REG - AstraZeneca PLC - KOMET Phase III trial met primary endpoint

AstraZenecaAnnouncement

12/11/2024 07:15

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RNS Number : 7968L  AstraZeneca PLC  12 November 2024

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 (http://www.astrazeneca.com/)  and follow the
Company on social media @AstraZeneca
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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. 2010;152A(2):327-332.

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
(https://www.mayoclinic.org/diseases-conditions/neurofibromatosis/symptoms-causes/syc-20350490)
. Accessed November 2024.

8.   National Health Service. Neurofibromatosis type 1, symptoms. Available
here (https://www.nhs.uk/conditions/neurofibromatosis-type-1/symptoms) .
Accessed November 2024.

9.   Cancer.Net. Neurofibromatosis type 1. Available here
(https://www.cancer.net/cancer-types/neurofibromatosis-type-1) . Accessed
November 2024.

10.  National Human Genome Research Institute. About neurofibromatosis.
Available here (https://www.genome.gov/Genetic-Disorders/Neurofibromatosis) .
Accessed November 2024.

11.  National Institute of Neurological Disorders and Stroke.
Neurofibromatosis. Available here
(https://catalog.ninds.nih.gov/sites/default/files/publications/neurofibromatosis_2.pdf)
. Accessed November 2024.

12.  Evans DGR, et al. Reduced life expectancy seen in hereditary diseases
which predispose to early-onset tumors. Appl Clin Genet. 2013;6:53-61.

13.  ClinicalTrials.gov. Efficacy and safety of selumetinib in adults with
NF1 who have symptomatic, inoperable plexiform neurofibromas (KOMET). NCT
Identifier: NCT04924608. Available here
(https://clinicaltrials.gov/study/NCT04924608#study-overview) . Accessed
November 2024.

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

 

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