Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers

Abstract

GSK2982772 is a highly selective inhibitor of receptor‐interacting protein kinase 1 (RIPK1) being developed to treat chronic inflammatory diseases. This first‐in‐human study evaluated safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of GSK2982772 administered orally to healthy male volunteers. This was a Phase I, randomized, placebo‐controlled, double‐blind study. In Part A, subjects received single ascending doses of GSK2982772 (0.1‐120 mg) or placebo in a crossover design during each of 4 treatment periods. In Part B, subjects received repeat doses of GSK2982772 (20 mg once daily [QD] to up to 120 mg twice daily [BID]) or placebo for 14 days. Part C was an open‐label relative bioavailability study comparing 20‐mg tablets vs capsules. Safety, tolerability, pharmacokinetics (PK), RIPK1 target engagement (TE), and pharmacodynamics (PD) were assessed. The most common adverse events (AEs) were contact dermatitis and headache. Most AEs were mild in intensity, and there were no deaths or serious AEs. The PK of GSK2982772 was approximately linear over the dose range studied (up to 120 mg BID). There was no evidence of drug accumulation upon repeat dosing. Greater than 90% RIPK1 TE was achieved over a 24‐hour period for the 60‐mg and 120‐mg BID dosing regimens. Single and repeat doses of GSK2982772 were safe and well tolerated. PK profiles showed dose linearity. The high levels of RIPK1 TE support progression into Phase II clinical trials for further clinical development.

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

“…Taken together, our results identify S166 autophosphorylation as an essential event for the activation of RIPK1-dependent cell death and the pathogenesis of inflammatory pathologies in vivo in relevant mouse models. These findings support the important role of S166 phosphorylation as a biomarker for RIPK1-mediated pathologies, which will be crucial in order to better stratify human patients to identify those that are more likely to benefit from treatment with RIPK1 inhibitors that reached phase II clinical trials 24,25 .…”

“…Furthermore, RIPK1 kinase activity emerged as driver of ischemic injury [18][19][20] as well as neurodegenerative diseases such as multiple sclerosis (MS) 21 , ALS (amyotrophic lateral sclerosis) 22 and Alzheimer's disease 23 . These studies identified RIPK1 kinase activity as a key factor contributing to the pathogenesis of inflammatory diseases, prompting the development of RIPK1 kinase inhibitors [24][25][26][27][28] that reached clinical trials for the treatment of inflammatory and neurodegenerative diseases as well as pancreatic cancer 24,25 .…”

Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity

“…The present study provides insight into the basic mechanisms underlying drug-induced hearing loss and, importantly, opens up avenues for pharmacological intervention toward clinical therapy. The potential clinical uses of the small-molecule inhibitor RIPK1 Nec-1s, which can pass the blood-brain barrier, are already being investigated for neurodegenerative diseases (Zhang et al, 2017), and clinical trials are underway for other necroptosis inhibitors (Weisel et al, 2017). It seems prudent that this class of medication may be translated into clinical studies to assess its otoprotective capabilities.…”

Necroptosis and apoptosis contribute to cisplatin and aminoglycoside ototoxicity

“…The present study provides insight into the basic mechanisms underlying drug-induced hearing loss, and importantly, opens up avenues for pharmacological intervention towards clinical therapy. The potential clinical uses of the small molecule inhibitor RIPK1 Nec-1s, which can pass the blood-brain barrier, are already being investigated for neurodegenerative diseases (Zhang et al, 2017), and clinical trials are underway for other necroptosis inhibitors (Weisel et al, 2017). It seems prudent that this class of medication may be translated to clinical studies to assess its otoprotective capabilities.…”