of its products and product candidates, expectations
regarding clinical data or results from clinical trials, the timing
of clinical trials, the timing or likelihood of regulatory approval
and commercialization of its product candidates, the timing or
likelihood of expansion into additional markets, the potential
utility of its formulation platforms and other statements
containing the words “will,” “would,” “continue,” 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, 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. Various factors 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, including the impact of COVID-19 on our
business operations and clinical activities, our ability to fund
our product development programs or commercialization efforts,
whether our clinical trials demonstrate efficacy and safety to the
satisfaction of the FDA or other regulatory authorities, and
whether our products will achieve and maintain market acceptance.
No assurance can be given that our expectations will be realized
and persons reading this communication are, therefore, cautioned
not to place undue reliance on these forward-looking statements.
Additional information about economic, competitive, governmental,
technological, and other factors that may affect Xeris is set forth
in the "Risk Factors" section of the most recently filed Quarterly
Report on Form 10-Q filed with the U.S. Securities and Exchange
Commission, the contents of which are not incorporated by reference
into, nor do they form a part of, this communication.
Forward-looking statements in this communication are based upon
information available to Xeris, as of the date of this
communication and, while believed to be reasonable, actual results
may differ materially. Subject to any obligations under applicable
law, Xeris does 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. Fleseriu, M. et al. Euro J Endocrinol. (published online
ahead of print 2022), EJE-22-0506. 2. Recorlev [prescribing
information]. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021. 3.
Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7(11):855-865.
4. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4: 611-29.
5. Plotz CM, et al. Am J Med. 1952 November;13(5):597-61
Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM,
Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to
Xeris Pharmaceuticals, Inc. All other trademarks referenced herein
are the property of their respective owners. All rights
reserved.
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version on businesswire.com: https://www.businesswire.com/news/home/20221101005535/en/
Investor Contact Allison Wey Senior Vice President,
Investor Relations and Corporate Communications
awey@xerispharma.com 312-736-1237
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