Novartis' STAMP Inhibitor Scemblix (Asciminib) Approved by FDA for CML, Demonstrates Superior Efficacy Over Pfizer’s Bosulif

Chronic MyeloidLeukemia(CML, Image source: openeducationalberta.ca)

October 30, 2021 /BioValleyBIOON/ -- Recently, the U.S. Food and Drug Administration (FDA) ApprovalNovartis(Novartis) Targeted anticancer drug Scemblix (asciminib, ABL001), a kinase inhibitor for the treatment of adults with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP) who have previously received at least 2 tyrosine kinase inhibitors (TKIs).

This indication was approved under the accelerated approval process based on the major molecular response rate (MMR). Continued approval for this indication will depend on confirmatory evidence.Clinical TrialValidation and description of clinical benefits in China. Data from the Phase 3 ASCEMBL study show that, compared withPfizerTargeted anticancer drugsCompared with Bosulif (bosutinib, 500mg once daily), treatment with Scemblix (40mg twice daily) for 24 weeks nearly doubled the MMR rate (25.5% vs 13.2%; p=0.029 for both arms).. In addition, compared with the Bosulif treatment group, the Scemblix treatment groupThe discontinuation rate due to adverse events was reduced more than threefold (7% vs 25%).

In the past few decades, although significant progress has been made in the treatment of CML, many patients receiving two or more TKI treatments experience intolerance. For instance, research analysis on patients who failed two TKI treatments found that up to 55% of the patients were intolerant to the treatment. Moreover, the drug resistance rate remains high among patients in later-stage treatments; in second-line treatment, at least 60% of patients fail to achieve MMR, and up to 56% of patients do not reach complete cytogenetic response within a two-year follow-up.GeneticsCytogenetic response (CCyR). Due to the lack of remaining treatment options and the absence of established third-line treatment standards according to guidelines, patients who are resistant or intolerant to two or more TKIs face a high risk of disease progression.

Chemical Structure of Asciminib (Source: medchemexpress.cn)

Active Pharmaceutical Ingredient of ScemblixAsciminib is a STAMP inhibitor that specifically targets the BCR-ABL1 protein myristoyl pocket (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 functions by targeting another part of the kinase, known as 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 resolve off-target activity, thereby improving patient outcomes.. In addition, the US FDA has granted asciminib Fast Track Designation (FTD). In February 2021,FDAGrant asciminibTwo Breakthrough Therapy Designations (BTD): (1) For the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+CML-CP) who have previously received at least 2 tyrosine kinase inhibitors (TKIs); (2) For the treatment of adult patients with Ph+CML-CP carrying the T315I mutation.

Currently, Novartis is conducting severalClinical Trial, evaluating asciminib for CML patients who have received multiple therapies, as well as in combination with other TKIs for the treatment of newDiagnosisCML patients. In this week's third-quarter earnings callMeetingUp,NovartisDisclosed, a study on asciminib as a first-line treatment has been initiated.

Results of the Phase 3 ASCEMBL Study (Image Source: Scemblix Prescribing Information)

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

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

Phase 3 ASCEMBL study was conducted in Ph+ CML-CP patients who were resistant or intolerant to at least two TKIs. In the study, 233 patients were randomly assigned to receive either asciminib (40 mg twice daily, n=157) or Bosulif (500 mg once daily, n=76). The results showed that the study met its primary endpoint:At week 24 of treatment, the major molecular response rate (MMR) in the asciminib group nearly doubled compared to the Bosulif group (25.5% vs 13.2%; p=0.029 for both arms).. In addition, at week 24 of treatment, the asciminib group showed complete cellularGeneticsThe study showed a higher cytogenetic response rate (CCyR: 40.8% vs 24.2%) and a higher deep molecular response rate (DMR): In the asciminib group, 10.8% and 8.9% of patients achieved MR4 and MR4.5, respectively, compared to 5.3% and 1.3% in the Bosulif group.At Week 48 of treatment, the MMR rate was 29% in the asciminib group and 13% in the Bosulif group.With a median follow-up of 20 months (range: 1 day to 36 months), the median duration of response (DOR) has not been reached in patients who achieved MMR at any time point.

Asciminib for the Treatment of Adult Patients with T315I-Mutated Ph+ CML-CPThe efficacy was evaluated in a multicenter, open-label study CABL001X2101 (NCT02081373). The efficacy was based on 45 patients treated with Scemblix (200mg, twice daily). The results showed,At Week 24 of treatment, MMR was 42% (19/45). By Week 96, MMR reached 49% (22/45).The median treatment duration was 108 weeks (range: 2-215 weeks). (Bioon.com)

Source of the original text:FDA approves Novartis chromic myeloid leukemia drug Scemblix(asciminib)