KOSELUGO(TM) (selumetinib) Approved In US For Pediatric Patients With Neurofibromatosis Type 1 Plexiform Neurofibromas

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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