The Society for Medicines Research was hosting the “Recent Disclosures of Clinical Candidates” meeting on Thursday 4th December. The talks covered an array of novel molecular therapeutics across several target classes and therapeutic areas, including oncology (inhibitors of BTK and Mdm2), pain (Nav1.7 modulation), CNS (highly selective M1 agonists and BACE1 inhibitors), bacterial infection (inhibitors of C. diff.) and allergic inflammation (intranasal TLR7 agonists). Below are a couple of highlights from the meeting.
Keith Biggadike (GSK) gave a talk on the discovery and early discovery of an intranasal TLR7 agonist.
GSK2245035 is a novel small molecule TLR7 agonist in development as an immunomodulatory, intranasal treatment for allergic airways disease aiming to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type1 interferons (IFN). Although the structure was not disclosed, a series of close analogues were described.
GSK2245035 was reported as a highly potent TLR7 agonist inducing IFNa production in human in vitro assays (pEC50 blood 9.5) whilst showing selectivity over the pro-inflammatory cytokine TNFa (pEC50 blood 5.0). The compound was also reported to be selective over the other Toll-Like Receptors (and in particular 3, 8 & 9), had low oral bioavailability and high clearance.
1% oral bioavailability, T1/2 (IV) 1.4h, Vss 2.7l/kg, PPB 73%
pEC50 blood 9.5 IFNa, pEC50 blood 5.0 TFNa
GSK2245035 showed comparable IFNa potency and IFNa/TNFa selectivity in Cynomolgus monkey and human blood cultures. Biomarkers of target engagement with IP-10 in Cynomolgus monkey were identified to support the dose selection in clinical studies.
Ian Storer (Pfizer Neusentis) made the first disclosure of one of Pfizer’s NaV1.7 modulator for the treatment of pain. The channel subtype NaV 1.7 has been shown to be essential for the normal sensation of pain. Ian’s presentation covered the identification and optimisation of an acyl sulphonamide series as the first generation of Nav1.7
The initial selectivity of the lead compound PF-5241328 came from an initial file screening and believed to bind to a novel voltage sensor domain. However, the initial series suffered from Cyp inhibition and poor PK. Further SAR optimisation led to acidic isosteres in the form of acyl sulphonamides
The selected compounds showed good in vitro ADME but had an invitro/invivo mismatch due to active transporters linked to the acidic series. High dose in man was also predicted due to the low clearance (1450 to 3150 ml/min/kg). Overall, 4 compounds were advanced to human microdose studies and showed poor PK which led to the series to be halted. Further disclosures on the follow up series are due to be presented mid 2015.