Disease Analysis: Chronic Myeloid Leukemia (CML)

Disease Overview

Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is a myeloproliferative disorder characterized by a single cytogenetic hallmark: the chromosomal translocation t(9;22)(q34;q11), known as the Philadelphia (Ph) chromosome. In a small minority of patients who exhibit the characteristics of CML, the Ph chromosome cannot be detected – this is referred to as Ph-negative CML, or atypical CML.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2018, there were 71,200 incident cases of chronic myeloid leukemia (CML) worldwide, and expects that number to increase to 76,100 incident cases by 2027.
• CML is a progressive rare disease and the third most common leukemia in the US. It occurs in all age groups; however, it is most common in older adults, with a median age at diagnosis of 67 years.
• Since the approval of Gleevec in 2001, tyrosine kinase inhibitors (TKIs) have been a mainstay in the treatment of CML. TKIs have greatly improved survival, with a five-year relative survival rate of 70.6% and most chronic-phase patients having a normal life expectancy. However, although TKIs have reduced the rate of progression to advanced phases, survival among advanced-phase patients remains poor.
• The success of Gleevec gave rise to a new generation of TKIs which are influential across all lines of the treatment paradigm. Second-generation TKIs Sprycel and Tasigna dominate the second-line setting, and after demonstrating superiority over Gleevec in the first-line setting, they also hold a large market share of the treatment-naïve patient population. Furthermore, second-generation TKI Bosulif, which was a later entry to the market, is influential in the third-line treatment setting. However, patent expiries for both Sprycel and Tasigna in the near future will hinder growth of the CML market in both the first- and second-line treatment settings.
• Iclusig and Scemblix are the only TKIs approved for the treatment of T315I mutation-positive patients. After a market suspension in 2013 and termination of the first-line Phase III EPIC trial due to safety concerns, Iclusig’s arterial occlusive event risk limits its commerciality. Iclusig’s usage is bound to the T315I mutation-positive patient population and heavily pretreated patients resistant to more than two TKIs.
• Scemblix, a novel BCR-ABL myristoyl pocket (STAMP) third-generation TKI, was recently approved for the treatment of T315I mutation-positive patients or patients treated with at least two prior TKIs. The FDA granted Scemblix breakthrough therapy designation in February 2021 based on the superior activity shown against Bosulif in the third-line Phase III ASCEMBL trial and promising efficacy shown in T315I mutation-positive patients. Novartis filed for EMA approval in the second half of 2021, and has intentions for a first-line label expansion in 2024.
• Vodobatinib is a novel selective TKI currently being studied in the fourth-line treatment setting, with Sun Pharma Advanced Research planning an NDA filing for the first half of 2023. However, vodobatinib’s overall commercial potential will be limited by the small size of the heavily pretreated target population.
• Chemotherapies struggle to gain market share against well-established TKIs in CML. Synribo is only approved in the US for the treatment of heavily pretreated patients, and its lower activity and complex dosing have seen the drug fail to compete with Iclusig. ASTX030, an oral form of azacitidine and cedazuridine, is the only non-TKI in development, but its late entry into the market will likely see it struggle to gain market share from established TKIs.
• The overall likelihood of approval of a Phase I hematologic asset is 8.6%, and the average probability a drug advances from Phase III is 58.1%. Hematology drugs, on average, take 9.5 years from Phase I to approval, compared to 9.7 years in the overall oncology space.
• Key recent events include US FDA approval of Scemblix in the third-line setting and in patients with a T315I mutation, and an NDA submission for approval of Dasynoc in the US based on bioequivalence study results.
• Key upcoming catalysts comprise an expected CHMP opinion and European approval decision for Scemblix.