BEQALZI Film-coated tablet Ref.[116693] Active ingredients: Sonrotoclax

Sonrotoclax exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

Administration of sonrotoclax has the potential to increase the QTc interval. The largest mean increase in QTc interval was 7 ms (upper confidence interval = 14 ms) after administration of sonrotoclax (320 mg once daily) with a low-fat meal in patients with mature B-cell malignancies. There is insufficient information to characterize the QTc effects of sonrotoclax at higher concentrations above recommended dose.

Sonrotoclax pharmacokinetics were determined following a single dose or at steady state at the approved recommended dosage of 320 mg once daily and are presented as mean (CV%), unless otherwise specified.

Sonrotoclax area under the plasma drug concentration-time curve (AUC0-24 h) is 3395 (55%) ng∙h/mL and maximum plasma concentration (C_max) is 353 (49%) ng/mL, following 320 mg once daily with a low-fat meal. Sonrotoclax C_max and AUC_0-tau increase in a less than dose proportional manner over the dosage range of 320 mg to 640 mg (1 to 2 times the highest approved recommended dosage). Limited systemic accumulation of sonrotoclax was observed following repeated administration.

Absorption

The median Tmax of sonrotoclax is 4 hours (ranged from 1 to 8 hours) following 320 mg once daily dosing.

Effect of Food

Sonrotoclax AUC and C_max increased by approximately 1.5-fold following administration with a low-fat meal (approximately 333-500 kilocalories, 25% fat calories). Sonrotoclax AUC increased by 2-fold and C_max by 2.4-fold following administration with a high-fat meal (1000 kilocalories, 50% fat).

Distribution

The geometric mean apparent volume of distribution of sonrotoclax is 482 (38%) L. Sonrotoclax plasma protein binding is 99% across a concentration range of 1 to 10 μM. The blood-to-plasma ratio is 0.6 to 0.7.

Elimination

The mean terminal elimination half-life (t½) of sonrotoclax ranges from 4 to 6 hours. The geometric mean apparent oral clearance (CL/F) of sonrotoclax is 94 (62%) L/h.

Metabolism

Sonrotoclax is primarily metabolized by CYP3A and to a lesser extent by CYP2C8 in vitro.

Excretion

After a single radiolabeled sonrotoclax dose of 20 mg to healthy subjects, approximately 86% of the dose was recovered in feces (19.5% unchanged) and 0.28% in urine (0.04% unchanged).

Specific Populations

No clinically meaningful differences in the pharmacokinetics of sonrotoclax were observed based on race, age (27-91 years), sex, weight (37-165 kg), mild to moderate renal impairment (eGFR ≥30 mL/min) or mild to moderate hepatic impairment (bilirubin ≤3× upper limit of normal (ULN) and any aspartate aminotransferase (AST)). The effect of severe renal impairment (eGFR <30 mL/min) or severe hepatic impairment (total bilirubin >3× ULN with any AST) on sonrotoclax pharmacokinetics is unknown.

Drug Interactions Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A inhibitors:

Sonrotoclax AUC increased 11-fold and C_max increased 4-fold following concomitant administration of itraconazole (strong CYP3A inhibitor and P-gp inhibitor).

Sonrotoclax AUC increased 13-fold and C_max increased 7-fold following concomitant administration of posaconazole (strong CYP3A inhibitor).

Strong CYP3A inducers:

Sonrotoclax AUC decreased to 35% and C_max to 58% following concomitant use of phenytoin (strong CYP3A inducer).

Other drugs:

No clinically significant differences in sonrotoclax pharmacokinetics were observed following concomitant administration with gastric acid reducing agents (proton pump inhibitors, H₂-receptor antagonists).

In Vitro Studies

CYP450 Enzymes:

Sonrotoclax is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Sonrotoclax inhibits CYP3A in vitro, but this is not anticipated to have a clinically meaningful impact. Sonrotoclax is not an inducer of CYP1A2, CYP2B6, or CYP3A4.

Transporters:

Sonrotoclax is a substrate of P-gp and BCRP but not OATP1B1 or OATP1B3. Sonrotoclax does not inhibit P-gp, BCRP OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K.

Carcinogenesis

Carcinogenicity studies have not been conducted with sonrotoclax.

Mutagenesis

Sonrotoclax was not mutagenic in a bacterial mutagenicity (Ames) assay and not clastogenic in a chromosome aberration assay in mammalian cells or in an in vivo bone marrow micronucleus assay in mice.

Impairment of Fertility

Fertility studies in animals have not been conducted with sonrotoclax. In a repeat dose, 13-week toxicity study in mice treated with oral administration of sonrotoclax at 20, 100, or 300 mg/kg/day, changes were reported in female reproductive organs at all doses, including the development of ovarian cysts, vaginal mucification, and uterine atrophy. At the dose of 20 mg/kg/day in mice, exposures (AUC) were approximately the same as the human exposure at the recommended dose. In a repeat dose, 13-week toxicity study in dogs treated with oral administration of sonrotoclax at 10, 30, or 100 mg/kg/day, changes were reported in male reproductive organs at all doses, including atrophy, necrosis, and vacuolation of the epididymis with reduced sperm, and atrophy of the prostate and testis. At the dose of 10 mg/kg/day in dogs, exposures were approximately 2 times the human exposure at the recommended dose. Reversibility was noted in both species by the end of the recovery period.

The efficacy of BEQALZI was evaluated in a single-arm, multicenter clinical trial, BGB-11417-201 (NCT05471843). Efficacy was based on 103 adults with relapsed or refractory MCL who previously received anti-CD20–based therapy and a BTK inhibitor. The trial required an ANC ≥1000/mm³, platelets ≥75,000/mm³, and AST and ALT ≤3 × upper limit of normal (ULN). The trial excluded patients with central nervous system lymphoma, prior BCL-2 inhibitor, or an ECOG performance status >2.

Following completion of the ramp-up dosing schedule, patients received BEQALZI at 320 mg orally once daily.

The median age was 68 years (range: 39 to 85 years); 74% were male; 58% were White, 33% Asian, and 3% Black or African American. Most patients (93%) had an ECOG performance of 0 to 1.

Patients had a median of 3 prior lines of therapy (range: 1 to 8), with 89% having at least 2 and 60% having at least 3 prior lines of therapy. All patients were exposed to at least one covalent or noncovalent BTK inhibitor, most commonly ibrutinib (53%), zanubrutinib (27%), and pirtobrutinib (14%). Other prior therapies included lenalidomide in 19%, autologous HSCT in 17%, and CAR-T therapy in 2%. The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low in 35%, intermediate in 36%, and high in 29% of patients. High ≥30%) Ki-67 expression was detected in 35% of patients.

Efficacy was established based on overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee (IRC) using 2014 Lugano criteria. Efficacy results are shown in Table 9. The median time to response was 1.9 months (range: 1.6 to 6.2). The estimated median follow-up for DOR was 11.9 months.

Table 9. Efficacy Results per IRC in Patients with Previously Treated MCL:

Abbreviations: CI: confidence interval; DOR: duration of response; NE: not estimable
^a Kaplan-Meier estimate.