Novartis' Scemblix (asciminib) has been granted approval by the European Commission (EC) for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who have been previously treated with two or more tyrosine kinase inhibitors (TKIs). This approval marks a significant advancement in CML therapy, offering a novel mechanism of action for patients who have developed resistance or intolerance to existing TKI treatments.
The EC's decision was based on the pivotal Phase III ASCEMBL trial results, which demonstrated a significant improvement in major molecular response (MMR) rates with Scemblix compared to bosutinib. Specifically, Scemblix nearly doubled the MMR rate at 24 weeks (25.5% vs. 13.2%, P=.029), and this was confirmed at 96 weeks (37.6% vs 15.8%). Furthermore, the trial showed a more than three-fold lower discontinuation rate due to adverse reactions with Scemblix (5.8%) compared to bosutinib (21.1%) at 24 weeks, which was also confirmed at 96 weeks (7.7% vs 26.3%).
Novel Mechanism of Action
Scemblix is the first CML treatment approved in Europe that functions as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. This unique mechanism allows the drug to specifically target the ABL myristoyl pocket, offering a different therapeutic approach for patients who have not responded well to traditional TKI therapies. The STAMP inhibition helps in overcoming mutations at the defective BCR::ABL1 gene, which is associated with the over-production of leukemic cells.
Clinical Significance
Dr. Andreas Hochhaus, Head of the Department of Hematology and Medical Oncology at Jena University Hospital in Germany, noted the importance of this approval, stating, "Until now, patients with CML in Europe had oral TKI therapies with the same mechanism of action to turn to, and those experiencing significant side effects or resistance to these treatment options would often cycle between these very similar therapies, with little success in controlling their disease or improving their quality of life. The approval of Scemblix in Europe is a timely milestone that will help many patients find hope for the management of their CML."
Ongoing Research and Global Approvals
Novartis is actively pursuing regulatory filings for Scemblix in multiple countries and regions globally. In October 2021, the US FDA granted accelerated approval for adult patients with Ph+ CML-CP previously treated with two or more TKIs and full approval for those with the T315I mutation. Scemblix has also received approval in countries including Japan, Switzerland, and the United Kingdom.
Future Studies
Scemblix is currently being evaluated in various treatment lines for CML-CP, both as a monotherapy and in combination therapies. The ASC4FIRST Phase III study (NCT04971226) is evaluating Scemblix in newly diagnosed adult patients with Ph+ CML-CP compared to an investigator-selected TKI, potentially expanding its use to first-line treatment.
