Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258).

M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients.

Pharmacologic profiling of corifollitropin alfa, the first developed sustained follicle stimulant.

Corifollitropin alfa (Elonva®, MSD, previously N.V. Organon or Schering-Plough Oss, The Netherlands) is a newly developed sustained follicle stimulant composed of the α subunit of human follicle-stimulating hormone (FSH) and a hybrid ß subunit formed by fusion of the human chorionic gonadotropin ß subunit carboxy terminal peptide with the ß subunit of human FSH. Binding characteristics of corifollitropin alfa at the rat FSH receptor and transactivation properties at the rat FSH receptor, human luteinizing hormone (LH) receptor, and human thyroid-stimulating hormone receptor (TSH receptor) were assessed in vitro. Bioactivity of corifollitropin alfa in rats was also assessed. Serum corifollitropin alfa levels in rats and dogs were used to derive the main pharmacokinetic parameters of corifollitropin alfa. Binding and transactivation profile of corifollitropin alfa to rat FSH receptor was specific and comparable to that of recombinant human FSH, with no intrinsic TSH receptor or LH receptor activation. From pharmacokinetic studies, circulating half-life of corifollitropin alfa was calculated to be 17.3h in rats and 46.9h in dogs, 1.5- to 2-fold longer than recombinant FSH. Corifollitropin alfa demonstrated a 2- to 4-fold increase in bioactivity (ovarian weight, serum estradiol and progesterone, ovulated ova) over recombinant FSH across all in vivo parameters assessed. These data demonstrate that corifollitropin alfa is a specific ligand with high affinity for FSH receptor, lacking intrinsic activity for LH receptor and TSH receptor. By virtue of its increased in vivo half-life, corifollitropin alfa can be a valuable alternative to FSH by acting as a sustained follicle stimulant.

In vitro and in vivo reproduction toxicology of 12 monoaminergic reuptake inhibitors: possible mechanisms of infrequent cardiovascular anomalies.

The rat Whole Embryo Culture (WEC) has been used to predict the potential teratogenicity of 12 selective/mixed monoaminergic reuptake inhibitors (MRUI). WEC results were compared with in vivo animal and human epidemiological teratogenicity data. In vitro, paroxetine and the positive control retinol were the only compounds identified as a clear teratogen, but developmental morphological indicators suggestive of a teratogenic potential were observed for most other MRUIs, including fluoxetine, citalopram and venlafaxine. No clear evidence of teratogenic potential was observed for three compounds, however, all compounds assessed showed a dose-dependent general embryotoxicity. In vivo testing of nine MRUIs for teratogenicity was limited by maternal toxicity (e.g. anorexia) without showing overt embryotoxicity (e.g. implantation loss). Next to complete absence, the cardiovascular (CV) anomalies observed (mostly) in rabbits ranged from a low incidence (e.g. above historical background of 0.35%) to a clear incidence (mean 4.1%). It is suggested that observed specific malformations in vitro (e.g. branchial bars deformed, displaced or additional otic system), not noted in any (historical) controls, may be early ontogenetic indicators for infrequent CV-anomalies observed in vivo. Despite the low incidence of anomalies in vitro or in vivo, they may yet be clinically relevant as in the case of paroxetine. Possible mechanisms are discussed, e.g. perturbed neural crest cell migration.