ASH Preview: Looking at the XPO1 target from ASH 2021

The annual American Society of Hematology (ASH) annual meeting is one of the largest and most comprehensive international academic conferences in the field of hematology in the world

ATG-010 (Celinisol) is an XPO1 inhibitor, the first and only nuclear export inhibitor (SINE) approved by the FDA

1.

XPO1 is responsible for the transport of more than 220 proteins and part of RNA out of the nucleus.

The vast majority of proteins are tumor suppressor proteins, as well as cell cycle regulatory proteins and apoptosis-related proteins, such as P53, P73, FOXO1, BRCA1 and so on

However, in tumor cells, XPO1 is often overexpressed.

Figure: Schematic diagram of XPO1 mediated nuclear export

2.

Selinexor, developed by Karyopharm Therapeutics, is the world's first and only XPO1 inhibitor approved for marketing.

In July 2019, Celiniso was granted accelerated approval by the FDA, combined with dexamethasone, for at least 4 therapies in the past and for at least 2 proteasome inhibitors (PI) and at least 2 immunosuppressive agents (ImiD) Patients with relapsed/refractory multiple myeloma (r/r MM) with an anti-CD38 monoclonal antibody

In June 2020, Celiniso was approved for the third-line treatment of diffuse large B-cell lymphoma indications.

In 2018, Deck Pharmaceuticals and Karyopharm Therapeutics launched a strategic cooperation, Deck Pharmaceuticals obtained the development and commercialization rights of Celiniso in Mainland China and Macau

3.

(1) Karyopharm Therapeutics is the world's leading enterprises XPO1 inhibitors, in addition to the successful development Kayseri NESO, the research and development pipeline also includes Eltanexor, Verdinexor and so on

Eltanexor (KPT-8602, ATG-016): Eltanexor is a second-generation SINE compound
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Compared with Celiniso, Eltanexor has a wider treatment window and is difficult to cross the blood-brain barrier.
It is expected to increase the frequency of administration and increase the exposure of the drug in the clinic
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Currently, Eltanexor is in phase I/II clinical trials to explore the performance of Eltanexor in multiple myeloma, colorectal cancer, castration-resistant prostate cancer, and myelodysplastic syndrome (MDS)
.

Verdinexor (KPT-335, ATG- 527) SINE is a new compound effective to inhibit the tumor cell lines canine nucleoprotein XPO1, also reduce the level of viral replication, currently in clinical stage Ⅰ
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In May 2017, Karyopharm signed a cooperation agreement with Anivive Lifesciences to exclusively research, develop and commercialize Verdinexor for the treatment of animal cancers worldwide
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Deqi Pharmaceuticals introduced Verdinexor to develop anti-inflammatory and antiviral indications for systemic lupus erythematosus (SLE) and CAEBV infection
.

(2) BIIB-100 is developed a healthy Bo XPO1 inhibitor indicated for amyotrophic lateral sclerosis (ALS), currently in clinical stage Ⅰ
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ALS, also known as gradual freezing disease, is a rare disease.
Mr.
Hawking suffers from ALS
.
The cause of ALS is the damage of motor neurons, and the etiology may be related to factors such as heredity and environment
.

(3) SL-801 is a reversible oral XPO1 inhibitor developed by Stemline Therapeutics, which has CRM1 degradation and anti-tumor activity
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The reversibility of its combination with XPO1 is expected to reduce drug side effects and increase the therapeutic index
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SL-801 is currently in clinical phase I, and its indications are solid tumors
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4.
Summary

XPO-1, as a nuclear export protein, has a broad development prospect.
It is not only closely related to the occurrence and development of various tumors, including hematological tumors and solid tumors, but also to autoimmune diseases (such as systemic lupus erythematosus) and neurodegenerative diseases ( Such as amyotrophic lateral sclerosis) is closely related
.
Celiniso was approved for multiple myeloma indications in 2019 and added DLBCL indications in 2020, providing new medication options for patients with advanced MM and DLBCL
.
Deck Pharmaceuticals has in-depth layout of the nuclear output track.
In January 2021, it submitted Celiniso's listing application to NMPA and obtained priority review qualifications.
It is expected to be the first to launch the first XPO1 inhibitor in China in early 2022 and land on the beach
.