Novartis' Scemblix Gains FDA Accelerated Approval for First-Line CML Treatment, Faces Internal Competition from Gleevec

On Tuesday local time, Novartis' Scemblix received FDA accelerated approval for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. Prior to this, Scemblix had already been approved by the FDA on October 19, 2021, for third-line treatment of Ph+ CML patients.

Scemblix is a STAMP inhibitor, with a novel mechanism of action. In the United States, only about 15% of Ph+ CML patients meet the criteria for third-line treatment,Meanwhile, due to the lack of alternative therapies for third-line treatment, Scemblix was quickly adopted once approved.Capture the market and become the standard treatment for third-line Ph+CML.

But to fully break into the first-line treatment market, Scemblix has to face some obstacles, with the main one being the company's legendary drug Gleevec (imatinib). As Novartis CEO Vas Narasimhan pointed out in an April conference call, despite the availability of several second-generation tyrosine kinase inhibitors (TKIs), such as Novartis' own Tasigna, some doctors remain loyal to Gleevec (imatinib) or its generic versions. For instance: even though more than two decades have passed since it was first approved by the FDA, Gleevec still generated $561 million in sales in 2023. Even Narasimhan had to admit that Novartis would need more time to turn this market around.

According to statistics,Currently, approximately 30% to 40% of frontline patients are still receiving treatment with Gleevec or generic imatinib.Novartis US President Bulto explained, "Many doctors have great trust in Gleevec after years of clinical practice, especially satisfied with its tolerability. Although there is a slight compromise in efficacy, it allows patients to take the medication for a longer time and achieve a higher survival rate."

On this basis, Novartis expects that the first users of Scemblix in frontline CML will be those who have already received second-generation TKIs.

However, Scemblix has a unique mechanism of action compared to second-generation TKIs, which could be a key factor in its entry into the first-line CML market. Aside from Scemblix, other existing CML TKIs theoretically operate through the same mechanism—suppressing the BCR-ABL protein by competitively binding with adenosine triphosphate (ATP). In contrast, Scemblix specifically targets the acylation pocket of ABL to inhibit enzyme activity.

Of course, Novartis also has great confidence in its own drugs. The results of a Phase 3 trial named ASC4FIRST showed that among the 405 patients recruited, they received either Scemblix or one of four other TKIs chosen by the investigators (including imatinib, nilotinib, dasatinib, and bosutinib). At week 48, 67.7% of the patients in the Scemblix group achieved a major molecular response (MMR), significantly higher than the 49% in the control group.

In the categories selected before randomization, the MMR rate was 69.3% in the Scemblix group and 40.2% in the imatinib group.

Moreover, researchers found that Scemblix had a good safety profile, with fewer unacceptable side effects compared to other TKIs. The percentage of patients who discontinued treatment due to adverse events was 4.5% in the Scemblix group, 11.1% in the Gleevec group, and 9.8% in the second-generation TKI group. The percentage of patients with at least one dose reduction or interruption was 39.5% in the Scemblix group, 49.5% in the Gleevec group, and 63.7% in the other TKI groups.

According to Novartis, the new approval is also supported by preliminary data from the Phase 2 ASC2ESCALATE study, which included patients who had previously tried a TKI but stopped for various reasons.

Despite all these arguments leaning in favor of Scemblix, an uncertainty remains: Tuesday's approval was based on accelerated approval, meaning Scemblix still requires additional patient outcome data for support. Early MMR is known to predict long-term benefits. However, the researchers of ASC4FIRST noted that more follow-up time is needed to evaluate some potential late-onset adverse events as well as the durability of response and survival outcomes. The Phase 3 trial is expected to be completed by early 2028.

Currently, the evolving FDA accelerated approval pathway has encountered a series of withdrawals. Whether Scemblix can break the curse of accelerated approval this time and when it will be able to step out of the shadow of its company's "big brother" in the front-line market remain to be seen. Yidu Medical will continue to follow up.

References:

1.Fierce pharma

2.Biospace

3.RTT news