(R)-N- (4-(chlorodifluoromethoxy)phenyl)- 6-(3- hydroxypyrrolidin-1- yl)-5- (1H-pyrazol- 5-yl)nicotinamide

Absorption

The median Tmax of asciminib following oral administration is 2.5 hours. At a dose of 80mg once daily, the steady-state Cmax and AUCtau were 1781 ng/mL and 15112 ng.h/mL, respectively. At a dose of 40mg twice daily, the steady-state Cmax and AUCtau were 793 ng/mL and 5262 ng.h/mL, respectively. At a dose of 200mg twice daily (for treatment of T315I mutants), the steady-state Cmax and AUCtau were 5642 ng/mL and 37547 ng.h/mL, respectively.
As compared to the fasted state, the co-administration of asciminib with a high-fat meal decreased the AUC and Cmax by 62% and 68%, respectively, and its co-administration with a low-fat meal decreased the AUC and Cmax by 30% and 35%, respectively.

Toxicity

There are no data regarding overdosage with asciminib. The effects associated with overdosage are likely to be consistent with the adverse effect profile of asciminib, and may therefore include significant hematological abnormalities and/or gastrointestinal effects, amongst others.

Description

Asciminib is the first-in-class Specifically Targeting the ABL1 Myristoyl Pocket (STAMP) inhibitor, which was granted accelerated approval in 2021 for patients with Philadelphia chromosomepositive (Ph+) chronic myeloid leukemia (CML) in chronic phase, previously treated with two or more tyrosine kinase inhibitors (TKIs), and for adult patients with Ph+ CML in chronic phase with the T315I mutation. Asciminib binds to a myristoyl site of the BCR-ABL1 protein and locks the protein into an inactive conformation through a mechanism distinct from those of all other orthosteric TKIs such as imatinib, thus overcoming drug resistance arising from ATPbinding site mutations. Asciminib mimics the function of the myristoylated N-terminus of ABL1 and restores the natural autoinhibition of the ABL1b protein.

The Uses of (R)-N- (4-(chlorodifluoromethoxy)phenyl)- 6-(3- hydroxypyrrolidin-1- yl)-5- (1H-pyrazol- 5-yl)nicotinamide

Asciminib comprises ABL kinase inhibitors and/or SLC7A11 inhibitors for the treatment of cancer and central nervous system (CNS) disorders.

Background

Asciminib is a tyrosine kinase inhibitor (TKI) used in the treatment of chronic-phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). More specifically, it is an inhibitor of the ABL1 kinase activity of the BCR-ABL1 fusion protein which serves as a driver of CML proliferation in most patients with the disease. It has also shown benefit in Ph+ CML with the T315I mutation, which produces a mutant BCR-ABL1 which is typically treatment-resistant as compared to wild-type BCR-ABL1.
Existing inhibitors of ABL compete at the ATP binding sites of these proteins and can be classified into those that target the active conformation of the kinase domain (dasatinib, bosutinib) and those that target the inactive kinase domain (imatinib, nilotinib, ponatinib). Asciminib is unique in that it acts as an allosteric inhibitor, binding at the myristoyl pocket of the BCR-ABL1 protein and locking it into an inactive conformation.
Asciminib received FDA approval on October 29, 2021 (Scemblix, Novartis AG).

Indications

Asciminib is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase who have been previously treated with ≥2 tyrosine kinase inhibitors. It is also indicated in the treatment of Ph+ CML in adult patients with the T315I mutation.

General Description

Class: non-receptor tyrosine kinase
Treatment: CML
Elimination half-life = 14.2 h
Protein binding = 97%

Pharmacokinetics

Asciminib exerts its therapeutic activity by inhibiting an oncogenic protein responsible for the proliferation of CML. It may be administered orally once or twice a day depending on the condition being treated. By increasing the total daily dose 5-fold as compared to standard therapy (80mg daily vs. 400mg daily), it can be used to treat Ph+ CML with the T315I mutation, a typically treatment-resistant variant of the disease.
As with many other chemotherapeutic agents, asciminib treatment can result in various forms of myelosuppression, including thrombocytopenia and neutropenia. Patients should receive frequent laboratory monitoring throughout therapy and dose adjustments may be required based on the severity of observed effects. Patients may also experience pancreatic and/or cardiovascular toxicity, both of which require frequent monitoring and may require dose adjustments as per prescribing information.

Metabolism

Asciminib is negligibly metabolized, with unchanged parent drug comprising the main drug component in plasma (~93%) and following excretion (~57% in feces). The main circulating metabolites are M30.5, M44, and M29.5, accounting for approximately 5%, 2%, and 0.4% of the total administered dose, respectively. The oxidative metabolism of asciminib is mediated by CYP3A4, and the glucuronidation of asciminib is mediated by UGT2B7 and UGT2B17.