Selinexor


Selinexor is a selective inhibitor of nuclear export used as an anti-cancer drug. It works by binding to exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.
The most common adverse reactions in people with diffuse large B-cell lymphoma, excluding laboratory abnormalities, were fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia.
Selinexor was granted accelerated approval by the U.S. Food and Drug Administration in July 2019, for use in combination with the corticosteroid dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma 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 clinical trials, it was associated with a high incidence of severe side effects, including low platelet counts and low blood sodium levels.
As of May 2020, it is in clinical trials for treatment of COVID-19 at locations including hospitals like Lehigh Valley Hospital.

Medical uses

Selinexor is approved for use in combination with the steroid dexamethasone in people with relapsed or refractory multiple myeloma 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, 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 approved an additional indication for selinexor to treat adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.

Adverse effects

In the clinical study used to support FDA approval, selinexor was associated with high rates of pancytopenia, including leukopenia, neutropenia, thrombocytopenia, and anemia. The most common non-hematological side effects were gastrointestinal reactions, hyponatremia, and fatigue. More than half of all patients who received the drug developed infections, including fatal cases of sepsis. However, these data are from an open-label trial, and thus cannot be compared to placebo or directly attributed to treatment.
The most common adverse reactions in people with diffuse large B-cell lymphoma, 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

Like other selective inhibitors of nuclear export, selinexor works by binding to exportin 1. XPO1 is a karyopherin which performs nuclear transport of several proteins, including tumor suppressors, oncogenes, and proteins involved in governing cell growth, from the cell nucleus to the cytoplasm; 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. In vitro, this effect appeared to spare normal 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 and dose-dependent effect, occurring because selinexor causes a buildup of the transcription factor STAT3 in the nucleus of hematopoietic stem cells, preventing their differentiation into mature megakaryocytes and thus slowing production of new platelets.

Chemistry

Selinexor is a fully synthetic small-molecule compound, developed by means of a structure-based drug design process known as induced-fit docking. It binds to a cysteine residue in the nuclear export signal groove of exportin 1. Although this bond is covalent, it is slowly reversible.

History

Selinexor was developed by Karyopharm Therapeutics, a pharmaceutical company focused on the development of drugs that target nuclear transport. 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 designation. The FDA granted the approval of Xpovio to Karyopharm Therapeutics.
In June 2020, the U.S. Food and Drug Administration approved an additional indication for selinexor to treat adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.
Approval was based on SADAL, 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.

Research

Under the codename KPT-330, selinexor was tested in several preclinical animal models of cancer, including pancreatic cancer, breast cancer, non-small-cell lung cancer, lymphomas, and acute and chronic leukemias. In humans, early clinical trials have been conducted in non-Hodgkin lymphoma, blast crisis, and a wide range of advanced or refractory solid tumors, including colon cancer, head and neck cancer, melanoma, ovarian cancer, and prostate cancer. Compassionate use in patients with acute myeloid leukemia 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, targeted therapy with bortezomib, carfilzomib, lenalidomide, pomalidomide, and a monoclonal antibody ; nearly all had also undergone hematopoietic stem cell transplantation 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.