Table 3.
Summary of development of copanlisib and idelalisib
| Feature | Copanlisib | Idelalisib |
|---|---|---|
| Core scaffold | Quinazoline | Quinazoline |
| Molecular weight | 480.53 | 415.42 |
| Ligand binding to p110 | Scott et al8 | Somoza et al10 |
| Molecule shape | Flat | Three-blade propeller |
| Extending from adenine pocket into: | Affinity pocket | Induced selectivity pocket |
| Contact residues | K833, D836, D841 (p110γ) | W760, M752 (p110δ) |
| Potency | Liu et al20 | Lannutti et al13 |
| IC50 of p110δ activity | 0.7 nM | 2.5 nM |
| Selectivity against p110δ | ||
| Compared to p110α | 0.7-fold | 328-fold |
| Compared to p110γ | 9-fold | 36-fold |
| Cytotoxicity against malignant B cells | Göckeritz et al57 | Göckeritz et al57 |
| IC50 for survival (48 hours) | ||
| SUDHL5 (GC-DLBCL) | ~0.03 µM | ~3 µM |
| JVM3 (B-PLL) | ~0.4 µM | ~20 µM |
| CLL samples | ~0.6 µM | ~30 µM |
| Clinical administration | Patnaik et al73 | Brown et al6 |
| Route | Intravenous | Oral |
| Dosing | Intermittent | Continuous |
| Standard treatment scheme | 60 mg once weekly (three times per 4-week cycle) | 150 mg twice daily |
| Pharmacokinetics | ||
| Cmax | ~0.9 µM | ~5.3 µM |
| Ctrough | ~0.01 µM | ~1.2 µM |
| t½ | 39.2 h | 8.2 h |
| Most frequent adverse effects | Dreyling et al79 | Gopal et al80 |
| % occurrence (≥ grade 3) | 41% hyperglycemia | 27% decreased neutrophils |
| (see Figure 5) | 24% hypertension | 21% elevated transaminases |
| 24% decreased neutrophils | 13% diarrhea | |
| Clinical efficacy | ||
| (see Table 2) | Dreyling et al79 | Gopal et al80 |
| Follicular lymphoma | 59% ORR, 14% CR | 54% ORR, 8% CR |
Notes: Copanlisib and idelalisib represent multi-targeted versus p110δ-selective PI3K inhibitors, but have the clinical application for treatment of relapsed or refractory follicular lymphoma in common. This table recapitulates important properties of both drugs and permits the comparison of biochemical and cellular IC50 values with clinically achieved plasma concentrations.
Abbreviations: CR, complete remission; DLBCL, diffuse large B-cell lymphoma; GC, germinal center; IC50, half maximal inhibitory concentration; ORR, overall response rate; PLL, prolymphocytic leukemia; Cmax, maximal achieved plasma concentration of drug during standard treatment; Ctrough, lowest concentration reached by a drug before the next dose is administered; t1/2, half life.