Negative topline results from two Phase 2 clinical trials have prompted Boehringer Ingelheim to halt further development of its phosphodiesterase E9A inhibitor, BI 409306, for Alzheimer’s disease (AD). The compound missed primary cognitive endpoints in both trials of prodromal AD. The company will continue to test BI 409306 as a potential therapy for schizophrenia, seeing if it staves off a first psychotic episode or prevents relapse.

  • The phosphodiesterase E9A inhibitor boosts cGMP and neurotransmission.
  • In two Phase 2 trials, treatment and placebo groups performed equally on cognitive tests.

In two three-month trials started in early 2015, Boehringer investigated whether BI 409306 improved cognition in prodromal AD (see NCT02337907 and NCT02240693). A total of 457 patients took either the drug, some as an add-on to donepezil, or placebo. Both trials used the neuropsychological test battery (NTB) as a primary endpoint, while secondary outcomes included the ADCS-MCI-ADL, CDR-SB, ADAS-Cog11, and ADCS-ADL. Results were pooled for topline data.

At the end of both studies, Boehringer scientists found no difference between drug and placebo groups on measures of efficacy. The company declined to offer further information, but told Alzforum that it plans to present at the Alzheimer's Association International Conference (AAIC) in Chicago in July of this year.

Also known as SUB 166499, BI 409306 targets phosphodiesterase E9A, an enzyme that reduces brain levels of cyclic guanosine monophosphate. Ordinarily, cGMP acts as a second messenger to transduce signals from glutamate and nitric oxide, but this pathway falters in patients with AD. By inhibiting PDE9A, BI 409306 aims to increase cGMP levels and improve both synaptic transmission and plasticity in the hippocampus and cerebral cortex.

A previous attempt at a PDE9A inhibitor failed in AD (Schwam et al., 2014). Boehringer plans to test BI 425809 in a Phase 2 trial for Alzheimer’s. This glycine transporter inhibitor purportedly increases NMDA receptor-mediated glutamatergic neurotransmission.—Gwyneth Dickey Zakaib


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Therapeutics Citations

  1. BI 409306
  2. Donepezil

Conference Citations

  1. Alzheimer's Association International Conference 2018

Paper Citations

  1. . A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer's disease. Curr Alzheimer Res. 2014;11(5):413-21. PubMed.

External Citations

  1. halt 
  2. NCT02337907
  3. NCT02240693
  4. Phase 2 trial

Further Reading


  1. . Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. Neuropharmacology. 2012 Apr;62(5-6):1964-74. PubMed.
  2. . Phosphodiesterase Inhibitors as a Therapeutic Approach to Neuroprotection and Repair. Int J Mol Sci. 2017 Mar 24;18(4) PubMed.
  3. . Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease. J Enzyme Inhib Med Chem. 2018 Dec;33(1):260-270. PubMed.