KOSELUGO® (selumetinib) Approved by FDA for Pediatric Patients Two Years and Older With Neurofibromatosis Type 1 and Symptomatic, Inoperable Plexiform Neurofibromas

AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. 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 FDA approval is based on positive results from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP)-sponsored Phase 2 SPRINT Stratum 1 trial coordinated by the NCI’s Center for Cancer Research, Pediatric Oncology Branch. This is the first regulatory approval of a medicine for the treatment of NF1 PN, a rare and debilitating genetic condition.

Results showed an overall response rate (ORR) of 66% [95% CI: 51, 79] in pediatric patients with NF1 and symptomatic, inoperable PN (n=33/50 patients) 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% tumor volume reduction. Of the 33 patients, all patients were confirmed partial response.

Serious adverse reactions can occur with KOSELUGO, including cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased creatinine phosphokinase (CPK), increased vitamin E levels and risk of bleeding, and fetal harm. Based on the type and severity of the adverse reaction, KOSELUGO may be interrupted, reduced and/or discontinued. For more information, see “Important Safety Information” below.

The most common adverse reactions (ARs) (reported in ≥40% of patients) were: vomiting (82%), rash (80%), abdominal pain (76%), diarrhea (70%), nausea (66%), dry skin (60%), fatigue (56%), musculoskeletal pain (58%), pyrexia (56%), rash acneiform (50%), stomatitis (50%), headache (48%), paronychia (48%), and pruritus (46%). The most common grade ≥ 3 ARs were diarrhea (16%), pyrexia (8%), vomiting (6%), rash (6%), paronychia (6%), acneiform rash (4%), dermatitis (4%), nausea (2%), headache (2%), skin infection (2%), and hematuria (2%). Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Dose interruptions and dose reductions due to an adverse reaction occurred in 80% and 24% of patients who received KOSELUGO, respectively.

Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca, 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.”

Dr. 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 to these patients.”

Brigitte C. Widemann, M.D., principal investigator of the SPRINT clinical trial and chief, National Cancer Institute 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.

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 here for Prescribing Information, including Patient Information (Medication Guide).

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 the profits will be due to Merck and will be recorded as alliance revenue. AstraZeneca will supply KOSELUGO.

About the SPRINT Trial

The SPRINT Phase 1/2 study was designed to evaluate the ORR in pediatric patients with NF1-related inoperable PNs treated with KOSELUGO monotherapy. The Phase 1 trial was designed to identify the optimal Phase 2 dosing regimen, and the results were published in The New England Journal of Medicine.

About KOSELUGO

KOSELUGO is an inhibitor of mitogen-activated protein 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 of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of KOSELUGO inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.

KOSELUGO was granted U.S. FDA Breakthrough Therapy Designation in April 2019, Rare Pediatric Disease Designation in December 2019, Orphan Drug Designation in February 2018, EU Orphan Designation in August 2018 and Swissmedic Orphan Drug Status in December 2018 for the treatment of pediatric patients with NF1 PNs.

About Neurofibromatosis Type 1 (NF1)

NF1 is a debilitating genetic condition that affects one in every 3,000 to 4,000 individuals. 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 to 50% of patients, tumors develop on the nerve sheaths (plexiform neurofibromas).

People with NF1 PN may experience a number of complications 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 the AstraZeneca and Merck Strategic Oncology Collaboration

In July 2017, AstraZeneca and Merck, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize certain oncology products, including KOSELUGO, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop these products in combination with other potential new medicines and as monotherapies. Independently, the companies will develop these oncology products in combination with their respective PD-L1 and PD-1 medicines.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

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