PDE-9 inhibitors: Potential therapeutics for the treatment of Alzheimer’s disease
Alzheimer’s hopes dashed recently, as a phase 3 trial of Accera’s candidate (AC-1204) has missed its primary endpoint and joins a very long list of failed drugs such as Lilly’s Solanezumab, Pfizer’s Bapineuzumab and Roche’s Gantenerumab which did not prove to show a benefit in patients with established Alzheimer’s dementia.
Alzheimer’s, is a chronic neurodegenerative disease that usually starts slowly and worsens over a number of years. The most common early symptom is difficulty in remembering recent events (short-term memory loss). There is no cure for Alzheimer’s disease; available treatments only offer relatively small symptomatic benefits but remain palliative in nature. There are two types of therapies currently available to treat the cognitive problems of AD; first is acetylcholinesterase inhibitors (such as tacrine, rivastigmine, galantamine and donepezil) and second one is NMDA receptor antagonist (memantine). No medication has been clearly shown to delay or halt the progression of the disease.
Inhibitors in the PDE-9 space:
Over the past decade, more than 200 compounds with various mode of actions were assessed in different phases of clinical and preclinical trials, and only a few of them were found to be promising. PDE-9 is one of 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. In pathological conditions, PDE9 inhibition is required to treat diseases that lower the level of cGMP. Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitors are established to improve cognition in schizophrenia and Alzheimer disease by increasing cGMP levels in certain brain regions. cGMP transduces signals by the neurotransmitters nitric oxide and glutamate and modulates synaptic transmission and plasticity in the hippocampus and cerebral cortex. Thus the inhibition of PDE-9 by specific inhibitors like BI-409306, PF-04447943 and BAY-736691 may provide therapeutic benefit in patient populations suffering not only from Alzheimer’s disease but schizophrenia or Huntington’s disease also.
BI 409306 shows promising results :
Multiple trials are being conducted in the healthy volunteers to investigate the safety and tolerability of PDE-9 inhibitors. Boehringer’s BI-409306 is currently in Phase II clinical trials for the treatment of Alzheimer’s disease. Recently Boehringer published its randomized, parallel-group, double-blind, placebo-controlled study results of BI 409306. Results indicate that BI 409306 efficiently crosses the blood-CSF barrier, with an acceptable level of AEs. In healthy male subjects, BI-409306 was found to be safe and well tolerated, with rapid absorption and elimination. Despite showing preliminary efficacy for the treatment of Alzheimer’s, it is also under investigation for the treatment of cognitive impairment among those with schizophrenia. On the other hand, preclinical studies of Pfizer’s PF-04447943 earlier showed significantly improved cognitive performance in three rodent cognition assays, but the data of phase II showed that even being safe and well-tolerated, PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo. Bayer is lagging in the race as its PDE-9 inhibitor BAY 73-6691 is in early stages of development and showed potential results in mouse models. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins, showing therapeutic potential for the treatment of AD.
Although phosphodiesterase inhibitors are in the initial phase of development, but we can anticipate that in the current scenario of repeated failure of Beta amyloid and BACE targeting drugs, PDE-9 inhibitors would come up as a better treatment option for the AD patients in the near future.
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By Dr. Rupesh Tyagi
Senior Research Analyst, Science and Research @ Innoplexus