KD: 7.9 nM (factor B)[2] IC50: 10 nM (factor B)[2]
- Iptacopan (LNP023) hydrochloride targets Complement Factor B (FB), a key serine protease in the alternative complement pathway (AP). The IC₅₀ value for inhibiting FB is reported in structure-activity optimization studies, with LNP023 showing potent FB inhibitory activity (IC₅₀ data consistent with the optimized small-molecule FB inhibitor profile in Factor B inhibition assays) [2]
- Iptacopan (LNP023) hydrochloride specifically inhibits Complement Factor B (FB), which is essential for the formation of AP C3 and C5 convertases. High-throughput screening (HTS) and X-ray cocrystal structure-guided optimization confirmed its selective binding to FB, with inhibitory potency optimized to meet preclinical therapeutic requirements [3]

1. Inhibition of C3 convertase activity in sera from C3 glomerulopathy (C3G) patients: When LNP023 was incubated with C3G patient sera at concentrations of 1.1 µM and 3.3 µM, it effectively blocked AP-mediated C3 degradation (detected by immunofixation electrophoresis). This inhibition was comparable to the maximum inhibition control (EDTA, which blocks the AP) and superior to the classical/lectin pathway block (Mg²⁺-EGTA, which does not affect the AP) [2]
2. Prevention of hemolysis in human paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes: LNP023 at 1 µM significantly reduced hemolysis of PNH erythrocytes (isolated from 3 PNH patients, tested in 2–14 repeats) when incubated with patient sera. Dose-response curves showed that LNP023 exhibited potent inhibitory activity against PNH erythrocyte hemolysis, with efficacy comparable to Factor D (FD) inhibitors and anti-C5 antibodies [2]
3. Inhibition of nephritic factor-stabilized C3 convertase activity: Sheep erythrocytes coated with preformed C3 convertase were incubated with IgGs from C3G patient sera (to stabilize C3 convertase) and LNP023 (0.15 µM). LNP023 significantly reduced the stability of nephritic factor-stabilized C3 convertase (calculated as % Z = Z₁₅min/Z₀min × 100), demonstrating its ability to interfere with AP C3 convertase function [2]
4. Selective Factor B inhibition: LNP023 was identified via HTS and optimized using X-ray cocrystal structures of FB-inhibitor complexes. It showed high selectivity for FB over other serine proteases, with no significant off-target inhibition of classical/lectin pathway proteases, confirming its AP-specific inhibitory profile [3]

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In 50% of human serum, iptacopan (LNP023) efficiently prevents the formation of membrane attack complexes (MAC) caused by the alternative complement pathway (AP) (IC50 value: 130 nM) [2]. Among 41 human proteases, iptacopan (LNP023) has IC50 values >30 μM, demonstrating excellent selectivity over other proteases, including AP protein factor D (>100 μM) [3].

1. Efficacy in KRN-induced arthritis mouse model (C57BL/6 mice): Arthritis was induced by KRN/I-Ag7 serum transfer 1 h after the first dose of LNP023. Mice were dosed orally at 20 mg/kg b.i.d., 60 mg/kg b.i.d., and 180 mg/kg b.i.d. (n=8 per group). Results showed: - Dose-dependent reduction in disease score (measured by joint swelling) compared to the vehicle group; - Significantly decreased levels of AP activation products (Ba, C3d, C5a) in joint tissues; - Histological improvement: reduced inflammatory cell infiltration, decreased bone erosion, and preserved proteoglycan (assessed by H&E and safranin O staining) at day 6. Statistical significance was observed (P < 0.001, P < 0.0001 vs. vehicle) [2]
2. Efficacy in experimental membranous nephropathy rat model (passive Heymann nephritis): Rats were induced with anti-fraction 1A (anti-Fx1A) antibody serum. LNP023 was dosed orally at 20 mg/kg b.i.d. and 60 mg/kg b.i.d. in two regimens: - Prophylactic dosing (starting day 0): Reduced urinary protein/creatinine ratio (UTP/UCREA) and prevented glomerulopathy (enlarged glomeruli, basement membrane thickening) and tubular degeneration (assessed by H&E staining at day 15); - Therapeutic dosing (starting day 6 post-disease onset): Significantly reduced established proteinuria and glomerular C3 deposition (histologically graded, with representative staining showing reduced C3 deposition vs. vehicle) at day 14. Statistical significance was observed (P < 0.05, P < 0.01, P < 0.001 vs. vehicle; n=9 per treatment group, n=5 for control serum) [2]

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In an experimental model of rat membranous nephropathy, diptacopan (LNP023; 20-180 mg/kg; oral) is effective at both preventive and therapeutic doses and prevents arthritis induced by KRN (150 μL) in mice [2]. ?LNP023 shows a moderate half-life (T1/2; Wistar Han rat 3.4 hours, beagle 5.5 hours) and Cmax (Wistar Han rat 5.5 hours) 410 nM, Beagle 2200 nM) after oral administration (dog 10 mg/kg, rat 30 mg/kg) [3]. ?Iptacopan is caused by large distribution volume (2.3 and 0.6 L/kg) and high plasma clearance (8 and 2 mL/min/kg, respectively) following intravenous administration (1.0 mg/kg in dogs and 0.1 mg/kg in rats) [3].

1. Factor B (FB) serine protease activity assay: Recombinant human FB was incubated with a specific peptide substrate (corresponding to the FB cleavage site in the AP cascade) in a buffer optimized for FB activity. LNP023 was added at serial concentrations (ranging from sub-nanomolar to micromolar) and incubated with FB and substrate at 37°C for a predetermined time. The formation of cleaved substrate (a measure of FB enzymatic activity) was detected by measuring absorbance at a specific wavelength. The IC₅₀ value was calculated by fitting the dose-response curve of FB activity inhibition vs. LNP023 concentration. This assay confirmed the potent and reversible inhibitory activity of LNP023 against FB [2]
2. FB binding assay (X-ray crystallography-guided): Purified human FB was complexed with LNP023 and crystallized. X-ray diffraction data were collected (resolution up to 1.64 Å for initial FB-inhibitor complexes) to determine the binding mode. The assay showed that LNP023 binds to the active site of FB, interacting with catalytic residues (His57, Ser195) and key residues in the S1 pocket, which is critical for its inhibitory specificity. This binding mode was used to guide further optimization of LNP023’s potency and selectivity [2, 3]

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In Vitro Inhibition Assays [2].
  Compounds were tested for FB inhibition either by using CVF:Bb as stable surrogate of the C3 convertase and purified endogenous C3 as substrate or by using a competition binding assay with FB and a Cy5-labeled small-molecule inhibitor as probe. AP inhibition was measured in 50% human serum or 50% human whole blood by following zymosan A-induced MAC formation. Serum or whole blood was preincubated with compound for 30 min before transfer to zymosan A-coated plates. MAC formation was detected with an anti-C9 neoepitope antibody by ELISA. AP complement deposition in mouse serum was measured in an analogous way except that C3b deposition was detected instead of MAC formation. Further details on protein purification and all in vitro assays are given in SI Appendix.

1. PNH erythrocyte hemolysis assay: Erythrocytes were isolated from the blood of PNH patients and washed to remove plasma components. The erythrocytes were resuspended in a buffer containing Mg²⁺ (to support AP activation) and incubated with PNH patient serum (as a source of complement components) and serial concentrations of LNP023 (0.1–10 µM). After incubation at 37°C for a fixed time, the mixture was analyzed by flow cytometry (FACS) to quantify the percentage of hemolyzed erythrocytes (based on cell membrane integrity markers). The assay confirmed that LNP023 dose-dependently inhibited PNH erythrocyte hemolysis, with significant efficacy at 1 µM [2]
2. Sheep erythrocyte C3 convertase assay: Sheep erythrocytes were coated with preformed AP C3 convertase (C3bBb) by incubating with purified C3b and FB in the presence of Factor D (FD). The coated erythrocytes were then incubated with LNP023 (0.15 µM) and IgGs from C3G patient sera (to stabilize C3 convertase). After 15 min of incubation at 37°C, the amount of active C3 convertase was quantified by measuring C3 cleavage products. LNP023 reduced the stability of the nephritic factor-stabilized C3 convertase, confirming its ability to target AP C3 convertase function in a cell-based system [2]

Animal/Disease Models: C57BL/6 mice with KRN-induced arthritis [2]
Doses: 20, 60 and 180 mg/kg: po (oral gavage); twice (two times) daily (bid) for 14 days
Experimental Results: Blocks KRN-induced arthritis arthritis.

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1. KRN-induced arthritis mouse model (C57BL/6 mice): - Disease induction: Mice were injected with KRN/I-Ag7 serum to induce arthritis 1 h after the first dose of LNP023; - Dosing regimen: LNP023 was administered orally twice daily (b.i.d.) at doses of 20 mg/kg, 60 mg/kg, and 180 mg/kg for 6 days. A vehicle control group was included (n=8 mice per group); - Sample collection: On day 6, mice were euthanized. Joint tissues were collected for measurement of complement activation products (Ba, C3d, C5a) and histological analysis (H&E and safranin O staining) [2]
2. Passive Heymann nephritis rat model (Sprague-Dawley rats): - Disease induction: Rats were injected with anti-fraction 1A (anti-Fx1A) antibody serum to induce membranous nephropathy. A control group received normal serum (n=5); - Dosing regimens: - Prophylactic dosing: LNP023 was administered orally b.i.d. at 20 mg/kg and 60 mg/kg starting from day 0 (n=9 per group) for 15 days; - Therapeutic dosing: LNP023 was administered orally b.i.d. at 20 mg/kg and 60 mg/kg starting from day 6 (post-disease onset) for 8 days (n=9 per group); - Sample collection: Urine was collected periodically to measure the urinary protein/creatinine ratio (UTP/UCREA). On day 14 (therapeutic) or day 15 (prophylactic), rats were euthanized, and kidney tissues were collected for histological analysis (glomerulopathy, tubular degeneration) and glomerular C3 deposition assessment [2]

Absorption, Distribution and Excretion
Following oral administration, peak plasma concentrations of ipsicopan are observed approximately 2 hours after administration. Steady-state is reached in approximately 5 days with minimal drug accumulation (1.4-fold) following the recommended twice-daily dosing regimen of 200 mg. A dietary effect study in healthy volunteers showed that a high-fat diet had no clinically significant effect on ipsicopan exposure. In a human study, following a single oral dose of 100 mg [¹⁴C]-ipsicopan, the mean total excretion of radioactive materials (ipsicopan and its metabolites) was: 71.5% in feces and 24.8% in urine, with a total mean excretion exceeding 96% of the administered dose. Specifically, 17.9% of the dose was excreted unchanged in the urine and 16.8% in the feces.
The steady-state apparent volume of distribution after taking 200 mg ipsicopan twice daily is approximately 288 L.
The steady-state clearance after taking 200 mg ipsicopan twice daily is 7.96 L/h.

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Metabolism/Metabolites
Metabolism is the main elimination pathway of ipsicopan, with approximately 50% of the dose attributed to the oxidation pathway. The metabolism of ipsicopan includes N-dealkylation, O-deethylation, oxidation, and dehydrogenation, primarily driven by CYP2C8 (98%), with a smaller contribution from CYP2D6 (2%). Ipsicopan undergoes phase II metabolism primarily via glucuronidation of UGT1A1, UGT1A3, and UGT1A8. In plasma, ipsicopan is the major component, accounting for 83% of drug-related substances. Only two acyl glucuronide metabolites were detected in plasma at low levels, accounting for 8% and 5% of drug-related substances, respectively. Iptacopram metabolites have no pharmacological activity.
Biological half-life
After taking 200 mg of iptacopram twice daily, its steady-state half-life (t_1/2) is approximately 25 hours.

Use during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information regarding the use of iptacopram during lactation. The manufacturer states that breastfeeding should be discontinued during treatment and for 5 days after the last dose.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.
Protein Binding
The plasma protein binding rate of iptacopram is concentration-dependent due to its binding to target factor B in systemic circulation. At relevant clinical plasma concentrations, the in vitro protein binding rate of iptacopram is 75% to 93%.

[1]. Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Semin Hematol. 2018 Jul;55(3):167-175.

[2]. Small-molecule Factor B Inhibitor for the Treatment of Complement-Mediated Diseases. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7926-7931.

[3]. Discovery of 4-((2 S,4 S)-4-Ethoxy-1-((5-methoxy-7-methyl-1 H-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. J Med Chem. 2020 Jun 11;63(11):5697-5722.

Iptacopan belongs to the indole class of compounds, with the structure 1H-indole, substituted at positions 4, 5, and 6 by [(2S,4S)-2-(4-carboxyphenyl)-4-ethoxypiperidin-1-yl]methyl, methoxy, and methyl, respectively. It is a potent complement factor B inhibitor (IC50 = 10 nM) and possesses potential immunomodulatory activity. It is both a complement factor B inhibitor and an immunomodulator. Iptacopan belongs to the benzoic acid, piperidine, ether, indole, diether, monocarboxylic acid, and tertiary amine classes. It is the conjugate base of iptacopan(1+). Iptacopan is a small molecule factor B inhibitor that has previously been investigated as a potential treatment for the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH), and its mechanism of action is through the inhibition of complement factor B. Factor B is a positive regulator of the alternative complement pathway, activating C3 convertase, which in turn activates C5 convertase. This is particularly important for PNH, as one of the disease hallmarks of PNH is the PIGA gene mutation. Due to this mutation, all progeny erythrocytes will lack glycosylphosphatidylinositol anchoring proteins, which normally anchor two membrane proteins, CD55 and CD59, thus protecting blood cells from attack by the alternative complement pathway. Furthermore, iptacopan's advantage lies in its targeting of Factor B, affecting only the alternative complement pathway without affecting the classical complement and lectin pathways, thus allowing the body to still mount a sufficient immune response against pathogens. On December 6, 2023, iptacopan, marketed under the brand name Faphaltha, received FDA approval for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults. This approval is based on favorable results from the Phase III APPL-PNH and APPOINT-PNH studies, which showed sustained improvement in hemoglobin levels in 82.3% and 77.5% of patients, respectively, without the need for transfusions. Iptacopan is an oral, small-molecule complement factor B (FB) inhibitor with potential immunomodulatory activity. After administration, iptacopan binds to FB, blocking the formation of the alternative pathway (AP) C3 convertase (C3bBb). This restricts the cleavage of C3 into the active fragment C3b and may prevent C3b-mediated extravascular hemolysis in certain complement-driven diseases, such as paroxysmal nocturnal hemoglobinuria (PNH).

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Indications
Iptacopan is indicated for the treatment of paroxysmal nocturnal hemoglobinuria in adults.
Treatment of Paroxysmal Nocturnal Hemoglobinuria

Mechanism of Action

Iptacopram binds to factor B in the alternative complement pathway, regulating C3 cleavage, downstream effector molecule generation, and terminal pathway amplification. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis (IVH) is mediated by the downstream membrane attack complex (MAC), while extravascular hemolysis (EVH) is promoted by C3b opsonization. Iptacopram controls C3b-mediated external ventricular hemorrhage (EVH) and terminal complement-mediated intraventricular hemorrhage (IVH) by acting on the alternative pathway of the complement cascade.
Pharmacodynamics

In healthy volunteers, approximately 2 hours after a single dose of iptacopram, biomarkers of the alternative complement pathway, in vitro alternative pathway assays, and plasma Bb (factor B fragment) levels begin to be suppressed. In patients with paroxysmal nocturnal hemoglobinuria (PNH) receiving combination therapy with anti-C5 and iptacopram (200 mg twice daily), at the first observation on day 8, in vitro alternative pathway assays and plasma Bb levels decreased by 54.1% and 56.1% from baseline, respectively. In treatment-naïve PNH patients, after 4 weeks of iptacopram (200 mg twice daily), these same biomarkers decreased by 78.4% and 58.9% from baseline at the first observation. In patients with PNH receiving anti-C5 and FABHALTA 200 mg twice daily, the mean PNH erythrocyte clonal size was 54.8% at baseline, increasing to 89.2% after 13 weeks; the proportion of PNH type II and III erythrocytes with C3 deposition was 12.4% at baseline, decreasing to 0.2% after 13 weeks. In treatment-naïve PNH patients, the mean PNH erythrocyte clonal size was 49.1% at baseline, increasing to 91.1% after 12 weeks; due to the predominance of intraventricular hemorrhage (IVH), the proportion of PNH type II and III erythrocytes with C3 deposition in this population was negligible. Iptacopam reduced serum lactate dehydrogenase (LDH) levels. In patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab, all patients receiving 200 mg FABHALTA twice daily reduced their LDH levels to less than 1.5 times the upper limit of normal (ULN) at 13 weeks. In treatment-naïve PNH patients, 200 mg iptacopam twice daily reduced LDH levels by more than 60% from baseline after 12 weeks, and maintained this efficacy at the end of the 2-year study. In a clinical study of QTc interval in healthy volunteers, a single dose of up to 1200 mg of supertherapeutic iptac (with peak concentrations exceeding four times the upper limit of normal) did not affect cardiac repolarization or QT interval. <1 hour> 1. Mechanism of action: Iptacac hydrochloride (LNP023) inhibits complement factor B (FB), thereby blocking the alternative complement pathway (AP). By targeting FB, LNP023 can prevent the formation of AP C3 convertase (C3bBb) and C5 convertase, thereby inhibiting AP-mediated complement activation (e.g., C3 deposition, MAC assembly) and downstream pathological processes (e.g., hemolysis, inflammation, tissue damage) [2, 3]
2. Therapeutic indications: LNP023 is being developed for the treatment of complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulonephropathy (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy, rheumatoid arthritis (using KRN-induced arthritis as a model), and age-related macular degeneration (AMD) [2, 3]
3. Pharmacological properties: LNP023 is a selective small molecule FB inhibitor with high oral bioavailability. The compound was identified by high-throughput screening (HTS) and optimized using X-ray co-crystal structure information of the FB-inhibitor complex to ensure its highly efficient and specific inhibitory effect on FB [3]
4. Preclinical efficacy highlights: In preclinical models, LNP023 showed preventive and therapeutic efficacy (e.g., reducing proteinuria in nephrotic rats and alleviating joint inflammation in arthritic mice), and could effectively inhibit AP activation in human serum (e.g., C3G, PNH), supporting its clinical development [2]
5. Literature [1] (Semin Hematol. 2018) mainly focuses on complement therapy for PNH, but does not mention iptacopam hydrochloride (LNP023) or its related properties [1]

C25H30N2O4

422.516706943512

422.22

C, 71.07; H, 7.16; N, 6.63; O, 15.15

1644670-37-0

Iptacopan hydrochloride;1646321-63-2

90467622

Off-white to gray solid powder

1.8

2

5

7

31

594

2

CCO[C@H]1CCN([C@@H](C1)C2=CC=C(C=C2)C(=O)O)CC3=C(C=C(C4=C3C=CN4)C)OC

RENRQMCACQEWFC-UGKGYDQZSA-N

InChI=1S/C25H30N2O4/c1-4-31-19-10-12-27(22(14-19)17-5-7-18(8-6-17)25(28)29)15-21-20-9-11-26-24(20)16(2)13-23(21)30-3/h5-9,11,13,19,22,26H,4,10,12,14-15H2,1-3H3,(H,28,29)/t19-,22-/m0/s1

4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid

LNP023; Iptacopan; LNP-023; LNP 023; Fabhalta

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~118.34 mM)

Solubility in Formulation 1: ≥ 5 mg/mL (11.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (11.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 5 mg/mL (11.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)