Green light for the reimbursement of asciminib, a drug with a new mechanism of action, aimed at the treatment of chronic myeloid leukemia (Official Gazette of 19 May). The drug – trade name Scemblix – developed by Novartis is indicated in particular for patients with Philadelphia chromosome positive chronic myeloid leukemia in the chronic phase with resistance or intolerance to at least two previous tyrosine kinase inhibitors. The green light from Aifa comes after the approval of the European Commission which took place last August.
Chronic myeloid leukemia
It is a rare blood cancer that affects about 100,000 people worldwide and almost 9,000 in Italy. It accounts for 15% of all leukemia cases and affects men 1.2-1.7 times more than women. It is caused by the uncontrolled proliferation of bone marrow stem cells and in over 90% of cases it is characterized by an acquired genetic alteration known as the Philadelphia chromosome.
New therapeutic options
Tyrosine kinase inhibitors (Tki) are the drugs used for treatment, but even today many second-line patients develop resistance or intolerance to the therapy, as recalled Fabrizio Bread, full professor, Federico II University of Naples, Director of UOC Hematology and Bone Marrow Transplants, AOU Federico II of Naples. “In this scenario – he continues – it is important to make available new therapeutic options in the third line, which are effective, well tolerated and capable of guaranteeing a good quality of life. It is very important for anyone living with chronic myeloid leukemia. The patients involved in an international survey in 11 countries, including Italy, indicate the importance of curbing the progression of the disease and achieving a good quality of life as the main objectives of treatment”.
Stamp inhibitors
Asciminib is the progenitor of a new generation of drugs, the so-called Stamp inhibitors (Specifically targeting the Abl myristoyl pocket) which specifically target the Abl myristoyl pocket. Thanks to its particular mechanism of action it is able to stop the progression of tumor cells in a highly effective and tolerable way with fewer adverse events.
Explains Fausto Castagnetti, Associate Professor, University of Bologna, “Seràgnoli” Hematology Institute, Ircss University Hospital of Bologna: “Although belonging to the class of Tkis, asciminib differs in a new mechanism of action. In fact, it does not bind to the Atp-ase site of the Bcr-Abl1 tyrosine kinase, but to the myristoyl site in the kinase domain of Bcr-Abl1. This binding has the advantage of being highly specific and stabilizing the Bcr-Abl protein in its closed, inactive conformation, arresting tumor progression with minimal side effects.”
The registration trial
The efficacy of asciminib is confirmed by data from the pivotal phase III study Ascembl which showed, after 24 weeks of treatment, an almost double major molecular response rate (25.5% vs 13.2%) compared to another inhibitor tyrosine kinase. Efficacy also confirmed at 96 weeks, with a greater molecular response rate of 37.6% for asciminib versus 15.8% for the other Tki.
There is also positive evidence for the new drug in long-term treatment. Massimo Brecciaassociate professor of La Sapienza University of Rome, Hematology Policlinico Umberto I of Rome reports: “The phase I trial evaluated the effects of asciminib in heavily pre-treated patients for a median duration of 4 years and demonstrated its safety, tolerability and long-term efficacy: not only did the majority of patients (70%) remain on asciminib treatment, but two-thirds achieved major molecular response or deep molecular response, two parameters that indicate the active state of the disease” .
Real-life data
The positive results of the drug are also confirmed by experience in clinical practice, as Breccia continues: “The Italian clinical experience on the use of asciminib in the compassionate use program conducted between 2019 and 2023 then highlighted the efficacy of the drug in maintaining and improving the molecular response (Mr) and its good tolerability profile. Furthermore, a survey by the Gimema Foundation investigated the perception of Italian haematologists on the use of this new therapeutic option: 89% would use it as a third-line treatment in resistant patients and 98% consider it – precisely because of its tolerability – a drug also for the elderly”.