Selumetinib (
),
sold under the brand name Koselugo, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
for the treatment of children, two years of age and older, with
neurofibromatosis type I (NF-1), a genetic disorder of the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
causing tumors to grow on nerves.
[ ] It is taken
by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
.
Common side effects include headache,
abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
and other problems of the
gastrointestinal tract,
fatigue, muscle pain, as well as dry skin and other skin problems.
Selumetinib was approved for medical use in the United States in April 2020,
and in the European Union in June 2021.
The U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) considers it to be a
first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...
.
Medical uses
Selumetinib is used for the treatment of neurofibromas in those with
neurofibromatosis type I (NF-1). This is a rare, progressive condition caused by a mutation or flaw in the gene coding for the protein
neurofibromin 1
Neurofibromin 1 (''NF1'') is a gene in humans that is located on chromosome 17. ''NF1'' codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. ' ...
.
NF-1 is usually diagnosed in early childhood and appears in an estimated one out of every 3,000 infants.
It is characterized by changes in skin coloring (
pigmentation
A pigment is a colored material that is completely or nearly insoluble in water. In contrast, dyes are typically soluble, at least at some stage in their use. Generally dyes are often organic compounds whereas pigments are often inorganic compoun ...
),
neurologic
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
and skeletal impairments and risk for development of
benign
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
and
malignant tumor
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
s throughout life.
It is approved specifically for children who have symptomatic, inoperable
plexiform neurofibromas (PN), which are tumors involving the
nerve sheaths (coating around nerve fibers) and can grow anywhere in the body, including the face, extremities, areas around the spine and deep in the body where they may affect organs. Between 30% and 50% of children born with NF-1 develop one or more PNs.
Pregnancy
Based on findings from animal studies, selumetinib may cause harm to a newborn baby when administered to a pregnant woman.
The FDA advises health care professionals to tell women of reproductive age, and men with female partners of reproductive potential, to use effective
contraception
Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...
during treatment with selumetinib, and for one week after the last dose.
Adverse effects
Common side effects are headache,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, vomiting,
abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.
Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
, diarrhea,
fatigue,
musculoskeletal pain
Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back. MSDs can arise from a sudden exertion (e.g., ...
(pain in the body affecting bones, muscles, ligaments, tendons and nerves), fever, dry skin,
acneiform rash (acne) and other
rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...
es,
stomatitis
Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration.
In its widest meaning, stomatitis can have a multitude of different cau ...
(inflammation of the mouth and lips),
paronychia
Paronychia is an inflammation of the skin around the nail, which can occur suddenly, when it is usually due to the bacterium ''Staphylococcus aureus'', or gradually when it is commonly caused by the fungus ''Candida albicans''. The term is fro ...
(infection in the skin that surrounds a toenail or fingernail) and
pruritus
Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
(itching).
Selumetinib can also cause serious side effects including
heart failure (manifested as ejection fraction decrease, or when the muscle of the left ventricle of the heart is not pumping as well as normal) and
eye toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
(acute and chronic damage to the eye) including
retinal vein occlusion
Central retinal vein occlusion, also CRVO, is when the central retinal vein becomes occluded, usually through thrombosis. The central retinal vein is the venous equivalent of the central retinal artery and both may become occluded. Since the centr ...
,
retinal pigment epithelial detachment and impaired vision.
Selumetinib can also cause increased
creatinine phosphokinase (CPK).
CPK is an enzyme found in the heart, brain and skeletal muscles.
When muscle tissue is damaged, CPK leaks into a person's blood, which can be a sign of
rhabdomyolysis (breakdown of skeletal muscle due to direct or indirect muscle injury).
Further, selumetinib capsules contain
vitamin E
Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vi ...
, and users are at an increased risk of bleeding if their daily intake of vitamin E exceeds the recommended or safe limits.
Interactions
As selumetinib is thought to be metabolized by the liver enzymes
CYP3A4 and
CYP2C19
Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...
,
use of moderate to strong CYP3A4
inhibitors (such as
grapefruit juice
Grapefruit juice is the juice from grapefruits. It is rich in vitamin C and ranges from sweet-tart to very sour. Variations include white grapefruit, pink grapefruit and ruby red grapefruit juice.The World's Healthiest Foods; Grapefruit. ''The ...
) and of the CYP2C19 inhibitor
fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to pr ...
is discouraged for people taking selumetinib.
Pharmacology
Mechanism of action
Selumetinib is a
kinase inhibitor
A protein kinase inhibitor is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function.
The phospha ...
, more specifically a selective inhibitor of the enzyme
mitogen-activated protein kinase kinase
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* ( ...
(MAPK kinase or MEK) subtypes
1 and
2. These enzymes are part of the
MAPK/ERK pathway, which regulates
cell proliferation (i.e., growth and division) and is overly active in many types of cancer.
[Selumetinib . Accessed 14 April 2021.]
History
Selumetinib was discovered by
Array BioPharma and was licensed to
AstraZeneca
AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...
. It has been investigated for the treatment of various types of cancer, such as
non-small cell lung cancer
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
(NSCLC) and
thyroid cancer
Thyroid cancer is cancer that develops from the tissues of the thyroid gland. It is a disease in which cells grow abnormally and have the potential to spread to other parts of the body. Symptoms can include swelling or a lump in the neck. C ...
.
The US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) granted the application for selumetinib
priority review
Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
,
breakthrough therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
, and
orphan drug designations.
It was granted a rare pediatric disease designation for the treatment of pediatric NF-1 along with a rare pediatric disease priority review voucher.
In April 2020, selumetinib was approved by the FDA for the treatment of children with NF-1.
[ ] It is the first drug approved in the US to treat this rare disease.
The approval was based on a clinical trial of children who had NF-1 and inoperable plexiform neurofibromas (defined as a PN that could not be completely removed without risk for substantial morbidity to the child), conducted by the
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
.
The
efficacy results were from 50 of the children who received the recommended dose and had routine evaluations of changes in tumor size and tumor-related morbidities during the trial.
The children received selumetinib 25 mg/m
2 orally twice a day until disease progression or until they experienced unacceptable adverse reactions.
The clinical trial measured the
overall response rate (ORR), defined as the percentage of subjects with a complete response and those who experienced more than a 20% reduction in PN volume on
MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
that was confirmed on a subsequent MRI within 3 to 6 months.
The ORR was 66% and all subjects had a partial response, meaning that no subjects had complete disappearance of the tumor.
Of these subjects, 82% had a response lasting 12 months or longer.
The trial was conducted at four sites in the United States.
Other clinical outcomes for subjects during selumetinib treatment included changes in PN-related disfigurement, symptoms and functional impairments.
Although the sample sizes of subjects assessed for each PN-related morbidity (such as disfigurement, pain, strength and mobility problems, airway compression, visual impairment and bladder or bowel dysfunction) were small, there appeared to be a trend of improvement in PN-related symptoms or functional deficits during treatment.
Research
Selumetinib has also been shown to inhibit growth of ''
GNAQ
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the ''GNAQ'' gene. Together with GNA11 (its paralogue), it functions as a Gq alpha subunit.
Function
Guanine nucleotide-binding proteins are a fam ...
'' mutated uveal melanoma cell lines. Furthermore, preliminary results suggest that selumetinib treatment of uveal melanoma patients can result in tumor shrinkage as the consequence of sustained inhibition of
ERK phosphorylation.
A
Phase II clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
about selumetinib in NSCLC was completed in September 2011; one about cancers with ''
BRAF'' mutations is ongoing .
In July 2015, selumetinib failed a Phase III trial testing whether the drug significantly prolonged the survival of patients in a study on
melanoma originating in the eye. In the 152-patient trial, a combination of selumetinib and
dacarbazine
Dacarbazine (DTIC), also known as imidazole carboxamide, is a chemotherapy medication used in the treatment of melanoma and Hodgkin's lymphoma. For Hodgkin's it is often used together with vinblastine, bleomycin, and doxorubicin. It is given ...
failed to improve
progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...
compared with just the old drug alone.
, there were other phase III trials registered for thyroid cancer, and ''
KRAS
''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cel ...
'' positive NSCLC. The combination of selumetinib to chemotherapy improved median progression-free survival in a trial of 510 patients with advanced ''KRAS''-mutant NSCLC just for one month, which was statistically not significant.
In November 2018, investigators working with
nasal polyp tissue ''in vitro'' demonstrated a synergistic effect of down regulating expression of p-MEK1 and p-
ERK1
Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene.
Function
The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) fami ...
when it was administered with
erythromycin.
References
Further reading
*
External links
*
*
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