scholarly journals Effect of Food on MDM2 Inhibitor KRT-232 Pharmacokinetics and Macrophage Inhibitory Cytokine-1 (MIC-1) Response in Healthy Volunteers

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Shekman Wong ◽  
Cecile Marie Krejsa ◽  
Dana Lee ◽  
Anna Harris ◽  
Emilie Simard ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Small Molecule ◽  
Geometric Mean ◽  
Wild Type ◽  
High Fat ◽  
Publicly Traded ◽  
Meal Test ◽  
Median Tmax ◽  
The Past ◽  
Mdm2 Inhibitor

Background: KRT-232 is a potent, selective, orally available, small-molecule drug that binds to mouse double minute 2 homolog (MDM2) and inhibits its interactions with tumor suppressor protein p53. KRT-232 is under development for treatment of myeloproliferative neoplasms, acute myeloid leukemia, and Merkel cell carcinoma. Increased serum MIC-1 (pg/mL) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with KRT-232 (Allard,HemaSphere, 2020;4:S1, Abstract EP519). The aim of this study was to assess the safety and effect of a high-fat meal on KRT-232 pharmacokinetics (PK) and MIC-1 PD of a new tablet formulation in healthy volunteers. This is the first characterization of a MDM2-inhibitor-induced MIC-1 response in healthy volunteers. Methods: KRT-232-105 was a single-center, open-label, 60-mg single-dose, 3-treatment, 4-period, and 3-sequence study with a partial replicate crossover design. Volunteers (N=30) were randomized to three treatment groups: A: new tablet, fasted (reference, dosed twice in Periods 2-4); B: new tablet, 30 min after a high-fat, high-calorie meal (test 1, dosed once in periods 2-4); C: current tablet, fasted (test 2, period 1 only). Plasma KRT-232, its acyl glucuronide metabolite (M1) and serum MIC-1 concentrations were measured over 0-96 h. Urine from group C was collected over 0-48 h. Doses were one week apart. All volunteers had aH pyloribreath test and were genotyped for UGT1A1*28 polymorphisms. Results: Volunteers were 43% female, 7% African American and 77% Hispanic/Latino. Mean age was 38.1 y (range, 18-54), and mean body mass index was 26.9 kg/m2 (range, 21.4-30.9). No deaths, serious adverse events (SAEs), or discontinuations were reported. Twenty-one treatment-emergent AEs (TEAEs) were observed in 13 (43%) volunteers; constipation was the most frequent AE, followed by headache. All TEAEs were grade 1 (n=17) or grade 2 (n=4: 1 headache event [possibly study drug-related] and 3 events of headache, influenza-like illness, and pharyngitis). Mean (SD) concentration-time plots of KRT-232 and M1 were similar across the 3 groups (Figure 1a and b). A second peak was observed, consistent with enterohepatic recirculation. With a meal (test 1), KRT-232 geometric least-squares mean (GLSM) maximum concentration (Cmax) was similar (431 and 442 ng/mL (GLSM ratio [90% CI], 103% [87.4-121]) and KRT-232 GLSM area under the curve (AUC0-t) decreased from 2858 to 2325 ng∙h/mL (GLSM ratio [90% CI], 81.4 [76.2-86.9]). Median time of Cmax (Tmax) was 2 h fasted and 3 h fed. Geometric mean half life (t1/2) was unchanged (17.0 vs 17.1 h). Under fasting conditions, the current tablet (C, test 2) vs new tablet (A, reference), KRT-232 GLSM Cmax decreased from 431 to 337 ng/mL (GLSM ratio [90% CI], 78.4% [72.0-85.3]) and KRT-232 GLSM AUC0-t had a possible small decrease (2858 and 2455 ng∙h/mL, GLSM ratio [90% CI], 85.9 [80.5-91.7]). Median Tmax (~2 h) and geometric mean t1/2 (17 h) were unchanged. The fraction of the KRT-232 dose in urine as KRT-232 and M1 was negligible at 0.0201% and 0.0220% of dose, respectively. KRT-232 is a carboxylic acid with pH-dependent solubility that increases with increasing pH.H pyloriinfection, which can increase stomach pH, did not have any discernable impact on KRT-232 PK. KRT-232 and M1 exposure in heterozygous UGT1A1*28 poor metabolizers (6/7 TA repeats, N=16) was generally comparable to exposure in wild-type (WT) UGT1A1*28 (6/6 TA repeats, N=12) subjects. MIC-1 concentrations in serum were variable and followed the PK time course with a median Tmax lag of ~8-12 h. Group A: Mean Cmax 2115 pg/mL, C0 (Baseline) 170 pg/mL, AUC0-T 89267 pg*h/mL and mean t1/2 27 h. MIC-1 Cmax and AUC were generally comparable over 96 h across groups (Figure 1c).Figure 1dshows the statistically significant correlation between KRT-232 AUC0-t and MIC-1 AUC0-t. Conclusions: Based on generally comparable PK, KRT-232 can be administered with or without food, and no dose adjustment is warranted with a new tablet formulation. KRT-232 PK was not affected byH pylori, inferring that higher gastric pH did not alter absorption of KRT-232. KRT-232 exposure in UGT1A1*28 heterozygous poor metabolizers was generally comparable to WT UGT1A1*28 wild type healthy volunteers. The 60-mg KRT-232 dose elicited a reproducible and robust MIC-1 response that correlated with KRT-232 exposure, indicating MDM2-p53 target engagement. Disclosures Wong: Kartos Therapeutics:Current Employment;AbbVie Biotherapeutics:Ended employment in the past 24 months.Krejsa:Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company;Seattle Genetics:Current equity holder in publicly-traded company;Acerta Pharma:Current equity holder in private company.Lee:Kartos Therapeutics:Current Employment.Harris:Gilead Sciences:Current equity holder in publicly-traded company;Kartos Therapeutics:Current Employment, Current equity holder in private company;BeiGene:Ended employment in the past 24 months;Clovis:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Simard:Certara:Current Employment;AltaScience:Ended employment in the past 24 months.Wang:Certara:Current Employment.Rubets:Certara:Current Employment.Allard:Certara:Consultancy, Ended employment in the past 24 months;CytomX Therapeutics:Ended employment in the past 24 months;Telios Pharma:Current Employment, Current equity holder in private company.Podoll:IV/PO, LLC:Consultancy.O'Reilly:Celerion:Current Employment.Slatter:Amgen:Divested equity in a private or publicly-traded company in the past 24 months;Kartos Therapeutics:Current Employment;AstraZeneca:Current equity holder in publicly-traded company. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor.

scholarly journals Rap-536 Induces Reticulocyte Maturation in Wild-Type Mice, Increases Survival of Beta-Thalassemic Reticulocytes, and Increases Red Blood Cells in a Mouse Model of Alpha-Thalassemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Melih Acar ◽  
Madhulika Jupelli ◽  
Roberto A. Abbiati ◽  
Harish N. Ramanathan ◽  
Cristina C. Santini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Wild Type ◽  
Publicly Traded ◽  
The Past ◽  
Alpha Thalassemia ◽  
Reticulocyte Maturation ◽  
Erythroid Maturation ◽  
Parameter Values

Luspatercept is a recombinant fusion protein that binds and sequesters several endogenous transforming growth factor-beta superfamily ligands, including growth differentiation factor 11, thereby diminishing Smad2/3 signaling in target cells involved in erythropoiesis. Luspatercept, and its murine analog RAP-536, have been shown to act as erythroid maturation agents via their effects on late-stage erythropoiesis by inducing erythroblast maturation, leading to increases in red blood cells (RBCs) and hemoglobin (Hb). This study demonstrated that thalassemic (th3/+) reticulocytes are unstable, and that RAP-536, in addition to its function as an erythroid maturation agent, modulates the maturation of wild-type (WT) and th3/+ reticulocytes. Furthermore, RAP-536 treatment increased RBCs and decreased bilirubin in a mouse model of alpha-thalassemia (129S-Hba-a1tm1Led/J). To examine whether acute RAP-536 treatment acts on reticulocytes and alters reticulocyte levels in blood, the blood of WT mice was analyzed 3, 12, and 24 hours, and 2, 3, 4, and 7 days after a single dose of RAP-536 (10 or 30 mg/kg) or vehicle. RAP-536 treatment increased RBCs, Hb, and hematocrit significantly at all time points, compared with vehicle. However, in mice treated with RAP-536, reticulocytes in blood decreased significantly on Days 2, 3, and 4 and returned to normal baseline levels on Day 7. Analysis of reticulocyte subpopulations in blood 3 days after RAP-536 treatment showed that the relative percentages of immature reticulocytes (CD71+ or high RNA content) within the blood reticulocyte population decreased, suggesting that reticulocytes released from the bone marrow (BM) were more mature and/or reticulocytes matured faster in blood. A quantitative pharmacology (QP) model was developed to explore which RAP-536-induced modulations of erythropoiesis in WT mice can simulate the experimental observations. The model represents erythroblast, reticulocyte, and RBC (erythrocyte) maturation stages in BM, peripheral blood, and spleen, in the presence or absence of a RAP-536 effect. The QP model consists of a system of ordinary differential equations, with homeostatic parameter values assigned from literature or experimental measures, and RAP-536-perturbed parameter values regressed by fitting the model to erythropoiesis data of RAP-536-treated WT mice. Comparison of model parameters for homeostatic versus RAP-536-perturbed states indicated that RAP-536 leads to an increase in the erythroblast-to-reticulocyte and reticulocyte-to-RBC conversion rates, the transfer of BM reticulocytes to blood, and a delayed increase in erythroblast production. To directly test whether RAP-536 treatment affects reticulocyte development in blood, comparative blood transfusion experiments were performed. Biotinylated GFP+ blood from WT mice (C57BL/6-Tg(UBC-GFP)30Scha/J) and biotinylated GFP− blood from th3/+ beta-thalassemic mice (B6.129P2-Hbb-b1tm1Unc Hbb-b2tm1Unc/J) were co-transfused into GFP− WT recipient mice (C57BL/6J), which were subsequently treated with RAP-536 or vehicle. In the donor reticulocyte population, th3/+ reticulocyte percentage decreased continuously up to 3 days after transfusion, suggesting that many of the th3/+ reticulocytes were eliminated before they could form RBCs. However, compared with vehicle, RAP-536 treatment led to increased persistence of the relative percentages of th3/+ reticulocytes (Figure A). Consequently, 7 days after transfusion, when most reticulocytes have matured to RBCs, the percentage of th3/+ RBC among donor RBCs was higher with RAP-536 (Figure B). Finally, treatment of an alpha-thalassemia mouse model (129S-Hba-a1tm1Led/J) with RAP-536 10 mg/kg for 8 weeks increased RBCs and hematocrit and reduced serum bilirubin, compared with vehicle. These results suggest that RAP-536 is, as previously shown, an erythroid maturation agent, which also modulates reticulocyte maturation in blood. In WT mice, RAP-536 modulated blood reticulocyte dynamics consistent with faster maturation. RAP-536 also prolonged the persistence of th3/+ reticulocytes and maintained a higher frequency of th3/+ RBCs. These data, together with the finding that RAP-536 reduces hemolysis in an experimental alpha-thalassemia disease model, suggest that luspatercept has the potential to improve anemias associated with hemolysis and/or reticulocytosis. Disclosures Acar: Bristol Myers Squibb: Ended employment in the past 24 months. Jupelli:Bristol Myers Squibb: Current Employment. Abbiati:Bristol Myers Squibb: Current Employment. Ramanathan:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Santini:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ratushny:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dunshee:Bristol Myers Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Lopes de Menezes:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. MacBeth:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Suragani:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Loos:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Schwickart:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Induction of Fetal Hemoglobin By FTX6058, a Novel Small Molecule Development Candidate

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Peter Rahl ◽  
Ivan Efremov ◽  
Billy Stuart ◽  
Keqiang Xie ◽  
Mark Roth ◽  
...  
Keyword(s):  
Small Molecule ◽  
Plasma Concentrations ◽  
Fetal Hemoglobin ◽  
Target Engagement ◽  
Publicly Traded ◽  
In Vivo Models ◽  
Α Subunit ◽  
The Past

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Novel Small Molecule MDM2 Inhibitor MI-63 Induces p53-Dependent Apoptosis in AML Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2596-2596
Author(s):  
Ismael Samudio ◽  
Martin Dietrich ◽  
Paul Corn ◽  
Dajun Yang ◽  
Gautam Borthakur
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Small Molecule ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Wild Type ◽  
Wild Type P53 ◽  
Induced Apoptosis ◽  
Related Proteins ◽  
Mdm2 Inhibitor

Abstract Although TP53 mutations are rare in acute myeloid leukemia (AML), inactivation of wild-type p53 protein frequently occurs through overexpression of its negative regulator MDM2 (murine double minute 2). We investigated the effects of MI-63, a small molecule that activates p53 by inhibition of MDM2-p53 interaction [ Ki value of 3 nM (J Med Chem.2006;49(12):3432–5)] in AML cell lines. Treatment with MI-63 triggered apoptosis (evidenced by loss of membrane potential and externalization of phosphatidylserine) in AML cell lines with wild-type p53 (OCI-AML-3 and MOLM13) in a time and concentration-dependent manner (IC50 at 72 hrs.= 2.5 μM for OCI-AML-3 and 1 μM for MOLM-13), while a p53-null AML cell line (HL-60) was resistant (IC50 not reached at 10 μM). Moreover, knockdown of p53 in OCI-AML3 cells rendered this cell line resistant to MI-63 induced apoptosis while control vector infected OCI-AML-3 cells remained as sensitive to MI-63 similar to the parental cells. Mechanistic studies showed that MI-63 blocks G1/S phase transition in AML cells with wild-type p53 resulting in accumulation of cells in G1 phase (percentage cells inG1 phase at 24 hrs. = 88.66% vs 43.49% in cultures with DMSO control) while MI-61, a skeletally related but inactive control compound failed to do so (41.63%). Treatment with MI-63 increased cellular levels of p53 and p53 dependent proteins in OCI-AML-3 cells that include p21 and BH3-only pro-apoptotic protein Puma and pro-apoptotic multi-domain Bcl-2 family member Bax. Additionally, MI-63 induced a profound decrease in the levels of MDM4, an MDM2 homolog that has been reported to mediate resistance to the effects of nutlin-3a, suggesting that MI-63 may offer a therapeutic advantage in cells expressing high levels of MDM4. Finally, supporting the concept that increased levels of p53 modulate the apoptotic rheostat both directly, by behaving as a BH3-only protein, and indirectly by increasing the levels of sensitizer BH3-only proteins, MI-63 potently synergized with AT-101, an orally available pan inhibitor of Bcl-2, Bcl-xL and Mcl-1 (currently being evaluated as an antitumor agent in Phase I/II trials by Ascenta Therapeutics), to induce mitochondrial dysfunction and apoptosis in OCI-AML-3 cells (average combination index = 0.055±0.019). Taken together our results support preclinical evaluation of novel small molecule MI-63 alone and in combination with Bcl-2 inhibitors for the therapy of AML. The studies in primary AML samples are ongoing. Fig.1: MI-63 Induced Apoptosis Requires Intact p53 Fig.1:. MI-63 Induced Apoptosis Requires Intact p53 Fig.2: Efect of MI-63 on p53 and Related Proteins (comparison with N3a, a known MDM2 inhibitor included) Fig.2:. Efect of MI-63 on p53 and Related Proteins (comparison with N3a, a known MDM2 inhibitor included)

scholarly journals Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

2010 ◽  
Vol 54 (7) ◽  
pp. 2775-2780 ◽  
Author(s):  
Gaik H. Soon ◽  
Ping Shen ◽  
Eu-Leong Yong ◽  
Paul Pham ◽  
Charles Flexner ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Half Life ◽  
Geometric Mean ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Time Curve ◽  
Once Daily ◽  
Drug Concentrations ◽  
Trough Concentrations

ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

scholarly journals New Acalabrutinib Formulation Enables Co-Administration with Proton Pump Inhibitors and Dosing in Patients Unable to Swallow Capsules (ELEVATE-PLUS)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4365-4365
Author(s):  
Shringi Sharma ◽  
Xavier Pepin ◽  
Harini Burri ◽  
Lianqing Zheng ◽  
Nataliya Kuptsova-Clarkson ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Geometric Mean ◽  
In Vitro Release ◽  
Alternative Methods ◽  
Publicly Traded ◽  
The Past ◽  
Pharmacologically Active ◽  
All Treatment ◽  
Privately Held

Abstract Introduction: Acalabrutinib (Calquence ®), a selective Bruton tyrosine kinase (BTK) inhibitor, is approved for the treatment of mantle cell lymphoma (relapsed/refractory) and chronic lymphocytic leukemia. Patients with hematologic malignancies may require acid-reducing agents (including proton pump inhibitors [PPIs]) for the treatment of gastroesophageal reflux or peptic ulcer disease. The solubility of acalabrutinib is reduced with increasing pH; concomitant administration of acalabrutinib capsules with PPIs reduces acalabrutinib exposure and is currently not recommended. Additionally, many cancer patients are unable to swallow capsules and require alternative methods to deliver acalabrutinib, such as a suspension administered orally or via a nasogastric (NG) tube. To enable the use of acalabrutinib in patients who require co-treatment with PPIs and/or are unable to swallow capsules, a new maleate salt of acalabrutinib, formulated as an immediate-release film-coated tablet (acalabrutinib maleate tablet [AMT]), has been developed which shows fast and complete in vitro release at all physiologic pH. We evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of AMT administered orally or via NG tube in the presence or absence of a PPI. In addition, the effect of food on AMT was evaluated to confirm the absence of a clinically relevant impact, consistent with acalabrutinib capsules. Methods: Three Phase 1, open-label, single-dose, cross-over studies were conducted in healthy subjects to establish PK similarity (bioequivalence) between 100-mg AMT and 100-mg acalabrutinib capsules (N=66); evaluate PPI effect by comparing PK of 100-mg AMT administered in the presence vs absence of rabeprazole (PPI; N=14); evaluate food effect by comparing PK of 100-mg AMT administered with a high-fat diet vs fasted (N=16); and assess PK following administration of 100-mg acalabrutinib maleate suspension (in 15 mL water) delivered via NG tube, in the presence vs absence of rabeprazole (N=20). PD was assessed by measuring BTK target occupancy (BTK-TO) in peripheral blood mononuclear cells across all treatment arms and studies. Results: Exposure geometric mean ratios and 90% confidence intervals (CIs) are shown in Table 1 with the PK profiles shown in Figure 1. Systemic exposures (C max and AUC) of acalabrutinib and its major pharmacologically active metabolite, ACP-5862, between AMT and acalabrutinib capsules were bioequivalent (&lt;5% difference in geometric mean exposures, with the 90% CI contained entirely within the pre-defined range of 80.00% and 125.00%). No clinically relevant difference in acalabrutinib/ACP-5862 exposures was observed following administration of AMT with and without PPI; C max was lower (≤~30% difference) and AUC higher (≤~16% difference) with similar BTK-TO (≥95%) across treatment arms. Additionally, no clinically relevant impact of food on acalabrutinib/ACP-5862 exposures was observed; C max was lower (≤~54% difference), with no impact on AUC (≤~3% difference) or BTK-TO (≥95% across treatment arms). Acalabrutinib/ACP-5862 exposures were comparable (≤10% difference) between 100-mg acalabrutinib maleate NG suspension and 100-mg acalabrutinib capsules. In addition, exposures were comparable (≤16% difference) following co-administration of acalabrutinib maleate NG suspension with and without PPI. Overall, the BTK-TO was comparable (≥95%) across all treatment arms. The new AMT formulation showed a well-tolerated safety profile with the majority of observed adverse events (AEs) mild in intensity and no serious AEs reported. No new safety concerns were observed for the AMT. Conclusions: Acalabrutinib maleate, administered as a tablet or suspension, is safe and well tolerated. Based on the PK (and associated variability), BTK-TO, and established exposure-efficacy/safety relationship, AMT clinical effect is expected to be comparable to acalabrutinib capsules at the approved 100-mg BID dosing, regardless of use of PPIs and ingestion of food. Additionally, AMT improves swallowing ability given the film coating and a 50% reduced volume compared with the capsule, and can be easily suspended in a small amount of water to allow dosing in patients unable to swallow tablets. Figure 1 Figure 1. Disclosures Sharma: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Pepin: AstraZeneca: Current Employment. Burri: AstraZeneca: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Zheng: AstraZeneca: Current Employment; Kite Pharma, a Group of Gilead: Ended employment in the past 24 months; Gilead Science Inc., AstraZeneca: Current equity holder in publicly-traded company; Gilead Science Inc.: Divested equity in a private or publicly-traded company in the past 24 months. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. de Jong: Acerta Pharma B.V. (A Member of the AstraZeneca Group): Current Employment. Yu: AstraZeneca: Current Employment; EMD Serono Research Institute: Ended employment in the past 24 months; AstraZeneca, Johnson and Johnson, AbbVie, Abbott: Current equity holder in publicly-traded company; Merck KGaA: Divested equity in a private or publicly-traded company in the past 24 months. MacArthur: AstraZeneca: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Majewski: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Ware: AstraZeneca: Current equity holder in publicly-traded company; Denali (DNLI) Therapeutics: Current equity holder in publicly-traded company. Mann: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Ramies: AstraZeneca: Consultancy. Munugalavadla: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Sheridan: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Tomkinson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: New Formulation

scholarly journals In Vitro Characterization of FTX6058, a Novel Small Molecule Fetal Hemoglobin Inducer for Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Billy Stuart ◽  
Peter Rahl ◽  
Kingsley Appiah ◽  
Ivan Efremov ◽  
Lorin Thompson ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Small Molecule ◽  
Fetal Hemoglobin ◽  
In Vitro Assays ◽  
Cell Disease ◽  
Publicly Traded ◽  
Α Subunit ◽  
The Past

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ) occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression and the resulting fetal hemoglobin (HbF) tetramer at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to approximately 30% HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. Preclinical studies using a variety of in vitro assays have demonstrated the potential of FTX-6058 as a clinical development candidate for potential treatment of hemoglobinopathies, such as SCD and ꞵ-thalassemia, via upregulation of HbF. IND enabling studies for FTX-6058 have been completed. Keywords: hemoglobin, fetal hemoglobin, HbF, HBG1/2, sickle cell disease, gene regulation Disclosures Stuart: Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rahl:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company.

scholarly journals An Enterohepatic Recirculation Population Pharmacokinetic and MIC-1 Pharmacokinetic-Pharmacodynamic Model for the MDM2 Inhibitor Navtemadlin (KRT-232) in Healthy Subjects

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4350-4350
Author(s):  
Lu Zhang ◽  
Bill Poland ◽  
Michelle Green ◽  
Shekman Wong ◽  
J. Greg Slatter
Keyword(s):  
Healthy Subjects ◽  
Food Effect ◽  
Plasma Concentrations ◽  
Effect Study ◽  
Time Data ◽  
Publicly Traded ◽  
First Order ◽  
The Past ◽  
Concentration Time ◽  
Mdm2 Inhibitor

Abstract Background: Murine double minute 2 (MDM2) is the primary negative regulator of the tumor suppressor protein, p53. Navtemadlin (KRT-232), a potent and selective, orally available MDM2 inhibitor restores p53 activity to drive apoptosis of cancer cells in TP53 WT malignancies. Navtemadlin is currently being evaluated in a phase 3 trial of patients with relapsed or refractory myelofibrosis, as well as in numerous phase 1b/2 trials in various hematologic malignancies and solid tumors. Serum macrophage inhibitor cytokine-1 (MIC-1) is a pharmacodynamic (PD) marker of p53-mediated activity in patients treated with navtemadlin (Allard et al. HemaSphere. 2020). Using pharmacokinetic (PK) and PD data from a healthy subject food effect study (Wong et al. Blood. 2020), we developed a population PK (PPK) model that characterized enterohepatic recirculation (EHR) as a half-life extending element in the PK profiles of navtemadlin and its major acyl glucuronide metabolite M1. MIC-1 PD data were incorporated into the model to quantify plasma concentration-driven MIC-1 excursions and to simulate PK and PD across time and dose in healthy subjects. Methods: PPK and PK-PD models were developed using the first-order conditional estimation with interaction (FOCE-I) method in NONMEM 7.4, with model covariates selected using a stepwise forward addition and backward elimination method based on a 5% significance level. Model quality was checked by inspecting model parameters and confidence intervals, as well as standard residual-based and simulation-based diagnostics, and prediction-corrected visual predictive checks. Navtemadlin plasma concentration and MIC-1 serum concentration-time data from the food effect study (KRT-232-105) were modeled (N=30 subjects after a single 60 mg navtemadlin dose). Candidate PPK semi-mechanistic models that described EHR with multi-compartment structures (gut, central, and peripheral compartments for navtemadlin, and central and gallbladder [GB] compartments for M1), first-order elimination, and mealtime effects on GB emptying were tested. Post hoc parameter estimates from the final PPK model were used to generate individual predicted navtemadlin plasma concentrations for the PK-PD model. Based on exploratory plots, the pharmacological mechanism of action of navtemadlin, and a bile acid recycling model (Guiastrennec et al. CPT Pharmacometrics Syst Pharmacol. 2018), an indirect response equation was selected for the MIC-1 effect compartment (Figure 1a). Results: Navtemadlin and M1 plasma concentrations, including a second peak attributed to EHR at ~8-12 h, were well described by a model with central and peripheral compartments, constant basal M1 release rate into bile (KBR BASAL), and incremental mealtime GB emptying rate (KBR MEAL, Figure 1a). Figure 1b shows simulated navtemadlin and M1 amounts in various compartments over time. Median oral clearance of navtemadlin was estimated at 36.35 L/h. Estimated median apparent oral clearance of navtemadlin in healthy subjects was higher than PPK estimates for patients with advanced solid tumors (24.9 L/h [Ma et al. Blood. 2019]). The median central and peripheral volumes of navtemadlin were 159 L and 390 L, respectively. Navtemadlin exposure was higher in healthy female subjects relative to male subjects. Between-subject variability in clearance was 31%. Typical MIC-1 maximum stimulatory effect (S max) was estimated at 6.82, close to the median maximum ratio of MIC-1 to baseline MIC-1 (7.29) in the observed data. SC 50 was estimated at 85.22 ng/mL, with a Hill coefficient of 2.02, indicating a relatively steep increase in MIC-1 serum concentration with increasing navtemadlin concentration. For both PPK and PK-PD models, diagnostic plots confirmed an adequate fit. Subjects with lower baseline MIC-1 had a larger response and reached a maximum MIC-1 concentration later. Older subjects had the largest covariate impact, with a higher MIC-1 response. Conclusion: A two-compartment PPK model with basal and incremental mealtime GB emptying rates captured concentration-time data for navtemadlin and its metabolite M1. EHR was evident and navtemadlin reabsorption following hydrolysis of biliary M1 in the intestine contributed to navtemadlin half-life. An indirect stimulatory PK-PD model effectively described the relationship between navtemadlin and MIC-1 in healthy subjects. Figure 1 Figure 1. Disclosures Zhang: Certara, Inc.: Current Employment; Milad Pharmaceutical Consulting, LLC.: Ended employment in the past 24 months. Wong: Kartos Therapeutics: Current Employment; AbbVie Biotherapeutics: Current equity holder in publicly-traded company. Slatter: Telios Pharma: Current holder of stock options in a privately-held company; Kartos Therapeutics: Current Employment, Current holder of stock options in a privately-held company; AstraZeneca: Current equity holder in publicly-traded company; Amgen: Divested equity in a private or publicly-traded company in the past 24 months. OffLabel Disclosure: Yes, navtemadlin (KRT-232) is an investigational small molecule MDM2 inhibitor.

Targeting the p53 tumor suppressor activity in glioblastomas using small molecule MDM2-inhibitor

2011 ◽  
Vol 42 (01) ◽  
Author(s):  
P. Monfared ◽  
T. Viel ◽  
G. Schneider ◽  
Y. Waerzeggers ◽  
S. Rapic ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Small Molecule ◽  
Suppressor Activity ◽  
P53 Tumor Suppressor ◽  
Tumor Suppressor Activity ◽  
Mdm2 Inhibitor

scholarly journals Small Molecule Inhibitors of Influenza Virus Entry

2021 ◽  
Vol 14 (6) ◽  
pp. 587
Author(s):  
Zhaoyu Chen ◽  
Qinghua Cui ◽  
Michael Caffrey ◽  
Lijun Rong ◽  
Ruikun Du
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Virus Entry ◽  
Critical Role ◽  
Structural Basis ◽  
Future Directions ◽  
The Past

Hemagglutinin (HA) plays a critical role during influenza virus receptor binding and subsequent membrane fusion process, thus HA has become a promising drug target. For the past several decades, we and other researchers have discovered a series of HA inhibitors mainly targeting its fusion machinery. In this review, we summarize the advances in HA-targeted development of small molecule inhibitors. Moreover, we discuss the structural basis and mode of action of these inhibitors, and speculate upon future directions toward more potent inhibitors of membrane fusion and potential anti-influenza drugs.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

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