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Unassigned

New Medicines

Nexpovio (EU), Xpovio (US)Penta-refractory multiple myeloma (MM)

Information

Nexpovio (EU), Xpovio (US)
New molecular entity
Menarini Stemline
Karyopharm Therapeutics

Development and Regulatory status

Approved (Licensed)
Approved (Licensed)
Launched
Yes
Dec 21Karyopharm Therapeutics and Menarini enter into an exclusive license agreement to commercialise Nexpovio in the EU and other European countries (including the UK), Latin America and other key countries [20].
Nov 21This product is no longer an orphan medicine in the EU. It was withdrawn from the Union Register of orphan medicinal products by the European Commission in February 2021 upon request of the marketing authorisation holder at the time of the granting of a marketing authorisation [19].
May 21NICE terminates its appraisal of selinexor as the company did not provide an evidence submission. Assume this means they currently have no plans to launch in the UK [18].
May 21Karyopharm therapeutics announce MHRA has granted selinexor conditional marketing authorization for use in combination with dexamethasone for 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 [17].
Mar 21Granted conditional approval in EU; continued authorisation for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial and is subject to additional monitoring [17].
Jan 21Recommended for conditional EU approval by CHMP - the full indication is "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." It should be prescribed by physicians experienced in the treatment of multiple myeloma. Conditional approval indicates that the information available is less than would usually be required, but that the medicine fulfils a significant unmet need and the benefit to risk balance is considered to be acceptable under those circumstances; the manufacturer will normally be expected to provide further clinical data to retain the marketing authorisation.[16]
Jan 21Licence application still under review by the EMA CHMP. At its October 2020 meeting, the Committee adopted a 3rd list of outstanding issues with a specific timetable, and agreed to consult a scientific advisory group and adopted a list of questions to this group [14,15].
Aug 19Karyopharm has responded to EMA list of consolidated questions, which was received in May 19. The EMA had switched from an accelerated review to a traditional review, to allow for extra time required for the company to revert and had also sent additional feedback. The feedback included the integrated inspection report, based on routine site audits and other activities. The company expects a decision by early 2020 [12].
Jul 19Launched in US [12].
Jul 19Approved in the US under accelerated approval [11].
Mar 19The FDA has pushed back the PDUFA action date for the New Drug Application (NDA) for selinexor from Apr 19 to Jul 19 to consider additional information submitted by Karyopharm as an amendment to the NDA [10].
Feb 19Filed in EU - MAA is being reviewed under EMA´s accelerated assessment programme [9].
Feb 19In FDA briefing materials, concerns were expressed over the safety profile of selinexor. The FDA considered that the proposed starting dose is not well tolerated given that data indicates dose-limiting toxicity. In the STORM trial, 23 pts died within 30 days of study treatment. Of those, 13 died due to disease progression and 10 due to a fatal treatment-emergent adverse event (TEAE). Severe TEAE´s were common (93.5% experienced at least one) and 60% experienced at least one serious adverse event. Most pts required dose modification due to a TEAE and 28% discontinued because of a TEAE. There were also issues with the trial design, which did not include a control group [8].
Nov 18The FDA accepted an application seeking accelerated approval for selinexor as a treatment for patients with penta-refractory multiple myeloma in Oct 18. The application has been granted priority review and a decision is expected by 6 Apr 19. If approved the company plan to market selinexor in the US in 1H 2019. A request for conditional approval for the same indication is expected to be submitted in the EU early 2019 [7].
May 18Karyopharm announced plans to file an NDA for selinexor in MM by the end of the year, with plans to submit a marketing authorization application to the EMA in 2019 [5].
May 18Selinexor was recently granted Fast-Track designation by the US FDA for this indication [5].

Category

CRM1 nuclear export inhibitor; inhibits export of tumour suppressor proteins from the nucleus, resulting in cel apoptosis.
Multiple myeloma is the second most common haematological cancer and is responsible for 15-20% of deaths from haematological cancer and about 2% of all deaths from cancer [3]. UK incidence in 2014 was about 1 in 11,500 (5,500 new cases) and rates are increasing. In 2010-11, five-year survival was 47% and ten-year survival 33%, but survival is age-related [4].
Penta-refractory multiple myeloma (MM)
Oral

Further information

Yes

Trial or other data

May 18Positive top-line data from PIIb STORM study of selinexor in pts with Penta-Refractory Multiple Myeloma. STORM (Selinexor Treatment of Refractory Myeloma) is an international, multi-centre, single-arm study (n=122) in heavily pretreated pts who each received 80mg oral selinexor twice weekly + low-dose dexamethasone (20mg twice weekly). Oral selinexor achieved a 25.4% overall response rate (95% CI 18 to 34%), which included two complete responses (CRs) and 29 partial (PRs) or very good partial responses (VGPRs). The median duration of response (DOR), a key secondary objective, was 4.4 months. Safety results were consistent with previously reported data (Vogl et al., J Clin Oncol, 2018). As anticipated, common adverse events (AEs) were nausea, vomiting, fatigue and reduced appetite and were primarily low grade and manageable with standard supportive care and/or dose modification. The most common hematologic AEs were Grade ≥3 cytopenias and were generally not associated with clinical sequelae [5].

Evidence based evaluations

Nexpovio (EU), Xpovio (US)Relapsed or refractory multiple myeloma - as second to fourth-line therapy in combination with bortezomib and dexamethasone

Information

Nexpovio (EU), Xpovio (US)
Licence extension / variation
Menarini Stemline
Karyopharm Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Recommended for approval (Positive opinion)
Launched
Yes
May 22EU positive opinion granted recommending a licence change to include use “in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy” [13].
Nov 21This product is no longer an orphan medicine in the EU. It was withdrawn from the Union Register of orphan medicinal products by the European Commission in February 2021 upon request of the marketing authorisation holder. It does have orphan status in the US [10,11].
May 21Pre-registration in EU. CHMP begins an assessment of an application for an extension of indication for Nexpovio in combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy [12].
Dec 20Approved in US [8].
Nov 20Karyopharm therapeutics announce plans to submit regulatory submission based on BOSTON study to EMA by end 2020 [9].
Jul 20US FDA accepts sNDA for treatment of patients with MM after at least one prior line of therapy [7].
Mar 20Karyopharm therapeutics announced plans to submit regulatory submission in Q2 2020 to the US FDA for this triple therapy regimen for 3rd line use in MM patients [5].

Category

First-in-class CRM1 nuclear export inhibitor; inhibits export of tumour suppressor proteins from the nucleus, resulting in cell apoptosis.
Multiple myeloma is the second most common haematological cancer and is responsible for 15-20% of deaths from haematological cancer and about 2% of all deaths from cancer [3]. UK incidence in 2014 was about 1 in 11,500 (5,500 new cases) and rates are increasing. In 2010-11, five-year survival was 47% and ten-year survival 33%, but survival is age-related [4].
Relapsed or refractory multiple myeloma - as second to fourth-line therapy in combination with bortezomib and dexamethasone
Oral

Further information

Yes

Trial or other data

Nov 20The PIII BOSTON study (n=402) found the addition of selinexor to bortezomib and dexamethasone was associated with improved progression-free survival (median 13.9 months vs 9.46 months with bortezomib plus dexamethasone; HR 0.70; 95% CI 0.53–0.93; p=0.0075) [6].
Mar 20Positive topline results from PIII BOSTON study announced which showed the once weekly triple therapy used 3rd line increased PFS by 4.47 months vs. std of care (twice-weekly Velcade + dexamethasone) in pts with MM (13.93 vs. 9.46 months). There were no new safety signals and no imbalance in deaths between the two study arms.[5]
Jan 20Primary outcome data now expected Jun 20 [4].
Jan 19Enrolment in the BOSTON study is complete. Top-line data are expected by the end of 2019, possibly into 2020 [3].
May 17Based on results from PII trials (NCT02343042, NCT02336815) Karyopharm initiates a multi-national pivotal randomised PIII trial of selinexor plus bortezomib plus dexamethasone vs. bortezomib plus dexamethasone. The trial (BOSTON, NCT03110562), is intended to enrol 364 patients with relapsed early-stage MM (1-3 prior lines of therapy) and has an estimated primary completion date of June 2020; joint primary outcomes are progression-free survival and overall response rate, both at 15 months [1,2].

Evidence based evaluations

Nexpovio (EU), Xpovio (US)Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Information

Nexpovio (EU), Xpovio (US)
Licence extension / variation
Menarini Stemline
Karyopharm Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Yes
Jun 20Approved in US for treatment of relapsed or refractory DLBCL that has not been otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy [4].
Feb 20Karyopharm expects to submit a Marketing Authorization Application to the European Medicines Agency in 2020 [1].
Feb 20The FDA has accepted for filing its supplemental New Drug Application seeking accelerated approval for oral selinexor (XPOVIO®) for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma [1].

Category

Blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins in cancer cells
The overall annual incidence of Diffuse large B-cell lymphoma (DLBCL) in Europe is 3.8/100,000 but the incidence increases with age and varies considerably across Europe [2].
Relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Intravenous

Trial or other data

Feb 20PIII trial (NCT02227251) Selinexor (KPT-330) in patients with Relapsed/Refractory diffuse large B-Cell lymphoma (DLBCL), primary completion date June 2020 [3].

Nexpovio (EU), Xpovio (US)Recurrent and advanced endometrial cancer - maintenance treatment after first or second-line chemotherapy

Information

Nexpovio (EU), Xpovio (US)
Licence extension / variation
Menarini Stemline
Karyopharm Therapeutics

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

First-in-class CRM1 nuclear export inhibitor; inhibits export of tumour suppressor proteins from the nucleus, resulting in cell apoptosis.
In the UK there are about 8,600 new cases per year [1].
Recurrent and advanced endometrial cancer - maintenance treatment after first or second-line chemotherapy
Oral

Evidence based evaluations

Nexpovio (EU), Xpovio (US)Advanced unresectable de-differentiated liposarcoma - third-line or greater

Information

Nexpovio (EU), Xpovio (US)
Licence extension / variation
Karyopharm Therapeutics
Karyopharm Therapeutics

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Yes
Jan 22No longer listed in company pipeline. Presume all development discontinued, as Karyopharm has previously announced that they will be applying for approval of "off-label" use in the US [12].

Category

CRM1 nuclear export inhibitor; inhibits export of tumour suppressor proteins from the nucleus, resulting in cell apoptosis.
Liposarcoma is the third most common specified soft tissue sarcoma, accounting for about 13% of all soft tissue sarcomas; reported incidence rates have increased from the mid-1990s, probably due to improved diagnosis and recording [2]. Incidence in England between 2007-9 was 6.2 cases per million [3]. Liposarcomas are divided into several classes - dedifferentiated liposarcoma is the least common type (about 5%)[4].
Advanced unresectable de-differentiated liposarcoma - third-line or greater
Oral

Further information

Yes

Evidence based evaluations