FDA Grants Priority Review to STAMP Inhibitor Asciminib for Ph+ CML

The FDA has accepted a new drug application (NDA) for asciminib (ABL001) and granted it priority review for the treatment of chronic myeloid leukemia (CML), following its submission under the FDA's Real-Time Oncology Review (RTOR) program, according to a press release from Novartis.¹

The NDA is supported by data from the phase 3 ASCEMBL trial of asciminib versus bosutinib (Bosulif) on patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase who were previously treated with 2 or more tyrosine kinase inhibitors (TKIs). Data from a phase 1 study of asciminib in patients with Ph+ CML in chronic phase who harbor a T315I mutation also support the NDA.

In ASCEMBL (NCT03106779), the primary end point of improvement in major molecular response (MMR) at 24 weeks was achieved in 2020. The MMR rate observed in the 157 patients treated with asciminib 40 mg twice daily was 25.5% compared with only 13.2% in the 76 patients treated with bosutinib 500 mg once daily, reaching a 12.2% difference between the 2 arms (95% CI, 2.19-22.3; 2-sided P = .029). Of those who had a response, the median time to MMR was 12.7 weeks with asciminib versus 14.3 weeks with bosutinib.²

Deep molecular responses were also observed in the patients and appeared to be better for patients treated with asciminib than those treated with bosutinib. In the asciminib versus the bosutinib arm, deep molecular responses were seen in 5.3% and 1.3%, respectively. The complete cytogenetic response rate at 24 weeks was 40.8% in the asciminib arm compared with 24.2% with the control therapy. Asciminib also appeared to improve MMR across the multiple subgroups assessed in the study.

All patients were assessed from safety. In these patients any-grade adverse events (AEs) were observed in 89.7% of the asciminib versus 96.1% of the bosutinib arm, and any-grade treatment-related AEs occurred in 63.5% and 88.2%, respectively. Serious AEs leading to fatality were observed in 1.3% of the experimental arm and 1.3% of the control arm. Nine AEs led to discontinuation of treatment with asciminib and 16 lead patients to discontinue bosutinib. Dose adjustment and or interruption occurred in 37.8% of the asciminib arm versus 60.5% of the bosutinib arm. Notably, 66.0% of patients treated with asciminib in the study required additional therapy compared with 88.2% of those treated with bosutinib. Also, 2 patients in the asciminib died due to ischemic stroke and arterial embolism, and 1 patient in the bosutinib arm died of septic shock.

The most frequently seen ≥3 AEs in the asciminib versus the bosutinib arm respectively were thrombocytopenia (17.3% vs 6.6%), neutropenia (14.7% vs 11.8%), diarrhea (0%, vs10.5%), and increased alanine aminotransferase (0.6% vs 14.5%).

ASCEMBL is identified as the first comparator study of therapies intended for the treatment of patients with resistant or intolerant CML. The efficacy result was considered to be statistically significant and clinically meaningful. The safety profile of asciminib in the study was also favorable. Taken together, these data support asciminib as a new treatment option for this patient population.

With a priority review designation, the FDA’s review of the NDA for asciminib will be swifter compared with the standard review period of 12 months. The agent was previously granted orphan drug and fast track designation by the FDA, as well as a breakthrough therapy designation treatment of adult patients with Ph+ CML in chronic phase who have been previously treated with 2 or more TKIs. The other indication for which asciminib has been granted orphan, drug, fast track, and breakthrough therapy designation is for the treatment of adult patients with Ph+ CML in chronic phase who harbor the T315I mutation.

_References:

_{1. FDA accelerates review of Novartis STAMP inhibitor asciminib (ABL001) for patients with chronic myeloid leukemia (CML). News release. Novartis. August 25, 2021. Accessed August 25, 2021. https://bit.ly/3gxtun6}

_{2. Hochhaus A, Boquimpani C, Rea D, et al. LBA-4 Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (Pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Presented at: 62nd American Society of Hematology Annual Meeting and Exhibition; December 5-8, 2020; Virtual. Abstract LBA-4.}