Having chalked up another failure in the casualty-strewn Alzheimer's disease (AD) space, Boehringer Ingelheim GmbH (BI) is giving up on BI-409306, a phosphodiesterase 9 (PDE9) inhibitor, but not on its mechanism of action, and will keep pursuing work on the same compound in schizophrenia.

BI, of Ingelheim, Germany, said trials with the candidate did not meet their efficacy endpoints against AD in an effort that was part of a wider trial program, designed to explore the efficacy of taking aim at malfunctioning glutamatergic brain circuits. BI-409306 was tested in patients with cognitive impairment and those with memory dysfunction in schizophrenia and in AD.

In AD, 12-week placebo-controlled trials enrolled 457 participants in order to investigate the efficacy, safety and tolerability of BI-409306 compared to placebo in patients with cognitive impairment due to AD. BI plans to review the complete results and offer them at the Alzheimer's Association International Conference in July in Chicago.

The company noted that it's still committed to solving the dementia riddle, as shown by the planned phase II trials testing another compound, BI-425809, a GlyT1 inhibitor, in a range of central nervous system indications which include AD.

In 2017, the number of people believed to be living with some form of dementia was 50 million, a number expected to double almost every 20 years, reaching 75 million by 2030 and 131.5 million by 2050.

With AD dropping off the BI-409306 program after BI's look at top-line phase II results, attention turns to a pair of studies in schizophrenia, aimed at prevention of relapse and at prevention of occurrence of a first psychotic episode. BI-409306 targets the glutamatergic signaling pathways in the brain to increase synaptic strength and plasticity – pathways that are malfunctioning in schizophrenia and are considered the pathophysiological basis of its positive, negative and cognitive symptoms. Dopaminergic pathways go awry, too, in schizophrenia, and cause the psychotic exacerbations characteristic of relapse. Since the dopaminergic and the glutamatergic systems interact in the pathophysiology of the disease, BI said, it's conceivable that inhibiting PDE9 might constitute an approach for prevention or reduction of symptomatic relapse.

Others believe blocking PDE9 could work in what might seem an unlikely indication, given BI's rationale: sickle cell disease (SCD). New York-based Pfizer Inc. has PF-04447943 at the phase I stage. (The company completed a phase II in AD with the same candidate in September 2010.

"Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo in these subjects with mild to moderate AD," concluded results published in Alzheimer's & Dementia in July 2011.)

Imara Inc., of Cambridge, Mass., has IMR-687 in a phase II SCD trial that's recruiting now. The compound was developed to target the same biochemical pathway as hydroxyurea, a chemotherapeutic agent, but without its safety issues. The idea is that IMR-687 will work by reducing red blood cell sickling and blockage of blood vessels that are the underlying causes of the pathology of SCD. The trial is expected to enroll 54 patients and test the daily, oral agent against placebo, with results due in June 2019.

Imara was founded in April 2016 by venture-backed orphan drug accelerator Cydan Development Inc., which financed the company with a $31 million series A round. Denmark's Lundbeckfond Ventures, one of Cydan's investors from the start, set the deal in motion by introducing Cydan's team to Copenhagen-based H. Lundbeck A/S, which had an array of PDE9 inhibitors in its portfolio – with, interestingly, the first target established as AD, although development was not moving quickly. Lundbeck acknowledged the SCD potential as well. (See BioWorld Today, April 15, 2016.)

And now, vitamin B3

SCD has been getting more press lately. At the American Society of Hematology meeting in December, Cambridge, Mass.-based Bluebird Bio Inc. offered updated data from the ongoing HGB-205 phase I/II trial, a seven-patient experiment with its Lentiglobin gene therapy product candidate in people with severe SCD and transfusion-dependent beta-thalassemia (TDT). Two of three SCD patients turned up greater than 45 percent total anti-sickling hemoglobin levels and meaningful clinical improvement, and all three show rising trajectory of HbAT87Q production in the first six months after infusion of the drug. The study also manifested ongoing transfusion independence up to 3.8 years in patients with TDT. Three of four patients reached normal or near-normal total hemoglobin levels. In the U.S., the median survival age for people with SCD is 44 years. (See BioWorld, Jan. 2, 2018.)

Research also has been done with the PDE9 mechanism in diabetes. A 2014 paper in the Journal of Medicinal Chemistry charted the evolution of the idea, starting with PDE3 inhibitors, advancing to PDE5 and others. The granddaddy of PDE9 inhibitors apparently is Leverkusen, Germany-based Bayer AG's BAY73-6691, on which results were published in 2005 in Molecular Pharmacology.

The prospects in AD, of course, held out the great hope, given how intractable the scourge has proved. As one drug after another fails, and as scientists continue to debate the amyloid and tau hypotheses, the Proceedings of the National Academy of Sciences reported last week that the supplement nicotinamide riboside (NR) – a form of vitamin B3 – prevented neurological damage and improved cognitive and physical function in a new mouse model of AD.

NR acts on the brain by normalizing levels of nicotinamide adenine dinucleotide (NAD+), a metabolite vital to cellular energy, stem cell self-renewal, and resistance to neuronal stress, as well as DNA repair. In AD, the brain's usual DNA repair activity is impaired, leading to mitochondrial dysfunction, lower neuron production, and increased neuronal dysfunction and inflammation, the NIH noted.

Specifically, based on their studies in human postmortem brain, researchers developed a new strain of mice mimicking major features of human AD such as tau pathology, failing synapses, neuronal death and cognitive impairment. Using the animal model, they tested the effects of an NR supplement by adding it to the drinking water of the mice. Over a three-month period, researchers found that mice who received NR showed reduced tau in their brains, but no change in amyloid-beta.

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