Topical Bimiralisib Shows Meaningful Cutaneous Drug Levels in Healthy Volunteers and Mycosis Fungoides Patients but No Clinical Activity in a First-in-Human, Randomized Controlled Trial

Abstract

Mycosis fungoides (MF) is a subtype of CTCL with a low incidence and high medical need for novel treatments. The objective of this randomized, placebo-controlled, double-blinded, first-in-human study was to evaluate safety, efficacy, cutaneous and systemic pharmacokinetics (PK) of topical bimiralisib in healthy volunteers (HVs) and MF patients. In this trial, a total of 6 HVs and 19 early-stage MF patients were treated with 2.0% bimiralisib gel and/or placebo. Drug efficacy was assessed by the Composite Assessment of Index Lesion Severity (CAILS) score, supported by objective measuring methods to quantify lesion severity. PK blood samples were collected frequently and cutaneous PK was investigated in skin punch biopsies on the last day of treatment. Local distribution of bimiralisib in HVs showed a mean exposure of 2.54 µg/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm² on 400 cm², with a mean C_avg of 0.96 ng/mL. Systemic exposure of bimiralisib was reached in all treated MF patients, and normalized plasma concentrations showed a 144% increased exposure compared to HVs, with an observed mean C_avg of 4.49 ng/mL and a mean cutaneous concentration of 5.3 µg/g. No difference in CAILS or objective lesion severity quantification upon 42 days of once-daily treatment was observed in the MF patient group. In general, the treatment was well tolerated in terms of local reactions as well as systemic adverse events. In conclusion, we showed that topical bimiralisib treatment leads to (i) meaningful cutaneous drug levels and (ii) well-tolerated systemic drug exposure in MF patients and (iii) a lack of clinical efficacy, in need of further exploration due to numerous unknown factors, before depreciation of topical bimiralisib as a novel therapeutic drug for CTCLs.

Keywords: CTCL; PI3K/mTOR; PQR309; bimiralisib; mycosis fungoides; pharmacokinetics.

Figure 1

Method of obtaining cutaneous pharmacokinetics of bimiralisib in HVs and early-stage MF patients. (A) Bimiralisib gel 2% is applied topically, in part A at the back of six HVs and in part B at 1–3 target MF lesions. (B) A full-thickness skin punch biopsy was taken on day 21 and day 42/84, respectively, for HVs and MF patients. Skin punch biopsy was snap-frozen within 5 min, processed and cryosectioned. A single section was used for H&E staining. (C) MALDI matrix spraying. (D) Prepared samples were ionized by a laser beam. (E) Seven tesla Matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry imaging (7T-MALDI-FTICR MSI) acquisition. (F) Acquired data are analyzed and MALDI images are acquired.

Figure 2

Study flow chart of part B with MF patients. ITT = intention to treat; PP = per protocol. Two patients were excluded for not meeting the inclusion criteria. Data of a single patient between days 28 and 42 were excluded due to a pharmacy dispensing error.

Figure 3

Clinical efficacy of bimiralisib 2.0% gel compared to placebo, by lesion improvement measured by CAILS in the per protocol population. (A) Absolute total CAILS score on days 14, 28 and 42 of daily topical gel application. No statistical significant difference in efficacy was detected between bimiralisib and placebo over time (p = 0.74) or on day 42 (p = 0.98). (B) Individual change of CAILS from baseline per patient. The dark blue bar indicates the patient shown in Figure 3C. (C) Clinical response of a single early-stage MF patient by Scarlet Red clinical pictures.

Figure 4

Bimiralisib pharmacokinetics in HVs and early-stage MF patients. (A) Individual plasma concentrations of 6 healthy volunteers after 7, 14 and 21 days of topical daily application ranged from 0.14 to 2.74 ng/mL. The red dotted line is the NOAEL Cmax (96.6 ng/mL). (B) Individual plasma concentrations of 9 MF patients, 6 patients after 42 days of daily topical application and 3 patients after 84 days of bimiralisib application. Concentrations ranged from 0.67 to 18.70 ng/mL. (C) Applied dose per application increased with increasing target lesions, as shown by exploratory analysis. Patients with a single target lesion applied less gel per dose (6.5 ± 2.4) in comparison to patients with two (8.2 ± 1.6) or three (8.6 ± 1.6) target lesions. (D) Normalized plasma concentration was 2.44-fold higher for patients compared to healthy volunteers. Boxplots show the first, median and third quartiles in the box; whiskers extend up to 1.5× the interquartile range. Dashed line is the log-transformed mean. Open dots are data below the LLOQ (1.0 ng/mL).

Figure 5

Individual cutaneous pharmacokinetics of a single HV compared to a single early-stage MF patient. Left to right: (I) Clinical picture. (II) H&E slide visualizing epidermis and dermis. (III) Bimiralisib distribution by MALDI image. Distribution in the lateral sides of the dermis of both biopsies is considered punch contamination. (IV) Penetration profile of areas selected without contamination.