BCX9930 is a potent, selective oral inhibitor of complement Factor D that inhibits the activation of the complement alternative pathway (AP) and has the potential for treatment of complement-mediated diseases. This was a first-in-human, randomized, double-blind, placebo-controlled study that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy participants. Safety and tolerability were evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 were measured using validated liquid chromatography-dual mass spectrometry; PD effects were assessed via multiple assays. Participants were enrolled into seven single dose cohorts (10-2000 mg) and eight multiple-dose cohorts (50-500 mg every 12 h [Q12h] and 1000-2000 mg every 24 h [Q24h]). Enrollment comprised 152 participants (122 received BCX9930 and 30 received placebo). Following BCX9930 administration, plasma exposure was approximately dose proportional across all doses. The effective half-life (t1/2) ranged from 6.45 to 7.75 h for Q12h doses at steady state. Clearance and times to maximum concentration (Tmax) were similar across all doses studied, without evidence of dose- or time-dependent clearance. BCX9930 administration resulted in rapid, potent, and dose-dependent AP inhibition. Doses ≥200mg Q12h and ≥1000 mg Q24h achieved maximal suppression (>98% relative to baseline levels) of AP activity over the full dosing interval. No clinically significant dose-related trends in adverse events (AEs), laboratory values, vital signs, or electrocardiograms were noted. BCX9930 was safe and generally well tolerated in this first-in-human study and displayed highly favorable PK and PD profiles. These results support Factor D inhibition as a promising strategy for treatment of complement-mediated diseases.

Herein, we report a pair of regioselective N 1- and N 2 -alkylations of a versatile indazole, methyl 5-bromo-1H-indazole-3-carboxylate (6) and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty N 1- and N 2-alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the N 1-substituted products when cesium is present and other non-covalent interactions (NCIs) drive the N 2-product formation. Methyl 1H-indazole-7-carboxylate (18) and 1H-indazole-3-carbonitrile (21) were also subjected to the reaction conditions and their mechanisms were evaluated. The N 1- and N 2-partial charges and Fukui indices were calculated for compounds 6, 18, and 21 via natural bond orbital (NBO) analyses which further support the suggested reaction pathways.

Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.