scholarly journals Ker-050, a Modified Actriia Ligand Trap, Alleviates Cytopenia Arising from Multiple Etiologies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 38-38
Author(s):  
Marina Feigenson ◽  
Remya Nathan ◽  
Keith Babbs ◽  
Christopher Materna ◽  
Claire C Tseng ◽  
...  
Keyword(s):  
Treated Group ◽  
System Control ◽  
Sprague Dawley ◽  
Publicly Traded ◽  
Private Company ◽  
Healthy Human ◽  
Total Blood ◽  
Acute Bleeding ◽  
Aged Mice ◽  
Data Support

Hemopoietic system control the production of circulating blood cells that have important functions from transport of oxygen and carbon dioxide, blood clotting to fighting infections. Not surprisingly, the system is tightly regulated and failure to replenish RBC can result in anemia and inadequate platelets increases the risk of bleeding. Impaired hematopoiesis and the consequential cytopenias are associated with aging, diseases characterized by ineffective hematopoiesis including myelodysplastic syndrome (MDS) and myelofibrosis and diseases that lead to loss of growth factors. A therapeutic that could act more globally on the hematopoietic pathway would have the potential to overcome cytopenia in many diseases. Signaling of the TGFβ superfamily regulates several stages of RBC maturation, and recent studies demonstrate that inhibition of TGFβ signaling can induce RBC production and increase circulating RBCs, HGB, and hematocrit (HCT). KER-050, a modified ActRIIA ligand trap, has been shown to increase RBCs in rodents and non-human primates, and to increase both RBCs and PLTs in healthy human volunteers. In the current studies, we aimed to test the efficacy of KER-050 in alleviating cytopenias caused by multiple conditions and to further delineate the effect of KER-050 on platelets. First, we examined whether RKER-050 (a research form of KER-050) can reverse anemia associated with aging and frailty. After 6 weeks of twice weekly treatment, 2-year-old aged, vehicle-treated (AV) mice had significantly lower RBCs, HGB, and HCT (-14.0%, -13.5%, -10.9%, respectively) relative to 11-week-old young vehicle-treated mice (YV). However, aged mice treated with RKER-050 had higher RBCs, HGB, and HCT (+12.3%, +10.0%, +9.1%, respectively) compared to AV, with levels indistinguishable from those of YV. These data support that RKER-050 can improve anemia that arises from aging. Next, we evaluated the efficacy of RKER-050 in the treatment of anemia in an animal model of MDS. NUP98-HOXD13 mice, a murine model of MDS, aged to 6 months and confirmed as anemic prior to treatment, were dosed twice weekly with either vehicle or RKER-050 for 6 weeks. Over this treatment period, vehicle-treated MDS mice continued to have significantly reduced RBCs, HGB, and HCT compared to wildtype controls. In contrast, RKER-050-treated MDS mice had increases in RBCs, HGB, and HCT (+10.9%, +11.2%, + 9.8%, respectively), achieving values comparable to the wild type control animal of the same age. These data support that RKER-050 reverses anemia in a mouse model of MDS. Finally, we evaluated whether RKER-050 can improve anemia after acute blood loss. Anemia was induced by bleeding 20% of total blood volume in Sprague Dawley rats followed by treatment with RKER-050 twice weekly. After phlebotomy, the RKER-050-treated group had early, robust increases in both RBCs and HGB that exceeded baseline levels, whereas decreased RBCs and HGB in the vehicle-treated group persisted longer. Moreover, while vehicle PLTs were unchanged over the study, RKER-050 treatment resulted in an increase in PLT count at Day 3 post-phlebotomy which remained elevated at Day 6. These data suggest that in cases of acute bleeding, RKER-050 not only rapidly increases RBCs but also PLTs, potentially demonstrating a pancytopenic effect of RKER-050. Our data suggest that RKER-050 is a fast-acting modulator of RBC maturation that rapidly increases RBCs, HGB, and HCT. The increases were observed in aged mice showing signs of age-associated anemia, as well as in mice with chronic conditions such as MDS. Moreover, RKER-050 showed rapid recovery in a model of acute bleeding with an effect on both erythropoiesis and thrombopoiesis. These results suggest that KER-050 could be developed for the treatment of anemias and potentially other cytopenias, including thrombocytopenia, arising from a variety of causes. Disclosures Feigenson: Keros Therapeutics: Current Employment. Nathan:Keros Therapeutics: Current Employment. Babbs:Keros Therapeutics: Current Employment. Materna:Keros Therapeutics: Current Employment. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14 ◽  
Author(s):  
Tae Min Kim ◽  
Nehal Lakhani ◽  
Justin Gainor ◽  
Manali Kamdar ◽  
Philip Fanning ◽  
...  
Keyword(s):  
Immune Response ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Tolerability Profile ◽  
Low Grade ◽  
Publicly Traded ◽  
Private Company ◽  
Non Hodgkin Lymphoma ◽  
Time Of Presentation

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.

Effect of fluoride on the proteomic profile of the hippocampus in rats

2015 ◽  
Vol 70 (5-6) ◽  
pp. 151-157 ◽  
Author(s):  
Ye Pan ◽  
Peng Lü ◽  
Lijing Yin ◽  
Keping Chen ◽  
Yuanqing He
Keyword(s):  
Body Weight ◽  
Spectroscopic Analysis ◽  
Physiological Saline ◽  
Treated Group ◽  
The Body ◽  
Learning Ability ◽  
Sprague Dawley ◽  
Acid Biosynthesis ◽  
Two Dimensional Gel Electrophoresis ◽  
Sprague Dawley Rats

Abstract Two-dimensional gel electrophoresis (2-DE) was used to detect fluoride-induced alterations in the proteome of the rat hippocampus. Male Sprague-Dawley rats (n=30) were subjected to treatments three weeks after weaning. Animals of the first group were injected intraperitoneally (i.p.) with aqueous NaF (20 mg/kg/body weight/day), the second group, injected with physiological saline, served as the control. After 30 days, the body weight of the fluoride-treated rats was lower than that of the control, and F– levels in serum were higher than in the control. The hippocampus was subjected to proteomic analysis, and the fluoride-treated group was found to contain 19 up-regulated and eight down-regulated proteins. The proteins, identified by mass-spectroscopic analysis of their fragments obtained after digestion, were found to be involved in amino acid biosynthesis, the insulin signaling pathway and various other crucial functions. Our results also provide useful information on the mechanism of the reduction of the learning ability and memory induced by F.

scholarly journals Ameliorative effects of Spinacia oleracea on sperm morphology, count, and motility by normalizing the obesity-induced oxidative stress in Sprague Dawley rats

2020 ◽  
Vol 14 (03) ◽  
pp. 124-127
Author(s):  
Somia Iqbal ◽  
Noman Sadiq ◽  
Saad Siddiqui ◽  
Hira Iqbal
Keyword(s):  
Sperm Concentration ◽  
Treated Group ◽  
Sperm Parameters ◽  
Control Group ◽  
Sprague Dawley ◽  
Normal Morphology ◽  
Sprague Dawley Rats ◽  
Group A ◽  
Group B ◽  
Experimental Group

Background: Obesity is a prevailing metabolic disorder that affects the functioning of the male reproductive system. Excessive adipose tissue enhances reactive oxygen species generation and is linked with male infertility. Spinach has demonstrated antioxidant effects. The present study was conducted to determine the antioxidant effects of spinach on sperm parameters in obese Sprague Dawley rats. Subjects and methods: This randomized control study was conducted at the animal house of the National Institute of Health Islamabad, Islamic International Medical College, Cosmesurge International Hospital, Rawalpindi, and Apollo lab, Islamabad, Pakistan from April 2016 to March 2017. Forty male Sprague Dawley rats having an age of 8 weeks and weight 160-200g were tagged from number 1 to 40. Every third rat was randomly allocated to control Group A (n=13) and remaining into the Experimental group (n=27). Rats of control Group A was given a standard diet while a high-fat diet was given to Experimental group rats to induce obesity for the duration of six weeks. Weight (g) was measured weekly and obesity was confirmed when rats attain more than 20% weight when compared with that of rats of control Group A. Then, after obesity induction, the experimental group was alienated into the obesity control group (Group B) and spinach treated group (Group C). For sample, rats of Group A and Group B were sacrificed, and the cauda epididymis of each rat was placed in a Petri dish containing normal saline and cut into pieces to allow the release of sperm and then sperm parameters (sperms concentration, motility, and morphology) were recorded under the microscope. Then, spinach (5% hot water extract) along with the persistence of fat diet was administered to Group C for 4 weeks and finally, sperm parameters were measured in this group. Results: Sperm concentration/ml, motility (%), and normal morphology (%) of Group B rats were significantly decreased as compared to Group A rats. However, sperm concentration/ml, motility (%), and normal morphology (%) of Group C (spinach treated group) rats was significantly increased (p<0.001) as compared to Group B (obesity control group) rats after administering spinach. Conclusion: The addition of Spinach in a normal diet regimen restores normal sperm morphology, improves sperm motility and concentration.

scholarly journals Histological changes of uterus after comparative treatment of female rats by Trigonella foenum-graecum seeds and combined oral contraceptive pills

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ahmed Kaid Naji Allow ◽  
Ayah Rebhi Hilles ◽  
Zainab Yousef ◽  
Norbaiyah Mohamed Bakrim ◽  
Belqees Ahmed ◽  
...  
Keyword(s):  
Body Weight ◽  
Oral Contraceptive ◽  
Treated Group ◽  
Sprague Dawley ◽  
Histological Changes ◽  
Fenugreek Seeds ◽  
Oral Contraceptive Pills ◽  
Trigonella Foenum Graecum ◽  
Combined Oral Contraceptive ◽  
Contraceptive Pills

Introduction: This study evaluates the histological changes of uterine tissue in the female Sprague Dawley rats after administration of Trigonella foenum-graecum (fenugreek) seeds in comparison to combined oral contraceptive pills (COCPs). Methods: Twenty four female Sprague Dawley strain rats of 8 weeks old were divided into A, B, and C groups. Group A was the control and B was administrated with 0.05 mg/kg body weight of COCPs for 15 days. Group C was treated with 750 mg/kg body weight of fenugreek seed aqueous (FSA) extract for 15 days. The uterine tissues were isolated and studied histologically. Results: The uterine weight in the FSA extract treated group was normal, while in the COCPs treated group it was insignificantly increased. The endometrial thickness and endometrial gland density were normal in the FSA extract treated group, while in the COCPs treated group it was atrophied. Decidual-like cells were observed in the COCPs treated group only. Conclusions: Endometrial atrophy and decidual-like cells were noted after COCPs treatment while in the FSA extract and control groups they were absent. The findings suggest that fenugreek seeds could be used as an alternative natural and safe contraceptive product.

scholarly journals Effects of Xiang Sha Yang Wei Wan on Ethanol-Induced Gastric Ulcer in Sprague Dawley Rats: a Histological Study

2020 ◽  
Vol 12 (2) ◽  
Author(s):  
Al-Qaraghuli AMS ◽  
Abdel Wahab EMN ◽  
Al-Ani IM ◽  
Faisal GG
Keyword(s):  
Gastric Ulcer ◽  
Oral Dose ◽  
Histological Study ◽  
Treated Group ◽  
Ethanol Administration ◽  
Gastric Mucosal Lesion ◽  
Sprague Dawley ◽  
Group I ◽  
Sprague Dawley Rats ◽  
Group Ii

Introduction: Xiang Sha Yang Wei Wan (XSYWW) is a Chinese traditional medicine that is used for gastrointestinal disorders, specifically gastric ulcer in many countries of South-East Asia. The aim of the study was to evaluate the potential effects of XSYWW on ethanol-induced gastric ulcer in rats by means of histological Study. On a similar basis of treatment, ranitidine, a conventional medication was used as gold standard. Methods: Fifty five male Sprague-Dawley rats (250-300 gm) were divided into four groups. Group I (ethanol treated group) was the control group and gastric ulcers were induced by administering 100% ethanol (1 ml/200 g). Group II (Pre-treatment group) was divided into two subgroups; they were orally fed with 1.0 gm/kg and 2.0 gm/kg respectively of XSYWW solution. Thirty minutes later they were administered with absolute ethanol as in group I. Group III, was given an oral dose of 2gm/kg of XSYWW solution after one hour of ethanol administration. Group IV was given an oral dose of 200mg/kg ranitidine solution after one hour of ethanol administration. Five rats from groups I, III and IV were sacrificed on day 1, 2 and 3 while the animals of group II were sacrificed one hour after ethanol administration. Results: Histological study of the stomachs from ethanol treated rats showed multiple ulcers of various depths that reached the muscularis and the serosa. Conclusion: Pre or post-treated rats with XSYWW showed that XSYWW has protective effect against ethanol-induced gastric mucosal lesion. However, there was a faster and more complete healing process in the ranitidine treated group when compared to the XSYWW treated subjects.

scholarly journals Venetoclax and Decitabine Show Robust Activity in Advanced Systemic Mastocytosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Tahani Atieh ◽  
Janet Woodroof ◽  
Abdulraheem Yacoub
Keyword(s):  
Overall Survival ◽  
Induction Chemotherapy ◽  
Systemic Mastocytosis ◽  
Objective Response ◽  
Publicly Traded ◽  
First Line ◽  
Private Company ◽  
Allogenic Stem Cell Transplantation ◽  
Best Response ◽  
Kit D816v

Systemic mastocytosis (SM) is a heterogeneous group of diseases characterized by the proliferation of abnormal mast cells in the bone marrow or other organs. 1 Activating mutations in KIT are found in the majority of patients, with the KIT D816V mutation being the most common .2 While patients with indolent systemic mastocytosis (ISM) have a life-expectancy similar to the general population, approximately 40-53% of patients with SM have an associated hematologic neoplasm (SM-AHN) with a median overall survival of 2 years. 1-3 Treatment of SM-AHN is primarily directed at the AHN as this determines overall survival, with symptomatic treatment for SM if needed.4 Midostaurin is the only approved agent for SM with KIT K816V mutation and overall response rates in SM-AHN are &lt;60%. 5-6 No agents are approved beyond first line. We present the unique case of an 81-year-old male who presented with SM and low risk CMML (46 XY with ASXL1, KIT (p.D816V), SRSF2, TET2, RUNX1, MSH2, CBL). He received first line therapy with midostaurin 100 mg twice a day and achieved an early partial response but progressed after 7 months with increasing mastocytosis burden, rising tryptase and transformation of CMML to AML (image 1). He was subsequently treated with combination standard dose decitabine and venetoclax. The best response for the AML was CRi which was achieved after the first cycle and continues to be ongoing over 12 months since initiation of therapy. We also observed objective response of the SM disease burden on BM exams and steady decline in tryptase levels that continues to be ongoing (figure 1 and 2). Best response by IWG-MRT-ECNM is partial remission achieved after 9 months of therapy. SM-AML is rare and can be diagnosed concomitantly with SM or as a transformation of an SM-AHN. Additional mutations are often present, with the presence of ASXL1 and RUNX1 being associated with a particularly poor prognosis.7-8 Treatment for SM-AML is similar to standard AML treatment with allogenic stem cell transplantation (ASCT) being preferred in those able to tolerate it. While ASCT is the only potential cure for both diseases, SM often persists even with response of the AML.9-11 In a case report of 11 patients with SM-AML, 8 patients received induction chemotherapy with cytarabine and daunorubicin while 3 received induction with cytarabine and idarubicine. Seven patients received ASCT but five relapsed and eventually expired. None of the 3 long-term survivors had a c-KIT D816V mutation and two of them received ASCT. In 7 out of the 10 patients in CR or after ASCT, SM persisted. 9 In 2 case reports of SM-AML with D816V mutation, treatment consisted of induction and consolidation chemotherapy plus dasatinib and chemotherapy with ASCT and dasatinib. Both patients achieved HCR but again had persistent SM.10-11 The activity of hypomethylating agents (HMA) with venetoclax has not previously been reported in patients with SM-AML. Venetoclax plus either HMAs or low-dose cytarabine was approved for the treatment of AML in the elderly and those unable to tolerate induction chemotherapy in 2018. Venetoclax is an oral inhibitor of BCL-2, an antiapoptotic protein important in the pathophysiology of AML. In the initial study, the CR/Cri rate was 68% with a median time to response of 1.2 cycles. Venetoclax has also shown activity in other hematologic malignancies, including chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.12 SM-AML is an aggressive disease with limited treatment options. To our knowledge, this is the first report of sustained response of both SM-AHN and AML using a HMA and venetoclax. Given the difference in response time and dynamics, this treatment combination seems to have activity in both disease clones independently. This case suggests a potential treatment option for this unmet need and demonstrates the importance of research into the utility of venetoclax in mast cell neoplasms. Disclosures Yacoub: Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.

scholarly journals Population Pharmacokinetics and Exposure-Response Analyses for Glofitamab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS Mitigation in Patients with Step-up Dosing

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Nassim Djebli ◽  
Peter N Morcos ◽  
Félix Jaminion ◽  
Elena Guerini ◽  
Nicole A Kratochwil ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Clinical Data ◽  
Bispecific Antibody ◽  
Response Rate ◽  
Publicly Traded ◽  
Private Company ◽  
The Past ◽  
Exposure Response ◽  
Poppk Model

Introduction: Glofitamab (RG6026; RO7082859; CD20-TCB) is a novel '2:1' format T-cell-engaging bispecific antibody that has two CD20 and one CD3 binding domains, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing in B-cell malignancies. Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in heavily pre-treated R/R NHL patients (pts; Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) 7 days prior to first administration of glofitamab was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). We previously investigated population pharmacokinetics (popPK) and exposure-response (ER) relationships for glofitamab in NP30179; NCT03075696 (Djebli N, et al. Blood 2019), where modelling indicated step-up dosing would further mitigate CRS while maximizing efficacy. The present analysis is an update of previous models, including confirmatory data from the first step-up dosing (SUD) pts. Methods: Pts with indolent (i) or aggressive (a) R/R NHL received glofitamab fixed dosing (0.005-25mg every 2 or 3 weeks) or SUD (n=31, 2.5/10/16 and 2.5/10/30mg) following single Gpt 1000mg on Cycle (C) 1 Day (D) −7 to mitigate CRS. Serial and sparse glofitamab, and sparse G PK data were used to develop a popPK model in NONMEM® software (v7.4). The cut-off date of April 17, 2020 enabled inclusion of 16 (2.5/10/16mg) and 15 (2.5/10/30mg) SUD pts. Physiologically relevant covariates were investigated for their potential influence on glofitamab PK variability. Using the established G popPK model (Gibiansky, et al. CPT Pharmacometrics Syst Pharmacol 2014), G concentration-time profiles were constructed to estimate glofitamab receptor occupancy (RO%) in the presence of G competing for CD20 receptors over time. The relationship between glofitamab AvgRO% over the first 24 hours and CRS, with a focus on Grade (Gr) ≥2 CRS (defined by ASTCT criteria [Lee, et al. 2019]) was investigated in iNHL and aNHL pts combined. ER relationships between glofitamab time-averaged RO% (AvgRO%) up to C3D1, which is when the first response assessment was taken, and complete response rate (CRR) were characterized in aNHL pts who reached C3D1. Results : PopPK were analyzed in 230 iNHL and aNHL pts with ≥1 PK sample (fixed and SUD). ER relationships were analyzed in 95 aNHL pts with PK/efficacy data at C3D1, and in 204 iNHL and aNHL pts with PK/safety data. Glofitamab PK were best described using a two-compartment PK model with linear clearance and were comparable in pts with iNHL and aNHL. The effect of bodyweight on volumes and clearances was retained. Positive ER relationships were observed between AvgRO% over the first 24 hours and Gr ≥2 CRS in both iNHL and aNHL pts (p=0.002; Figure 1A), and between AvgRO% up to C3D1 and efficacy in aNHL pts (p=0.008; Figure 1B). Based on previous ER analyses (Djebli, et al. Blood 2019) of data from pts receiving fixed dosing, a SUD regimen (2.5/10/30mg Q3W) was selected to optimize the benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whilst allowing escalation to a higher dose associated with better clinical response. Updated ER analysis from fixed (n=199) and SUD (n=31) pts predicts an AvgRO% in the first 24 hours of 0.16% (0.10-0.29%), corresponding to a predicted Gr ≥2 CRS rate of 23.3% (20.8-26.8%) in iNHL and aNHL pts, and an AvgRO% to C3D1 of 0.75% (0.49-1.98%) corresponding to an anticipated CRR at Cycle 3 of 46.1% (42.7-53.8%) in aNHL pts. In comparison, clinical data from aNHL and iNHL pts receiving 2.5/10/16 and 2.5/10/30mg SUD (Hutchings, et al. ASH 2020) demonstrated a Gr ≥2 CRS rate of 21.6 % following the 2.5mg glofitamab dose (n=37), and a complete metabolic response rate of 40.6% (n=32). Conclusions: Glofitamab PopPK and ER relationships for efficacy/safety were updated, including data from SUD pts. These models and emerging SUD clinical data confirm that in NHL pts, the SUD regimen allowed glofitamab escalation up to 30mg to maximize efficacy while minimizing the risk of increased CRS at the first administration. These models are being developed further to support optimal biological-dose selection of glofitamab, both as monotherapy and in combination with other agents. Disclosures Djebli: F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Morcos:F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Jaminion:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Guerini:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Kratochwil:F. Hoffmann-La Roche: Current Employment. Justies:F. Hoffmann-La Roche: Current Employment. Schick:F. Hoffmann-La Roche: Current Employment. Kwan:Genentech, Inc./ F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Carlile:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. OffLabel Disclosure: Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.

scholarly journals Echocardiographic Changes of Carfilzomib Therapy in Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Waled Bahaj ◽  
Anas Albawaliz ◽  
Madeline E Begemann ◽  
Anuj Shrestha ◽  
Brett Sperry ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Systolic Dysfunction ◽  
Community Setting ◽  
Categorical Variables ◽  
Cardiac Complications ◽  
Publicly Traded ◽  
Private Company ◽  
Chi Square ◽  
Difficult Decision ◽  
The Past

Introduction: Carfilzomib is a proteasome inhibitor that is known to be associated with cardiotoxicity. Current clinical data on Carfilzomib associated with cardiotoxicity is generated in clinical trials from which patients with severe cardiovascular comorbidities were excluded. In this study, we have reported real-word experience on outcome of cardiotoxicity in patients managed by physicians in a community setting. Methods: We performed a retrospective analysis evaluating for cardiac complications in MM patients who received Carfilzomib at our institution in the last 5 years. Pre- and post-therapy echocardiogram findings were compared. Chi-square tests were used to compare categorical variables with an α level set at 0.05 for statistical significance. Results: Among the 28 identified patients who had pre- and post- Carfilzomib therapy echocardiogram imaging, (18 patients, 64%) had at least one echocardiographic abnormality. The main changes were in heart functions (10/28), whereas systolic dysfunction is seen in 9 patients while only one patient had diastolic dysfunction, pulmonary artery pressure (6/28), and wall motion abnormalities (5/28). (11/28) patients had disease progression. We did not notice any correlation to variables such as; age, duration of therapy, dose differences, and number of lines of therapies. Furthermore, two patients were rechallenged with Carfilzomib after echocardiographic worsening; one of them tolerated the treatment well, while the other had further worsening that led to holding the therapy. Conclusion: Several echocardiographic changes could be related to Carfilzomib therapy. Our study was limited due to the sample size and the retrospective nature of the analysis. Larger studies are needed to detect and correlate more echocardiogram variables in this population. Rechallenging these patients with Carfilzomib, particularly during relapse stages, will remain a difficult decision especially if the therapy was effective. Disclosures Raza: Advisory board Incyte, Amgen, Celgene, Kite, Janseen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Moderna: Current equity holder in publicly-traded company; Drrx: Divested equity in a private or publicly-traded company in the past 24 months; Gilead, Sierra, Abbot, Acasti, Amicus: Current equity holder in private company; Received Honorarium/speaker bureu from Janseen, Celgene, Takeda: Ended employment in the past 24 months, Honoraria, Speakers Bureau.

scholarly journals Identification of Potential Therapeutic Targets in the Liver of Pioglitazone-Treated Type 2 Diabetes Sprague-Dawley Rats via Expression Profile Chip and iTRAQ Assay

2018 ◽  
Vol 2018 ◽  
pp. 1-9
Author(s):  
Zhong-Xia Lu ◽  
Wen-Jun Xu ◽  
Yang-Sheng Wu ◽  
Chang-Yu Li ◽  
Yi-Tao Chen
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Differentially Expressed Genes ◽  
Fasting Blood Glucose ◽  
Treated Group ◽  
Differentially Expressed ◽  
Model Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

The aim of the present study was to identify key antidiabetic nodes in the livers of pioglitazone-treated type 2 diabetes mellitus Sprague-Dawley rats by transcriptomic and proteomic analysis. Rats were randomly divided into the control, the diabetes model, and the pioglitazone-treated groups. After treatment with pioglitazone for 11 weeks, the effects on fasting blood glucose, body weight, and blood biochemistry parameters were evaluated. Microarray and iTRAQ analysis were used to determine the differentially expressed genes/proteins in rat livers. 1.5-fold changes in gene expression and 1.2-fold changes in protein were set as the screening criteria. After treatment with pioglitazone for 11 weeks, fasting blood glucose in pioglitazone-treated rats was significantly lower than that in the model group. There was a tendency for pioglitazone to reduce TC, TG, TP, ALB, BUN, and HDL-c levels. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) were applied to analyze differentially expressed genes/proteins. Furthermore, Western blotting and RT-qPCR were used to validate the results of microarray and iTRAQ. In conclusion, Cyp7a1, Cp, and RT1-EC2 are differentially expressed genes/proteins since they showed a similar trend in rats in the model group and the pioglitazone-treated group.

Biochemical effect of varied mixtures of extracts of Vernonia amygdalina (bitter leaf) and Gnetum africanum (Okazi leaf) on alloxan induced diabetic wistar rats

2021 ◽  
Vol 20 (1) ◽  
pp. 17-30
Author(s):  
M.O. Ifeanacho ◽  
R.B Oshotse
Keyword(s):  
Diabetes Mellitus ◽  
Wistar Rats ◽  
Treated Group ◽  
The Body ◽  
Blood Protein ◽  
Steady Increase ◽  
Vernonia Amygdalina ◽  
Leaf Extracts ◽  
Biochemical Effect ◽  
Total Blood

Diabetes mellitus is prevalent in many countries of the world, affecting all ages both in developing and developed nations. The use of plants as remedies or preventive therapies has increased over the years. The study investigated the biochemical changes caused by  combined leaf extracts of Vernonia amygdalina (bitter leaf) and Gnetum africanum (okazi leaf) on alloxan induced diabetic wistar rats.Aqueous extracts of the leaves were prepared using the conventional method.Forty male wistar rats weighing 150-180g were  grouped into eight (five rats each). Group 1 was the normal control while diabetes was induced using alloxan (160mg/ kg)in groups 2-8.Group 2 received no treatment while groups 3-7 received varied ratios of the extracts at (BI/OK|10:90%), (BI/OK|30:70%),  (BI/OK|50:50%), (BI/OK|70:30%) and (BI/OK|90:10%). Group 8 was the diabetic control treated with the standard diabetic drug (Metformin). The animals were weighed and blood glucose was determined at 7-day intervals. They were sacrificed on the 28th day and blood samples collected for serum protein, serum electrolyte, urea, creatinine, liver enzymes and markers of oxidative stress analyses.  The results showed steady increase in the body weights (g) of the rats with (BI/OK|70:30)% treated group showing the highest increase (175.40±1.28). The fasting blood sugar (mg/dl) showed timedependent reduction in all the treated diabeti groups with (BI/OK|90:10)% having the highest (56.20±1.65) reduction. There was a significant increase (p<0.05) in total blood protein concentration (g/dl) in all the treated groups. The results of this study showed time and ratio dependent effect on the parameters measured. Since the two plants are staple vegetables in some countries, their utilization particularly in appropriate combinations should be encouraged. Key words: Extracts, bitter leaf, waterleaf, diabetes mellitus, biochemical parameters.

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