Name: BI 409306
Synonyms: SUB 166499
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Boehringer Ingelheim
BI 409306 is an inhibitor of phosphodisterase 9A. PDE9A is a drug target for cognitive decline in Alzheimer's and other diseases because this enzyme reduces brain levels of the second messenger cyclic guanosine monophosphate. cGMP transduces signals by the neurotransmitters nitric oxide and glutamate. This pathway modulates synaptic transmission and plasticity in the hippocampus and cerebral cortex, and is reduced in AD brain (Zhihui 2013).
No peer-reviewed publications are published on BI 409306. Prior, and since terminated, PDE9A inhibitors have been reported to increase CSF levels of cGMP and to increase hippocampal expression of the glutamate receptor subunit GluR1. They were reported to affect indicators of synaptic plasticity, such as increasing LTP in rat hippocampal slices and enhancing memory and attention on a range of behavioral assays in rats (van der Staay et al., 2008; Hutson et al., 2011; Kroker et al., 2012; Vardigan et al., 2011). Research on therapeutic PDE9A inhibitors goes back to at least 2005 (Wunder et al., 2005).
Starting in 2011, Boehringer Ingelheim thus far has conducted 13 Phase 1 studies, testing both tablets and liquid formulations for this compound in a total of about 550 people in Germany, Belgium, South Korea, and the United States. Eight studies were in healthy volunteers, three in people with Alzheimer's disease and schizophrenia. The studies assessed safety, tolerability, pharmacokinetics and -dynamics, drug interactions, single or ascending doses given once or twice daily, as well as the effect of food on BI 409306's metabolism.
Two recent Phase 1 trials, initiated in 2015, specifically assess cardiac effects and disorders of the eye, respectively. At AAIC 2015, Boehringer Ingelheim presented data from a prior Phase 1 trial in Japanese and Chinese healthy male volunteers, which noted light phobia and other visual adverse effects (Wunderlich et al., 2015, available as AAIC abstract on company website).
In December 2014 and January 2015, respectively, two three-month, multinational Phase 2 trials of BI 409306 began in patients with prodromal AD. One study will compare four doses of BI 409306 to placebo in 288 people with mild to moderate Alzheimer's who have not taken a cholesterase inhibitor or memantine in the past three months; the other will compare the same doses as add-on therapy in 336 patients who also take donepezil. For both studies, the primary outcome measure is the neuropsychological test battery (NTB), secondary outcomes include the ADCS-MCI-ADL, CDR-SB, ADAS-Cog11, and ADCS-ADL.
BI 409306 is also being evaluated for cognitive benefit in schizophrenia. For all trials of this compounds, see clinicaltrials.gov.
- Wunderlich KA, Tanimoto N, Grosche A, Zrenner E, Pekny M, Reichenbach A, Seeliger MW, Pannicke T, Perez MT. Retinal functional alterations in mice lacking intermediate filament proteins glial fibrillary acidic protein and vimentin. FASEB J. 2015 Dec;29(12):4815-28. Epub 2015 Aug 6 PubMed.
- Zhihui Q. Modulating nitric oxide signaling in the CNS for Alzheimer's disease therapy. Future Med Chem. 2013 Aug;5(12):1451-68. PubMed.
- van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schröder UH, Hendrix M. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology. 2008 Oct;55(5):908-18. PubMed.
- Hutson PH, Finger EN, Magliaro BC, Smith SM, Converso A, Sanderson PE, Mullins D, Hyde LA, Eschle BK, Turnbull Z, Sloan H, Guzzi M, Zhang X, Wang A, Rindgen D, Mazzola R, Vivian JA, Eddins D, Uslaner JM, Bednar R, Gambone C, Le-Mair W, Marino MJ, Sachs N, Xu G, Parmentier-Batteur S. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in. Neuropharmacology. 2011 Sep;61(4):665-76. PubMed.
- Kroker KS, Rast G, Giovannini R, Marti A, Dorner-Ciossek C, Rosenbrock H. Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. Neuropharmacology. 2012 Apr;62(5-6):1964-74. PubMed.
- Vardigan JD, Converso A, Hutson PH, Uslaner JM. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 attenuates a scopolamine-induced deficit in a novel rodent attention task. J Neurogenet. 2011 Dec;25(4):120-6. PubMed.
- Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Mol Pharmacol. 2005 Dec;68(6):1775-81. PubMed.
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