12 November 2024
Koselugo
showed
statistically significant and clinically meaningful objective
response rate vs. placebo in adults with neurofibromatosis type 1
in global KOMET Phase III trial
Results
demonstrated reduction in tumour volume, building on established
safety and efficacy profile of Koselugo in children and supporting
expanded use in adults
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.
NF1 is a rare, progressive genetic
condition affecting an estimated 1.7 million individuals worldwide,
approximately 70% of whom are adults.1,2 In 30-50% of
patients, tumours develop on the nerve sheaths and may cause
debilitating symptoms.3-8 NF1 is usually diagnosed in
early childhood, however, NF1 often progresses into
adulthood.9,10 There are no approved treatments for
adults, leaving many to experience disfigurement, dysfunction,
persistent pain or endure multiple
surgeries.11
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."
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."
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."
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.
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 at a forthcoming medical
meeting. AstraZeneca and MSD are jointly developing and commercialising Koselugo globally.
Notes
NF1
NF1 is a rare, progressive, genetic condition
that is caused by a spontaneous or inherited mutation in the NF1
gene.3,11 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).4,11 These PNs can cause
clinical issues such as disfigurement, motor dysfunction, pain,
airway dysfunction, visual impairment and bladder or bowel
dysfunction.4-8 PNs begin during early childhood, with
varying degrees of severity, and can reduce life expectancy by up
to 15 years.5,8,11,12
KOMET
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.13
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).13
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.13
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 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.
AstraZeneca
and MSD Strategic Collaboration
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.
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. A pioneering
leader in rare disease for more than three decades, Alexion was the
first to translate the complex biology of the complement system
into transformative medicines, and today it continues to build a
diversified pipeline across disease areas with significant unmet
need, using an array of innovative modalities. As part of
AstraZeneca, Alexion is continually expanding its global geographic
footprint to serve more rare disease patients around the world. It
is headquartered in Boston, US.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) 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. Based in Cambridge, UK, AstraZeneca's innovative
medicines are sold in more than 125 countries and used by millions
of patients worldwide. Please visit astrazeneca.com and follow
the Company on social media @AstraZeneca
Contacts
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References
1. Evans DG, et al.
Birth incidence and prevalence of tumor-prone syndromes: estimates
from a UK family genetic register service. Am J Med Genet A.
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2. Ejerskov C, et al.
Clinical characteristics and management of children and adults with
neurofibromatosis type 1 and plexiform neurofibromas in Denmark: a
nationwide study. Oncol
Ther. 2023;11(1):97-110.
3. Tamura R. Current
understanding of neurofibromatosis type 1, 2, and schwannomatosis.
Int J Mol Sci.
2021;22(11):5850.
4. Gross AM, et al.
Selumetinib in children with inoperable plexiform
neurofibromas. N Engl J Med.
2020;382(15):1430-1442.
5. Hirbe AC, et al.
Neurofibromatosis type 1: a multidisciplinary approach to care.
Lancet Neurol.
2014;13:834-843.
6. Dombi E, et al.
Activity of selumetinib in neurofibromatosis type 1-related
plexiform neurofibromas. N Engl J
Med. 2016;375:2550-2560.
7. Mayo Clinic.
Neurofibromatosis. Available
here. Accessed November
2024.
8. National Health
Service. Neurofibromatosis type 1, symptoms. Available
here.
Accessed November 2024.
9. Cancer.Net. Neurofibromatosis type 1. Available
here.
Accessed November 2024.
10. National Human Genome Research Institute. About
neurofibromatosis. Available here.
Accessed November 2024.
11. National Institute of
Neurological Disorders and Stroke. Neurofibromatosis.
Available
here. Accessed November
2024.
12. Evans DGR, et al. Reduced
life expectancy seen in hereditary diseases which predispose to
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13. ClinicalTrials.gov.
Efficacy and safety of selumetinib in adults with NF1 who have
symptomatic, inoperable plexiform neurofibromas (KOMET). NCT
Identifier: NCT04924608. Available here.
Accessed November 2024.
Adrian Kemp
Company Secretary
AstraZeneca PLC