A two-part, phase 1, randomized, single blind, placebo-controlled, single centre study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LAS191954 following oral administration of single and multiple ascending doses in healthy male volunteers - LAS191954 SAD/MAD study

Start Date25 May 2016

Sponsor / Collaborator

Almirall SA

100 Clinical Results associated with LAS-191954

100 Translational Medicine associated with LAS-191954

100 Patents (Medical) associated with LAS-191954

Literatures (Medical) associated with LAS-191954

12 Jan 2017·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

Q3 · MEDICINE

Article

Author: Taltavull, Joan ; Paris, Stéphane ; Bravo, Mónica ; Soria, Salomé ; Bernal, Francisco Javier ; Hernández, Begoña ; Lehner, Martin D. ; Armengol, Clara ; Caturla, Juan Francisco ; Sabaté, Mar ; Miralpeix, Montserrat ; Gréco, Angelique ; Gràcia, Jordi ; Domínguez, María ; Erra, Montse ; Cabedo, Judit ; Calama, Elena

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure-activity relationships and structure-property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

Frontiers in ImmunologyQ2 · MEDICINE

Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Q2 · MEDICINE

ArticleOA

Author: Aulí, Mariona ; Ludwig, Ralf J ; Bieber, Katja ; Kasprick, Anika ; Koga, Hiroshi ; Zillikens, Detlef ; Pont, Mercè ; Godessart, Núria ; Balagué, Cristina ; López, Rosa

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal-epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

100 Deals associated with LAS-191954

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Indication	Highest Phase	Country/Location	Organization	Date
Epidermolysis Bullosa Acquisita	Preclinical	ES	Almirall SA	12 Jul 2018

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