TIDMAZN
RNS Number : 6683C
AstraZeneca PLC
22 June 2021
22 June 2021 07:00 BST
Koselugo approved in the EU for children with
neurofibromatosis type 1 and plexiform neurofibromas
First medicine approved in the EU to treat this rare and
debilitating genetic condition
SPRINT Phase II trial showed Koselugo reduced tumour
volume, reducing pain and improving quality of life
AstraZeneca and MSD's Koselugo (selumetinib) has been granted
conditional approval in the European Union (EU) for the treatment
of symptomatic, inoperable plexiform neurofibromas (PN) in
paediatric patients with neurofibromatosis type 1 (NF1) aged three
years and above.
NF1 is a debilitating genetic condition affecting one in 3,000
individuals worldwide.(1,2) In 30-50% of people with NF1, tumours
develop on the nerve sheaths (plexiform neurofibromas) and can
cause clinical issues such as disfigurement, motor dysfunction,
pain, airway dysfunction, visual impairment and bladder or bowel
dysfunction.(3-7)
The approval by the European Commission was based on positive
results from the SPRINT Stratum 1 Phase II trial sponsored by the
National Institute of Health's National Cancer Institute (NCI)
Cancer Therapy Evaluation Program (CTEP). This trial showed
Koselugo reduced the size of inoperable tumours in children,
reducing pain and improving quality of life.(7,8) This is the first
approval of a medicine for NF1 PN in the EU and follows the
positive recommendation by the Committee for Medicinal Products for
Human Use of the European Medicines Agency in April 2021. Safety
and efficacy data from the SPRINT Phase II trial with longer follow
up will be provided as one of the conditions of approval.
Brigitte C. Widemann, MD, Principal Investigator of the SPRINT
trial and Chief, NCI Pediatric Oncology Branch, said: "For children
with neurofibromatosis type 1, plexiform neurofibromas can grow and
develop so significantly that, in some cases, it becomes
debilitating. In the SPRINT trial, selumetinib shrank
NF1-associated PNs in 66% of patients and showed clinically
meaningful improvements in PN-related symptoms."
Dave Fredrickson, Executive Vice President, Oncology Business
Unit, said: "As the first medicine approved in the EU for patients
with neurofibromatosis type 1, Koselugo has the potential to
transform the way plexiform neurofibromas are managed and treated.
The SPRINT data showed that Koselugo not only shrank tumours in
some children, but also reduced pain and improved their quality of
life. This significant milestone was made possible thanks to our
research partners, the National Cancer Institute, the
Neurofibromatosis Therapeutic Acceleration Program, the Children's
Tumor Foundation, the patient community and every child, parent and
doctor involved in the clinical trial."
Roy Baynes, Senior Vice President and Head of Global Clinical
Development, Chief Medical Officer, MSD Research Laboratories,
said: "Before this approval, surgery was the only treatment option
for children in the EU with neurofibromatosis type 1 plexiform
neurofibromas. This approval marks a significant step forward in
addressing the debilitating impact of these tumours."
The SPRINT Stratum 1 Phase II trial showed Koselugo demonstrated
an objective response rate (ORR) of 66% (33 of 50 patients,
confirmed partial response) in paediatric patients with NF1 PN when
treated with Koselugo as twice-daily oral monotherapy.(8) ORR is
defined as the percentage of patients with confirmed complete
(disappearance of PN) or partial response (at least 20% reduction
in tumour volume).(8) Results were published in The New England
Journal of Medicine.(7)
Koselugo is approved in the US and several other countries for
the treatment of paediatric patients with NF1 and symptomatic,
inoperable PN. Further regulatory submissions are underway.
Clinical trials of Koselugo in adult patients with NF1 PN,
including an alternative age-appropriate formulation for paediatric
patients, are scheduled to begin this year.
NF1
NF1 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) and skin pigmentation
(so-called 'café au lait' spots). In 30-50% of people, tumours
develop on the nerve sheaths.(1,3,9,10) These PN can cause clinical
issues such as pain, motor dysfunction, airway dysfunction,
bladder/bowel dysfunction and disfigurement, as well as having the
potential to transform into malignant peripheral nerve sheath
tumours.(4-7,10) PN begin developing during early childhood, with
varying degrees of severity, and can reduce life expectancy by
eight to 15 years.(3,6,11,12)
SPRINT
The SPRINT Stratum 1 Phase II trial was designed to evaluate the
objective response rate and impact on patient-reported and
functional outcomes in paediatric patients with NF1-related
inoperable PNs treated with selumetinib monotherapy.(7) This trial
sponsored by NCI CTEP was conducted under a Cooperative Research
and Development Agreement between NCI and AstraZeneca with
additional support from Neurofibromatosis Therapeutic Acceleration
Program (NTAP).
Koselugo
Koselugo (selumetinib) is an inhibitor of mitogen-activated
protein kinase kinases 1 and 2 (MEK1/2).(8) 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.(13)
Koselugo received US FDA Breakthrough Therapy Designation in
April 2019, Rare Pediatric Disease Designation in December 2019 and
US Orphan Drug Designation in February 2018. Further orphan
designations have been granted in the EU, Japan, Russia,
Switzerland, South Korea, Taiwan and Australia.
AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth,
NJ, US, known as MSD outside the US and Canada, announced a global
strategic oncology collaboration to co-develop and co-commercialise
Lynparza, the world's first PARP inhibitor, and Koselugo
(selumetinib), a mitogen-activated protein kinase (MEK) inhibitor,
for multiple cancer types. Working together, the companies will
develop Lynparza and Koselugo in combination with other potential
new medicines and as monotherapies. Independently, the companies
will develop Lynparza and Koselugo in combination with their
respective PD-L1 and PD-1 medicines.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyse changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
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 and BioPharmaceuticals, including Cardiovascular, Renal
& Metabolism, and Respiratory & Immunology. Based in
Cambridge, UK, AstraZeneca operates in over 100 countries, and its
innovative medicines are used by millions of patients worldwide.
Please visit astrazeneca.com and follow the Company on Twitter
@AstraZeneca.
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References
1. Cancer.Net. Neurofibromatosis Type 1. Available at:
https://www.cancer.net/cancer-types/neurofibromatosis-type 1 .
Accessed June 2021.
2. National Human Genome Research Institute. About
Neurofibromatosis. Available at:
https://www.genome.gov/Genetic-Disorders/Neurofibromatosis .
Accessed June 2021.
3. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a
multidisciplinary approach to care. Lancet Neurol. 2014;13:834-43.
doi: 10.1016/S1474-4422(14)70063-8.
4. Dombi E, Baldwin A, Marcus LJ, et al. Activity of selumetinib
in neurofibromatosis type 1-related plexiform neurofibromas. N Engl
J Med. 2016;375:2550-2560. doi: 10.1056/NEJMoa1605943.
5. Mayo Clinic. Neurofibromatosis. Available at:
https://www.mayoclinic.org/diseases-conditions/neurofibromatosis/symptoms-causes/syc-20350490
. Accessed June 2021.
6. NHS. Neurofibromatosis Type 1, Symptoms. Available at
https://www.nhs.uk/conditions/neurofibromatosis-type 1/symptoms .
Accessed June 2021.
7. Gross AM, et al. Selumetinib in Children with Inoperable
Plexiform Neurofibromas. N Engl J Med. 2020 Apr
9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735.
8. European Medicines Agency. Koselugo summary of product
characteristics. Accessed June 2021.
9. Jett K, Friedman JM. Clinical and genetic aspects of
neurofibromatosis 1. Genet Med. 2010:12(1):1-11. doi:
10.1097/GIM.0b013e3181bf15e3. PMID: 20027112.
10. Ghalayani P, Saberi Z, Sardari, F. Neurofibromatosis Type I
(von Recklinghausen's Disease): A Family Case Report and Literature
Review. Dent Res J. 2012;9(4):483-488.
11. Evans DGR, Ingham SL. Reduced Life Expectancy Seen in
Hereditary Diseases Which Predispose to Early Onset Tumors. Appl
Clin Genet. 2013;6:53-61.
12. NIH National Institute of Neurological Disorders and Stroke.
Neurofibromatosis Fact Sheet. Available at:
https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/neurofibromatosis-fact-sheet
. Accessed June 2021.
13. Koselugo (selumetinib) [prescribing information].
Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.
Adrian Kemp
Company Secretary
AstraZeneca PLC
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