Novartis Receives FDA Breakthrough Therapy Designations for STAMP Inhibitor Asciminib in Chronic Myeloid Leukemia

February 09, 2021 News /BioonBIOON/ --Novartis(Novartis) recently announced that the U.S. Food and Drug Administration (FDA) has been granted two Breakthrough Therapy Designations (BTD) for the targeted anticancer drug asciminib (ABL001): (1) for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in patients who have previously received at least two tyrosine kinase inhibitor (TKI) therapiesLeukemia(1) Adult patients with chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML-CP); (2) For the treatment of adult patients with Ph+ CML-CP harboring the T315I mutation.

Asciminib is a STAMP inhibitor that has previously been approved in the United StatesFDAGranted Fast Track Designation (FTD). This drug is a specific agent that targets the myristoyl pocket of the BCR-ABL1 protein (STAMP), locking BCR-ABL1 in an inactive conformation. Currently marketed competing drugs work by binding to the ATP-binding site of the BCR-ABL1 protein. In contrast, asciminib acts on another part of this kinase, namely the ABL myristoyl pocket.

As a STAMP inhibitor, asciminib can overcome mutations at the ATP-binding site of BCR-ABL1, which may help address TKI resistance in later-stage CML treatment and potentially mitigate off-target activity, thereby improving patient prognosis. Currently,NovartisMultiple studies are currently underwayClinical Trial, to evaluate asciminib in patients with chronic myeloid leukemia (CML) who have received multiple prior therapies, as well as in combination with other tyrosine kinase inhibitors (TKIs) for the treatment of newlyDiagnosisof CML patients.

FDAGranting of BTD to asciminib, based on: (1) the results of the Phase III ASCEMBL study, which was conducted in adult patients with Ph+ CML-CP who were resistant or intolerant to at least two TKIs, comparing asciminib with Bosulif (bosutinib,Pfizerproduct) were compared; (2) the results of a Phase I study that enrolled patients with Ph+ CML, some of whom carried the T315I mutation.

The results from these two studies were presented at the 2020 American Society of Hematology (ASH) Annual Meeting.NovartisThe plan is to submit the marketing application for asciminib in the first half of 2021, inFDACenter of Excellence in Oncology Real-TimeTumorReview under the academic review project.

Chemical Structure of Asciminib (Image source: medchemexpress.cn)

In recent years, progress has been made in the treatment of CML. Clinicians can choose from a limited number of TKIs when treating patients with Ph+ CML, includingNovartisGleevec (Glivec, imatinib) and Tasigna (nilotinib). Most patients receiving drug therapy remain alive after 10 years, but there is still a risk of disease progression.

Although patients who develop resistance to initial therapy can switch to another TKI (i.e., sequential TKI therapy), many approved therapeutic agents target the same ATP-binding site on the ABL1 kinase. The similarity among these therapies means that a mutation in one region of this kinase can render many drugs ineffective. In other words, sequential TKI therapy may be associated with increased resistance and intolerance.

The Phase 3 ASCEMBL study was conducted in patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (Ph+ CML-CP) who were resistant or intolerant to at least two tyrosine kinase inhibitors (TKIs). In the study, 233 patients were randomized to receive either asciminib (40 mg twice daily; n=157) or Bosulif (500 mg once daily; n=76).

Data showed that the study met its primary endpoint: at Week 24 of treatment,Compared with the Bosulif group, the major molecular response (MMR) rate in the asciminib group nearly doubled (25.5% vs 13.2%; p=0.029 for both arms).Furthermore, at Week 24 of treatment, the asciminib group compared with the Bosulif groupComplete CellHeredityHigher complete cytogenetic response rate (CCyR: 40.8% vs 24.2%) and higher deep molecular response rate (DMR):In the asciminib group, 10.8% and 8.9% of patients achieved MR4 and MR4.5, respectively, compared with 5.3% and 1.3% in the Bosulif group.

The incidence of grade ≥3 adverse events (AEs) was 50.6% in the asciminib group and 60.5% in the Bosulif group. In the asciminib group, 5.8% of patients discontinued treatment due to AEs, compared with 21.1% in the Bosulif group. Similarly, the frequency of AEs requiring dose interruption and/or dose adjustment was lower in the asciminib group than in the Bosulif group (37.8% vs. 60.5%). At the data cutoff for the ASH annual meeting, a higher proportion of patients were still receiving treatment in the asciminib group compared with the Bosulif group (61.8% vs. 30.3%).

The most common grade ≥3 adverse events (incidence >10%) in the asciminib group were thrombocytopenia (17.3%) and neutropenia (14.7%), whereas in the Bosulif group, they were elevated alanine aminotransferase (ALT) (14.5%), neutropenia (11.8%), and diarrhea (10.5%). Two patients (1.3%) in the asciminib group experienced ischemicStrokeand arterial embolism) resulted in death; one patient (1.3%) in the Bosulif group died (due to septic shock). The most common adverse events (all grades; ≥20%): thrombocytopenia (28.8%) and neutropenia (21.8%) in the asciminib group; diarrhea (71.1%), nausea (46.1%), increased ALT (27.6%), vomiting (26.3%), rash (23.7%), increased aspartate aminotransferase (21.1%), neutropenia (21.1%), and thrombocytopenia (18.4%) in the Bosulif group. (Bioon.com)

Original source: Novartis receivesFDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia