BCL2 plays a pivotal role in regulating apoptosis and is consistently expressed in various cancers. Venetoclax, the sole approved BCL2 inhibitor, is indicated for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia (AML), yet its use is complicated by gastrointestinal side effects and tumor lysis syndrome (TLS). ICP-248 has been developed as a potent and highly selective BCL2 inhibitor. Preclinical studies have shown it possesses favorable pharmacokinetics, a wide safety margin, and excellent safety profile. It also demonstrates synergistic anti-tumor effects when combined with Orelabrutinib, a novel and highly selective BTK inhibitor. 

ICP-248 is currently being evaluated in an ongoing Phase I trial to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy in patients with relapsed or refractory B-cell malignancies. Eligible patients include those with CLL/SLL and B-cell non-Hodgkin lymphomas (NHLs) who failed on available therapies. In March 2024, InnoCare Pharma also received clearance for an investigational new drug application to conduct a clinical trial of ICP-248 plus orelabrutinib in China for CLL/SLL.

The results presented at the EHA 2024 Congress demonstrates ICP-248 well tolerated safety profile and promising efficacy with dose-dependent effect in relapsed or refractory B-cell malignancies. 

Efficacy outcomes 

• ORR was 100% in the 100 mg dose level, with three patients achieved CR

• One response each in 80 mg and 50 mg dose levels

• Two patients in 100mg and one patient in 50 mg were with uMRD

• Prompt tumor cell decrease since C1D1 with initial dose 10 mg

• Reduction in SPD was observed in all dose levels with dose-dependent effect

In terms of safety, the maximum tolerated dose (MTD) was not reached. No dose limiting toxicities (DLTs) up to 100 mg were observed. Most treatment-emergent adverse events (TEAEs) were grade 1-2. Grade 3 or higher TEAEs were reported in 7 (58%) patients; no grade 5 TEAES. No Gl toxicity was reported. Most common drug-related TEAEs occurring in >20% of patients were neutropenia, leukopenia, hypokalemia and hypocalcemia. One case of laboratory tumor lysis syndrome (TLS) reported in one patient with baseline high tumor burden, recovering within 48 hours and treatment resumed.

Conclusion 

The foundation for hematological malignancies with overall survival improvements has been targeting the BCL2 family proteins. BTK inhibitors have completely changed the way that B cell malignancies are treated, particularly CLL/SLL and MCL. Because of these inhibitors, the standard of care for CLL has changed from being repeated cycles of fixed-duration chemotherapy to a daily oral medication. In first-line CLL treatment, BTK inhibitors have demonstrated increased OS compared to fludarabine, cyclophosphamide and rituximab (FCR) chemoimmunotherapy. Along with this,  BTK inhibitors improved PFS when compared to conventional chemoimmunotherapy. 

Even with these developments, BTK inhibitors do not totally cure the condition, and uMRD illness remissions are not common. This means that therapy must continue, which raises the possibility of resistance and chronic toxicity. ICP-248 has shown encouraging efficacy and is well tolerated, especially in cases of relapsed or refractory B-cell malignancies. All patients showed improvement at 100 mg, and three even experienced complete remission. ICP-248 stands out from other BCL-2 inhibitors based on preliminary data that show a strong safety profile and acceptable pharmacokinetics with high exposure at relatively low dosage levels.

In March 2024, Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) approved the IND for the combination therapy using orelabrutinib for the treatment of 1L CLL/SLL. The findings of this trial may help ICP-248  plus orelabrutinib combination therapy in the treatment of 1L CLL/SLL and other NHL conditions. This might be advantageous for Innocare’s global expansion. As part of the company's worldwide development plan, the FDA authorized ICP-248 for clinical studies in January 2024.