Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)

Miller, Bruce E.; Mayer, Ruth; Goyal, Navin; Bal, Joanne; Dallow, Nigel; Boyce, Malcolm; Carpenter, Donald C.; Churchill, Alison; Heslop, Teresa; Lazaar, Aili L.

doi:10.1111/bcp.13398

Cited by 41 publications

(46 citation statements)

References 24 publications

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“…First, AZD7986 caused dose‐dependent skin events, but the timing of events did not correlate with the dynamics of NE activity. Second, our skin findings appear less prominent than the seven cases of skin desquamation reported for the irreversible DPP1 inhibitor GSK2793660, even though GSK2793660 showed no clear effect on NSP activity . In fact, contrary to the findings in our study, the frequency and intensity of skin events caused by GSK2793660 led to premature study termination.…”

Section: Discussioncontrasting

confidence: 99%

“…It has been hypothesized that NSPs play a crucial role in epidermal barrier function, and that imbalance in proteolytic activity may cause various skin disorders such as redness and scaling. 32 However, as suggested by Miller et al, 19 an alternative explanation for the skin events may be that DPP1 also plays an important role in maintaining the structural integrity of plantar and palmar epidermal surfaces, by contributing to the processing of keratins. 33 This hypothesis is supported by the observations in this study.…”

Section: Discussionmentioning

confidence: 98%

“…The idea that different pathways are responsible for the desirable (reduced NSP activity) and undesirable (skin symptoms) effects of DPP1 inhibition, could possibly also explain the discrepancy in NSP inhibition and frequency of skin events between GSK2793660 and AZD7986. Although GSK2793660 was reported to achieve sustained, near‐complete DPP1 inhibition in whole blood, this does not necessarily imply a continuous high level of DPP1 inhibition in all cells and tissues. In fact, GSK2793660 was administered once daily, but in contrast to AZD7986, exhibited a very short half‐life (1.5 hours).…”

Section: Discussionmentioning

confidence: 99%

“…inhibitor GSK2793660. 19 However, although the authors report sustained inhibition of DPP1 in whole blood during 21 days of dosing, little to no effect on NSP activity was demonstrated. Instead, the only clear downstream effect reported was epidermal desquamation on palmar and plantar surfaces, findings not unlike clinical manifestations of PLS.…”

Section: Study Highlightsmentioning

confidence: 97%

“…The effect of DPP1 inhibition in humans has previously been investigated in a phase I study with the irreversible DPP1 inhibitor GSK2793660 . However, although the authors report sustained inhibition of DPP1 in whole blood during 21 days of dosing, little to no effect on NSP activity was demonstrated.…”

mentioning

confidence: 99%

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Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo‐controlled, first‐in‐human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure‐dependent, indirect manner—consistent with in vitro and preclinical predictions. Several dose‐dependent, possibly DPP1‐related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Study Highlightsmentioning

confidence: 97%

mentioning

confidence: 99%

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Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Palmer

Mäenpää

Jauhiainen

et al. 2018

Clin Pharma and Therapeutics

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E‐64c‐Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1’‐S2’ Area

Tromsdorf¹,

Grundhuber²,

Sommerhoff³

et al. 2023

ChemMedChem

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The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro‐inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E‐64c‐hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n‐butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1’‐S2’ area was now investigated by a combinatorial approach, showing that Nle‐tryptamide is a ligand superior to the initially used Leu‐isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.

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BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis

et al. 2023

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Background Airway inflammation in chronic inflammatory lung diseases (e.g. bronchiectasis) is partly mediated by neutrophil-derived serine protease (NSP)/antiprotease imbalance. NSPs are activated during neutrophil myelopoiesis in bone marrow by cathepsin C (CatC; DPP1). CatC is therefore an attractive target to reduce NSP activity in the lungs of patients with bronchiectasis, restoring the protease/antiprotease balance. We report results from the preclinical pharmacological assessment of the novel CatC inhibitor BI 1291583. Methods Binding kinetics of BI 1291583 to human CatC were determined by surface plasmon resonance. In vitro inhibition of human CatC activity was determined by CatC-specific fluorescent assay, and selectivity was assessed against related cathepsins and unrelated proteases. Inhibition of NSP neutrophil elastase (NE) production was assessed in a human neutrophil progenitor cell line. In vivo inhibition of NE and NSP proteinase 3 (PR3) in bronchoalveolar lavage fluid (BALF) neutrophils after lipopolysaccharide (LPS) challenge and distribution of BI 1291583 was determined in a mouse model. Results BI 1291583 bound human CatC in a covalent, reversible manner, selectively and fully inhibiting CatC enzymatic activity. This inhibition translated to concentration-dependent inhibition of NE activation in U937 cells and dose-dependent, almost-complete inhibition of NE and PR3 activity in BALF neutrophils in an in vivo LPS-challenge model in mice. BI 1291583 exhibited up to 100 times the exposure in the target tissue bone marrow compared with plasma. Conclusion BI 1291583-mediated inhibition of CatC is expected to restore the protease–antiprotease balance in the lungs of patients with chronic airway inflammatory diseases such as bronchiectasis.

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Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)

Cited by 41 publications

References 24 publications

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

E‐64c‐Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1’‐S2’ Area

BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis

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