Lifesciences Inc Research Articles

Short- and Mid-Term Results of Pulmonary Valve Replacement with the Inspiris Valve

BackgroundVarious bioprosthetic valves are used off-label for pulmonary valve replacement (PVR), but there is no consensus on whether a particular valve is best for this application. Recently, the Inspiris Resilia valve (Edwards Lifesciences Inc) was approved for aortic valve replacement, and surgeons have begun using it for PVR. There is limited evidence on the performance of the Inspiris valve compared with other valves in the pulmonary position. MethodsThis study reviewed all patients who underwent PVR with a size 19- to 29-mm Inspiris valve or Mosaic valve (Medtronic Inc) from 2007 to 2022 at Lucile Packard Children's Hospital Stanford (Palo Alto, CA). Midterm outcomes included freedom from moderate or severe pulmonary regurgitation (PR), a maximum Doppler gradient ≥36 mm Hg, and freedom from reintervention. ResultsA total of 225 consecutive patients who underwent PVR with a size 19- to 29-mm Mosaic (n = 163) or Inspiris (n = 62) valve were included. There was no difference in baseline characteristics. Early postoperative gradients were low in both groups but higher in the Mosaic cohort, and neither group had more than mild PR on discharge. On univariable and multivariable analysis, Inspiris valves were significantly more likely to develop moderate or greater PR over time. There was no significant difference between the valves in freedom from reintervention or from a maximum gradient ≥36 mm Hg. ConclusionsEarly and short-term gradients were similar in patients undergoing PVR with Inspiris and Mosaic valves, but significant PR was more common in patients who received an Inspiris valve. These preliminary findings suggest that the durability of the Inspiris valve in the pulmonary position may not be superior to that of other bioprosthetic valves used for PVR.

89-OR: Immunoprivileged Hydrogels Extend Functionality of Islets in Immunocompetent Animals

Background: Despite the promise of current islet cell transplantation, the need for systemic immune suppression significantly limits its utility for patients with diabetes. Until safe and immune-evasive cells are realized, physical immuno-protection offers an alternate route to allogeneic islet implants. Our proprietary synthetic hydrogels provide shape-agnostic, robust and retrievable Islet environments with anti-fouling and non-fibrotic properties. Methods: Rat and human donor islets were encapsulated and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and pigs to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. Next generation shape-agnostic hydrogels were also tested for in-vitro and in-vivo function. Results: Our hydrogels enabled rapid and persistent blood glucose control for 140+ days in immunocompetent mice with marginal loads of 1000 rat IEQ/mouse. Human donor islet function in mice was extended to day 45 (~8x longer than free human islets), with C-peptide detected at day 50, and corresponding HbA1c decreases. Our hydrogels showed minimal fibrosis when explanted after 45 days and showed robustness and integrity at day 340 post-implant in immunocompetent mice. Next-gen shape-agnostic hydrogels successfully excluded immune components including IgG and maintained good islet function in vitro. Our data also demonstrate function of human donor islets in immunocompetent pigs, based on C-peptide and cell viability data. Conclusion: Our proprietary synthetic and retrievable hydrogels show strong immune protection in xenogenic transplants of donor islets into immune-competent animals. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality, without immunosuppression. Disclosure H.Stover: Employee; Allarta Life Science Inc.

Apo-B Levels and Abdominal Aortic Wall Thickness in Hypercholesterolemic Rats Treated with Red Guava Fruit

Background: Coronary heart disease (CHD) is mainly related to hypercholesterolemia. Sometimes CHD occurs in people with normal cholesterol. Therefore, it is necessary to study other factors that cause CHD: apolipoprotein B (apo-B). Atherosclerosis is a marker of CHD, characterized by the thickening of the walls of blood vessels and the narrowing of blood vessels. Non-pharmacologically, CHD can be managed by consuming foods with high fiber and antioxidants, such as red guava fruit. Objectives: This research aimed to analyze the consequence of red guava fruit on the Apo-B levels and the thickness of the abdominal aortic wall in hypercholesterolemic rats. Methods: The research design was a pre and post-test and a randomized control group. Fifty hypercholesterolemic adults male Sprague Dawley rats were given red guava fruit. The primary treatment used red guava fruit as a treatment group, referring to the fiber requirement of 38 g/day, and simvastatin as a positive control group based on a human dose of 10 mg/day, the conversion of human to mouse dose, according to Laurence-Bacarach is 0.018. The negative control group was hypercholesterolemic rats. The standard feed for the rats was based on AIN93. The Enzyme-linked Immunosorbent Assay method measures apo-B levels, Kit For apo-B Rattus norwegicus, Catalog No. E92003Ra, produced by Uscn Life Science Inc. The aorta was taken after going through general anesthesia and thoracotomy. Furthermore, the aorta was processed for making histological preparations with hematoxylin-eosin (HE) staining to observe histopathological changes. Results: Observation of aortic wall thickness using a microscope with a magnification of 400X. Simvastatin and red guava fruit have reduced Apo-B by 7% and 6%, respectively. Conclusions: The performance of red guava fruit in reducing Apo-B concentration and the thickness of the abdominal aortic wall was equal to the simvastatin.

Echocardiographic Assessment of Melody Versus Sapien Valves FollowingTranscatheter Pulmonary ValveReplacement.

The aim of this study was to compare the immediate and midterm echocardiographic performance of the Melody (Medtronic Inc) and Sapien (Edwards Lifesciences Inc) valves after transcatheter pulmonary valve replacement (TPVR) in native and conduit right ventricular outflow tracts (RVOTs). TPVR is now a common procedure, but limited data exist comparing postimplantation echocardiographic findings between Melody and Sapien valves. This was a single-institution retrospective cohort study of all patients who underwent successful TPVR from 2011 to 2020. Patient demographics, procedural details, and immediate and midterm echocardiographic findings were collected and compared between valve types using the Wilcoxon rank sum, chi-square, or Fisher exact test as appropriate. Subgroups were analyzed individually and were adjusted for multiple comparisons using the Bonferroni method. A total of 328 patients underwent successful TPVR (Melody: n=202, Sapien: n=126). The groups had a similar baseline age, weight, and diagnosis. The most common indications for TPVR were pulmonary stenosis (32.2%) or mixed disease (46%) in the Melody group and pulmonary insufficiency in the Sapien group (52.4%) (P< 0.001). Sapien valves were more often placed in native RVOTs (43.7% vs 18.8%; P< 0.001). The discharge and follow-up mean and peak Doppler gradients were similar between the Melody and Sapien groups. Valves implanted in native RVOTs had significantly lower postimplantation gradients at each follow-up period. Echocardiographic performance after TPVR was generally acceptable and similar when comparing Melody and Sapien valves despite differences in the indication and anatomy in each group. The peak and mean gradients were lower in transcatheter valves implanted in native RVOTs compared with those implanted in conduits or bioprosthetic valves.

997. RLS-0071 Improves Survival in a Rat Model of Intestinal Necrosis

BackgroundIntestinal necrosis and perforation are potentially life-threatening medical conditions that can lead to bacterial sepsis and systemic inflammatory response syndrome. Various etiologies can compromise the intestinal wall causing leakage of luminal contents including enteric bacteria and precipitate aggressive immunological responses including the complement system and neutrophils. RLS-0071 is a peptide inhibitor of the classical and lectin pathways and known modulator of various neutrophil mediated effectors including myeloperoxidase activity and NETosis.MethodsIn this study we evaluated the extent to which immunomodulation via inhibition of the complement system and neutrophil effectors would alter survival in the setting of intestinal necrosis. Adolescent male Long-Evans rats were subject to cecal ligation and puncture (CLP) with one cohort receiving 40 mg/kg of RLS-0071 thirty minutes after surgery while the control group received no treatment. Survival of the rats was then assessed up to 5 days after surgery. ResultsAnimals treated with RLS-0071 demonstrated nearly 1.5-fold increase in survival compared to the untreated group. In order to further elucidate the increase in survival we explored inflammatory responses as assessed by markers of NETosis i.e., free DNA in plasma, and the pro-inflammatory cytokine, IL-6. A reduction in blood levels of free DNA and the inflammatory cytokine IL-6 were observed for animals treated with RLS-0071.RLS-0071 increases survival of rats after cecal ligation Kaplan-Meier survival curve assessment. The red line indicates the outcome after 75% CLP in animals not receiving treatment (n=13), whereas red curves represent the outcome after animals received a single dose of 40 mg/kg RLS-0071 (n=11).RLS-0071 reduces free DNA levels in the blood Plasma was isolated before surgery (pre-bleed) (n=7) and from animals subject to CLP with (n=4) and without (n=3) RLS-0071 administration 24 hours post-surgery. Plasma samples were incubated with PicoGreen. Fluorescence was read at an excitation wavelength of 485 nm and an emission wavelength of 520nm in a microplate reader. Data are means and standard error of the meansRLS-0071 reduces IL-6 levels in the blood Plasma was isolated before surgery (pre-bleed) (n=8) and from animals subject to CLP with (n=3) and without (n=5) RLS-0071 administration 24 hours post-surgery. Plasma samples were analyzed in an IL-6 ELISA according to the manufacturer’s instructions. Data are means and standard error of the means.ConclusionThe results of these experiments demonstrate that RLS-0071 can increase survival after intestinal perforation by multi-pronged modulation of complement activation, neutrophil immune mechanisms and cytokine mediated inflammatory responses.Disclosures Kenji Cunnion, MD, MPH, ReAlta Life Sciences Inc (Board Member, Employee, Shareholder) Parvathi Kumar, MBBS, ReAlta Life Sciences Inc (Employee) Brittany Lassiter, BS, ReAlta Life Sciences Inc (Employee) Katherine LaValle, DVM, ReAlta Life Sciences Inc (Employee) Neel Krishna, PhD, ReAlta Life Sciences Inc (Employee, Shareholder)

Minimally invasive and robotic approaches to mitral valve surgery: Transthoracic aortic crossclamping is optimal

Minimally invasive and robotic approaches to mitral valve surgery: Transthoracic aortic crossclamping is optimal

Cytotoxicity and the Effect of Temperature on Physical Properties and Chemical Composition of a New Calcium Silicate–based Root Canal Sealer

IntroductionThe suitability of EndoSequence BC Sealer (BC Sealer; Brasseler USA, Savannah, GA) for warm vertical compaction has been questioned. The aim was to evaluate the cytotoxicity and the effect of heating on the physicochemical properties of a new calcium-based root canal sealer (EndoSequence BC Sealer HiFlow [HiFlow]) in comparison with EndoSequence BC Sealer. MethodsHuman periodontal ligament fibroblasts were incubated for 1, 2, or 3 days with material extracts of different concentrations, and cell viability was evaluated by Cell Counting Kit-8 (Enzo Life Sciences Inc, Burlington, Ontario, Canada). The setting time, flow, film thickness, microhardness, radiopacity, and radiopacity of the 2 sealers were measured according to ISO 6786/2012. The continuous changes in viscosity were tested by a stress-controlled rheometer at shear rates ranging from 0.01–10 s−1 and different temperatures, and chemical composition was assessed by Fourier-transform infrared spectroscopy. ResultsCell viability was significantly decreased on day 3 for the 1:4 diluted extract from both materials. The setting time, microhardness, and solubility of HiFlow were similar to BC Sealer at 37°C and 100°C. HiFlow had significantly higher flow and radiopacity than BC Sealer at room temperature (P < .05), and when heated, HiFlow retained its higher flow and lower film thickness (P < .05). Both sealers showed decreasing viscosity with increasing shear rate, and at a shear rate of 0.01 and 0.1 s−1, HiFlow exhibited lower viscosity than BC Sealer at all temperatures measured. The chemical composition of the 2 sealers was not changed by heating. ConclusionsHiFlow showed better performance on flow/viscosity and film thickness, especially under high temperatures, which are generated by the commonly used warm vertical compaction technique.

281-LB: PBI-4547 Orchestrates a Cross Talk between Liver and White Adipose Tissues to Correct Metabolic Reprogramming

Introduction: Nonalcoholic Fatty Liver Diseases (NAFLD), characterized by fatty acid and glucose metabolism dysregulation, is highly prevalent in all regions of the world. PBI-4547 is an orally active compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes and fibrosis in different rodent models. The goal of the current study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. Mice fed with the HFD were then treated or not with PBI-4547 (10 mg/kg, oral once a day) for 6 weeks. Liver/WAT histology and mRNA gene profile were examined. HepG2 hepatocytes were also used for in vitro experiments. Blood glucose, serum insulin level, serum triglyceride and adiponectin were followed over the 6 weeks of treatment. Results: PBI-4547 treatment led to a significant reduction of hepatic steatosis, ballooning and total NAFLD score. Inflammation and fibrosis in white adipose tissues were also significantly reduced by PBI-4547. Adiponectin levels were also increased by PBI-4547. Metabolomic study from liver extracts revealed that PBI-4547 restored back to normal the levels of amino acids, Krebs cycle and energy-related intermediates. Uncoupling Proteins (Ucp2/3 in liver and Ucp1 in WAT) were also increased by PBI-4547 suggesting that PBI-4547 could affect mitochondria and increase energy expenditure. Oxygen consumption rate analyses confirmed that PBI-4547 reduces Oxphos-related ATP production and increased proton leak in HepG2 hepatocytes. In such way, PBI-4547 increased glucose and fatty acid metabolism improving insulin resistance and β-cell function. Conclusions: These results indicate that PBI-4547 offers the potential as a novel therapy for NAFLD, diabetes and associated metabolic syndrome. Disclosure J. Simard: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Thibodeau: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. R. Corpuz: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Life Sciences Inc. Stock/Shareholder; Self; Prometic Life Sciences Inc.

1148-P: Cenicriviroc Safety in over 1,200 Subjects

Background: The treatment landscape of nonalcoholic steatohepatitis (NASH) is changing rapidly; drug safety is key as most patients will need long-term treatment. Cenicriviroc (CVC) is an oral antagonist of C-C chemokine receptors 2/5 in Phase 3 development for NASH. We report cumulative safety data from CVC studies. Methods: Studies included single- and multi-dose Phase 1 in healthy volunteers and cirrhosis, Phase 2 in NASH and HIV-1, and Phase 3 in progress. Treatment-emergent AEs (TEAEs), lab abnormalities, and causality were assessed. Results: As of July 2018, &amp;gt;1220 adults received CVC and had available safety data. In Phase 1 studies (N=580), TEAEs in ≥2% of CVC subjects included headache, nasopharyngitis, abdominal pain, nausea, vomiting, diarrhea, contact dermatitis, and somnolence in single-dose studies, and headache and constipation in multi-dose studies, mostly mild or moderate. In Child-Pugh A or B cirrhosis subjects (n=16), CVC dosing for 14 days was well tolerated, with no safety concerns identified. Single-dose administration was well tolerated in subjects with severe hepatic impairment (Child-Pugh C). In Phase 2 studies (N=442), incidence and severity of TEAEs, discontinuation due to TEAEs, and lab abnormalities were similar in CVC vs. comparator; no life-threatening TEAEs (Grade 4) or deaths occurred with CVC. In subjects with NASH and liver fibrosis on CVC for 1 year (n=144), TEAEs in ≥2% of subjects of at least moderate severity (Grade ≥2) were fatigue (2.8%) and diarrhea (2.1%). One serious AE (SAE) [0.3%] was assessed as drug related (Grade 2 arrhythmia). CVC was well tolerated in a 10-day dose-escalation study in HIV-1 (n=44). In HIV patients treated with ≤48 weeks of CVC (n=115), Grade ≥2 TEAEs in ≥2% of subjects were nausea (2.0%). No SAE was assessed as drug related. One CVC subject discontinued due to an AE (Grade 2 depression). To date in Phase 3, no new safety signals have been identified. Conclusions: CVC was safe in &amp;gt;1200 subjects treated to date, including those with NASH and liver fibrosis, HIV-1, and hepatic impairment. Disclosure M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. B. Tan: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal.

136-OR: Efficacy of Cenicriviroc (CVC) in Adults with NASH-Induced Liver Fibrosis

Background: Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of type 2 diabetes and can progress to advanced fibrosis (AF), associated with significant increase in morbidity and mortality. CVC is an oral C-C chemokine receptor 2/5 antagonist being evaluated to treat liver fibrosis in adults with NASH. This study describes antifibrotic effects seen in the Phase 2b CENTAUR study overall and those with AF (F3) specifically. Methods: Adults with confirmed NASH, nonalcoholic fatty liver disease activity score ≥4, and liver fibrosis Stages F1-3 (NASH CRN) received CVC 150 mg daily (Arm A) or placebo (PBO; Arm C) for 2 years; Arm B received PBO in Year (Y)1 and CVC in Y2. Liver biopsies were assessed blind at baseline (BL), Y1, and Y2 by a central pathologist. Improvement in fibrosis and serum inflammatory markers were assessed in subjects with evaluable biopsies at BL, Y1, and Y2 (modified intent-to-treat [mITT] population). Results: Of 289 adults randomized (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), 28.6% (36/126) vs. 19.0% (24/126) achieved ≥1-stage fibrosis improvement at Y1 in CVC vs. PBO arms (mITT) overall. Of 97 AF subjects at BL (mean age 57.8 years, mean BMI 34.1 kg/m2, 69.0% diabetes), 38.3% (18/47) vs. 28.0% (14/50) achieved this endpoint in CVC vs. PBO arms (mITT). Overall, 60.0% (18/30) in Arm A vs. 30.0% (3/10) in Arm C maintained benefit at Y2 (mITT). In AF subjects, 85.7% (12/14) in Arm A vs. 60.0% (3/5) in Arm C maintained benefit at Y2 (mITT). Greater reductions in hs-CRP, fibrinogen, IL-6, IL-8, and IL-1β were observed with CVC. In AF subjects, these changes were more pronounced. Overall and with AF, adverse events were comparable for CVC and PBO; no deaths occurred. Conclusion: CVC was well tolerated and provided antifibrotic benefit in adults with NASH and fibrosis, especially those with AF. Most subjects achieving ≥1-stage fibrosis improvement at Y1 maintained benefit at Y2, with reductions in inflammatory biomarkers, supporting the ongoing Phase 3 study of CVC in NASH. Disclosure N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. H. Landgren: Employee; Self; Allergan. A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.

528-P: The Effect of Angiotensin II (ANG II) Infusion on Plasma Uric Acid (PUA) in Patients with Type 1 Diabetes (T1D)

PUA is associated with renin angiotensin aldosterone system (RAAS) activation, which promotes hypertension and kidney disease in T1D. Our aims were to examine (1) the effect of an ANG II infusion on PUA and (2) the association between PUA and systemic and renal hemodynamic responses to ANG II over a wide range of T1D duration. In this post hoc analysis, blood pressure, PUA, GFRinulin and ERPFPAH were measured during a euglycemic clamp before and after an ANG II infusion (1 ng·kg-1·min-1) in participants with T1D: 49 young (26.2±5.5 years) and 62 older (66.0±7.9 years) adults and healthy controls (HC): 27 young (25.1±4.6 years), and 72 older (64.6±8.0 years) adults. ANG II infusion caused a greater decline in GFRinulin in older vs. younger adults with T1D; there was no such difference between older vs. younger HC adults. ANG II decreased PUA more in HC than T1D in both age groups (p&amp;lt;0.0001, Figure 1). Decreases in PUA in response to ANG II infusion did not correlate with changes in renal or systemic hemodynamic parameters. Our findings suggest that ANG II infusion reduces PUA, potentially through direct effects on the ANG II type 1 receptor (AT1R). The presence of T1D attenuates PUA lowering effects irrespective of diabetes duration, suggesting an interaction between hyperglycemia, RAAS signaling pathways and PUA. Further studies are required to better understand the effects of AT1R receptor signaling on PUA concentrations. Disclosure Y. Lytvyn: None. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. L. Lovblom: None. A. Katz: None. A. Lytvyn: None. G. Boulet: Other Relationship; Self; Medtronic. M.A. Farooqi: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. A. Advani: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Dexcom, Inc., Novo Nordisk A/S. Research Support; Self; Boehringer Ingelheim International GmbH. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312)

1164-P: Effects of Cenicriviroc in Adults with NASH on Inflammatory Cytokines and Metabolic Parameters

Background: Hepatic fat accumulation modulates innate immunity causing recruitment of bone marrow derived macrophages/activation of Kupffer cells, resulting in inflammatory changes associated with the development of insulin resistance and NASH. Monocyte recruitment/infiltration into the liver is mediated by C-C chemokine receptor 2 (CCR2). CCR5 promotes obesity-induced insulin resistance/hepatic steatosis in murine models. Cenicriviroc (CVC) is an oral CCR2/CCR5 antagonist in Phase 3 development for NASH. We evaluated effects of CVC on inflammatory cytokines and HbA1c in NASH subjects. Methods: Adults with NASH and liver fibrosis were randomized 1:1 to CVC 150 mg or placebo (PBO) [Phase 2 CENTAUR study]. Cytokines and metabolic parameters were assessed. Results: In 289 randomized adults (mean age 54 years, mean BMI 33.9 kg/m2, 52.0% diabetes), CCL2 significantly increased from baseline (BL) in CVC vs. PBO. For CVC, hs-CRP, IL-6, IL-8 and IL-1β decreased from BL; HbA1c decreased for CVC at all time points but increased for PBO at Days 180 and 360 (Table). Changes were consistent over time and more pronounced in those with advanced liver fibrosis. Conclusions: CVC was associated with elevation of CCL2 and decreased hs-CRP/inflammatory cytokines, suggesting strong target engagement and a therapeutic impact on the inflammatory milieu associated with insulin resistance that may be reflected in lower HbA1c. Disclosure A.D. Coviello: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Allergan, Bristol-Myers Squibb Company, GENFIT. Speaker's Bureau; Self; Novo Nordisk Inc. R.W. Charlton: Employee; Self; Allergan. E.B. Martins: Employee; Self; Allergan. Stock/Shareholder; Self; Allergan. J. Yuan: None. N. Alkhouri: Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Other Relationship; Self; Allergan, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc.

499-P: The Relative Roles of Pro-oxidant Enzymes Nox4 and Nox5 in Diabetic Kidney Disease

Background: Renal oxidative stress plays an important role in mediating kidney injury in diabetes. There is increasing evidences that recently discovered pro-oxidant enzyme, Nox5 plays a significant role in human diabetic kidney disease (DKD). We examined the role of Nox5 in human DKD, in human renal cell populations as well as in a high fat fed and alloxan rabbit model of DKD. In addition, we also examined the contribution of Nox5 in the in DKD in the absence of Nox4 expression using renal cell specific Nox5Tg mice. Results: Expression of Nox5 was increased in both glomerular and tubular compartments of kidney biopsies obtained from diabetic individuals. Nox5 is the Nox isoform which shows the highest upregulation in response to high glucose. Silencing of Nox5 reduces ROS formation and expression of proinflammatory and profibrotic cytokines and growth factors as well as putative elements that are implicated in DKD. Our data also suggest that Nox5 is upstream of Nox4 and that Nox5 inhibition downregulates Nox4, but not vice versa. High fat feeding and alloxan induced diabetes rabbits showed upregulation of Nox5 and increased ROS in association with increased mesangial area, ECM protein accumulation and upregulation of a range of pro-inflammatory (MCP-1) and pro-fibrotic genes (CTGF) as analysed by RNAseq and confirmed by RT-PCR. In addition, over expression of Nox5 in mesangial cells of Nox4 KO diabetic mice demonstrated 30% increase in albuminuria, mesangial expansion, increased renal injury and inflammation via enhanced ROS production. Conclusions: These studies will for the first time explore in a comprehensive manner the role of Nox5 in recently generated Nox5KO rabbit models in the context of type 1 and type 2 diabetes as well as delineate the relative role of Nox4 versus Nox5 in diabetic complications. These studies will provide evidence if Nox5 blockade alone or combined with Nox4/Nox5 blockade is the optimal approach to treat and prevent diabetic complications, in particular nephropathy. Disclosure J.C. Jha: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Lilly Diabetes. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Bayer AG, Merck Sharp &amp; Dohme Corp., Novartis AG. C. Kennedy: Research Support; Self; Prometic Life Sciences Inc. K. Jandeleit-Dahm: Advisory Panel; Self; Australian Diabetes Society, Genkyotex. Consultant; Self; Metavention.

1876-P: Impact of Diabetes on Liver Disease Progression in Patients with Advanced Fibrosis Due to Nonalcoholic Steatohepatitis (NASH)

Background: Diabetes is a risk factor for advanced fibrosis due to NASH, but the effect of diabetes on disease progression is not well-characterized. Here, we describe clinical outcomes for patients with and without diabetes in two negative, randomized, placebo-controlled trials of simtuzumab. Methods: 217 patients with bridging fibrosis (F3) and 258 subjects with compensated cirrhosis (F4) were enrolled. Liver biopsies were reviewed by a central pathologist at screening and weeks 48 and 96. Patients were stratified based on the presence or absence of diabetes. Adjudicated clinical outcomes included: esophageal varices, variceal bleeding, ascites, hepatic encephalopathy, ≥2 point increase in Child-Pugh-Turcotte score, MELD &amp;gt;15, or death. Results: 145 (67%) of patients with F3 and 179 (69%) of patients with F4 had diabetes at baseline. Median age was 56 years. By week 96, 25% (31/129) of F3 patients with diabetes had progressed to cirrhosis, compared to 18% (11/67) of patients without diabetes [p=0.27]. Cirrhotic (F4) patients with diabetes had a higher rate of clinical events (Figure). Conclusion: Diabetes is common in patients with advanced fibrosis due to NASH and associated with numerically higher rates of progression. Larger studies are needed to confirm these findings. Patients with diabetes have a high unmet need for therapies that target advanced fibrosis due to NASH. Disclosure A.J. Sanyal: Consultant; Self; Ardelyx, Boehringer Ingelheim Pharmaceuticals, Inc., Exhalenz, Gilead Sciences, Inc., Hemoshear, Intercept Pharmaceuticals, Inc., Lilly, Mallinckrodt Pharmaceuticals, Nimbus Therapeutics, Nitto Denko, Novartis Pharmaceuticals Corporation, Pfizer Inc. Employee; Self; Sanyal Bio. Research Support; Self; Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Echosens, Galectin Therapeutics Inc., Immuron Ltd, Merck &amp; Co., Inc., Salix Pharmaceuticals, Sequanna. Stock/Shareholder; Self; Akarna Therapeutics, GENFIT, Natural Shield, NewCo LLC, Tiziana. Other Relationship; Self; Elsevier, UpToDate. M.F. Abdelmalek: Advisory Panel; Self; Allergan, Bristol-Myers Squibb Company, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Prometic Life Sciences Inc. Consultant; Self; TaiwanJ Pharmaceuticals Co., Ltd. Research Support; Self; Akcea Therapeutics, Allergan, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Galectin Therapeutics Inc., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Prometheus, Shire, TaiwanJ Pharmaceuticals Co., Ltd. Speaker's Bureau; Self; Alexion Pharmaceuticals, Inc. S. Caldwell: Research Support; Self; Conatus Pharmaceuticals Inc., Galmed Pharmaceuticals Ltd., GENFIT, Gilead Sciences, Inc., Halyard, Mallinckrodt Pharmaceuticals, TARGET PharmaSolutions, Vital Therapy, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Dova. M.L. Shiffman: Advisory Panel; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. Research Support; Self; Allergan, Conatus, Enanta Pharmaceuticals, Inc., Exhalenz, GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Novartis AG, Shire. Speaker's Bureau; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. R. Ghalib: None. E. Lawitz: Research Support; Self; birdrock bio, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Conatus Pharmaceuticals Inc., Durect Corporation, Enanta Pharmaceuticals, Inc., Galmed Pharmaceuticals Ltd., GENFIT, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., madrigal, Novartis AG, octeta, Zydus Cadila. D. Jiang: Employee; Self; Gilead Sciences, Inc. R.E. Aguilar Schall: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. B.J. McColgan: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Myers: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Djedjos: Employee; Self; Gilead Sciences, Inc. A. Muir: Advisory Panel; Self; AbbVie Inc., Gilead Sciences, Inc. Research Support; Self; AbbVie Inc., Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., NGM Biopharmaceuticals. V. Ratziu: Other Relationship; Self; Gilead Sciences, Inc. N. Afdhal: Advisory Panel; Self; Gilead Sciences, Inc., Ligand Pharmaceuticals, Inc. Consultant; Self; Echosens. Employee; Self; Spring bank Pharmaceuticals. Z. Goodman: None. J. Bosch: Advisory Panel; Self; Actelion Pharmaceuticals US, Inc., Conatus Pharmaceuticals Inc., Exhalenz. S.A. Harrison: Advisory Panel; Self; Gilead Sciences, Inc. Funding Gilead Sciences, Inc.

538-P: Copeptin and Renin Angiotensin Aldosterone System (RAAS) Activation in Long-Standing Type 1 Diabetes (T1D)

It remains unclear why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). Vasopressin and its surrogate copeptin have been implicated in the pathogenesis of DKD. We hypothesized that DKD resistors would be distinguished from those with DKD by copeptin concentrations. Renal hemodynamic function, including renal vascular resistance (RVR), was measured by inulin and para-aminohippurate clearance at baseline and after intravenous infusion of angiotensin II as a measure of RAAS activation in 75 participants (65±8 years, HbA1c 7.4±0.8%) with prolonged T1D durations (≥50 years) and in equal numbers of nondiabetic controls (66±8 years). Copeptin was measured by B·R·A·H·M·S proAVP copeptin KRYPTOR assay. Participants with T1D were categorized as DKD resistors (n=50) if they had eGFR ≥60 ml/min/1.73 m2 and 24-hour urine albumin excretion (UAE) &amp;lt;30 mg/d, and as DKD (n=25) if they had eGFR &amp;lt;60 ml/min/1.73 m2 or 24-hour UAE &amp;gt;30 mg/d at their screening visit. Multivariable linear regression (adjusted for age, sex and HbA1c) was used to evaluate the relationships with copeptin. DKD resistors had lower copeptin (least square geometric means, 95% CI: 4.0 [3.4-4.8] pmol/l) compared to those with DKD (5.8 [4.5-7.6] pmol/l, p=0.02) and the nondiabetic controls (4.8 [4.1-5.5] pmol/l, p=0.01) adjusting for age, sex and HbA1c. In T1D, copeptin inversely associated with GFR (adjusted β±SE: -8.0±3.2, p=0.02) and positively with renin concentration (50.3±24.9, p=0.049) after multivariable adjustments. These relationships were not evident in nondiabetic controls. Further, copeptin inversely associated with change in RVR following exogenous angiotensin II only in participants with T1D (adjusted β±SE: -6.9±3.4, p=0.04). In longstanding T1D, copeptin associated with intrarenal RAAS activation and renal hemodynamic function, suggesting a possible interplay between vasopressin and RAAS in the pathogenesis of DKD. Disclosure P. Bjornstad: Advisory Panel; Self; Horizon, XORTX. Consultant; Self; Bayer US, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company. J.A. Lovshin: Consultant; Self; Eli Lilly and Company, Intarcia Therapeutics, Inc., Prometic Life Sciences Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. Y. Lytvyn: None. P. Wiromrat: None. L.T. Chung: None. C.L. Vinovskis: None. L. Lovblom: None. G. Boulet: Other Relationship; Self; Medtronic. V.S. Lai: None. J.M. Tse: None. L. Cham: None. A. Orszag: None. A. Weisman: None. H.A. Keenan: Employee; Self; Sanofi Genzyme. M.H. Brent: Advisory Panel; Self; AbbVie Inc., Bayer Canada, Novartis Canada. Research Support; Self; Bayer Canada, Novartis Canada, Roche Canada. N. Paul: Consultant; Self; Bayer AG. V. Bril: Advisory Panel; Self; Akcea Therapeutics, Alexion Pharmaceuticals, Inc., Alnylam, CSL Behring. Consultant; Self; Pfizer Inc. Research Support; Self; Baxter, Biogen, Grifols, UCB, Inc. B.A. Perkins: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Boehringer Ingelheim International GmbH, Insulet Corporation. Research Support; Self; Boehringer Ingelheim International GmbH. Other Relationship; Self; Abbott, Boehringer Ingelheim International GmbH, Lilly Diabetes, Medtronic, Novo Nordisk Inc., Sanofi. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. Funding JDRF (17-2013-312, 2-SRA-2018-627-M-B)

PBI-4547 Prevents Progression of Prediabetic Condition to Type 1 Diabetes in NOD Mice

Introduction: PBI-4547 is a novel orally active compound that is being developed for potential clinical use in patients suffering from metabolic and inflammatory/fibrosis-related diseases. This study examined the effect of PBI-4547 in NOD mice, a model of type 1 diabetes. Our objective was to demonstrate the efficacy of PBI-4547 to stop the progression of diabetes in mice exhibiting prediabetic glucose escalation. Methods: NOD/ShiLtJ female mice (8 weeks of age) were followed up to the appearance of the first sign of hyperglycemia (three consecutive weeks of glucose increase (over 7 mmol/l). Once identified as prediabetic, mice were randomly allocated to control (receiving vehicle (water)) or PBI-4547 (25 mg/kg/day) groups for treatment by daily gastric gavage for 8 to 12 weeks. Results: Mice treated with vehicle (n=9) evolved to a moderate to severe diabetic condition (glucose levels 11.7-37 mmol/l). Most of these vehicle-treated mice (6/9) survived only a few weeks after the onset of the prediabetic condition. At the opposite, NOD mice treated with PBI-4547 all showed a reversal of their hyperglycemia and none of the observed animals (n=12) evolved to a chronic hyperglycemia (over 11 mmol/l). Survival was also significantly improved in the group treated with PBI-4547 with 8 of 12 mice surviving more than 10 weeks after the onset of treatment. Analysis of insulinemia showed a significant difference between both groups. Immunohistological analysis of pancreas recovered at euthanasia revealed a significant reduction in islet inflammatory cell infiltration. Moreover, NOD mice treated with PBI-4547 maintained normoglycemia despite a reduced number of islets. In fact, PBI-4547 reduced by 30% the number of severely damaged islets. Conclusions: These data suggest that PBI-4547 could preclude the evolution of diabetes in a type 1 model. Disclosure F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. K. Hince: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. W. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. S. Létourneau: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

PBI-4547 Reverses Diabetes and Metabolic Syndrome through Regulation of Lipid/Glucose Metabolism, ß-Oxidation and Fibrosis in Liver, and White Adipose Tissue in ob/ob Mice

Introduction and Aims: Given the expected rise in the prevalence of obesity and type 2 diabetes, hepatic steatosis will, if not already, become an epidemic. The aim of this study was to determine the mechanism of action of PBI-4547 on diabetic complications. Methods: ob/ob mice (6 weeks old) were treated with vehicle or PBI-4547 (10, 25 and 50 mg/kg, oral once a day) from day 1 through 105. Liver and white adipose tissue (WAT) histology, blood glucose, serum triglyceride and adiponectin levels were examined. Gene expression of pro-inflammatory/fibrotic markers, metabolic and mitochondrial fatty acid transport and oxidation (FAO) regulators, and PPAR gene expression were determined in liver and WAT. Results: Blood glucose, cholesterol and triglyceride levels were strongly reduced by PBI-4547. ob/ob mice displayed severe liver steatosis which was completely reversed with PBI-4547. PBI-4547 significantly reduced fibrosis, inflammatory cell infiltration, and adipocyte size in WAT. Serum level of adiponectin was reduced in ob/ob mice and increased with PBI-4547. In liver, PBI-4547 reduced TNF-α, collagen I, III and IV, α-SMA, fibronectin, MMP-2, TIMP1, ICAM, PDGFα, TGFβ1, PPARδ and PPARγ, FASN, but increased mitochondrial FA transport and oxidation (ACOX-1, CD36, FABP4, CPT1β, PDK4). In WAT, PBI-4547 reduced TNF-α, collagen types I, IV and VI, MMP-2, MCP-1, F4/80, increased PPARα and PPARγ, and also increased ACOX-1, CD36, FASN, FABP4, COX4I1, SREBF1, PGC1-α, UCP-1 (by 160X, suggesting browning of adipose tissue), CPT1α, CPT1β and PDK4. Furthermore, PBI-4547 increased adiponectin and its receptors, and abolished vaspin gene expression. Conclusions: PBI-4547 is a potential novel therapy for diabetes and hepatic steatosis through its pleiotropic activities on glucose and lipid metabolism, by improving mitochondrial dysfunction, by inducing browning of adipose tissue, and by regulating adipokines. Disclosure L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

PBI-4050 Improves Metabolic Regulation and Diabetic Nephropathy through Reduction of ER Stress, Pro-Inflammatory/Fibrotic Markers, Galectin-3 Expression, and Inflammatory Cell Infiltration in ob/ob Mouse Model

Background: PBI-4050 displays anti-inflammatory/fibrotic properties with metabolic regulation. PBI-4050 has been shown to reduce glycated hemoglobin levels, and different biomarkers related to kidney and heart injury in a phase II open label clinical trial in patients suffering from type 2 diabetes with metabolic syndrome. PBI-4050 has also completed with success an open label phase II clinical trial in patients with idiopathic pulmonary fibrosis (IPF) and in patients with Alström Syndrome. The aim of this study was to investigate the effect of PBI-4050 on diabetic nephropathy in leptin deficient ob/ob mice, a model of type 2 diabetes and metabolic syndrome. Methods: ob/ob mice were treated with vehicle or PBI-4050 (200 mg/kg, oral once a day) from day 1 to 105. OGTT, triglycerides, adiponectin and serum insulin levels, as well as inflammatory cell infiltration and pro-inflammatory/fibrotic gene expression and histology of kidney and white adipose tissue (WAT) were examined. Results: PBI-4050 improved glucose metabolism, reduced serum triglycerides and insulin levels, and increased serum adiponectin levels. In kidneys, PBI-4050 reduced ER stress (p-PERK, ATF-6, CHOP and p-IRE1). Furthermore, PBI-4050 reduced α-SMA, fibronectin and CTGF gene expression. Pro-inflammatory/remodeling markers expression (MRC-1, MCP-1 and MMP-2) were also reduced with PBI-4050 treatment. Moreover, histological analysis revealed that PBI-4050 reduced collagen deposition in glomeruli. Specific immunostaining also showed that PBI-4050 significantly reduced galectin-3 expression in kidney and WAT. Finally, PBI-4050 reduced the expression levels of inflammatory cell infiltration markers (Ly6G and F4/80) in kidney. Conclusions: These results suggest that PBI-4050 is a strong potential candidate for the treatment of metabolic diseases and related diabetic nephropathy. Disclosure J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Cloutier: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Laverdure: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Richard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

PBI-4547 Improves Glucose Metabolism and Insulin Resistance, and Reduces Liver Damage in a High-Fat Diet Mouse Model of Obesity and Metabolic Syndrome

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of a host of diseases, including nonalcoholic fatty liver disease (NAFLD). PBI-4547 is a novel first-in-class orally active antidiabetic compound which displays pleiotropic activities and has been shown to reduce NASH, diabetes, and renal fibrosis in different animal models. The aim of this study was to investigate the effects of PBI-4547 in a mouse model of high-fat diet-induced obesity and metabolic syndrome. Methods: C57BL/6 mice were fed with either a standard or a high-fat diet (HFD, Harlan, TD.06414) for 14 weeks. These mice were divided in three groups [normal chow, HFD + vehicle, and HFD + PBI-4547 (10 mg/kg, oral once a day)] and treated for an additional 6 weeks. Blood glucose, serum insulin level, serum triglyceride and adiponectin, liver histology, as well as liver and white adipose tissue (WAT) pro-inflammatory/fibrotic gene expression were examined. Results: In an oral glucose tolerance test, PBI-4547 increased glucose metabolism compared to the HFD control group. Insulin resistance (measured by HOMA-IR) and β cell function (HOMA1-β) were improved by PBI-4547. Serum triglyceride level was significantly reduced by PBI-4547 while adiponectin in serum was significantly increased. Histological analysis showed a significant reduction of hepatic steatosis and ballooning by PBI-4547. To further characterize the activity of PBI-4547, quantitative RT-PCR analysis of pro-fibrotic markers was performed, demonstrating that PBI-4547 reduced CTGF and MMP2 gene expression in the liver as well as CTGF, MCP-1, MMP2 and collagen type I gene expression in the WAT. Conclusions: Taken together, these results suggest that PBI-4547 offers the potential as a novel therapy for nonalcoholic fatty liver disease, obesity and associated metabolic syndrome. Disclosure M. Leduc: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. B. Grouix: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. M. Tremblay: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. L. Gervais: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F. Sarra-Bournet: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. A. Felton: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. J. Simard: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. F.A. Leblond: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc. P. Laurin: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc.. Board Member; Self; Prometic Life Sciences Inc. L. Gagnon: Employee; Self; Prometic Biosciences Inc.. Stock/Shareholder; Self; Prometic Life Sciences Inc..

Sometimes patience pays off: When amputation is the alternative

Extended lower extremities defects due to systemic diseases can lead to amputation. This study aims to illustrate the successful treatment of two patients with chronic and therapy-resistant soft tissue defects of the lower leg, which healed with the use of gamma-irradiated human skin allograft (Gammagraft™, Promethean LifeSciences Inc, Pittsbourgh, PA/USA) and artificial dermis (Integra™, Integra LifeSciences Corporation, Plainsboro, NJ/USA) respectively. Both patients presented at admission with extended lower leg necrotic ulcers and both had a positive history of vasculopathy. The patient A was a 42 years old, male, with Scleromyxedema (SM) and the patient B was a 52 years old, female, diabetic and thrombophilic, which also suffered from Systemic Lupus Erythematosus (SLE). Serial wound debridements, amputation of single toes and skin grafting, were paired with modern reconstructive tools, like hydrosurgery system (Versajet◊, Smith &amp; Nephew, London/UK), Vacuum Assisted Closure system (VAC®, KCI, San Antonio, Tx/USA) and tissue engineered products: Gammagraft™ on patient A and Integra™ on patient B. The follow up revealed a long-term durable coverage of the defects. While there is no evidence to support a gold standard for extended chronic lower extremities defects of such origin, whose other alternative seems to be amputation, we believe that patience combined with the use of different reconstructive methods can add another valuable tool in our armamentarium and should considered as a valid reconstructive option.