Phase 3 Clinical Study of Novel Selective Inhibitor of Nuclear Export Selinexor with New Combination Therapy for Multiple Myeloma Meets Primary Endpoint
Release date：
2020-03-02
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– Combination of Once-Weekly XPOVIO® (selinexor), Once-Weekly Velcade® (bortezomib) plus Dexamethasone (SVd) Results in Statistically Significant Reduction in the Risk of Disease Progression or Death Compared to Standard Twice-Weekly Velcade® plus Dexamethasone (Vd) Regimen
– Regulatory submission to FDA planned in Q2 2020; data to be submitted for presentation at upcoming medical meetings
– 47% increase in median PFS on Svd versus Vd
Shanghai, China and Massachusetts, USA, March 3，2020 — Antengene’s Partner Karyopharm (NASDAQ: KPTI) announced that the Phase 3 BOSTON study of Selinexor (XPOVIO®) in combination with Velcade® （bortezomib） and low-dose dexamethasone (SVd) compared to Velcade® and low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy met the primary endpoint of progression-free survival (PFS). The median PFS was 13.93 months in the SVd arm and 9.46 months in the Vd arm, representing a 4.47 month (47%) increase in median PFS (hazard ratio=0.70; p=0.0066). There were no new safety signals on the SVd arm and there was no imbalance in deaths between the two arms in the study. The full top-line data will be submitted for presentation at upcoming medical meetings.
XPOVIO® is the first Selective Inhibitor of Nuclear Export (SINE) for clinical use in the world. The U.S. Food and Drug Administration (FDA) approved XPOVIO® in combination with low-dose dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors on July 3, 2019. In addition, on February 19, 2020, the FDA accepted supplemental New Drug Application (sNDA) seeking accelerated approval for selinexor as a treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who have received at least two prior therapies and announced a PDUFA date of June 23, 2020. The European Marketing Authorization Application (MAA) of selinexor has been submitted to the European Medicines Agency (EMA). Antengene expects to submit its New Drug Application (NDA) in China this year.
In the BOSTON Phase 3 study, the SVd arm obviously reduced the dose of drugs used compared to the control arm, in which the dose of bortezomib was reduced by 40% and the dose of dexamethasone was reduced by 25%. In addition, compared to the STORM study conducted in patients with penta-exposed, triple-class refractory multiple myeloma (refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide and daratumumab), the dose of selinexor in the BOSTON study was also further reduced, from 80 mg twice a week (STORM) to 100 mg once a week (BOSTON).
At present, in vivo and in vitro studies have demonstrated that the combination of selinexor and bortezomib can synergistically promote the accumulation of multiple tumor suppressor proteins （TSPs） in the nucleus, increase the level of TSPs, and partially overcome the resistance of proteasome inhibitors. This synergy contributes to the superiority of the SVd regimen against the Sd and Vd regimen, and this effect-enhancing and toxicity-reducing treatment will provide patients with relapsed or refractory multiple myeloma with a safer and more effective treatment option.
“From STORM to BOSTON and from Sd to SVd, selinexor continues to expand the breadth and depth of its therapeutic field through the combination with established drugs. The BOSTON study data further demonstrated the clinical value of selinexor as an antitumor drug with a novel mechanism and its great potential for patient treatment. It is believed that in the near future, selinexor will become the backbone drug for the treatment of multiple myeloma.” said Dr. Jay Mei, founder, chairman and CEO of Antengene. “It is not only the wish of doctors and patients but also our mission that selinexor can be used for treating a wider range of patients through multi-drug combination and dose reduction. We will promote the market launch of selinexor in China as fast as we can, so that Chinese patients could benefit from this innovation as soon as possible.”
The remarkable result of the BOSTON study showed that patients receiving SVd therapy had a 47% longer median PFS than the standard treatment group. This represented another important advance in the treatment of relapsed or refractory multiple myeloma. Detailed data will be submitted during the upcoming medical conference to share the results with the medical community. These data will be submitted to the FDA as soon as possible as part of a supplemental NDA new drug application, seeking to expand the approved indications of XPOVIO® to second-line treatment for patients with relapsed or refractory multiple myeloma. If approved, the SVd regimen will be the first and only FDA-approved once-weekly Velcade® regimen among the Velcade® combination therapies for the treatment of recurrent myeloma.
About the BOSTON phase 3 clinical trial
Randomized, active comparator-controlled, open-label, multicenter study designed to compare the efficacy, safety and certain health-related quality of life (HR-QoL) parameters of once-weekly XPOVIO (selinexor) in combination with once-weekly Velcade® (bortezomib) plus low-dose dexamethasone (SVd) versus twice-weekly Velcade plus low-dose dexamethasone (Vd) in adult patients with relapsed or refractory multiple myeloma who have received 1-3 prior lines of therapy, the BOSTON study enrolled approximately 402 patients. Patients randomized to the SVd arm received selinexor (100mg once-weekly), Velcade (1.3 mg/m2 once-weekly given subcutaneously) and dexamethasone (40mg weekly). Patients randomized to the Vd arm received Velcade® (twice-weekly) plus low-dose dexamethasone. The primary endpoint of the study is progression-free survival (PFS) and key secondary endpoints include overall response rate (ORR), among others. Additionally, the BOSTON study allows for patients on the Vd control arm to crossover to the SVd arm following objective (quantitative) progression of disease. The BOSTON study is being conducted at over 150 clinical sites internationally. Vd is a standard therapy for previously treated patients with multiple myeloma that is given by injection twice-weekly.
About Selinexor
Selinexor (XPOVIO®) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). Selinexor blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.
Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. A supplemental New Drug Application was recently submitted to the FDA seeking accelerated approval for selinexor as a new treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and selinexor has received Fast Track and Orphan designation from the FDA for this patient population.
Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade® (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO). Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.
About Antengene
Antengene is a China-and-U.S. based biopharmaceutical company focusing on drug discovery, clinical development and the commercialization of innovative therapeutics to meet unmet medical needs. Antengene aims to provide the most advanced and first-in-class anti-cancer drugs and other treatments for patients in China，Asia and around the world. In April 2017, Celgene (now officially acquired by Bristol-Myers Squibb, and become the world’s top ten pharmaceutical company after the merge), a global leading innovative biopharmaceutical company became a long-term strategic partner and obtained an equity position in Antengene. In January 2020, former Celgene chairman and CEO Mark J. Alles joined Antengene Board of Directors and former Celgene China GM John Chin joined the company as Chief Business Officer.
At present, Antengene’s pipeline includes six clinical stage products:
ATG-010 (selinexor) is the first oral selective inhibitor of nuclear export compound with novel mechanisms in the world. In 2019, the U.S. FDA approved ATG-010 in combination with low-dose dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma. Currently, the registered clinical trials of ATG-010 in relapsed refractory multiple myeloma (RRMM) and diffuse large B-cell lymphoma (DLBCL) is ongoing in China. The compound is also in late clinical development for various other hematologic malignancies and solid tumors. In addition, preclinical studies have shown that inhibitors of nuclear protein export can effectively treat KRAS mutant tumor, and related clinical studies will be conducted within the year; ATG-008 is a second-generation dual mTORC1/2 inhibitor and is in a multi-regional clinical trial for treatment of advanced liver cancer, lung cancer, and several other tumors; ATG-016 is a second-generation oral selective inhibitor of nuclear export protein, and is currently being studied in myelodysplastic syndrome (MDS) as well as in several clinical trials of solid tumors, including colorectal cancer (CRC) and prostate cancer (PrC) ; ATG-019 is the first-in-class PAK4/NAMPT dual-target inhibitors, and is currently been studied in a number of clinical trials including non-Hodgkin’s lymphoma （NHL）, colorectal cancer, lung cancer, and melanoma. In addition, preclinical studies have demonstrated that ATG-019 in combination with anti-PD-1 antibodies can effectively improve the anti-tumor activity and is effective in patients who acquire resistance to anti-PD-1 therapy. Related clinical trial is about to initiate; ATG-527 is an innovative product under development for antiviral and treatment of autoimmune diseases, and has been in clinical trials conducted in Epstein-Barr virus (EBV), respiratory syncytial virus (RSV) infection, cytomegalovirus (CMV) infection and Systemic lupus erythematosus (SLE) and other related diseases; ATG-017 is a potent and selective small molecule extracellular signal–regulated kinases 1 and 2 (ERK1/2) inhibitor, in clinical development for the treatment of various solid tumors, non-Hodgkin’s lymphoma, acute myelocytic leukemia (AML) and multiple myeloma. In addition, the drug discovery team of Antengene focuses on the early preclinical development of multiple innovative target drugs in the fields of small molecule, monoclonal and bi-specific antibodies. For more information, please visit www.antengene.com.
About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (Nasdaq: KPTI) is an oncology-focused pharmaceutical company dedicated to the discovery, development, and commercialization of novel first-in-class drugs directed against nuclear export and related targets for the treatment of cancer and other major diseases. Karyopharm’s SINE compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharm’s lead compound, XPOVIO® (selinexor), received accelerated approval from the FDA in July 2019 in combination with dexamethasone as a treatment for patients with heavily pretreated multiple myeloma. An MAA for selinexor is also currently under review by the EMA for the same indication. The Company recently submitted a New Drug Application to the FDA seeking approval for XPOVIO in patients with DLBCL. In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm has several investigational programs in clinical or preclinical development. For more information, please visit www.karyopharm.com.
