FDA Grants SL-401 Priority Review for Rare Hematologic Cancer

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The FDA has granted a priority review designation to a biologics license application (BLA) for SL-401 (tagraxofusp, Elzonris) for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to Stemline Therapeutics, the developer of the novel stemness inhibitor.

The drug is directed at the IL-3 receptor, which is overexpressed on cancer stem cells and/or tumor bulk in many hematologic malignancies.¹ SL-401 is being investigated as a first-line or later treatment in patients with BPDCN in a phase I/II trial (NCT02113982).

Positive findings from the trial were presented at the 2017 ASH Annual Meeting, where SL-401 demonstrated strong activity in patients with BPDCN.² Across 3 stages of the trial, 42 patients received SL-401 at a dose of 12 μg/kg each day. In first-line BPDCN, the overall response rate (ORR) was 90% (26 out of 29 evaluable patients), with a complete response (CR) rate of 72% (21 of 29).

After therapy with SL-401, 45% of patients (13 of 29) were bridged to stem cell transplant (SCT). In patients with relapsed/refractory BPDCN, the ORR was 69% (9 of 13), with a 38% CR rate (5 of 13), and 1 patient was bridged to SCT.

The median overall survival was not reached in patients who received SL-401 therapy in the first-line setting. In the pivotal stage 3 cohort, the study met its primary endpoint with a 54% CR rate (7 of 13). The ORR was 77% and 46% of patients were bridged to SCT (6 of 13). The most common treatment-related adverse events (AEs) were alanine aminotransferase increase (52%), aspartate aminotransferase increase (50%), hypoalbuminemia (50%), and thrombocytopenia (38%). Capillary leak syndrome was also noted in 19% of patients, which was grade 5 in 1 patient.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the BLA by February 21, 2019.

“The acceptance of our BLA for filing and grant of priority review represent tremendous milestones for Stemline and the BPDCN patient community. We would like to thank the patients and their families who participated in our clinical trials, as well as recognize the tireless work of our investigators and entire Stemline team. Given both priority and breakthrough status, our commercial organization is positioning itself to rapidly launch Elzonris, if approved, to ensure this important new treatment reaches patients as quickly as possible,” Ivan Bergstein, MD, Stemline’s CEO, said in a statement.

The most significant adverse event (AE) associated with SL-401 is the risk of capillary leak syndrome. During the phase I/II study, all patients are being closely monitored for signs of capillary leak. Other AEs associated with the drug are mostly grade 1/2 in severity, and include hypoalbuminemia, increases in aspartate and alanine aminotransferase, and thrombocytopenia.¹

BPDCN affects mostly elderly patients, who may not be able to tolerate chemotherapies. SL-401 may have a better safety and toxicity profile for this patient population due to its targeted mechanism of action. The drug is an IL-3 conjugated truncated diphtheria toxin, which essentially delivers diphtheria toxin to cells that have the IL-3 receptor. Many hematologic malignancies have CD123 expression, but BPDCN in particular has characteristically high expression. When the diphtheria toxin penetrates a cell, it binds to and ADP-ribosylates elongation factor 2, a factor necessary for protein translation. When the protein synthesis process is inhibited, the cell dies by apoptosis.

References

1. Pemmaraju N, Sweet KL, Lane AA, et al. Ongoing phase 2 clinical trial of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): stage 1 and stage 2 results. Poster presented at: the 59th American Society of Hematology Annual Meeting; December 9-12, 2017; Atlanta, GA. http://www.stemline.com/ScientifcPresDownloads/SL-401/BPDCN%20Pivotal%20Results%20ASH%202017.pdf. Accessed April 9, 2018.
2. Stemline Therapeutics presents detailed SL-401 pivotal data in BPDCN at ASH and kicks off its BPDCN awareness campaign; updated results from ongoing trials in additional malignancies also presented [press release]. New York, NY: Stemline Therapeutics, Inc; December 13, 2017. http://ir.stemline.com/news-releases/news-release-details/stemline-therapeutics-presents-detailed-sl-401-pivotal-data. Accessed April 4, 2018.