Name: BI 409306
Synonyms: SUB 166499
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia
U.S. FDA Status: Alzheimer's Disease (Discontinued), Schizophrenia (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 on BI 409396 preclinical data are published, but Boehringer Ingelheim published at the 2015 AAIC conference that BI 409306 increased hippocampal LTP and improved performance in an episodic memory task in rats (Rosenbrock et al., 2015). 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).
As of spring 2018, Boehringer Ingelheim had conducted 16 Phase 1 studies of this compound, testing both tablets and liquid formulations in a total of about 550 people in Germany, Belgium, South Korea, and the United States. Fourteen studies were in healthy volunteers, two in people with Alzheimer's disease or schizophrenia. The studies assessed safety, tolerability, pharmacokinetics and -dynamics of single or ascending doses given once or twice daily, as well as drug-drug interactions and the effect of food on BI 409306's metabolism. Company researchers reported at AAIC that the compound did not interact with donepezil (Wunderlich et al., 2017).
Three recent Phase 1 trials, initiated in 2015 and 2017, evaluate cardiac effects, disorders of the eye, and drug interactions with the antibiotic rifampicin, 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). Safety and pharmacokinetic data on 80 healthy volunteers were formally published (Moschetti et al., 2016).
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 compared 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 compared the same doses as add-on therapy in 336 patients who also take donepezil. For both studies, the primary outcome measure was the neuropsychological test battery (NTB); secondary outcomes included the ADCS-MCI-ADL, CDR-SB, ADAS-Cog11, and ADCS-ADL (Wunderlich et al., 2016). In February 2018, Boehringer Ingelheim announced topline results from both trials, for which data were pooled. There was no difference between drug and placebo groups on the primary outcome, and the company decided to stop developing this compound for AD (see Feb 2018 news).
BI 409306 continues being evaluated in schizophrenia. Results of one Phase 2 trial, which missed its primary endpoint of cognitive improvement, are published (Sand et al., 2017).
For all trials of this compounds, see clinicaltrials.gov.
Clinical Trial Timeline
- Wunderlich G, Schultheis C, Link J, Schultz A, Voelk C. Investigation of Pharmacokinetic Drug-Drug Interaction Following Oral Administration of BI 409306 and Donepezil in Healthy Subjects. Alzheimer's & Dementia, July 2017, Volume 13, Issue 7, Supplement
- 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.
- 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.
- Wunderlich G, Thamer C, Roehrle M, Garcia Jr M, Frölich L, Dubois B. Study Design and Characteristics of Two Phase Ii Proof-of-Concept Clinical Trials of the pde9 Inhibitor Bi 409306 in Early Alzheimer's Disease. Alzheimer's & Dementia, July 2016, Volume 12, Issue 7, Supplement
- Brown D, Nakagome K, Cordes J, Brenner R, Gründer G, Keefe RS, Riesenberg R, Walling DP, Daniels K, Wang L, McGinniss J, Sand M. Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial. Schizophr Bull. 2018 May 1; 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.
- Rosenbrock H, Marti A, Koros E, F, Fuchs H, Giovannini R, Dorner-Ciossek C. Improving synaptic plasticity and cognitive function in rodents by the novel phosphodiesterase 9A inhibitor bi 409306. Alzheimer's & Dementia, July 2015, Volume 11, Issue 7, Supplement
- 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.
No Available Further Reading