Name: 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 2)
Company: Boehringer Ingelheim
This compound is a glycine transporter inhibitor that is being developed for the treatment of schizophrenia but was discontinued for Alzheimer's disease. 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). 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 on this compound are published.
In March 2014, Boehringer Ingelheim started up a series of Phase 1 trials—seven as of May 2018—to evaluate the safety, bioavailability, and pharmacokinetics 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 showing BI 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 pharmacokinetic 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). Pharmacokinetics 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 topline 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.
For all trials of this compound, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 31 Jul 2020
- Moschetti V, Boland K, Feifel U, Hoch A, Zimdahl-Gelling H, Sand M. First-in-human study assessing safety, tolerability and pharmacokinetics 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.
- 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 Pharmacokinetics. Clin Drug Investig. 2018 Aug;38(8):737-750. PubMed.
- 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 Pharmacokinetics 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.
- Moschetti V, Desch M, Goetz S, Liesenfeld KH, Rosenbrock H, Kammerer KP, Wunderlich G, Wind S. Safety, Tolerability and Pharmacokinetics 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 Pharmacokinet. 2018 Apr;43(2):239-249. PubMed.
- 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.
- Tsuda Y, Ugai H, Wunderlich G, Shin JG. Pharmacokinetics 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.
- Lakhan SE, Caro M, Hadzimichalis N. NMDA Receptor Activity in Neuropsychiatric Disorders. Front Psychiatry. 2013;4:52. Epub 2013 Jun 10 PubMed.
- Hashimoto K. Glycine transport inhibitors for the treatment of schizophrenia. Open Med Chem J. 2010 May 27;4:10-9. PubMed.
- Harvey PD, Bowie CR, McDonald S, Podhorna J. Evaluation of the Efficacy of BI 425809 Pharmacotherapy in Patients with Schizophrenia Receiving Computerized Cognitive Training: Methodology for a Double-blind, Randomized, Parallel-group Trial. Clin Drug Investig. 2020 Apr;40(4):377-385. PubMed.