KYPROLIS is an Amgen product that utilizes
Captisol® in its formulation
Approval based on the CANDOR and EQUULEUS
Studies
Ligand Pharmaceuticals Incorporated (NASDAQ: LGND)
announces that a major Captisol customer Amgen (NASDAQ: AMGN) has
received U.S. Food and Drug Administration (FDA) approval for the
expansion of the KYPROLIS® (carfilzomib) U.S. prescribing
information to include its use in combination with DARZALEX®
(daratumumab) plus dexamethasone (DKd) in once- and twice-weekly
dosing regimens for the treatment of patients with relapsed or
refractory multiple myeloma (R/R MM) who have received one to three
previous lines of therapy.
“We are proud of the ongoing work by Amgen to expand the use of
KYPROLIS in combination with other therapies. This FDA approval
came earlier than we had anticipated and allows for KYPROLIS to be
used with DARZALEX and dexamethasone in patients in the U.S. with
an incurable type of blood cancer,” said John Higgins, Chief
Executive Officer of Ligand. “We are very pleased with the impact
that Captisol-enabled medicines are having to-date in 2020 for the
treatment of multiple serious diseases, including
relapsed/refractory multiple myeloma and COVID-19.”
The CANDOR trial was the first Phase 3 randomized trial to
compare DKd versus KYPROLIS and dexamethasone (Kd) alone in R/R MM
patients. The study met its primary endpoint and resulted in a 37%
reduction in the risk of disease progression or death in patients
receiving DKd (HR=0.63; 95% CI: 0.464, 0.854; 1-sided
p-value=0.0014) compared to Kd alone.
In CANDOR, the safety of DKd was generally consistent with the
known safety profiles of the individual agents. The most frequently
reported (≥ 20% of subjects in either the DKd or Kd treatment arm)
treatment-emergent adverse events (AEs) included infusion-related
reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, upper
respiratory tract infection, thrombocytopenia, neutropenia,
lymphopenia, cough, dyspnea and insomnia, headache and back pain.
The incidence of treatment-emergent Grade 3 or higher, serious and
fatal AEs was higher in the DKd arm compared to the Kd arm. The
most common reason for fatal treatment-emergent AEs in both arms
was infection. The rate of treatment discontinuation due to AEs was
similar in both arms.
The expansion of KYPROLIS's prescribing information to include
once-weekly dosing of KYPROLIS within the DKd regimen was supported
by the open-label, multi-cohort Phase 1b EQUULEUS trial, in which
the safety and efficacy of DKd was assessed among R/R MM patients
using a once-weekly dosing regimen for KYPROLIS.
Amgen has submitted additional marketing applications
globally.
DARZALEX® is a registered trademark of Janssen Pharmaceutica
NV.
About Captisol®
Captisol is a patent-protected, chemically modified cyclodextrin
with a structure designed to optimize the solubility and stability
of drugs. Captisol was invented and initially developed by
scientists in the laboratories of Dr. Valentino Stella, University
Distinguished Professor at the University of Kansas’ Higuchi
Biosciences Center for specific use in drug development and
formulation. This unique technology has enabled several
FDA-approved products, including Amgen’s KYPROLIS®, Baxter
International’s NEXTERONE®, Gilead’s VEKLURY®, Acrotech
Biopharma L.L.C.’s and CASI Pharmaceuticals’ EVOMELA®,
Melinta Therapeutics’ BAXDELA™ and Sage Therapeutics’ ZULRESSO™.
There are many Captisol-enabled products currently in various
stages of development.
About CANDOR
CANDOR, a randomized, open-label Phase 3 study of KYPROLIS,
DARZALEX and dexamethasone (DKd) compared to KYPROLIS and
dexamethasone (Kd), has evaluated 466 relapsed or refractory
multiple myeloma patients who have received one to three prior
therapies. Patients were treated until disease progression. The
primary endpoint was progression-free survival (PFS), and the key
secondary endpoints were overall response rate, minimal residual
disease and overall survival. PFS was defined as time from
randomization until disease progression or death from any
cause.
In the first arm, patients received KYPROLIS twice weekly at 56
mg/m2 and dexamethasone in combination with DARZALEX. In the second
arm (control), patients received KYPROLIS twice weekly at 56 mg/m2
and dexamethasone.
CANDOR was initiated as part of a collaboration with Janssen,
and under the terms of the agreement, Janssen co-funded the study.
For more information about this trial, please visit
www.clinicaltrials.gov under trial identification number
NCT03158688.
About EQUULEUS
EQUULEUS was an open-label, Phase 1b, multi-cohort trial that
evaluated the combination of KYPROLIS with intravenous DARZALEX and
dexamethasone in 85 patients with relapsed or refractory multiple
myeloma who had received one to three prior lines of therapy.
KYPROLIS was evaluated at a starting dose of 20 mg/m2, which was
increased to 70 mg/m2 on Cycle 1, Day 8 and onward.
The most frequently reported all-grade, treatment-emergent AEs
(occurring in 20% or more of patients) were thrombocytopenia,
respiratory tract infection, anemia, nausea, fatigue, vomiting,
diarrhea, pyrexia, neutropenia, lymphopenia, infusion related
reactions, dyspnea, cough, insomnia, hypertension, headache and
back pain.
At a median follow-up of 16.6 months, the overall response rate
was 81% in all treated patients: 21% achieved a stringent complete
response, 14% a complete response, 33% a very good partial response
and 13% a partial response.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by
a recurring pattern of remission and relapse.1 It is a rare and
life-threatening disease that accounts for approximately one
percent of all cancers.2,3 Worldwide, approximately 160,000 people
are diagnosed with multiple myeloma each year, and 106,000 patient
deaths are reported on an annual basis.4
About KYPROLIS® (carfilzomib)
Proteasomes play an important role in cell function and growth
by breaking down proteins that are damaged or no longer needed.4
KYPROLIS has been shown to block proteasomes, leading to an
excessive build-up of proteins within cells.5 In some cells,
KYPROLIS can cause cell death, especially in myeloma cells because
they are more likely to contain a higher amount of abnormal
proteins.4,5
Since its first approval in 2012, approximately 150,000 patients
worldwide have received KYPROLIS.6 KYPROLIS is approved in the U.S.
for the following:
- for the treatment of patients with relapsed or refractory
multiple myeloma who have received one to three lines of therapy in
combination with
- Lenalidomide and dexamethasone; or
- Dexamethasone; or
- Daratumumab and dexamethasone.
- as a single agent for the treatment of patients with relapsed
or refractory multiple myeloma who have received one or more lines
of therapy.
KYPROLIS is also approved in Algeria, Argentina, Australia,
Bahrain, Belarus, Brazil, Canada, Chile, Colombia, Ecuador, Egypt,
European Union, Hong Kong, India, Israel, Japan, Jordan,
Kazakhstan, Kuwait, Lebanon, Macao, Malaysia, Mexico, Morocco, New
Zealand, Oman, Peru, Philippines, Qatar, Russia, Saudi Arabia,
Serbia, Singapore, S. Africa, S. Korea, Switzerland, Taiwan,
Thailand, Turkey and United Arab Emirates.
U.S. KYPROLIS® (carfilzomib) Important Safety
Information
INDICATIONS
- KYPROLIS® (carfilzomib) is indicated in combination with
dexamethasone or with lenalidomide plus dexamethasone or with
daratumumab and dexamethasone for the treatment of adult patients
with relapsed or refractory multiple myeloma who have received one
to three lines of therapy.
- KYPROLIS® is indicated as a single agent for the treatment of
adult patients with relapsed or refractory multiple myeloma who
have received one or more lines of therapy.
IMPORTANT SAFETY INFORMATION FOR KYPROLIS
Cardiac Toxicities
- New onset or worsening of pre-existing cardiac failure (e.g.,
congestive heart failure, pulmonary edema, decreased ejection
fraction), restrictive cardiomyopathy, myocardial ischemia, and
myocardial infarction including fatalities have occurred following
administration of KYPROLIS. Some events occurred in patients with
normal baseline ventricular function. Death due to cardiac arrest
has occurred within one day of administration.
- Monitor patients for signs or symptoms of cardiac failure or
ischemia. Evaluate promptly if cardiac toxicity is suspected.
Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until
recovery, and consider whether to restart at 1 dose level reduction
based on a benefit/risk assessment.
- While adequate hydration is required prior to each dose in
Cycle 1, monitor all patients for evidence of volume overload,
especially patients at risk for cardiac failure. Adjust total fluid
intake as clinically appropriate.
- For patients ≥75 years, the risk of cardiac failure is
increased. Patients with New York Heart Association Class III and
IV heart failure, recent myocardial infarction, conduction
abnormalities, angina, or arrhythmias may be at greater risk for
cardiac complications and should have a comprehensive medical
assessment prior to starting treatment with KYPROLIS and remain
under close follow-up with fluid management.
Acute Renal Failure
- Cases of acute renal failure, including some fatal renal
failure events, and renal insufficiency adverse events (including
renal failure) have occurred. Acute renal failure was reported more
frequently in patients with advanced relapsed and refractory
multiple myeloma who received KYPROLIS monotherapy. Monitor renal
function with regular measurement of the serum creatinine and/or
estimated creatinine clearance. Reduce or withhold dose as
appropriate.
Tumor Lysis Syndrome
- Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes,
have occurred. Patients with a high tumor burden should be
considered at greater risk for TLS. Adequate hydration is required
prior to each dose in Cycle 1, and in subsequent cycles as needed.
Consider uric acid lowering drugs in patients at risk for TLS.
Monitor for evidence of TLS during treatment and manage promptly,
and withhold until resolved.
Pulmonary Toxicity
- Acute Respiratory Distress Syndrome (ARDS), acute respiratory
failure, and acute diffuse infiltrative pulmonary disease such as
pneumonitis and interstitial lung disease have occurred. Some
events have been fatal. In the event of drug–induced pulmonary
toxicity, discontinue KYPROLIS.
Pulmonary Hypertension
- Pulmonary arterial hypertension (PAH) was reported. Evaluate
with cardiac imaging and/or other tests as indicated. Withhold
KYPROLIS for PAH until resolved or returned to baseline and
consider whether to restart based on a benefit/risk
assessment.
Dyspnea
- Dyspnea was reported in patients treated with KYPROLIS.
Evaluate dyspnea to exclude cardiopulmonary conditions including
cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3
or 4 dyspnea until resolved or returned to baseline. Consider
whether to restart based on a benefit/risk assessment.
Hypertension
- Hypertension, including hypertensive crisis and hypertensive
emergency, has been observed, some fatal. Control hypertension
prior to starting KYPROLIS. Monitor blood pressure regularly in all
patients. If hypertension cannot be adequately controlled, withhold
KYPROLIS and evaluate. Consider whether to restart based on a
benefit/risk assessment.
Venous Thrombosis
- Venous thromboembolic events (including deep venous thrombosis
and pulmonary embolism) have been observed. Thromboprophylaxis is
recommended for patients being treated with the combination of
KYPROLIS with dexamethasone or with lenalidomide plus
dexamethasone. The thromboprophylaxis regimen should be based on an
assessment of the patient's underlying risks.
- Patients using hormonal contraception associated with a risk of
thrombosis should consider an alternative method of effective
contraception during treatment.
Infusion Reactions
- Infusion reactions, including life–threatening reactions, have
occurred. Signs and symptoms include fever, chills, arthralgia,
myalgia, facial flushing, facial edema, laryngeal edema, vomiting,
weakness, shortness of breath, hypotension, syncope, chest
tightness, or angina. These reactions can occur immediately
following or up to 24 hours after administration. Premedicate with
dexamethasone to reduce the incidence and severity of infusion
reactions. Inform patients of the risk and of symptoms and seek
immediate medical attention if they occur.
Hemorrhage
- Fatal or serious cases of hemorrhage have been reported.
Hemorrhagic events have included gastrointestinal, pulmonary, and
intracranial hemorrhage and epistaxis. Promptly evaluate signs and
symptoms of blood loss. Reduce or withhold dose as
appropriate.
Thrombocytopenia
- KYPROLIS causes thrombocytopenia with recovery to baseline
platelet count usually by the start of the next cycle. Monitor
platelet counts frequently during treatment. Reduce or withhold
dose as appropriate.
Hepatic Toxicity and Hepatic Failure
- Cases of hepatic failure, including fatal cases, have occurred.
KYPROLIS can cause increased serum transaminases. Monitor liver
enzymes regularly regardless of baseline values. Reduce or withhold
dose as appropriate.
Thrombotic Microangiopathy
- Cases of thrombotic microangiopathy, including thrombotic
thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS),
including fatal outcome, have occurred. Monitor for signs and
symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the
diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The
safety of reinitiating KYPROLIS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)
- Cases of PRES have occurred in patients receiving KYPROLIS. If
PRES is suspected, discontinue and evaluate with appropriate
imaging. The safety of reinitiating KYPROLIS is not known.
Increased Fatal and Serious Toxicities in Combination with
Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible
Patients
- In a clinical trial of transplant-ineligible patients with
newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and
prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a
higher incidence of serious and fatal adverse events was observed
in patients in the KMP arm. KMP is not indicated for
transplant-ineligible patients with newly diagnosed multiple
myeloma.
Embryo-fetal Toxicity
- KYPROLIS can cause fetal harm when administered to a pregnant
woman.
- Females of reproductive potential should be advised to avoid
becoming pregnant while being treated with KYPROLIS and for 6
months following the final dose. Males of reproductive potential
should be advised to avoid fathering a child while being treated
with KYPROLIS and for 3 months following the final dose. If this
drug is used during pregnancy, or if pregnancy occurs while taking
this drug, the patient should be apprised of the potential hazard
to the fetus.
Adverse Reactions
- The most common adverse reactions in the combination therapy
trials: anemia, diarrhea, dyspnea, fatigue, thrombocytopenia,
pyrexia, insomnia, cough, upper respiratory tract infection,
hypertension.
- The most common adverse reactions in monotherapy trials:
anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea,
diarrhea, headache, cough, edema peripheral.
Please see accompanying full Prescribing Information at
www.kyprolis.com.
About Ligand Pharmaceuticals
Ligand is a revenue-generating biopharmaceutical company focused
on developing or acquiring technologies that help pharmaceutical
companies discover and develop medicines. Our business model
creates value for stockholders by providing a diversified portfolio
of biotech and pharmaceutical product revenue streams that are
supported by an efficient and low corporate cost structure. Our
goal is to offer investors an opportunity to participate in the
promise of the biotech industry in a profitable, diversified and
lower-risk business than a typical biotech company. Our business
model is based on doing what we do best: drug discovery,
early-stage drug development, product reformulation and partnering.
We partner with other pharmaceutical companies to leverage what
they do best (late-stage development, regulatory management and
commercialization) to ultimately generate our revenue. Ligand’s
OmniAb® technology platform is a patent-protected transgenic animal
platform used in the discovery of fully human mono- and bispecific
therapeutic antibodies. The Captisol platform technology is a
patent-protected, chemically modified cyclodextrin with a structure
designed to optimize the solubility and stability of drugs. The
Vernalis Design Platform (VDP) integrates protein structure
determination and engineering, fragment screening and molecular
modeling, with medicinal chemistry, to help enable success in novel
drug discovery programs against highly-challenging targets. Ab
Initio™ technology and services for the design and preparation of
customized antigens enable the successful discovery of therapeutic
antibodies against difficult-to-access cellular targets. Ligand has
established multiple alliances, licenses and other business
relationships with the world’s leading pharmaceutical companies
including Amgen, Merck, Pfizer, Sanofi, Janssen, Takeda, Servier,
Gilead Sciences and Baxter International. For more information,
please visit www.ligand.com.
Follow Ligand on Twitter @Ligand_LGND.
Forward-Looking Statements
This news release contains forward-looking statements by Ligand
that involve risks and uncertainties and reflect Ligand's judgment
as of the date of this release. Words such as “plans,” “believes,”
“expects,” “anticipates,” and “will,” and similar expressions, are
intended to identify forward-looking statements. These
forward-looking statements include, without limitation, statements
regarding: whether KYPROLIS will be used in combination with
DARZALEX to treat patients with R/R MM; Ligand’s expectation that
Amgen will be a major Captisol customer; and estimates of the
number of patients with multiple myeloma. Actual events or results
may differ from Ligand's expectations due to risks and
uncertainties inherent in Ligand’s business, including, without
limitation: patients and physicians may not prescribe KYPROLIS in
combination with DARZALEX for the treatment of R/R MM; Ligand may
not receive expected revenue from royalties from sales of KYPROLIS
or related Captisol sales the COVID-19 pandemic has disrupted
Ligand’s and its partners’ business, including delaying
manufacturing, preclinical studies and clinical trials and product
sales, and impairing global economic activity, all of which could
materially and adversely impact Ligand’s results of operations and
financial condition; Ligand may be unable to scale-up the supply of
Captisol or at acceptable prices; Amgen may not execute on its
sales and marketing plans for marketed products for which Ligand
has an economic interest; Ligand or its partners may not be able to
protect their intellectual property and patents covering certain
products and technologies may be challenged or invalidated; and
Ligand's partners may terminate any of its agreements or
development or commercialization of any of its products. The
failure to meet expectations with respect to any of the foregoing
matters may reduce Ligand's stock price. Additional information
concerning these and other risk factors affecting Ligand can be
found in prior press releases available at www.ligand.com as well
as in Ligand's public periodic filings with the Securities and
Exchange Commission available at www.sec.gov. Ligand disclaims any
intent or obligation to update these forward-looking statements
beyond the date of this release, including the possibility of
additional contract revenue we may receive. This caution is made
under the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995.
Other Disclaimers and Trademarks
The information in this press release regarding certain
third-party products and programs, including KYPROLIS, an Amgen
product, comes from information publicly released by the owners of
such products and programs. Ligand is not responsible for, and has
no role in, the development of such products or programs.
Ligand owns or has rights to trademarks and copyrights that it
uses in connection with the operation of its business including its
corporate name, logos and websites. Other trademarks and copyrights
appearing in this press release are the property of their
respective owners. The trademarks Ligand owns include Ligand®,
Captisol® and OmniAb®. Solely for convenience, some of the
trademarks and copyrights referred to in this press release are
listed without the ®, © and ™ symbols, but Ligand will assert, to
the fullest extent under applicable law, its rights to its
trademarks and copyrights.
References:
- Kumar S., et al. NCCN Guidelines Insights: Multiple Myeloma.
The Journal of the National Comprehensive Cancer Network. Jan 2018;
Volume 16: Issue 1. https://doi.org/10.6004/jnccn.2018.0002.
- Jakubowiak A. Management strategies for relapsed/refractory
multiple myeloma: current clinical perspectives. Semin Hematol.
2012 Jul; 49 Suppl 1: S16-S32.
- GLOBOCAN 2018. Multiple Myeloma. Available at:
http://gco.iarc.fr/today/data/factsheets/cancers/35-Multiple-myeloma-fact-sheet.pdf.
Accessed November 15, 2019.
- Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors
in multiple myeloma: 10 years later. Blood. 2012 Aug
2;120(5):947-59.
- Kortuem KM and Stewart AK. Carfilzomib. Blood. 2013 Feb
7;121(6):893-7.
- Amgen Data on File.
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Ligand Pharmaceuticals Incorporated Patrick O’Brien
investors@ligand.com (858) 550-7893 Twitter: @Ligand_LGND
LHA Investor Relations Bruce Voss bvoss@lhai.com (310)
691-7100
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