Biocatalytic paths to the synthesis of selected metabolites of Iptacopan
In a recent paper published in celebration of the 20th birthday of the Swiss Industrial Biocatalysis Consortium, various applications of industrial biocatalysis were described [1]. One example from Novartis highlighted the production of analytical reference standards to access metabolites of Iptacopan (Fabhalta®) to support human ADME studies.
Iptacopan is a complement B factor inhibitor approved in the US and EU for the treatment of paroxysmal nocturnal hemoglobinuria and proteinuria. In March 2025, oral Fabhalta was approved by the FDA for treatment of C3 glomerulopathy, making it the first and only drug approved for this condition.
Metabolism of Iptacopan
According to prescribing information for Fabhalta® [2,3], hepatic metabolism is the predominant elimination pathway of Iptacopan via N-dealkylation, O-deethylation, oxidation, and dehydrogenation. This is mostly driven by CYP2C8 (98%) with a small contribution from CYP2D6 (2%). Iptacopan is also glucuronidated by UGT1A1, UGT1A3, and UGT1A8 to two acyl glucuronides, detected in plasma at 8% and 5% of the drug related species. Iptacopan metabolites are reported to be pharmacologically inactive.
A paper describing the radiolabelled human ADME study [4] details the metabolites observed with the primary biotransformation pathways being oxidative metabolism via CYP2C8 to M2 and acyl glucuronidation via UGT1A1 to M8 and M9.
Routes to synthesis of Iptacopan metabolites
Various biocatalytic methods were used in the preparation of metabolites of Iptacopan [1]. This included initial use of animal liver S9 fractions, human recombinant CYPs, and later, microbial biotransformation to access larger quantities of the direct acyl glucuronide M8.
- After screening a panel of human recombinant CYPs, CYP1A1 was selected to scale up for the production of the hydroxylated metabolite M6 (5a).
- The direct and indirect acyl glucuronides M8 and M9 (6a and 6b) were initially produced using horse liver S9.
- To produce more of the direct acyl glucuronide M8, a microbial biotransformation route was established following screening of a panel of microorganisms to identify the best strain. This avoided the use of animal tissues and removed the need to supplement with exogenous UDPGA.
Biocatalytic paths to synthesis of selected metabolites of Iptacopan
Stability of acyl glucuronides M8 and M9
James et al. [4] reported on the stability of the circulating acyl glucuronides. Investigations in phosphate buffer revealed half-lives of 1.6 hours and 2.0 hrs for M8 and M9 respectively. Several acyl glucuronide isomers of both M8 and M9 were detected, with additional hydrolysis of M8 to the parent compound. Studies in rat suggested that both M8 and M9 are potentially hydrolysed back to Iptacopan and M2 respectively by bacterial enzymes in the gut.
Neither of the acyl glucuronides were considered major, both being <10% of total drug-related exposure. In toxicity studies, exposure to M8 at the no-observed-adverse-effect level was similar to the human exposure at the highest phase 3 dose. Exposure to M9 was lower but was detected in circulation of both rats and dogs, and in the bile of rats.
Overall the data obtained suggested a low risk associated with both circulating acyl glucuronides.
References
[1] Bisagni, S., Eggimann, F., Eichhorn, E., Hanlon, S., Iding, H., Kravina, A., Le Chapelain, C., Neufeld, K., Rigger, L., Schroer, K., Snajdrova, R., & Siirola, E. (2025). The Swiss Industrial Biocatalysis Consortium (SIBC) turns 20!. CHIMIA, 79(5), 299-311. https://doi.org/10.2533/chimia.2025.299
[2] https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/218276s000lbl.pdf
[3] https://ec.europa.eu/health/documents/community-register/2024/20240517162437/anx_162437_en.pdf
