Novartis has released updated data on its BCR-ABL1 inhibitor, Scemblix (asciminib), which received accelerated approval from the FDA for the treatment of chronic myeloid leukaemia (CML) patients resistant or intolerant to two prior therapies in October this year. The 48-week update from the Phase III ASCEMBL trial was recently presented at the 63rd American Society for Hematology annual meeting. It showed a continued improvement over Pfizer’s second-generation tyrosine kinase inhibitor Bosulif (bosutinib), with over double the number of patients in the Scemblix arm achieving a major molecular response (29.3% versus 13.2% for patients in the Bosulif arm). Patients receiving Scemblix also experienced fewer adverse events than those receiving Bosulif (7.1% versus 25%).

Scemblix marks the first new therapy approval for patients with CML since Takeda/Incyte’s Iclusig (ponatinib) entered the market in 2012 and it is the first agent to target the ABL myristoyl pocket, differentiating it from other marketed drugs. The toxicity profile is also of particular interest. Alongside Iclusig, Scemblix is now the second drug approved for use in patients with T315I mutations. These patients generally have poor prognoses and prior to Iclusig’s approval had no therapeutic options other than stem cell transplant. However, though highly potent, Iclusig has struggled with a side-effect profile that includes a heightened risk of cardiovascular adverse events. Although some risk may be mitigated by dose reduction in responding patients, as per the OPTIC study, this still precludes many patients from taking this drug unless absolutely necessary. Should the adverse event profile of Scemblix prove to be as good as the initial results suggest, Scemblix is likely to see significant sales in the third line of treatment.

However, Novartis has aspirations for Scemblix beyond third-line use, and currently has multiple trials underway examining Scemblix’s efficacy in treatment-naïve patients. This patient group will be tougher to penetrate, with generic versions of first-generation inhibitor Gleevec (imatinib) available. Many patients are started on Gleevec or generic imatinib already, with both the overall cost of therapy and the greater tolerability associated with imatinib strongly influencing prescribing patterns. The patent expiries of other marketed agents in the near term will also complicate the situation.

One aspect that could work in Novartis’ favour is the higher percentage of patients achieving deep molecular responses on Scemblix than on Bosulif (10.8% and 7.6% versus 3.9% and 1.3% for patients achieving deep molecular responses, termed MR4 or MR4.5, respectively). In recent years, there has been an increased focus on the quality of life for CML patients and multiple trials have examined the utility of therapy discontinuation in patients who have been in deep molecular response for several years. To be considered for this, patients must have achieved MR4 or MR4.5 (these describe 4 and 4.5 log reductions in BCR-ABL1 levels). Second-generation inhibitors successfully competed with Gleevec and subsequently generic imatinib, in part due to their greater efficacy in eliciting deep molecular responses in patients despite the fact that overall survival is not significantly different between Gleevec and second-generation inhibitors. Should Scemblix’s advantage over second-generation inhibitors in terms of deep molecular responses hold up in the first line, combined with a potentially easier-to-manage side effect profile, Scemblix could become the next blockbuster drug in the CML market. Accordingly, GlobalData estimates sales of $893.4m in the US by 2030.