Exactly three years after an initial FDA green light for the third-line treatment of leukemia, Novartis’ Scemblix has won an accelerated approval to treat newly diagnosed patients.
Tuesday, the FDA cleared Scemblix to treat patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase. The first-line nod marks an important step for the Gleevec follow-up on its way toward reaching the company’s peak sales projection of $3 billion.
Only about 15% of Ph+ CML patients reach the third-line treatment setting, Victor Bulto, Novartis’ U.S. president, noted in an interview with Fierce Pharma.
The Swiss drugmaker has its work cut out in this use. While Scemblix has quickly become the standard of care in third-line Ph+ CML because of a lack of alternative treatments, the first-line market will feature a couple hurdles for the new entrant.
As Novartis CEO Vas Narasimhan pointed out during a conference call in April, some doctors remain loyal to Gleevec (imatinib) or generics despite the availability of multiple second-generation tyrosine kinase inhibitors (TKIs) such as Novartis’ own Tasigna. Case in point: Gleevec generated $561 million sales in 2023, more than two decades since its initial FDA approval. That market will take Novartis longer to flip, Narasimhan acknowledged.
“There’s a number of physicians who are very comfortable using Gleevec after that many years, and they’re very comfortable with its tolerability, particularly,” Bulto explained. “So they know they’re sacrificing a little bit on efficacy, but it allows patients to stay on the medicine for longer and has better survivorship.”
By Bulto’s estimate, some 30% to 40% of first-line patients today are being treated with Gleevec or generic imatinib.
Novartis expects the first adopters of Scemblix in first-line CML will be those that have already embraced second-generated TKIs.
“However, we believe that over time […] given the very good tolerability profile that we have, and the fact that we’ve compared ourselves to both second-generation TKIs and to imatinib in a clinical trial, we will also be able to convince these [healthcare providers] and patients who are on imatinib that this is a good option as well for them,” Bulto said of Scemblix.
Bulto was referencing results from the phase 3 ASC4FIRST trial. The study enrolled 405 patients to receive either Scemblix or one of four other investigator-selected TKIs, including imatinib. A major molecular response (MMR) at Week 48 was recorded in 67.7% of patients in the Scemblix arm, significantly better than the 49% in the control group.
In a pre-randomization-selected class, the MMR rate was 69.3% in the Scemblix group versus 40.2% in the imatinib group.
In addition, investigators found the safety profile of Scemblix to be favorable, with fewer unacceptable side effects than the other TKIs. The percentage of patients who discontinued treatment because of adverse events was 4.5% for Scemblix versus 11.1% for Gleevec and 9.8% for second-generation TKIs. The percentage of patients who had at least one case of dose reduction or interruption was 39.5% for Scemblix, 49.5% for Gleevec and 63.7% for the other TKIs.
The new approval was also supported by preliminary data from the phase 2 ASC2ESCALATE study, which included patients who had previously tried one prior TKI but discontinued for various reasons, according to Novartis.
One important factor that could help Scemblix penetrate the first-line CML market is its differentiated mechanism of action compared with second-generation TKIs, Bulto argued. Aside from Scemblix, other existing CML TKIs conceptually work the same way—they inhibit the BCR-ABL protein by competitive binding to the adenosine triphosphate. By comparison, Scemblix specifically targets the ABL myristoyl pocket to inhibit kinase activity.
Despite all these arguments in favor of Scemblix, there’s one piece of uncertainty: Tuesday’s approval is an accelerated approval that needs to be backed by additional patient outcomes data. In a 2023 Blood Cancer Journal editorial, Vinay Prasad, M.D., a hematologist oncologist at the University of California, San Francisco, argued that the National Comprehensive Cancer Network guidelines should put imatinib as the preferred first-line chronic-phase CML drug. Some of his arguments touched on the lack of an overall survival benefit from second-generation TKIs and their higher costs. Prasad has been vocally skeptical about new therapies that have not shown an overall survival advantage.
Early MMR is known to be predictive of longer-term benefits. But ASC4FIRST’s investigators noted that more follow-up time is needed to assess some potential late-onset adverse events as well as durability of response and survival outcomes. The phase 3 trial currently bears an estimated completion date in early 2028.
Luckily for Novartis, Scemblix has patent protection into the mid-2030s and is not expected to be up for mandated price reductions from the Inflation Reduction Act thanks to its rare disease indication, according to the company.