Regulatory Decision Summary for Calquence

The purpose of this New Drug Submission (NDS) was to obtain market authorization for a new dosage form (tablets) and a change of the drug substance from acalabrutinib to acalabrutinib maleate.

Calquence (acalabrutinib) is currently approved as 100 mg capsules (NDS, Control # 214504) with the active ingredient supplied as acalabrutinib. The sponsor has developed a new 100 mg acalabrutinib maleate film-coated tablet (supplied as 129 mg acalabrutinib maleate, 100 mg free base equivalent dose), with an improved solubility profile compared to the currently marketed capsule formulation. This new formulation ensures complete drug dissolution regardless of pH conditions in the gastrointestinal tract, will allow acalabrutinib to be co-administered with gastric acid reducing agents, and will simplify the medication regimen for patients. The indications for acalabrutinib did not change.

This NDS was based on the results of 2 Phase I studies in healthy subjects (D8223C00013 and D8220C00018). These studies evaluated acalabrutinib maleate tablet (AMT) in reference to the marketed acalabrutinib capsules.

Study D8223C00013 evaluated the oral bioavailability between acalabrutinib maleate tablet (AMT) and the currently marketed acalabrutinib capsule formulation. The study was conducted in healthy subjects who received two treatments (single doses), each separated by a washout period of at least 5-days. This study compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety between the 100 mg AMT and 100 mg acalabrutinib capsule. Following the oral administration of a single 100 mg dose of AMT in the fasted state, the median time to reach maximum concentration (t_max) was 0.52 hours, which is similar to the t_max observed for acalabrutinib capsule at 0.58 hours. For AMT, the mean elimination half-life (t_1/2) associated with terminal slope (λz) of a semi-logarithmic concentration-time curve is approximately 1.6 hours for acalabrutinib and approximately 7 hours for the active metabolite ACP-5862. Both formulations (AMT and capsules) had similar exposure (C_max and AUC), with the 90% confidence intervals for the geometric mean ratios of exposure contained within the pre-defined bioequivalent margin of 80% to 125%. No differences in Bruton tyrosine kinase target occupancy (BTK-TO) were observed between the two formulations. The BTK-TO was greater than 95% at post-dose time points of 4 and 12 hours in healthy subjects for both formulations. Safety and tolerability were comparable following administration of the AMT and acalabrutinib capsule formulations.

Study D8220C00018 (ACE-HV-115) evaluated the relative bioavailability, Proton Pump Inhibitor (PPI - rabeprazole) effect, food effect and particle size effect. For AMT, food reduced acalabrutinib C_max by approximately 54% for acalabrutinib, and 36% for metabolite ACP-5862, with no effect on overall AUC. Co-administration of PPI (rabeprazole) with AMT had no clinically meaningful effect on the PK exposures of acalabrutinib and metabolite ACP-5862; acalabrutinib C_max was lower (~24%) and AUCs were higher (up to 17%), with ACP-5862, C_max ~30% lower and AUCs comparable in the presence versus absence of rabeprazole. There were no differences in BTK-TO following administration of AMT with or without food or with rabeprazole. C_max values observed for the tablets for three different particle size variants did not correlate with the drug substance particle size.

Based on the PK, PD, and safety data from studies D8223C00013 and D8220C00018, the 100 mg AMT and 100 mg acalabrutinib capsule formulations are considered to be bioequivalent and have equivalent oral bioavailability, except when administered concomitantly with PPIs and other acid reducing agents.

Regarding the food effect, although a reduction in the acalabrutinib C_max values (54%) was observed after a high-fat diet, there was no clinically significant change in the extent of exposure (AUC) or BTK-TO. This indicates that AMT can be taken with or without food.

Particle size effect was determined using three different variants (target particle size, larger than target size, and smaller than target size). The C_max values observed for the tablets did not correlate with the drug substance particle size. The studies demonstrated that there is no solubility or dissolution rate limitation to the absorption of acalabrutinib from AMT in healthy individuals in the fasted state at the range of particle sizes studied.

Most adverse events (AE) reported in both studies were mild grade 1, and consistent with the previously observed safety profile for the currently approved capsule. There were no fatal or serious (grade 3 or higher) AEs reported in either study.

The key findings and conclusions reached by the bioequivalence and bioavailability studies in this submission demonstrate that the new formulation (AMT) can be co-administered with acid reducing agents such as PPIs. There is uncertainty regarding the safety and efficacy of AMT in Chronic Lymphocytic Leukemia (CLL) and/or Chronic Myelogenous Leukemia MCL patients considering that these studies were conducted in only health subjects. However, given that the bioequivalence between the two formulations has been established, it is acceptable to use the new formulation in CLL and MCL patients.

Overall, the anticipated benefits of Calquence are expected to outweigh the potential risks when used under the conditions of use recommended in the approved Product Monograph (PM).