FDA Grants Orphan Drug Designation to Eltanexor for Myelodysplastic Syndromes

The FDA has granted an orphan drug designation to eltanexor, an investigational novel SINE compound, as a potential therapeutic option for patients with myelodysplastic syndromes.

The FDA has granted an orphan drug designation to eltanexor (KPT-8602), an investigational novel SINE compound, as a potential therapeutic option for patients with myelodysplastic syndromes (MDS), according to an announcement from Karyopharm Therapeutics, Inc.1

Eltanexor was designed to bind with and inhibit the nuclear export protein XP01, resulting in the accumulation of tumor suppressor proteins in the cell nucleus. This process is known to reinitiate and intensify the tumor suppressor function and is hypothesized to result in selective induction of apoptosis in cancer cells as normal cells are largely spared.

“We are pleased to receive the FDA’s orphan drug designation for eltanexor in MDS and believe it reinforces eltanexor’s potential to improve clinical outcomes for patients with hypomethylating agent [HMA]–refractory MDS,” Richard Paulson, president and chief executive officer of Karyopharm, Inc., stated in a press release. “We are focused on advancing our ongoing clinical trials and remain steadfast in our commitment to bringing this new treatment option to patients and their families.”

Preclinical findings with the agent have underscored that the agent has a wide therapeutic window, with minimal penetration of the blood-brain barrier; as such, the agent can serve as another option for several cancer indications.

In animal models, oral eltanexor resulted in a lower percentage of loss of body weight and improved food consumption compared with selinexor (Xpovio), another SINE compound. Based on these observations, investigators have deduced that more frequent dosing is possible with eltanexor than selinexor, which also allows for a longer period of exposure.

Moreover, data from an investigator-sponsored phase 1 trial showed that eltanexor monotherapy elicited an overall response rate (ORR) of 53% and an overall survival (OS) of 9.9 months in patients with HMA-refractory MDS, which compares favorably with the historical survival ranging from 4 to 6 months in this population.

Eltanexor is also under evaluation as a single agent and in combination with both approved and investigational agents in patients with several kinds of hematologic and solid tumors as part of an ongoing, open-label phase 1/2 study (KCP-8602-801; NCT02649790).2,3

The trial enrolled patients with higher-risk MDS, defined as high-risk or intermediate-2 disease per the International Prognostic Scoring System (IPSS), and 5% to 19% myeloblasts. To be eligible for enrollment, patients needed to be at least 18 years of age, and have acceptable hepatic and renal function.

Patients could not have undergone major surgery within 4 weeks before day 1 of cycle 1 of the trial, nor could they have impaired cardiac function or significant cardiac disease; uncontrolled active severe systemic infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week of treatment; known symptomatic brain metastases; or select prior malignancies.

A total of 20 patients were enrolled to the trial, and 15 were evaluable for efficacy in a subgroup analysis presented during the 2021 ASCO Annual Meeting. Eltanexor was examined at the following 2 doses in these patients: 10 mg (n = 5) or 20 mg (n = 15) given daily for 5 days per week of a 28-day treatment cycle.

Among the 15 evaluable patients, the median age was 76 years (range, 62-89). Ninety-three percent of patients had IPSS high- or intermediate-2–risk disease, and the median number of prior treatment regimens received was 2 (range, 1-4).

Data showed that among the 20 total enrolled patients, 35% achieved a marrow complete response (mCR), and 25% had stable disease; in these patients the total disease control rate equated to 60%. In the 15 efficacy-evaluable patients, 47% experienced an mCR with treatment, and 33% had stable disease.

When breaking it down by dosing, all patients in the 10-mg cohort experienced clinical benefit with eltanexor, with 60% of patients achieving an mCR and 40% experiencing stable disease. These rates were 40% and 30%, respectively, in those 20-mg cohort.

Moreover, 4 patients experienced hematologic improvement (HI) and became transfusion independent for at least 8 weeks, including 2 patients with trilineage HI.

Among the 7 patients who achieved a mCR with eltanexor, the OS was noted to be significantly longer than for the 8 patients who did not, at a median of 11.86 months and 8.67 months, respectively (HR, 0.27; P = .05). Those who achieved a mCR with treatment also had significantly longer OS than those who experienced disease progression (n = 3), who experienced a median OS of 3.15 months (HR, 0.23; P = .04).

Additionally, the 12 patients who experienced disease control were noted to have a numerically longer median OS than those with disease progression, at 9.86 months and 3.15 months, respectively (HR, 0.38; P = .09). Those with HI experienced a median OS of 10.58 months with eltanexor.


  1. Karyopharm receives orphan drug designation from FDA for eltanexor for the treatment of myelodysplastic syndromes. News release. Karyopharm Therapeutics, Inc.; January 24, 2022. Accessed January 24, 2022. https://bit.ly/35lX8sH
  2. Study of the safety, tolerability and efficacy of KPT-8602 in participants with relapsed/refractory cancer indications. ClinicalTrials.gov. Updated December 30, 2021. Accessed January 24, 2022. https://clinicaltrials.gov/ct2/show/NCT02649790
  3. Lee S, Mohan S, Knupp J, et al. Updated overall survival of eltanexor for the treatment of patients with hypomethylating agent refractory myelodysplastic syndrome. J Clin Oncol. 2021;39(suppl 15):e19037. doi:10.1200/JCO.2021.39.15_suppl.e19037