Scemblix signals a shift in Iclusig’s monopoly status in Korea

Novartis' Scemblix (asciminib), a fourth-generation tyrosine kinase inhibitor (TKI) developed to treat chronic myeloid leukemia (CML), has received the green light for orphan drug designation for the indication of treating patients with T315I-positive chronic phase CML, and will compete with Takeda's Iclusig (ponatinib), which dominates the Korean market.

According to the Central Pharmaceutical Review Committee (CPRC) meeting minutes released by the Ministry of Food and Drug Safety on May 11, Scemblix has won approval for orphan drug designation for treating T315I-positive CML.

The deliberation on medical and pharmaceutical policies was conducted in writing from May 21 to 23 and was attended by nine of the 12 subcommittee members.

First, all nine members of the subcommittee participating in the review agreed to grant Scemblix orphan drug designation for treating T315I-positive CML.

However, they were split on whether Scemblix had “significantly” improved safety and efficacy compared to the existing third-generation drug, Iclusig.

“Orphan drug designation is appropriate when the disease for which the application is made is a disease for which no treatment or drug has been developed or when the drug significantly improves safety or efficacy over existing alternatives,” one member said. “However, the meaning of ‘significantly’ in the orphan drug designation criteria usually implies a statistically significant difference, and it is not reasonable to conclude that a drug significantly improves safety or efficacy based on the results of a phase I clinical trial. Given the limited number of CML patients with the T315I mutation, it will be some time before clinical studies directly comparing Scemblix and Iclusig are published."

The member continued, “Our review of the submitted phase 1 data supports the safety and efficacy of Scemblix in CML patients with the T315I mutation. While Iclusig is associated with an increased risk of cardiovascular adverse events and is not recommended in patients with risk factors or comorbidities, including cardiovascular and arterial occlusive disease, Scemblix has been shown to have a limited risk of these events in phase 1, and showed some benefit in patients who were previously treated with Iclusig."

Leukemia, a sister journal of Nature, recently published two-year follow-up results from a phase 1 trial evaluating Scemblix monotherapy in patients with chronic phase T315I-positive CML previously treated with one or more TKIs. The results showed that Scemblix 200 mg twice daily provided a meaningful risk-benefit profile regardless of prior Iclusig treatment.

Some 62.2 percent of patients treated with Scemblix achieved a BCR::ABL1 ≤1 percent on the International Scale (IS), compared to 47.6 percent and 81.3 percent in the previously Iclusig-treated and untreated arms, respectively.

In addition, 48.9 percent of the 45 evaluable patients achieved a major molecular response (MMR, BCR::ABL1IS ≤0.1 percent), compared to MMR rates of 34.6 percent and 68.4 percent in the previously Iclusig-treated and untreated arms, respectively.

The most common grade 3 or higher adverse events were increased lipase levels (18.8 percent) and thrombocytopenia (14.6 percent), and only five (10.4 percent) patients treated with Scemblix discontinued treatment due to adverse events.

Advances in targeted cancer drugs have made CML patients transplant-free and significantly improved survival rates. However, there are still limitations, as patients develop resistance or intolerance to repeated TKI treatments, and survival rates decrease with each treatment.

Resistance is primarily driven by BCR::ABL1 mutations, of which the T315I mutation is one of the most frequently identified. It occurs in 2 to 16 percent of patients resistant to first—and second-generation agents and increases in frequency with subsequent treatment.

However, only Iclusig is currently available for patients with the T315I mutation, leaving a large unmet need for new treatment options.

Scemblix, a fourth-generation drug, has shown efficacy in patients with the T315I mutation, signaling competition for Iclusig.

Scemblix also showed significant efficacy in patients who had failed with Iclusig and is free of the major safety concerns of Iclusig, namely cardiac toxicity, and industry insiders are showing interest in seeing how the treatment pattern for second-line CML will change if the two start to compete.