• 14 Nov 2024
• Admin
• News Article

Komet Phase III Trial of Koselugo Shows Significant Changes in Neurofibromatosis Type 1

KOMET phase III trial of Koselugo shows statistically significant and clinically meaningful ORR vs. placebo in adults with neurofibromatosis type 1

Overview

Positive high-level results of KOMET, the largest, global randomised double-blind placebo-controlled multicentre phase III trial in adults with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN), showed that Koselugo (selumetinib), an oral, selective MEK inhibitor, met its primary endpoint, demonstrating a statistically significant and clinically meaningful objective response rate (ORR) versus placebo in these adult patients.

About the Genetic Diasability: NF1

• NF1 is a rare, progressive genetic condition affecting an estimated 1.7 million individuals worldwide, approximately 70% of whom are adults. 
• In 30-50% of patients, tumours develop on the nerve sheaths and may cause debilitating symptoms. 
• NF1 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.

Statement from the Principal Investigator: KOMET Trial

Prof. Ignacio Blanco Guillermo, MD, PhD, chairman of the Genetic Counselling and Clinical Genetics Programme at the Germans Trias i Pujol University Hospital, Chairman of the Spanish National Reference Centre for Adult Patients with Neurofibromatosis and Principal Investigator of the KOMET trial, said: “With limited options to manage NF1 PN 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.”

Words from the CEO: Alexion, AstraZeneca Rare Disease

• Marc Dunoyer, chief executive officer, Alexion, AstraZeneca Rare Disease, said: “These promising results demonstrate that Koselugo, the first and only approved targeted therapy for certain children with NF1 PN, 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 III trial in adults with NF1 PN, 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.”

Statement from the MSD Research Laboratories

Scot Ebbinghaus, MD, vice president, global clinical development, MSD 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 III KOMET trial demonstrate the potential to expand the use of Koselugo beyond paediatric patients to also treat adult patients living with this rare and challenging genetic condition.”

The Objective Response Rate

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 tumour volume) by cycle 16 (28 days per cycle) as determined by independent central review (ICR) per response evaluation in neurofibromatosis and schwannomatosis (REiNS) criteria.

Safety Profile

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.

Koselugo Data Sharing with Regulatory Authorities

• Alexion, AstraZeneca Rare Disease will share these data with regulatory authorities and present at a forthcoming medical meeting. 
• AstraZeneca and MSD are jointly developing and commercialising Koselugo globally.

More on NF1 Condition

• NF1 is a rare, progressive, genetic condition that is caused by a spontaneous or inherited mutation in the NF1 gene. 
• NF1 is associated with a variety of symptoms, including soft lumps on and under the skin (cutaneous neurofibromas) and, in 30-50% of patients, tumours 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. 
• PNs begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.

The KOMET Trial

• KOMET is a global phase III randomised, double-blind, placebo-controlled, multicentre trial 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 North America, South America, Europe, Asia and Australia, with participants’ baseline characteristics, including gender and distribution of PNs, reflective of the global adult NF1 patient population. 
• Patients were enrolled and randomised to receive Koselugo or placebo (1:1) for 12 28-day cycles. 
• Participants were required to have diagnosis of NF1, at least one symptomatic, inoperable 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 enrolment.
• Primary outcome- The primary endpoint is confirmed ORR by cycle 16 as assessed by ICR. 
• ORR is defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumour volume).

What happened post 12 cycles?

• 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 24 cycles of treatment have the option to participate in a long-term extension period and continue to receive Koselugo.

About the Drug: Koselugo

• Koselugo (selumetinib) 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 tumour cells to grow in an unregulated way creating so-called plexiform neurofibromas (PN). 
• By blocking these enzymes, Koselugo slows down the growth of tumour cells and, therefore, the PN growth.

Koselugo Approvals

Koselugo is approved in the US, EU, Japan, China and other countries and has been granted Orphan Drug Designation in the US, EU, Japan and other countries for the treatment of certain paediatric patients with NF1 who have symptomatic, inoperable PN.

Strategic Partnership for Drug Development

• In July 2017, AstraZeneca and Merck & Co., Inc., Rahway, NJ, US, known as MSD outside the US and Canada, announced a global strategic collaboration to co-develop and co-commercialise 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.

About Alexion

Alexion, AstraZeneca Rare Disease, is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and delivery of life-changing medicines.

The AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in oncology, rare diseases, and biopharmaceuticals, including cardiovascular, renal & metabolism, and respiratory & immunology.