KOSELUGO® (selumetinib) Showed Significant and Clinically Meaningful Improvement in Objective Response Rate Versus Placebo in Adults With Neurofibromatosis Type 1 who Have Symptomatic, Inoperable Plexiform Neurofibromas in Global Phase 3 KOMET Trial

These results showed reduction in tumor volume, building on the established safety and efficacy profile of KOSELUGO in certain children and has the potential to support expanded use in certain adults

RAHWAY, N.J.--(BUSINESS WIRE)-- Alexion, AstraZeneca Rare Disease and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced positive topline results from the Phase 3 KOMET trial, which is the largest, global randomized double-blind placebo-controlled multicenter Phase 3 trial in adults with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). Topline results showed that KOSELUGO, an oral, selective MEK inhibitor, demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR), the study’s primary endpoint, versus placebo, in these adult patients.

Neurofibromatosis type 1 is a rare, progressive genetic condition affecting an estimated 1.7 million people worldwide, approximately 70% of whom are adults. In 30-50% of patients, tumors develop on the nerve sheaths and may cause debilitating symptoms. Neurofibromatosis type 1 is usually diagnosed in early childhood; however, NF1 often progresses into adulthood. There are no approved treatments for adults, leaving many to experience disfigurement, dysfunction, persistent pain or endure multiple surgeries.

Professor Ignacio Blanco Guillermo, M.D., Ph.D., chairman, genetic counseling and clinical genetics program at the Germans Trias i Pujol University Hospital, chairman, Spanish National Reference Center for Adult Patients with Neurofibromatosis and principal investigator of the KOMET trial, said, “With limited options to manage NF1 plexiform neurofibromas in adults, many patients experience functional impairment and symptoms, which can substantially impact their lives. These clinically meaningful data show KOSELUGO has the potential to make a positive impact in patient care by reducing the size of plexiform neurofibromas.”

Marc Dunoyer, chief executive officer, Alexion, said, “These promising results demonstrate that KOSELUGO, the first and only approved targeted therapy for certain children with NF1 plexiform neurofibromas, now has the potential to benefit adult patients for whom there are no approved targeted therapies. As the largest and only global placebo-controlled Phase 3 trial in adults with NF1 plexiform neurofibromas, KOMET reinforces our leadership in advancing potential treatment options for people living with this debilitating disease. We look forward to sharing these findings with regulatory authorities.”

Dr. Scot Ebbinghaus, vice president, global clinical development, Merck Research Laboratories, said, “Adults with NF1 are in critical need of treatment options to help manage symptomatic, inoperable plexiform neurofibromas. These positive results from the Phase 3 KOMET trial demonstrate the potential to expand the use of KOSELUGO beyond pediatric patients to also treat adult patients living with this rare and challenging genetic condition.”

In the trial, ORR was defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumor volume) by cycle 16 (28 days per cycle) as determined by independent central review (ICR) per response evaluation in neurofibromatosis and schwannomatosis (REiNS) criteria.

The safety profile of KOSELUGO in this study was consistent with that observed in clinical trials among children and adolescents. No new safety signals were identified.

Alexion, AstraZeneca Rare Disease will share these data with regulatory authorities and present these data at a forthcoming medical meeting. AstraZeneca and Merck are jointly developing and commercializing KOSELUGO globally.

About KOMET
KOMET is a global randomized, double-blind, placebo-controlled, multi-center Phase 3 trial (ClinicalTrials.gov, NCT04924608) designed to evaluate the efficacy and safety of KOSELUGO in adults with NF1 who have symptomatic, inoperable PNs. The trial enrolled 145 adults from 13 countries across the U.S., Asia, Australia, South America and Europe, with participants’ baseline characteristics, including gender and distribution of PNs, reflective of the global adult NF1 patient population. Patients were enrolled and randomized 1:1 to receive KOSELUGO or placebo for twelve 28-day cycles. Participants were required to have diagnosis of NF1 at least one, symptomatic, inoperable target PN measurable by volumetric MRI analysis, chronic PN pain score documented during screening, adequate organ and marrow function and stable chronic PN pain medication use at enrollment.

The primary endpoint is confirmed ORR by cycle 16 as assessed by ICR. Objective response rate is defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumor volume).

After 12 cycles, patients on placebo were switched to KOSELUGO and patients on KOSELUGO remained on treatment for an additional 12 cycles. Patients who had the opportunity to complete both treatment periods 24 cycles of treatment have the option to participate in a long-term extension period and continue to receive KOSELUGO.

About NF1
Neurofibromatosis type 1 is a rare, progressive, genetic condition that is caused by a spontaneous or inherited mutation in the NF1 gene. Neurofibromatosis type 1 is associated with a variety of symptoms, including soft lumps on and under the skin (cutaneous neurofibromas) and, in 30-50% of patients, tumors develop on the nerve sheaths (PNs). These PNs can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction. Plexiform neurofibromas begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.

About KOSELUGO^® (selumetinib)
KOSELUGO is a kinase inhibitor that blocks specific enzymes (MEK1 and MEK2), which are involved in stimulating cells to grow. In NF1, these enzymes are overactive, causing tumor cells to grow in an unregulated way creating so-called plexiform neurofibromas (PN). By blocking these enzymes, KOSELUGO slows down the growth of tumor cells, and, therefore, the PN growth.

KOSELUGO is approved in the U.S., European Union (EU), Japan, China and has been granted Orphan Drug Designation in the U.S., EU, Japan and other countries for the treatment of pediatric patients with NF1 PN who have symptomatic, inoperable PN.

KOSELUGO (selumetinib) Indication in the U.S.
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).

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Cardiomyopathy. A decrease in left ventricular ejection fraction (LVEF) ≥10% below baseline occurred in pediatric patients who received KOSELUGO in SPRINT with some experiencing decreased LVEF below the institutional lower limit of normal (LLN), including one patient with Grade 3. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. 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. Retinal pigment epithelial detachment (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 retinal vein occlusion (RVO). Withhold KOSELUGO in patients with RPED, conduct ophthalmic assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose.

Gastrointestinal Toxicity. Diarrhea occurred, including Grade 3. Diarrhea resulting in permanent discontinuation, dose interruption or dose reduction occurred. Advise patients to start an anti-diarrheal agent (eg, 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. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred, in addition to rash resulting in dose interruption or dose reduction. 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, including Grade 3 or 4 resulting in dose reduction. Increased CPK concurrent with myalgia occurred, 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 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 which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. 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 due to increased risk of bleeding. 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 during pregnancy. 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 patients of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.

ADVERSE REACTIONS
Common adverse reactions ≥40% include vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, musculoskeletal pain, fatigue, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.

DRUG INTERACTIONS
Effect of Other Drugs on KOSELUGO
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 with KOSELUGO. If coadministration cannot be avoided, reduce KOSELUGO dosage.

Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce KOSELUGO efficacy. Avoid concomitant use with KOSELUGO.

SPECIAL POPULATIONS
Pregnancy & Lactation. Verify the pregnancy status of patients of reproductive potential prior to initiating KOSELUGO. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.

About the AstraZeneca and Merck strategic collaboration
In July 2017, AstraZeneca and Merck, known as MSD outside of the United States and Canada, announced a global strategic collaboration to co-develop and co-commercialize LYNPARZA (olaparib), a first-in-class PARP inhibitor, and KOSELUGO. Working together, the companies will develop LYNPARZA and KOSELUGO in combination with other potential new medicines and as monotherapies.

Merck’s focus on cancer
Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.

About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information and Patient Information (Medication Guide) for KOSELUGO (selumetinib) at https://alexion.com/Documents/koselugo_uspi.pdf

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