Avelestat for treatment of graft rejection, occlusive bronchiobronchitis syndrome and graft versus host disease
A technology for graft rejection and bronchiolitis, applied in the field of avelestat or its pharmaceutically acceptable salt and/or solvate, capable of solving problems such as increased risk of infection and high risk of adverse events
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Embodiment 1
[0126] Example 1 - Avelestat is a Potent and Specific Inhibitor of Neutrophil Elastase (NE)
[0127] As discussed further in [3], the following results were obtained.
[0128] Avelestat has high binding affinity for human NE (K D =9.5nM) and effectively inhibited NE activity. Calculation of avilestat for human NE p IC 50 (IC 50 ) and K i The values were 7.9 (12 nM) and 9.4 nM, respectively.
[0129] Avelestat is at least 600-fold more selective for human NE compared to another serine protease, cathepsin G, and is comparable to other serine proteases (protease-3, chymotrypsin, pancreatic elastase, and trypsin) In contrast, the selectivity for human NE is at least 1900-fold higher.
[0130] Avelestat showed good cross potency against NE from other species, including mice.
[0131] in whole blood, cell-related and burst release assays p IC 50 (IC 50 ) values were 7.36 (44 nM), 7.32 (48 nM) and 7.30 (50 nM), respectively.
[0132] The results presented show that ...
Embodiment 2
[0133] Example 2 - Avelestat shows protection against GVHD
[0134] This preclinical study was conducted to evaluate the efficacy of avelelostat in the prevention of GVHD. Given the similar potency of avilestat against murine and human NE (pIC50 6.5 vs 7.9), preclinical murine studies are reasonable [3].
[0135] The murine model of GVHD used in this study is described in [4]. BALB / c recipients received lethal irradiation (8.5 Gy whole body irradiation) before transplantation of T cell depleted bone marrow + / - purified T cells from B10.D2 donors. Negative controls received T cell depleted bone marrow (TCDBM) only (no T cells, no GVHD), while positive controls received TCDBM + 2 x 10 6 T cells (100% lethal GVHD). In the treatment groups, mice received avelelostat at 20 mg / kg, 50 mg / kg, and 200 mg / kg per day on days -1 to 45 via a premixed custom diet or as a powder added to wet food. These doses are based on theoretical considerations and previous work in rodents (eg [5])...
Embodiment 3
[0150] Example 3 - Prevention of BOS in Patients After Lung Transplantation
[0151] Avelestat was administered as part of a multicenter, randomized, standard-of-care controlled study to demonstrate that, in addition to standard immunosuppression regimens, Avelenostat improved survival when given prophylactically to lung transplant recipients and efficacy and safety in the prevention of BOS.
[0152] During the study period, starting immediately after lung transplantation, patients were administered avilestat at doses up to 240 mg twice daily. Therapy lasts 2 years and can be extended for up to 5 years.
[0153] Inclusion criteria:
[0154] patients who have received lung transplantation (single or double),
[0155] · Patients who are able to consent and enroll within 30 days of receiving a lung transplant.
[0156] Exclusion criteria:
[0157] History of heart-lung transplant, lung retransplantation, or another solid organ transplant
[0158] Clinically significant st...
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