On July 21, 2022 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, and the Menarini Group ("Menarini"), a privately-held, leading international pharmaceutical company, reported that the European Commission (EC) has granted Marketing Authorisation for NEXPOVIO (selinexor), a first-in-class, oral exportin 1 (XPO1) inhibitor, in combination with once-weekly bortezomib (Velcade) and low-dose dexamethasone (SVd) for the treatment of adults with multiple myeloma who have received at least one prior therapy (Press release, Karyopharm, JUL 21, 2022, View Source [SID1234616838]). With this approval for the extension of NEXPOVIO’s indication in the European Union (EU), the conditional marketing authorisation is now converted to a full approval. The marketing authorisation, which marks the second indication for NEXPOVIO, is valid in all 27 member states of the EU as well as Iceland, Liechtenstein, Norway, and Northern Ireland. Stemline Therapeutics B.V., a wholly owned subsidiary of the Menarini Group, will be responsible for all commercialization activities in Europe.

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The approval follows a positive opinion granted in May 2022 by the CHMP based on results from the Phase 3 BOSTON study that demonstrated once-weekly SVd resulted in a statistically significant reduction in the risk of disease progression or death compared to standard twice-weekly bortezomib plus dexamethasone (Vd) regimen. The results from the BOSTON study were published in The Lancet (Grosicki, et al.) in November 2020.

"The European Commission’s approval of an expanded use of NEXPOVIO provides another option for patients with multiple myeloma who have relapsed, or become resistant to current treatment regimens," said Richard Paulson, President and Chief Executive Officer of Karyopharm. "Our decision to pursue approval for this patient population is indicative of our commitment to expand access to selinexor across the globe and we look forward to working closely with Menarini who will commercialize NEXPOVIO in Europe."

"The approval of NEXPOVIO marks an important step forward for patients in Europe where nearly 51,000 new cases of multiple myeloma are diagnosed each year and therapeutic options are limited," said Elcin Barker Ergun, Chief Executive Officer of Menarini. "We are committed to offering patients and physicians a valuable new treatment option and are working hard to make NEXPOVIO available in different European countries as quickly as possible."

About the BOSTON study

The Marketing Authorisation is based upon the Phase 3 BOSTON (Bortezomib, Selinexor and Dexamethasone) study, which was a multi-center, randomized study (NCT03110562) that evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy. The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly SVd versus twice-weekly Vd. The primary endpoint of the study was progression-free survival and key secondary endpoints included overall response rate, rate of peripheral neuropathy, and others. To learn more about this study, please refer to Karyopharm and Menarini’s press release on the positive CHMP opinion issued on May 20, 2022.

About Multiple Myeloma in Europe

Multiple myeloma is an incurable cancer with significant morbidity and the second most common hematologic malignancy. According to the World Health Organization, in 2020, there were approximately 51,000 new cases and 32,000 deaths from multiple myeloma in Europe1. While the treatment of multiple myeloma has improved over the last 20 years, and overall survival has increased considerably, the disease remains incurable, and nearly all patients will eventually relapse and develop disease that is refractory to all approved anti-myeloma therapies. Therefore, there continues to be a high unmet medical need for new therapies, particularly those with novel mechanisms of action.

About NEXPOVIO (selinexor)

NEXPOVIO, which is marketed as XPOVIO in the U.S., has been approved in the following oncology indications by the European Commission: (i) in combination with dexamethasone for the treatment of multiple myeloma in adult patients 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; and (ii) in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy.

The expanded NEXPOVIO indication now allows adult patients with multiple myeloma to be treated in earlier lines of therapy. The indication for NEXPOVIO is valid in the EU Member States as well as Iceland, Liechtenstein, Norway, and Northern Ireland. NEXPOVIO is also approved in the UK under a Conditional Marketing Authorisation. The extension of indication in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy is currently under review by Medicines and Healthcare Products Regulatory Agency.

NEXPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor. NEXPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). NEXPOVIO 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.

Please see NEXPOVIO Summary of Product Characteristics and European Public Assessment Report at View Source

UNITED STATES IMPORTANT SAFETY INFORMATION

Contraindications: Hypersensitivity to selinexor.

Special warnings and precautions for use:

Recommended concomitant treatments
Patients should be advised to maintain adequate fluid and caloric intake throughout treatment. Intravenous hydration should be considered for patients at risk of dehydration.
Prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents should be provided prior to and during treatment with NEXPOVIO.

Haematology:
Patients should have their complete blood counts (CBC) assessed at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment.

Thrombocytopenia:
Thrombocytopenic events (thrombocytopenia and platelet count decreased) were frequently reported in adult patients receiving selinexor, which can be severe (Grade 3/4). Patients should be monitored for signs and symptoms of bleeding and evaluated promptly.

Neutropenia:
Severe neutropenia (Grade 3/4) has been reported with selinexor.
Patients with neutropenia should be monitored for signs of infection and evaluated promptly.

Gastrointestinal toxicity:
Nausea, vomiting, diarrhoea, which sometimes can be severe and may require the use of anti-emetic and anti-diarrhoeal medicinal products.

Weight loss and anorexia:
Patients should have their body weight, nutritional status and volume checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment.

Confusional state and dizziness:
Patients should be instructed to avoid situations where dizziness or confusional state may be a problem and to not take other medicinal products that may cause dizziness or confusional state without adequate medical advice. Patients should be advised not to drive or operate heavy machinery until symptoms resolve.

Hyponatraemia:
Patients should have their sodium levels checked at baseline, during treatment, and as clinically indicated. Monitoring should be more frequent during the first two months of treatment.

Cataract:
Selinexor can cause new onset or exacerbation of cataract. Ophthalmologic evaluation may be performed as clinically indicated. Cataract should be treated as per medical guidelines, including surgery if warranted.

Tumour lysis syndrome (TLS):
TLS has been reported in patients receiving therapy with selinexor. Patients at a high risk for TLS should be monitored closely. Treat TLS promptly in accordance with institutional guidelines.

Fertility, pregnancy and lactation
Women of childbearing potential/contraception in males and females:
Women of childbearing potential and male adult patients of reproductive potential should be advised to use effective contraceptive measures or abstain from sexual intercourse while being treated with selinexor and for at least 1 week following the last dose of selinexor.

Pregnancy:
There are no data from the use of selinexor in pregnant women. Selinexor is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding:
It is unknown whether selinexor or its metabolites are excreted in human milk. A risk to breast-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with selinexor and for 1 week after the last dose.

Undesirable effects
Summary of the safety profile
The most frequent adverse reactions (≥30%) of selinexor in combination with dexamethasone were nausea, thrombocytopenia, fatigue, anaemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatraemia, neutropenia and leukopenia.

The most commonly reported serious adverse reactions (≥3%) were pneumonia, sepsis, thrombocytopenia, acute kidney injury, and anaemia.

Description of selected adverse reactions
Infections: Infection was the most common non-haematological toxicity. Upper respiratory tract infection and pneumonia were the most commonly reported infections with 25% of reported infections being serious and fatal infections occurring in 3% of treated adult patients.

Elderly population
Patients 75 years and older had a higher incidence of discontinuation due to an adverse reaction, higher incidence of serious adverse reactions, and higher incidence of fatal adverse reactions.

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after Authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.