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 (Phase 2), Schizophrenia (Phase 2)
Company: Boehringer Ingelheim
This compound is a glycine transporter inhibitor being developed for Alzheimer's disease and schizophrenia. The rationale behind this treatment approach is that abnormalities in glutamateric signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in both these diseases, hence boosting NMDA receptor function may 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 (Moschetti et al., 2018). 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 healthy 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). Later, 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).
In August 2016, a Phase 2 study started comparing four different, undisclosed doses of BI 425809 to placebo, taken for three months, in 585 people with early signs of Alzheimer's dementia. The primary outcome is change on the ADAS-cog11; secondary outcomes are change on the ADCS-ADL and CIBIC+ scales. The trial makes no use of biomarkers. It takes place at 27 sites in North America, Austria, Finland, France, Germany, Greece, Hungary and Spain, and is set to run until September 2020.
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: 25 May 2018
- 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, 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.
- Lakhan SE, Caro M, Hadzimichalis N. NMDA Receptor Activity in Neuropsychiatric Disorders. Front Psychiatry. 2013;4:52. Epub 2013 Jun 10 PubMed.
No Available Further Reading