First‐in‐human study of milvexian,an oral,direct, small molecule factor XIa inhibitor

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T_1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Factor XI (FXI) amplifies thrombin generation and has a limited role in hemostasis. Targeted FXI inhibition may reduce the burden of vascular and thromboembolic diseases while preserving hemostasis.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety/tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the selective, direct, small molecule FXIa inhibitor milvexian.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Single and multiple ascending doses of milvexian up to 500 mg were generally safe and well‐tolerated, with no clinically significant bleeding events. Milvexian plasma concentration was dose proportional at doses up to 200 mg q.d. The milvexian half‐life is suitable for q.d. or b.i.d. dosing. Milvexian exhibited low renal excretion and low overall variability in PK and PD parameters.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

These results can inform the future clinical development of milvexian.     

Fractures in children with Pompe disease: a potentiallong-term complication

Background  Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Classic infantile-onset disease, characterized by cardiomegaly and profound weakness, leads to death in the first year of life from cardiorespiratory failure. Reversal of cardiomyopathy and improved motor function have been shown in clinical trials of rhGAA enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme), recently approved for clinical use. Increased survival potentially unmasks long-term complications of this previously lethal disease, including risk of skeletal fracture, recently identified at our institution and not previously reported in children with Pompe disease. Objective  To report the risk of fracture in children with Pompe disease with increased survival with ERT. Materials and methods  We present four cases of fracture in patients with classic infantile Pompe disease treated with ERT at our institution, and review a study database for additional reports of fracture in this population. Results  We review 19 fractures in 14 children with Pompe disease on ERT. Conclusion  Radiologists should be familiar with and vigilant for the association of fractures and increased survival on ERT in children with Pompe disease. We discuss potential mechanisms, implications for radiographic surveillance, potential intervention, and needs for further research. Laura E. Case and Rabi Hanna contributed equally to this study.     

Percutaneous Image-Guided Irreversible Electroporation for the Treatment of Unresectable,Locally Advanced Pancreatic Adenocarcinoma

Purpose

To describe safety and effectiveness of percutaneous irreversible electroporation (IRE) for treatment of unresectable, locally advanced pancreatic adenocarcinoma (LAPC).

Hyperthermic preconditioning protects pig islet grafts from early inflammation but enhances rejection in immunocompetent mice

The induction of heat shock proteins (HSP) protects isolated islet cells against the cytotoxicity of inflammatory mediators in vitro. Very little information is available about the effect of HSP overexpression on function of preconditioned islet grafts. The present study investigated the function of heat-exposed pig islets after transplantation into immunocompetent mice in comparison with in vitro resistance against inflammatory mediators. Pig islets were preconditioned at 43 degrees C or sham treated prior to subcapsular transplantation into diabetic C57/Bl6j mice. Nondiabetic mice simultaneously receiving preconditioned and control islets were subjected to bilateral nephrectomy for determination of pig insulin. Resistance against H2O2, NO, human Il-1beta, IFN-gamma, or TNF-alpha was assessed by trypan blue exclusion and insulin determination. Heat-induced protein expression was confirmed by Western blot analysis. Graft preconditioning increased resistance against H2O2, NO, or cytokines (p < 0.05) but decreased survival in nondiabetic mice (p < 0.05) and function in diabetic mice (p < 0.01). Upregulation of caspase-3 activity as well as Bax, Fas, FasL, and DFF expression (p < 0.05) indicated simultaneous induction of apoptosis. The coexpression of HSP and proapoptotic proteins reveals the dual character of the stress response simultaneously starting mechanisms for protection and apoptosis. In vitro assays seem to reflect only insufficiently the situation of islets after transplantation.     

Is peritoneal dialysis adequate for hypercatabolic acute renal failure in developing countries?

BACKGROUND: Peritoneal dialysis (PD) is a therapeutic option for acute renal failure (ARF) in developing countries, despite concerns about inadequacy. Shorter and more efficient tidal peritoneal dialysis (TPD) was compared with continuous equilibrating peritoneal dialysis (CEPD) therapy in ARF by using their adequacies as accepted standards and analyzing the solute reduction indices (SRI). METHODS: A prospective, randomized crossover trial was performed in patients with mild to moderate hypercatabolic ARF who were assigned to CEPD and TPD therapy after an adequate washout period. Solute clearances (Kt/V, normalized creatinine clearances) were compared to NKF guidelines. Potassium and phosphate clearances, dextrose absorption, protein losses and costs were compared. Kt/V was compared to SRIdialysate, SRIKt/V. RESULTS: Eighty-seven patients with ARF received 236 sessions of dialysis (118 in each treatment). TPD resulted in higher clearances of solutes than CEPD (creatinine and urea clearances in mL/min of 9.94 +/- 2.93, 6.74 +/- 1.63 and 19.85 +/- 1.95, 10.63+/- 2.62, respectively, P=0.001). TPD and CEPD normalized creatinine clearances (L/week/1.73 m2 BSA) and Kt/V values were 68.5 +/- 4.43, 58.85 +/- 2.57 and 2.43 +/- 0.87, 1.80 +/- 0.32, respectively. CEPD did not meet standards of adequacy. TPD resulted in greater potassium and phosphate clearances, less dextrose absorption and was less expensive. CEPD resulted in less protein loss. Kt/V corresponded to SRIdialysate 0.88 +/- 0.12 (P=0.076). CONCLUSION: TPD produced higher solute clearances in less time with greater protein loss. CEPD just fell short to meet the dialysis adequacy standard. However, both TPD and CEPD are reasonable options for mild-moderate hypercatabolic ARF. Kt/V appropriately estimates solute removal in PD.     

Porcine islet graft function is affected by pretreatment with a caspase-3 inhibitor

During the isolation procedure and after transplantation islets are subjected to numerous variables associated with the induction of apoptosis. The present study investigated the effect of transient pretreatment with caspase inhibitors on function and survival of transplanted pig islets. Isolated porcine islets (3000 IEQ) were incubated overnight in 200 microM of the caspase-3 inhibitor DEVD-CMK prior to transplantation into diabetic nude mice. Glucose-stimulated insulin release of pretreated islets was assessed during static incubation. DEVD-CMK successfully prevented the expression of capase-3 and DFF as demonstrated in heat-shocked pig islets. Nevertheless, transient pretreatment of freshly isolated pig islets with DEVD-CMK resulted in a significantly decreased final graft function of 50.0% (n = 16) compared to 85.7% (n = 14) in control islets (p < 0.05). Glucose-stimulated insulin release of porcine islets (n = 6) was not significantly effected by overnight culture with DEVD-CMK. Morphological assessment revealed that this caspase-3 inhibitor significantly increased the percentage of necrosis to a small, but nevertheless significant, extent in comparison to control islets (p < 0.05). The study demonstrates that short-time pretreatment with the caspase-3 inhibitor DEVD-CMK reduces the capacity of transplanted porcine islets to restore normoglycemia in diabetic nude mice.