Selinexor sold under the brand name Xpovio among others, is a
selective inhibitor of nuclear export Selective inhibitors of nuclear export (SINEs or SINE compounds) are drugs that block exportin 1 (XPO1 or CRM1), a protein involved in transport from the cell nucleus to the cytoplasm. This causes cell cycle arrest and cell death by apoptosis. Th ...
used as an
anti-cancer medication
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. It works by blocking the action of
exportin 1 and thus blocking the
transport
Transport (in British English), or transportation (in American English), is the intentional movement of humans, animals, and goods from one location to another. Modes of transport include air, land (rail and road), water, cable, pipeline, an ...
of several proteins involved in cancer-cell growth from the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, which ultimately arrests the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
and leads to
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
It is the first drug with this
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
.
The most common side effects include nausea (feeling sick), vomiting, decreased appetite, weight loss, diarrhea, tiredness, thrombocytopenia (low blood-platelet counts), anaemia (low red-blood cell counts), low levels of white blood cells and hyponatraemia (low blood sodium levels).
Selinexor was granted
accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...
by 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) in July 2019, for use in combination with the corticosteroid
dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...
for the treatment of adults with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.
[ ] In December 2020, selinexor was approved by the FDA in combination with
bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy.
In clinical trials, it was associated with a high incidence of severe side effects, including
low platelet counts and
low blood sodium levels.
[ ]
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 ...
. Selinexor was approved for medical use in the European Union in March 2021.
Medical uses
Selinexor is approved in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy.
Selinexor is also approved for use in combination with the steroid
dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...
in people with relapsed or refractory
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
who have received at least four prior therapies and whose disease is refractory to at least two proteosome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody (so-called "quad-refractory" or "penta-refractory" myeloma),
for whom no other treatment options are available.
It is the first drug to be approved for this indication.
In June 2020, 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) approved an additional indication for selinexor to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.
[ ]
In the European Union, selinexor is indicated in combination with dexamethasone for the treatment of multiple myeloma in adults who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
Adverse effects
In the clinical study (the BOSTON study) used to support FDA approval in patients with multiple myeloma after at least one prior therapy (once-weekly selinexor in combination with once-weekly bortezomib and dexamethasone),the most common adverse reactions were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from other selinexor studies. Most adverse reactions were manageable with dose modifications and/or standard supportive care. The most common non-hematologic adverse reactions were fatigue (59%), nausea (50%), decreased appetite (35%), and diarrhea (32%) and were mostly Grade 1 and 2 events. The most common Grade 3 and 4 adverse reactions were thrombocytopenia (43%), lymphopenia (38%), fatigue (28%) and anemia (17%).
The most common adverse reactions (incidence ≥20%) in people with diffuse large B-cell lymphoma (DLBCL), excluding laboratory abnormalities, were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia.
Grade 3-4 laboratory abnormalities in ≥15% were thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia.
Serious adverse reactions occurred in 46% of people, most often from infection.
Thrombocytopenia was the leading cause of dose modifications.
Gastrointestinal toxicity developed in 80% of people and any grade hyponatremia developed in 61%.
Central neurological adverse reactions occurred in 25% of people, including dizziness and mental status changes.
The prescribing information provides warnings and precautions for thrombocytopenia, neutropenia, gastrointestinal toxicity, hyponatremia, serious infection, neurological toxicity, and embryo-fetal toxicity.
Mechanism of action
![RanGTPcycle](https://upload.wikimedia.org/wikipedia/commons/1/1e/RanGTPcycle.png)
Like other
selective inhibitors of nuclear export (SINEs), selinexor works by binding to
exportin 1 (also known as XPO1 or CRM1). XPO1 is a
karyopherin
Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm (or nucleoplasm). Generally, karyopherin-mediated transport occurs through ...
which performs
nuclear transport Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecule ...
of several proteins, including
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s,
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s, and proteins involved in governing cell growth, from the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
; it is often
overexpressed and its function misregulated in several types of cancer.
By inhibiting the XPO1 protein, SINEs lead to a buildup of tumor suppressors in the nucleus of malignant cells and reduce levels of oncogene products which drive cell proliferation. This ultimately leads to cell cycle arrest and death of cancer cells by
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
''In vitro'', this effect appeared to spare normal (non-malignant) cells.
Inhibiting XPO1 affects many different cells in the body which may explain the incidence of adverse reactions to selinexor.
Thrombocytopenia, for example, is a
mechanistic
The mechanical philosophy is a form of natural philosophy which compares the universe to a large-scale mechanism (i.e. a machine). The mechanical philosophy is associated with the scientific revolution of early modern Europe. One of the first expo ...
and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor
STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family.
Function
STAT3 is a member of the STAT protein family. In respons ...
in the nucleus of
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s, preventing their differentiation into mature
megakaryocyte
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
s (platelet-producing cells) and thus slowing production of new platelets.
Chemistry
Selinexor is a fully synthetic
small-molecule
Within the fields of molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs ar ...
compound, developed by means of a
structure-based drug design
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activ ...
process known as
induced-fit docking. It binds to a
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
residue in the
nuclear export signal
A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...
groove of exportin 1. Although this bond is
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
, it is slowly
reversible.
History
Selinexor was developed by Karyopharm Therapeutics, a pharmaceutical company focused on the development of drugs that target
nuclear transport Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecule ...
. It was approved in the United States in July 2019,
on the basis of a single-arm Phase IIb clinical trial. The FDA decided to grant accelerated approval despite a previous recommendation from an FDA Advisory Committee Panel which had voted 8–5 to delay approving the drug until the results from an ongoing Phase III study were known.
Selinexor in combination with dexamethasone was granted accelerated approval and was granted
orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
designation.
The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
In June 2020, 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) approved an additional indication for selinexor to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.
Approval was based on SADAL (KCP-330-009; NCT02227251), a multicenter, single-arm, open-label trial in participants with DLBCL after two to five systemic regimens.
Participants received selinexor 60 mg orally on days one and three of each week.
In December 2020, the FDA expanded selinexor's approved indication to include its combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy.
Society and culture
Legal status
On 28 January 2021, the
Committee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...
(CHMP) of the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Nexpovio intended for the treatment of relapsed and refractory multiple myeloma.
The applicant for this medicinal product is Karyopharm Europe GmbH.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] Selinexor was approved for medical use in the European Union in March 2021.
Research
Under the codename KPT-330, selinexor was tested in several preclinical
animal model
An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s of cancer, including
pancreatic cancer
Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
,
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
,
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 sm ...
,
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
s, and acute and chronic
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
s.
In humans, early clinical trials (phase I) have been conducted in
non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
,
blast crisis, and a wide range of advanced or refractory solid tumors, including
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...
,
head and neck cancer
Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...
,
melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
,
ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
, and
prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
.
Compassionate use
Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life ...
in patients with
acute myeloid leukemia
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...
has also been reported.
The pivotal clinical trial which served to support approval of selinexor for people with relapsed/refractory multiple myeloma was an open-label study of 122 patients known as the STORM trial.
In all of the enrolled patients, patients had been treated with a median of seven prior treatment regimens including conventional
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
,
targeted therapy
Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks ...
with
bortezomib
Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...
,
carfilzomib
Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.
The U. ...
,
lenalidomide,
pomalidomide
Pomalidomide ( INN; marketed as Pomalyst in the US and Imnovid in the European Union and Russia) is a derivative of thalidomide marketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator.
Pomalidomide was approved in Februa ...
, and a
monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodies ca ...
(
daratumumab
Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly de ...
or
isatuximab
Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.
The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell), infusion r ...
);
nearly all had also undergone
hematopoietic stem cell transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...
but had disease that continued to progress.
The
overall response rate was 26%, including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months.
As of 2019, phase I/II and III trials are ongoing,
including the use of selinexor in other cancers and in combinations with other drugs used for multiple myeloma.
In November 2020, results from the multi-center, Phase III, randomized study (NCT03110562) which evaluated 402 participants with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy were published in The Lancet.
The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly selinexor in combination with once-weekly Velcade® (bortezomib) plus low-dose dexamethasone (SVd) versus twice-weekly Velcade® plus low-dose dexamethasone (Vd). The primary endpoint of the study was progression-free survival (PFS) and key secondary endpoints included overall response rate (ORR), rate of peripheral neuropathy, and others. Additionally, the BOSTON study allowed for patients on the Vd control arm to crossover to the SVd arm following objective (quantitative) progression of disease verified by an Independent Review Committee (IRC). The BOSTON study was conducted at over 150 clinical sites internationally.
Although the study had one of the highest proportions of patients with high-risk cytogenetics (~50%) as compared with other Velcade-based studies in previously treated myeloma, the median PFS in the SVd arm was 13.93 months compared to 9.46 months in the Vd arm, representing a 4.47 month (47%) increase in median PFS (hazard ratio
R0.70; p=0.0075). The SVd group also demonstrated a significantly greater ORR compared to the Vd group (76.4% vs. 62.3%, p=0.0012). Patients who had received only one prior line of therapy also demonstrated a higher ORR on the SVd arm as compared to the Vd arm (80.8% vs. 65.7%, p=0.0082). Importantly, SVd therapy compared to Vd therapy showed consistent PFS benefit and higher ORR across several important subgroups.
In 2020, selinexor underwent a
clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
for treatment of
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
.
LVHN Among Early Participants to Test Cancer Drug as COVID-19 Treatment
, Lehigh Valley Hospital–Cedar Crest
Lehigh Valley Hospital, also known as Lehigh Valley Hospital-Cedar Crest, is a hospital in Allentown, Pennsylvania.
Lehigh Valley Hospital is the largest hospital in the Lehigh Valley metropolitan region and the third largest hospital in Pennsyl ...
(LVHN) website, 7 May 2020 In this phase 2 randomized placebo-controlled single-blind trial named XPORT-CoV-1001 with a total of 190 participants with severe COVID-19, treatment with selinexor resulted in higher mortality (16% vs. 9%) and more serious adverse event A serious adverse event (SAE) in human drug trials is defined as any untoward medical occurrence that at any dose
#Results in death
#Is life-threatening
#Requires inpatient hospitalization or causes prolongation of existing hospitalization
#Results ...
s (23% vs. 16%) than placebo.
References
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