First medicine approved to treat this rare and
debilitating genetic condition
AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US
(Merck: known as MSD outside the US and Canada) today announced
that the US Food and Drug Administration (FDA) has approved the
kinase inhibitor KOSELUGO™ (selumetinib) for the treatment of
pediatric patients two years of age and older with
neurofibromatosis type 1 (NF1) who have symptomatic, inoperable
plexiform neurofibromas (PN).
The approval by the FDA was based on positive results from the
National Cancer Institute (NCI) Cancer Therapy Evaluation Program
(CTEP)-sponsored Phase II SPRINT Stratum 1 trial coordinated by the
NCI’s Center for Cancer Research, Pediatric Oncology Branch. This
is the first regulatory approval anywhere in the world of a
medicine for the treatment of NF1 PN.
NF1 is a rare and debilitating genetic condition. Some 30-50% of
patients with NF1 experience PN - tumors growing inside their nerve
sheaths. These PN can cause clinical issues such as pain, motor
dysfunction, airway dysfunction, bowel/bladder dysfunction and
disfigurement.
Results showed an overall response rate (ORR) of 66% (33 of 50
patients, confirmed partial response) in pediatric patients with
NF1 PN when treated with KOSELUGO as a twice-daily oral
monotherapy. ORR is defined as the percentage of patients with
confirmed complete or partial response of at least 20% reduction in
tumor volume.
Dave Frederickson, Executive Vice-President, Oncology Business
Unit, said: “For the first time, patients and families impacted by
this incurable genetic condition have an approved medicine to treat
the resulting plexiform neurofibromas. I would like to thank our
research partners, the NCI, the Neurofibromatosis Therapeutic
Acceleration Program (NTAP), the Children’s Tumor Foundation (CTF),
the NF1 patient community and, most importantly, the children,
parents and doctors who participated in the SPRINT clinical trial
program.”
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, Merck Research Laboratories,
said: “Previously, there were no medicines approved for this
disease. This approval has the potential to change how symptomatic,
inoperable NF1 plexiform neurofibromas are treated and provides new
hope for these patients.”
Brigitte C. Widemann, MD, Principal Investigator of the SPRINT
clinical trial and Chief, National Cancer Institute (NCI) Pediatric
Oncology Branch, said: “KOSELUGO has made a difference for many
children in this trial. This is an important treatment advance for
patients and their families.”
AstraZeneca and Merck are jointly developing and commercializing
KOSELUGO globally under a license agreement.
Priority Review Voucher AstraZeneca has received a
Priority Review Voucher (PRV) under the Rare Pediatric Disease
Designation Program intended to encourage development of new
medicines for rare pediatric diseases. A PRV entitles the holder to
FDA Priority Review of a single New Drug Application or Biologics
License Application, which reduces the target review time and has
led to an expedited approval.
Financial considerations In accordance with the existing
collaboration agreement between Merck and AstraZeneca, following
approval and upcoming launch, AstraZeneca will book all monotherapy
Product Sales of KOSELUGO; half of gross profits will be due to
Merck and will be recorded under Cost of Sales. Any potential
future sales-related milestone payments will be recorded under
Collaboration Revenue. AstraZeneca will supply KOSELUGO.
The most common adverse reactions (reported in ≥40% of patients)
were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry
skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash,
stomatitis, headache, paronychia, and pruritus.
IMPORTANT SAFETY INFORMATION
- Cardiomyopathy. A decrease in left ventricular ejection
fraction (LVEF) ≥ 10% below baseline occurred in 23% of 74
pediatric patients who received KOSELUGO in SPRINT. Four percent of
patients experienced decreased LVEF below the institutional lower
limit of normal (LLN). Grade 3 decreased LVEF occurred in one
patient and resulted in dose reduction. All patients with decreased
LVEF were asymptomatic and identified during routine
echocardiography. Decreased LVEF resolved in 71% of these patients.
Decreased LVEF resulting in permanent discontinuation of KOSELUGO
occurred in a pediatric population with NF1 in an expanded access
program. The safety of KOSELUGO has not been established in
patients with a history of impaired LVEF or a baseline ejection
fraction that is below the institutional LLN. Assess ejection
fraction by echocardiogram prior to initiating treatment, every 3
months during the first year of treatment, every 6 months
thereafter, and as clinically indicated. Withhold, reduce dose, or
permanently discontinue KOSELUGO based on severity of adverse
reaction. In patients who interrupt KOSELUGO for decreased LVEF,
obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon
resolution of decreased LVEF, obtain an echocardiogram or a cardiac
MRI every 2 to 3 months.
- Ocular Toxicity. Blurred vision, photophobia, cataracts,
and ocular hypertension occurred in 15% of 74 pediatric patients
receiving KOSELUGO in SPRINT. Blurred vision resulted in dose
interruption in 2.7% of patients. Ocular toxicity resolved in 82%
of 11 patients. RPED occurred in the pediatric population during
treatment with single agent KOSELUGO and resulted in permanent
discontinuation. Conduct ophthalmic assessments prior to initiating
KOSELUGO, at regular intervals during treatment, and for new or
worsening visual changes. Permanently discontinue KOSELUGO in
patients with RVO. Withhold KOSELUGO in patients with RPED, conduct
ophthalmic assessments every 3 weeks until resolution, and resume
KOSELUGO at a reduced dose. For other ocular toxicities, withhold,
reduce dose, or permanently discontinue KOSELUGO based on severity
of adverse reaction.
- Gastrointestinal Toxicity. Diarrhea occurred in 77% of
74 pediatric patients who received KOSELUGO in SPRINT, including
Grade 3 in 15% of patients. Diarrhea resulting in permanent
discontinuation occurred in 1.4% of patients. Diarrhea resulting in
dose interruption or dose reduction occurred in 15% and 1.4% of
patients, respectively. The median time to first onset of diarrhea
was 17 days and the median duration was 2 days. Advise patients to
start an anti-diarrheal agent (e.g., loperamide) and to increase
fluid intake immediately after the first episode of diarrhea.
Withhold, reduce dose, or permanently discontinue KOSELUGO based on
severity of adverse reaction.
- Skin Toxicity. Rash occurred in 91% of 74 pediatric
patients who received KOSELUGO in SPRINT. The most frequent rashes
included dermatitis acneiform (54%), maculopapular rash (39%), and
eczema (28%). Grade 3 rash occurred in 8% of patients. Rash
resulted in dose interruption in 11% of patients and dose reduction
in 4% of patients. Monitor for severe skin rashes. Withhold, reduce
dose, or permanently discontinue KOSELUGO based on severity of
adverse reaction.
- Increased Creatinine Phosphokinase (CPK).
Increased CPK occurred in 76% of 74 pediatric patients who received
KOSELUGO in SPRINT, including Grade 3 or 4 in 9% of patients.
Increased CPK resulted in dose reduction in 7% of patients.
Increased CPK concurrent with myalgia occurred in 8% of patients,
including one patient who permanently discontinued KOSELUGO for
myalgia. Obtain serum CPK prior to initiating KOSELUGO,
periodically during treatment, and as clinically indicated. If
increased CPK occurs, evaluate patients for rhabdomyolysis or other
causes. Withhold, reduce dose, or permanently discontinue KOSELUGO
based on severity of adverse reaction.
- Increased Levels of Vitamin E and Risk of Bleeding.
KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg
vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol
1000 succinate (TPGS); while KOSELUGO 25 mg capsules contain 36 mg
vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and
antagonize vitamin K-dependent clotting factors. Daily vitamin E
intake that exceeds the recommended or safe limits may increase the
risk of bleeding. Supplemental vitamin E is not recommended if
daily vitamin E intake (including the amount of vitamin E in
KOSELUGO and supplement) will exceed the recommended or safe
limits. An increased risk of bleeding may occur in patients who are
coadministered vitamin-K antagonists or anti-platelet antagonists
with KOSELUGO. Monitor for bleeding in these patients and increase
international normalized ratio (INR), in patients taking a
vitamin-K antagonist. Perform anticoagulant assessments more
frequently and adjust the dose of vitamin K antagonists or
anti-platelet agents as appropriate.
- Embryo-Fetal Toxicity. Based on findings from animal
studies, KOSELUGO can cause fetal harm when administered to a
pregnant woman. In animal studies, administration of selumetinib to
mice during organogenesis caused reduced fetal weight, adverse
structural defects, and effects on embryo-fetal survival at
approximate exposures > 5 times the human exposure at the
clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective contraception during treatment with KOSELUGO and
for 1 week after the last dose. Advise males with female partners
of reproductive potential to use effective contraception during
treatment with KOSELUGO and for 1 week after the last dose.
- Due to the potential for adverse reactions in a breastfed
child, advise women not to breastfeed during treatment with
KOSELUGO and for 1 week after the last dose.
- Concomitant use of KOSELUGO with a strong or moderate CYP3A4
inhibitor or fluconazole increased selumetinib plasma
concentrations which may increase the risk of adverse reactions.
Avoid coadministration of strong or moderate CYP3A4 inhibitors or
fluconazole with KOSELUGO. If coadministration with strong or
moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce
KOSEULGO dosage.
- Concomitant use of KOSELUGO with a strong or moderate CYP3A4
inducer decreased selumetinib plasma concentrations which may
reduce KOSELUGO efficacy. Avoid concomitant use of strong or
moderate CYP3A4 inducers with KOSELUGO.
- Most common adverse reactions (≥ 40% of patients) are:
vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin,
musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis,
headache, paronychia, and pruritus.
INDICATION KOSELUGO is indicated for the treatment of
pediatric patients 2 years of age and older with neurofibromatosis
type 1 (NF1) who have symptomatic, inoperable plexiform
neurofibromas (PN).
Please click on Prescribing Information, including Patient
Information (Medication Guide).
NOTES TO EDITORS
About NF1 with Plexiform Neurofibromas (PN)
Neurofibromatosis type 1 (NF1) is an incurable genetic condition
that affects one in every 3,000 individuals in the US. It is caused
by a spontaneous or inherited mutation in the NF1 gene and is
associated with many symptoms, including soft lumps on and under
the skin (cutaneous neurofibromas), skin pigmentation (so-called
“cafe au lait” spots) and, in 30-50% of patients, tumors develop on
the nerve sheaths (plexiform neurofibromas). These plexiform
neurofibromas can cause clinical issues such as disfigurement,
motor dysfunction, pain, airway dysfunction, visual impairment, and
bladder/bowel dysfunction.
PN begin during early childhood, with varying degrees of
severity, and can reduce life expectancy by up to 15 years.
About SPRINT The SPRINT Phase I/II study was designed to
evaluate the Overall Response Rate in pediatric patients with
NF1-related inoperable PN treated with KOSELUGO monotherapy. The
Phase I trial was designed to identify the optimal Phase II dosing
regimen, and the results were published in The New England Journal
of Medicine. This trial sponsored by NCI CTEP was conducted under a
Cooperative Research and Development Agreement between NCI and
AstraZeneca with additional support from NTAP.
About KOSELUGO KOSELUGO (selumetinib) is an inhibitor of
mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2
proteins are upstream regulators of the extracellular
signal-related kinase (ERK) pathway. Both MEK and ERK are critical
components of the RAS-regulated RAF-MEK-ERK pathway, which is often
activated in different types of cancers. In genetically modified
mouse models, oral dosing of selumetinib inhibited ERK
phosphorylation, and reduced neurofibroma numbers, volume, and
proliferation.
KOSELUGO was granted US FDA Breakthrough Therapy Designation in
April 2019, Rare Pediatric Disease Designation in December 2019 and
Orphan Drug Designation in February 2018 for the treatment of
pediatric patients with NF1 plexiform neurofibromas.
About the AstraZeneca and Merck Strategic Oncology
Collaboration In July 2017, AstraZeneca and Merck & Co.,
Inc., Kenilworth, NJ, US, known as Merck & Co outside the
United States and Canada, announced a global strategic oncology
collaboration to co-develop and co-commercialize LYNPARZA, the
world’s first PARP inhibitor, and KOSELUGO, a MEK inhibitor, for
multiple cancer types. Working together, the companies will develop
LYNPARZA and KOSELUGO in combination with other potential new
medicines and as monotherapies. Independently, the companies will
develop KOSELUGO and LYNPARZA in combination with their respective
PD-L1 and PD-1 medicines.
About AstraZeneca in Oncology AstraZeneca has a
deep-rooted heritage in Oncology and offers a quickly growing
portfolio of new medicines that has the potential to transform
patients’ lives and the Company’s future. With at least six new
medicines to be launched between 2014 and 2020, and a broad
pipeline of small molecules and biologics in development, we are
committed to advance Oncology as a growth driver for AstraZeneca
focused on lung, ovarian, breast and blood cancers. In addition to
our core capabilities, we actively pursue innovative partnerships
and investments that accelerate the delivery of our strategy, as
illustrated by our investment in Acerta Pharma in hematology.
By harnessing the power of four scientific platforms –
Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response
and Antibody-Drug Conjugates – and by championing the development
of personalized combinations, AstraZeneca has the vision to
redefine cancer treatment and one day eliminate cancer as a cause
of death.
About AstraZeneca AstraZeneca is a global, science-led
biopharmaceutical company that focuses on the discovery,
development and commercialization of prescription medicines,
primarily for the treatment of diseases in three therapy areas -
Oncology, Cardiovascular, Renal & Metabolism and Respiratory.
AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more
information, please visit www.astrazeneca-us.com and follow the
Company on Twitter @AstraZenecaUS.
US-34286 Last Updated 4/20
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