Principia Biopharma (United States)

Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is one of the most common canine autoimmune skin diseases. To determine the safety and efficacy of the BTKi PRN1008 in the treatment of cPF. Four privately owned dogs. Four dogs diagnosed with PF were administered BTKi PRN1008. Initial dosages approximated to 15mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for 20 weeks, attempting to decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels and urinalyses, and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Serum anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin (Ig)G titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells (PBMC). All four dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. Three dogs continued to improve and sustained near complete remission by 20 weeks, at which point three responses were considered "good" and one "fair". Final daily dosages were in the range 17-33mg/kg. Anti-DSC-1 IgG titre decreased dramatically in one dog, was undetectable in two and was uninterpretable in one dog. No dogs had detectable IgG to DSG1. A possible adverse event occurred in one dog. BTKi PRN1008 monotherapy may have some beneficial effects in some cases of cPF.

The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim. Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production. The systemic half-lives of filgrastim (2.6h) and pegfilgrastim (10.1h) were as expected. The effective half-life of chemotherapy was 9.6h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model. This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12weeks of simeprevir 150mg, daclatasvir 60mg and sofosbuvir 400mg, once daily. The primary efficacy endpoint was sustained virologic response 12weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

Abstract Discovering drug candidates that exhibit durable on-target pharmacology upon oral dosing has been extremely challenging for the pharmaceutical industry. The introduction of a covalent bond between a small molecule drug and its pharmacological target has the potential to achieve prolonged target inhibition with minimal systemic drug exposure. Several irreversible covalent inhibitors employing this strategy have been approved or are in late stage clinical development for the treatment of various cancer indications such as multiple myeloma (carfilzomib), lymphoma (ibrutinib), lung cancer (afatinib) and breast cancer (neratinib). However, the discovery process for covalent drugs presents unique challenges. Identification and optimization of lead molecules require screening assays that measure the degree of covalent engagement with the target, both in vitro and in vivo. In addition, the reactive chemistries often employed for covalent bonding can impart poor ADME properties, requiring IV administration or high oral doses. Principia Biopharma, a pioneer in covalent drug discovery and development, has overcome many of these challenges in the discovery of PRN1371, a covalent irreversible inhibitor of fibroblast growth factor receptor (FGFR) 1-4 with long target residence time. Aberrant signaling of the FGF/FGFR pathway is an oncogenic driver in many solid tumors. Early reports from Phase 1/2 studies with reversible ATP competitive inhibitors have demonstrated encouraging efficacy from FGFR inhibition in the treatment of bladder, lung, and breast cancers. However, some results are difficult to interpret due to the poor selectivity of the drugs used. Aberrant pathway activation may be a consequence of FGF ligand overexpression or changes to the FGF receptor including mutations, translocations/fusions, and protein overexpression. Such genetic alterations in one or more isoforms of FGFR have been reported in many solid tumors including bladder, breast, cervical, endometrial, gastric, hepatocellular, lung, and ovarian cancers. There remains a compelling medical need to identify a highly selective inhibitor of all four FGFR family members, FGFR1-4, to improve clinical responses in patients while minimizing off-target toxicity. PRN1371 is the culmination of a drug discovery program focused upon the creation of an oral, low dose, highly selective, potent, and irreversible inhibitor of FGFR1-4. Starting from a 7-oxopyridopyrimidine core, a series of covalent inhibitors were designed to incorporate a Michael acceptor appropriately positioned to engage Cys 488 in a covalent bond. Extensive SAR was generated using a FRET-based biochemical occupancy assay to measure the durability of drug binding over time. Molecules were optimized for prolonged FGFR residence time and potent inhibition of pERK in HUVEC cells upon FGF stimulation. Advanced leads with suitable cellular potency were studied in vivo, using an FGF-induced CCL2 readout in mice. The relationship between plasma drug concentration (PK) and pharmacological inhibition of CCL2 production (PD) in mice provided essential guidance in selecting optimal drug candidates. To assess the ADME liabilities of the Michael acceptor, in vitro microsomal stability and thiol reactivity assays were used. The final selection of PRN1371 as a clinical candidate was based upon the ideal combination of exquisite selectivity, potent and prolonged pharmacodynamic inhibition of FGFR1-4 in vivo and high predicted human oral bioavailability. PRN1371 is now evaluated in a Phase 1/2 open-label, multicenter clinical trial for solid tumors (ClinicalTrials.gov: NCT02608125). Citation Format: Ken A. Brameld. Discovery of the highly selective covalent FGFR1-4 inhibitor PRN1371, currently in development for the treatment of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY30-01.

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.

Abstract Snowboard manufacturers attempt to design boards with mechanical properties that provide desirable ride and handling characteristics, adequate strength, and low manufacturing costs. Snowboards are typically a sandwich composite of several individual layers that vary significantly in geometry and composition. To better understand the influence of core materials and construction on a board's stiffness, ultimate failure load, and stored energy, several commercially available snowboards were tested to failure in three point bending. A series of representative boards were tested with three different core materials: foam, wood, and honeycomb. The results show that stiffness and ultimate failure load are most strongly influenced by the core wrap thickness, while the energy storage is most strongly influenced by the core material and construction method used.