FDA Grants Orphan Drug Designation to Silmitasertib for Biliary Tract Cancer

The FDA has granted an orphan drug designation to silmitasertib (CX-4945) for use as a potential therapeutic option in patients with biliary tract cancer, according to a recent announcement from Senhwa Biosciences, Inc., the drug developer.¹

The first-in-class molecule drug was designed to target the CK2 pathway and perform as a CK2 inhibitor. Preclinical findings have indicated that CK2 inhibition via silmitasertib prevented DNA repair, induced apoptosis, and improved the antitumor activity of gemcitabine and cisplatin. Moreover, other data have indicated that the agent is easy to administer due to its oral formulation, and that it is safe and well tolerated in humans.

“We are pleased to receive orphan drug designation for silmitasertib for the treatment of biliary tract cancer, a rare, malignant disease for which there are no effective therapies,” Mei-Hui Kuo, acting chief executive officer of Senhwa Biosciences, stated in a press release. “[This designation] represents an important regulatory milestone that has the potential to expedite the clinical development of silmitasertib, which is a potent and selective CK2 inhibitor.”

Beyond biliary tract cancer, silmitasertib is under evaluation in patients with severe COVID-19 (NCT04668209), in patients with basal cell carcinoma (NCT03897036), and in those with recurrent medulloblastoma who may or may not have undergone surgery (NCT03904862).

The agent was also examined in combination with gemcitabine and cisplatin as a frontline treatment in patients with locally advanced or metastatic cholangiocarcinoma, as part of the multicenter, phase 1b/2 S4-13-001 trial (NCT02128282).²

The first portion of the research included dose-escalation, -expansion, and exploratory cohorts evaluating the agent at doses that ranged from 200 mg to 1000 mg twice daily for 6 days in the escalation and expansion cohorts and 10 to 21 days of continuous dosing in the exploratory cohorts. In the phase 2 portion, participants were given silmitasertib at a twice-daily dose of 1000 mg for 10 days in combination with gemcitabine and cisplatin on days 1 and 8 as part of a 21-day cycle, or gemcitabine/cisplatin alone.

In the dose-escalation cohort, the maximum tolerated dose of silmitasertib was identified to be a twice-daily dose of 1000 mg; this was then used in the expansion and exploratory cohorts.

The primary efficacy outcome measure for the trial was progression-free survival (PFS).

The trial enrolled a total of 88 patients (intent-to-treat population), and 87 patients received treatment. Of those who received the agent, 50 did so as part of the phase 1b portion of the research and 37 did so as part of the phase 2 portion. Fifty-five patients were able to complete at least 1 full cycle of treatment with any dose interruptions or reductions; these patients comprised the modified ITT population (mITT).

The median age among the 87 patients who received treatment was 60 years (range, 38-84), 55% were male, and 50% were Asian, 48% were White, and 2% were another race. Moreover, 51% of patients were from the United States, 35% were from Taiwan, and 14% were from Korea. Most patients had metastatic disease (81.6%), with an intrahepatic primary tumor site (85.0%), and an ECOG performance status of 1 (65.5%).

Results from the interim analysis were presented during the 2021 Gastrointestinal Cancers Symposium and showed that in the mITT population (n = 55), the median PFS was 11.2 months (95% CI, 7.6-14.7) with silmitasertib, with a 10-month PFS rate of 56.1% (95% CI, 38.8%-70.2%).

Moreover, the median overall survival (OS) achieved with the agent in this population was 17.4 months (95% CI, 13.4-25.7). Silmitasertib also elicited an objective response rate of 32.1%, and a disease control rate of 79.3%. Sixty-six percent of patients experienced a CA 19-9 reduction with treatment.

Regarding safety, 99% reported at least 1 treatment-emergent adverse effect (TEAE), but most were only mild or moderate in severity.

The most common TEAEs experienced with silmitasertib in the 87 patents who comprised the safety population included diarrhea (70%), nausea (59%), fatigue (47%), anemia (39%), vomiting (39%), decreased platelet count (32%), pyrexia (32%), decreased appetite (31%), neutropenia (31%), decreased neutrophil count (29%), abdominal pain (29%), thrombocytopenia (28%), and decrease white blood cell count (21%).

Moreover, 91% of patients experienced TEAEs that were determined to be related to treatment. The most frequently reported treatment-related toxicities included diarrhea (66%), nausea (51%), vomiting (33%), fatigue (31%), anemia (22%), neutropenia (16%), thrombocytopenia (15%), decreased appetite (15%), decreased neutrophil count (12%), asthenia (10%), decreased platelet count (10%), hypokalemia (10%), and decreased white blood cell count (9%).

Previously, in August 2021, the FDA granted a fast track designation to silmitasertib for use in patients with recurrent sonic hedgehog–driven medulloblastoma.³

References

1. Senhwa’s silmitasertib receives US FDA orphan drug designation for the treatment of biliary tract cancer. News release. Senhwa Biosciences, Inc.; January 20, 2022. Accessed January 21, 2022. https://prn.to/3FP7NIZ
2. Borad MJ, Bai L-Y, Chen M-H, et al. Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for pateints with locally advanced or metastatic cholangiocarcinoma: a phase Ib/II study. J Clin Oncol. 2021;39(suppl 3):312. doi:10.1200/JCO.2021.39.3_suppl.312
3. Senhwa’s silmitasertib receives US FDA fast track designation for the treatment of recurrent sonic hedgehog driven medulloblastoma. News release. Senhwa Biosciences, Inc.; August 18, 2021. Accessed January 21, 2022. https://prn.to/3gxUjax