Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases

Abstract

The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (41), which is currently being evaluated clinically in several diverse AP mediated indications.

Tipping the balance: intricate roles of the complement system in disease and therapy

“…While this indication focus may prove limiting when considering the availability of pegcetacoplan, the oral bioavailability of danicopan may open opportunities in other indications. Oral application is also the administration route of choice for the factor B (FB) inhibitor iptacopan (Novartis) [ 103 ]. As the Bb fragment of FB constitutes the enzymatic principle of the C3 convertase, iptacopan also inhibits already assembled convertases, which may provide a particular benefit over FD inhibitors in C3G, which is driven by highly stable convertases.…”

Halting targeted and collateral damage to red blood cells by the complement system

“… n.s. Preclinical Taligen Therapeutics [ 125 ] IONIS-FB-LRX Antisense RNA inhibitor SC Age-related macular degeneration; IgA nephropathy II Ionis NCT04014335 LNP023 Small molecule inhibitor Oral PNH; IgA nephropathy; C3 glomerulopathy III Novartis [ 126 ] Factor D ACH-5228 (ALXN2050) Small molecule inhibitor Oral PNH II Achillion/Alexion NCT04170023 ACH-5448 Small molecule inhibitor Oral PNH Preclinical Achillion Lampalizumab Monoclonal antibody (Fab) ITV Geographic atrophy/age-related macular degeneration III Genentech [ 127 ] Danicopan (ACH-4471) Small molecule inhibitor Oral PNH II Danicopan is currently studied in a phase III trial as an add-on to C5 inhibition in order to prevent extravascular hemolysis (ALPHA study) Achillion/Alexion [ 128 ] BCX9930 Small molecule inhibitor Oral PNH I/II BioCryst NCT04170023 MASP3 OMS906 Monoclonal antibody IV PNH Preclinical Inhibits the AP as MASP3 is the protein responsible for cleavage of pro-factor D into FD. Omeros Factor H Anti-FH.07 Potentiating monoclonal antibody n.s.…”

“…Conversely, inhibiting properdin does not completely block C3 convertase formation but rather shortens its activity [ 144 ]. Inhibition of the AP as a mechanism of action has been demonstrated to be effective in animal models of antibody-induced arthritis and membranous nephropathy, and several clinical trials in PNH are currently in progress [ 126 ]. Especially, LNP023 ( ClinicalTrials.gov : NCT03439839), ACH-5228 ( ClinicalTrials.gov : NCT03439839), danicopan ( ClinicalTrials.gov : NCT04170023), and BCX9930 ( ClinicalTrials.gov : NCT04469645) are of particular interest as these can be administered orally (Table 2 ).…”

Expanding the Role of Complement Therapies: The Case for Lupus Nephritis

“…Although not currently being studied in LN, complement fB and fD inhibitors are being evaluated in other glomerular diseases such as IgA nephropathy and C3 glomerulopathy. These include a small molecule fB inhibitor (NCT03373461), an anti-sense oligonucleotide against factor B (NCT04014335), and a small molecule fD inhibitor (NCT03369236) [62,63]. Targeting fB and fD in LN would also be expected to be effective.…”