Olverembatinib

Olverembatinib More Info

Olverembatinib is a third-generation BCR-ABL tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma, specifically designed to overcome resistance mechanisms in chronic myeloid leukemia (CML) and other hematologic malignancies.

Core Features

Mechanism of Action:

Olverembatinib is an ATP-competitive inhibitor that targets both wild-type BCR-ABL and a broad spectrum of BCR-ABL mutants, including the highly resistant T315I mutation. It binds to the ATP-binding site, preventing the activation of downstream signaling pathways critical for cancer cell proliferation and survival.

In vitro, it effectively suppresses the activation of BCR-ABL and downstream proteins such as Crkl and STAT5 in CML cell lines.

Pharmacological Profile:

Potency: Exhibits low nanomolar inhibitory concentrations (IC50) for both wild-type BCR-ABL (0.34 nM) and BCR-ABL(T315I) (0.68 nM).

Spectrum: In addition to BCR-ABL, preclinical studies indicate activity against other kinases, including FLT3, PDGFR, and FGFR1, suggesting potential broader applications.

Chemical Properties:

Molecular Formula: C₁₅H₂₁N₅O₄S

Molecular Weight: 491.53 g/mol

Formulation: Supplied as Olverembatinib dimesylate, a stable powder that requires storage at -20°C in a dry environment, with a shelf life of up to 3 years.

Pharmacokinetics:

Demonstrates good oral bioavailability (approximately 48.7% in rat models).

Primarily metabolized by the CYP3A4 enzyme, with a minor contribution from CYP2C9.

Clinical Development & Indications

Olverembatinib has rapidly progressed from preclinical studies to clinical use, particularly targeting patients with limited treatment options due to drug resistance.

Regulatory Status:

China: Approved for adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harboring the T315I mutation, as well as for CML-CP patients resistant or intolerant to first- and second-generation TKIs. The drug is covered by the China National Reimbursement Drug List (NRDL).

International: Designated as an orphan medicinal product in the European Union for the treatment of CML. It has also received orphan drug designations from the FDA and EMA for CML, Ph+ acute lymphoblastic leukemia (Ph+ ALL), and SDH-deficient gastrointestinal stromal tumor (GIST).

Clinical Efficacy:

CML: Clinical trials have demonstrated significant efficacy in patients with both chronic and accelerated phases of CML, including those with the T315I mutation. In accelerated-phase CML, olverembatinib has shown promising efficacy and a manageable safety profile.

Other Indications: Emerging data suggest potential benefits in rare diseases such as 8p11 myeloproliferative syndrome with BCR-FGFR1 fusion and SDH-deficient GIST, highlighting its multi-kinase inhibitory capabilities.

Commercialization:

The drug is commercially available in China under the brand name "Nairike" , and it is jointly commercialized by Ascentage Pharma and Innovent Biologics.

Overall, Olverembatinib represents a significant advancement in targeted therapy for hematologic malignancies, offering a potent treatment option for patients who have exhausted other TKI therapies.