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... Show moreMycosis 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 Cavg 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 Cavg 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. Show less
Wind, S.S.; Jansen, M.A.A.; Rijsbergen, M.; Esdonk, M.J. van; Ziagkos, D.; Cheng, W.C.; ... ; Rissmann, R. 2022
Simple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and... Show moreSimple Summary Primary cutaneous T-cell lymphomas (CTCLs) are a group of lymphomas that present in the skin without extracutaneous localizations at diagnosis. Recent studies in clinical and translational research augmented our understanding of the pathogenesis and pathophysiology of different subtypes of CTCL, enabling the identification of novel therapeutic drug targets. In this study, the primary focus is on bimiralisib gel 2%, a dual pan-class PI3K/mTOR inhibitor, and its potential to inhibit the PI3K/AKT/mTOR signaling pathway as a novel therapeutic target in CTCL. 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 mu g/g in the epidermis. A systemic concentration was observed after application of a target dose of 2 mg/cm(2) on 400 cm(2), 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 mu g/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. Show less
Anchoring DNA via hydrophobic units into the membrane of vesicles allows tagging of these nanocontainers with sequence information. Moreover, the hybridization of DNA on the surface of liposomes... Show moreAnchoring DNA via hydrophobic units into the membrane of vesicles allows tagging of these nanocontainers with sequence information. Moreover, the hybridization of DNA on the surface of liposomes enables sequence specific functionalization, vesicle aggregation, and vesicle fusion. Specifically, DNA‐hybridization‐based approaches for fusion employing oligonucleotides terminally modified with one or two anchoring units were hindered by a limited degree of full fusion or by significant leakage during fusion. The current work deals with a new strategy for anchoring oligonucleotides on a membrane by lipid‐modified nucleobases rather than by attaching hydrophobic units to the 3′‐ or 5′‐termini. The lipid anchors were incorporated into the DNA sequence via phosphoramidite nucleotide building blocks during automated solid‐phase synthesis allowing variation of the number and position of hydrophobic units along the DNA backbone. Single‐stranded DNA functionalized with four lipid‐modified nucleobases was stably grafted onto the membrane of lipid vesicles. It was found that the orientation of DNA hybridization and the number of anchoring units play a crucial role in liposomal fusion, which in the most efficient system reached remarkable 29 % content mixing without notable leakage. Show less
Anchoring DNA via hydrophobic units into the membrane of vesicles allows tagging of these nanocontainers with sequence information. Moreover, the hybridization of DNA on the surface of liposomes... Show moreAnchoring DNA via hydrophobic units into the membrane of vesicles allows tagging of these nanocontainers with sequence information. Moreover, the hybridization of DNA on the surface of liposomes enables sequence specific functionalization, vesicle aggregation, and vesicle fusion. Specifically, DNA‐hybridization‐based approaches for fusion employing oligonucleotides terminally modified with one or two anchoring units were hindered by a limited degree of full fusion or by significant leakage during fusion. The current work deals with a new strategy for anchoring oligonucleotides on a membrane by lipid‐modified nucleobases rather than by attaching hydrophobic units to the 3′‐ or 5′‐termini. The lipid anchors were incorporated into the DNA sequence via phosphoramidite nucleotide building blocks during automated solid‐phase synthesis allowing variation of the number and position of hydrophobic units along the DNA backbone. Single‐stranded DNA functionalized with four lipid‐modified nucleobases was stably grafted onto the membrane of lipid vesicles. It was found that the orientation of DNA hybridization and the number of anchoring units play a crucial role in liposomal fusion, which in the most efficient system reached remarkable 29 % content mixing without notable leakage. Show less
