re: "And these are drugs that showed promising preclinical and Phase 2 results."
Not all that promising, really: "Overview
Name: Idalopirdine Synonyms: Lu AE58054, SGS 518 Chemical Name: 2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine Therapy Type: Small Molecule (timeline) Target Type: Other Neurotransmitters (timeline) Condition(s): Alzheimer's Disease, Schizophrenia U.S. FDA Status: Alzheimer's Disease (Phase 3), Schizophrenia (Inactive) Company: Eli Lilly & Co., H. Lundbeck, Otsuka Pharmaceutical Co., Ltd.
Background
This orally available drug is an antagonist of the serotonin 6 (5-HT6) receptor. This receptor subtype is expressed primarily in the brain, particularly in the cerebral cortex and hippocampus, where it has been proposed to play a role in cognitive impairments associated with schizophrenia and Alzheimer's disease. The 5-HT6 receptor antagonists are thought to enhance cholinergic, glutamatergic, noradrenergic, and dopaminergic neurotransmission. Apart from some affinity for adrenergic receptors, Lu AE58054 has been reported to be highly selective over other G-protein coupled receptors. The compound enters the brain and was able to dose-dependently reverse deficits in a rat model of cognitive impairment (Upton et al., 2008; Arnt et al., 2010)."
Adrenergic receptors trigger the "fight or flight" response. More so than "10 cups of coffee", the wide spread effects of an adrenaline rush are going to perk the person up temporarily. But it takes its toll and cannot be maintained. "Lu AE58054 is being developed as a symptomatic adjunct to cholinesterase inhibitor treatment in Alzheimer's disease. Lu AE58054 was originally discovered by Lilly, which licensed it to the biotechnology company Saegis for clinical development in cognitive impairment in thinking disorders such as schizophrenia. In 2006, Saegis was acquired by Lundbeck, which in October 2013 launched a global Phase 3 program in AD. This program consists of four trials planned to enroll a total of about 3,000 patients (see company press release).
Findings
No Phase 1 trials on this drug are listed in publicly available databases. In 2005, Saegis conducted a Phase 2a trial in 20 schizophrenia patients in the United States, evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of giving this drug as an add-on to Risperidone (see company press release). In 2009 and 2010, Lundbeck conducted a Phase 2 trial in Europe and Asia to evaluate the compound as an adjunct to Risperidone for its effect on cognitive deficits in 124 patients with schizophrenia. Results were not published in the peer-reviewed literature, but development of Lu AE58054 for cognitive deficits in schizophrenia appears to have ended."
And it did not end well, apparently. "In 2010 and 2011, Lundbeck evaluated Lu AE58054 in a Phase 2 study in 278 patients with probable Alzheimer's disease. Conducted in Australia, Canada, and Europe, the trial compared the effects of a six-month course of 90 mg/day of Lu AE58054 with 10 mg/day of Donepezil to the same dose of placebo. In June 2012, the company announced that the trial had met its primary cognition endpoint as measured by the ADAS-cog. On secondary endpoints, such as measures of global status and activities of daily living, Lu AE58054 treatment showed trends for a benefit but fell short of achieving statistical significance. Elevated liver enzymes in the treatment group, and higher dropout than in the placebo group, were also noted in this trial (see Jun 2012 news).
ADAS-cog is heavy on immediate recall and spatial recognition of geometric shapes, important cognitive functions, for sure, but these things can vary depending on whether the person is paying attention, and how much natural sleep they get. Continuously stimulating a person to greater alertness may boost this kind of test scores for a while but it is not a good thing. There may be a tendency to dismiss 2-73's non-narcotic benefit to alleviate insomnia, however, the brain needs sleep to repair itself, lack of sleep even causes further damage.
What's bad about AD, is forgetting things already known, such as family recipes, or even how to cook most things, even though they had been proficient at it for years. 2-73 is shown to produce especially good results in this area. All indications are that it is a good drug, an excellent candidate for a new AD SOC.
AE58054 is just yet another crappy drug to which lipstick is being applied in the form of these large trials, staged to compensate for the high dropout rate due to it not working and making people sick(er).
re:"Biotech investing is risky and pumping does no one any favors"
Neither does equating apples to oranges. Yes, they are both fruits, but dismissing the relative potential of one investment over another in the same field affords a similar disservice.
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