Iclepertin | ALZFORUM (2024)

Name: Iclepertin
Synonyms: BI 425809
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (Phase 3)
Company: Boehringer Ingelheim

This compound is a glycine transporter inhibitor that was being develped for the treatment of Alzheimer's disease, then discontinued; it remains in development for schizophrenia. The rationale behind this approach is that abnormalities in glutamatergic signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in both these diseases, hence boosting NMDA receptor function might benefit synaptic plasticity and cognition (Lakhan et al., 2013;Rosenbrock et al., 2022). The amino acid neurotransmitter glycine is an obligatory NMDA receptor co-agonist. Glycine transporters GlyT-1 and GlyT-2 located in presynaptic and astrocyte membranes take up glycine into the nerve terminal and adjacent glial cells, thus modulating glycine levels in the synaptic cleft (Hashimoto, 2010). By blocking these receptors, BI 425809 is proposed to increase glycine levels and its ability to modulate NMDA receptor function.No preclinical data related to Alzheimer’s are published on this compound.

In March 2014, Boehringer Ingelheim started up a series of Phase 1 trials—seven as of May 2018—to evaluate the safety, bioavailability, and pharmaco*kinetics of BI 425809, as well as its potential interactions with commonly used drugs. These trials were conducted in 298 young and elderly men and women in Germany, Belgium, and Korea. Single- and multiple-ascending-dose results were reported as showingBI 425809 to be generally well-tolerated and suitable for once-daily dosing (Moschetti et al., 2016;Moschetti et al., 2018).In one multiple-dosing study, healthy volunteers showed a dose-dependent increase in CSF glycine by an average of 50 percent two weeks after the last administration (Rosenbrock et al., 2018). Detailed pharmaco*kinetic and safety data from a study in 83 healthy men were reported as showing safety and tolerability within the target dose range of up to 25 mg. Higher doses generate adverse events previously reported for glycine reuptake inhibition, such as drowsiness, fatigue, vertigo, blurred vision (Moschetti et al., 2018;Hirayasu et al., 2016).Pharmaco*kinetics and safety were similar in Caucasian, Chinese, and Japanese adults (Tsuda et al., 2019).

In August 2016, a Phase 2 study started comparing 2, 5, 10, or 25 mg daily doses of BI 425809 to placebo, taken for three months, in 610 people with early signs of Alzheimer's dementia. The primary outcome was change on the ADAS-Cog11; secondary outcomes were change on the ADCS-ADL and CIBIC+ scales. The trial made no use of biomarkers. It took place at 27 sites in North America, Austria, Finland, France, Germany, Greece, Hungary, and Spain. The study was completed in October 2019. In February 2020, Boehringer Ingelheim announced that top-line data indicated the trial was negative and that further development for Alzheimer's had stopped (press release). Data presented at the July 2020 AAIC showed that the drug had not improved cognition on any of the primary or secondary measures compared with placebo at any dose.The results were published after peer review (Wunderlich et al., 2023).

For all trials of this compound, see clinicaltrials.gov.

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Paper Citations

1. Moschetti V, Boland K, Feifel U, Hoch A, Zimdahl-Gelling H, Sand M.First-in-human study assessing safety, tolerability and pharmaco*kinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males. Br J Clin Pharmacol. 2016 Nov;82(5):1315-1324. Epub 2016 Aug 22 PubMed.
2. Moschetti V, Schlecker C, Wind S, Goetz S, Schmitt H, Schultz A, Liesenfeld KH, Wunderlich G, Desch M.Multiple Rising Doses of Oral BI 425809, a GlyT1 Inhibitor, in Young and Elderly Healthy Volunteers: A Randomised, Double-Blind, Phase I Study Investigating Safety and Pharmaco*kinetics. Clin Drug Investig. 2018 Aug;38(8):737-750. PubMed.
3. Rosenbrock H, Desch M, Kleiner O, Dorner-Ciossek C, Schmid B, Keller S, Schlecker C, Moschetti V, Goetz S, Liesenfeld KH, Fillon G, Giovannini R, Ramael S, Wunderlich G, Wind S.Evaluation of Pharmaco*kinetics and Pharmacodynamics of BI 425809, a Novel GlyT1 Inhibitor: Translational Studies. Clin Transl Sci. 2018 Nov;11(6):616-623. Epub 2018 Aug 23 PubMed.
4. Moschetti V, Desch M, Goetz S, Liesenfeld KH, Rosenbrock H, Kammerer KP, Wunderlich G, Wind S.Safety, Tolerability and Pharmaco*kinetics of Oral BI 425809, a Glycine Transporter 1 Inhibitor, in Healthy Male Volunteers: A Partially Randomised, Single-Blind, Placebo-Controlled, First-in-Human Study. Eur J Drug Metab Pharmaco*kinet. 2018 Apr;43(2):239-249. PubMed.
5. Hirayasu Y, Sato S, Takahashi H, Iida S, Shuto N, Yoshida S, Funatogawa T, Yamada T, Higuchi T.A double-blind randomized study assessing safety and efficacy following one-year adjunctive treatment with bitopertin, a glycine reuptake inhibitor, in Japanese patients with schizophrenia. BMC Psychiatry. 2016 Mar 15;16:66. PubMed.
6. Tsuda Y, Ugai H, Wunderlich G, Shin JG.Pharmaco*kinetics of Single Doses of BI 425809 in Healthy Chinese and Japanese Subjects: A Randomized Study. Clin Ther. 2019 May;41(5):961-971. Epub 2019 Apr 17 PubMed.
7. Wunderlich G, Blahova Z, Garcia M, Jessen F.Efficacy and safety of the novel GlyT1 inhibitor BI 425809 in Alzheimer's dementia: a randomized controlled trial. Alzheimers Res Ther. 2023 Jan 28;15(1):24. PubMed.
8. Lakhan SE, Caro M, Hadzimichalis N.NMDA Receptor Activity in Neuropsychiatric Disorders. Front Psychiatry. 2013;4:52. Epub 2013 Jun 10 PubMed.
9. Rosenbrock H, Dorner-Ciossek C, Giovannini R, Schmid B, Schuelert N.Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia. J Pharmacol Exp Ther. 2022 Aug;382(2):223-232. Epub 2022 Jun 5 PubMed.
10. Hashimoto K.Glycine transport inhibitors for the treatment of schizophrenia. Open Med Chem J. 2010 May 27;4:10-9. PubMed.

External Citations

1. press release
2. clinicaltrials.gov