Scemblix ( Asciminib ) has received accelerated approval by the US Food and Drug Administration (FDA) for adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP).

The accelerated approval is based on major molecular response ( MMR ) rate at week 48 from the ASC4FIRST phase III trial that has compared once daily Asciminib to all other investigator-selected (IS) standard of care (SoC) tyrosine kinase inhibitors (TKIs) (Imatinib, Nilotinib, Dasatinib, and Bosutinib). In the study, Asciminib has demonstrated superior MMR rates in both primary endpoints at week 48 versus investigator-selected standard of care tyrosine kinase inhibitors ( IS SoC TKIs ) and Imatinib alone.

Continued approval for the newly diagnosed indication may be contingent upon verification and description of clinical benefit from confirmatory evidence.

The expanded indication in Ph+ CML-CP increases the population eligible for Scemblix by approximately four times, including newly diagnosed and previously treated adults. Newly diagnosed patients will now have access to a treatment that has shown superior efficacy versus all standard of care therapies and a favorable safety and tolerability profile.

While tyrosine kinase inhibitors have transformed chronic myeloid leukemia into a chronic disease, efficacy and safety challenges continue to hinder long-term treatment success for many patients. Many newly diagnosed patients do not meet molecular response goals, and many discontinue or change treatment due to intolerance. Nearly half of patients with chronic myeloid leukemia do not meet efficacy milestones (MMR) and almost one in four patients discontinue or switch treatment within one year.

The FDA approval of Scemblix is based on results from the phase III ASC4FIRST trial in patients newly diagnosed with Ph+ CML-CP.
Data showed:

- nearly 20% more patients treated with Asciminib achieved MMR versus IS SoC TKIs (Imatinib, Nilotinib, Dasatinib and Bosutinib) (68% vs 49%, less than 0.001) and nearly 30% more patients achieved MMR versus Imatinib alone (69% vs 40%, less than 0.001) at week 48;

- Asciminib is the first chronic myeloid leukemia treatment to show superior efficacy along with a favorable safety and tolerability profile versus Imatinib and second generation tyrosine kinase inhibitors, with fewer treatment-related grade greater than or equal to 3 adverse events (25.5% vs 33% and 42%), dose reductions (6% vs 14% and 24%), and half the rate of adverse events leading to treatment discontinuation (4.5% vs 11% and 9.8%);

- patients treated with Asciminib have also achieved deeper rates of molecular responses including MR4 compared with IS-TKIs and Imatinib alone (41% vs 22% and 16%) by week 48;

- in newly diagnosed patients, the safety profile was consistent with previous registration studies with no new safety concerns observed. The most common adverse reactions (greater than or equal to 20%) were musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain and diarrhea.

The ASC4FIRST trial remains ongoing, with the next scheduled analysis at week 96 to evaluate the key secondary endpoint (MMR at week 96) and additional secondary endpoints.

The approval was also supported by preliminary data from the phase II ASC2ESCALATE study, which has included Ph+ CML-CP patients who have been previously treated with one prior tyrosine kinase inhibitor with discontinuation due to treatment failure, warning, or intolerance.

ASC4FIRST trial

ASC4FIRST is a phase III, head-to-head, multi-center, open-label, randomized study of oral Asciminib 80 mg QD versus IS first- or second-generation tyrosine kinase inhibitors (Imatinib, Nilotinib, Dasatinib or Bosutinib) in 405 adult patients with newly diagnosed Ph+ CML-CP1.
The two primary endpoints of the study are to compare efficacy of Asciminib versus IS SoC TKIs and to compare efficacy versus that of tyrosine kinase inhibitor within the stratum of participants with Imatinib as pre-randomization selected tyrosine kinase inhibitor, based on proportion of patients that achieve MMR at week 48.

Asciminib

Asciminib is the first CML treatment that works by Specifically Targeting the ABL Myristoyl Pocket ( referred to as a STAMP inhibitor ). The current approved CML treatments are tyrosine kinase inhibitors that target the ATP-binding site (ATP-competitive). ( Xagena )

Source: Novartis, 2024

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