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Saturday, August 24, 2019 1:40:10 PM
Would seem strange for one of their few positive company-specific mentions in this Nature publication to have had incorrect facts listed regarding Anavex FDA granted fast-track status.
One would expect that the authors would’ve obtained that information from a reliable source if accurate?
Original publication submission on 3/28/19 then revised on 7/7/19.
Probably just a coincidence that Anavex filed for the $250 million shelf registration 4 days prior on 7/3/19.
https://www.nature.com/articles/s41392-019-0063-8
credit greenspam3
Excerpts:
"At present, clinical drug treatments are mainly divided into two categories: acetylcholinesterase inhibitors (AChEIs), represented by donepezil, and the antagonist of N-methyl-D-aspartic acid (NMDA) receptor, represented by memantine (Table 1).48 As neurotransmitter regulators, these drugs can only relieve symptoms for a short time but cannot delay the progression of AD. Recent failures and the limited progress of therapeutics in phase III clinical trials suggest that it is time to consider alternative strategies for AD treatment.49”
"Aß-targeting monoclonal antibodies (mAbs) are the major passive immunotherapy treatments for AD. For example, solanezumab (Eli Lilly), which can bind monomeric and soluble Aß, failed to show curative effects in AD patients in phase III, although solanezumab effectively reduced free plasma Aß concentrations by more than 90%.93 Gantenerumab (Roche/Genentech) is a mAb that binds oligomeric and fibrillar Aß and can activate the microglia-mediated phagocytic clearance of plaques. However, it also failed in phase III.94 Crenezumab (Roche/Genentech/AC Immune) is a mAb that can bind to various Aß, including monomers, oligomers, and fibrils. On January 30, 2019, Roche announced the termination of two phase III trials of crenezumab in AD patients. Aducanumab (Biogen Idec) is a mAb that targets aggregated forms of Aß. Although aducanumab can significantly reduce Aß deposition, Biogen and Eisai announced the discontinuation of trials of aducanumab on March 21, 2019. Together, the failure of these trials strongly suggests that it is better to treat Aß deposits as a pathological feature rather than as part of a major mechanistic hypothesis.”
"BACE1 inhibitors aim to reduce Aß and have been tested for years. However, no BACE1 inhibitors have passed clinical trials. Verubecestat (MK-8931, Merck & Co.) reduced Aß levels by up to 90% in the cerebrospinal fluid (CSF) in AD. However, Merck no longer listed verubecestat in its research pipeline since verubecestat did not improve cognitive decline in AD patients and was associated with unfavorable side effects.95 Lanabecestat (AZD3293, AstraZeneca/Eli Lilly) is another BACE1 inhibitor that can lower CSF Aß levels by up to 75%. However, on June 12, 2018, phase II/III trials of lanabecestat were discontinued due to a lack of efficacy. The BACE1 inhibitor atabecestat (JNJ-54861911, Janssen) induced a robust reduction in Aß levels by up to 95% in a phase I trial. However, Janssen announced the discontinuation of this program on May 17, 2018. The latest news regarding the BACE inhibitor umibecestat (Novartis/Amgen) was released on July 11, 2019; it was announced that the evaluation of umibecestat was discontinued in phase II/III trials since an assessment demonstrated a worsening of cognitive function. Elenbecestat (E2609, Eisai) is another BACE1 inhibitor that can reduce CSF Aß levels by up to 80%96,97 and is now in phase III trials (shown in Table 2). Although all BACE1 inhibitors seem to reduce CSF Aß levels, the failure of trials of solanezumab, which can reduce free plasma Aß concentrations by more than 90%,93 may be sufficient to lead us to pessimistic expectations, especially considering that the treatment worsened cognition and induced side effects.”
"Mannose oligosaccharide diacid (GV-971) was developed by researchers at the Shanghai Institute of Medicine, the Chinese Academy of Sciences, the Ocean University of China, and the Shanghai Green Valley Pharmaceutical Co., Ltd. GV-971 is an oceanic oligosaccharide molecule extracted from seaweed. GV-971 may capture multiple fragments of Aß in multiple sites and multiple states, inhibit the formation of Aß filaments, and depolymerize filaments into nontoxic monomers330,331; however, an understanding of the exact mechanism is still lacking. GV-971 has been reported to improve learning and memory in Aß-treated mice.332 In phase II trials, GV-971 improved cognition in AD patients.333 In addition, a phase III clinical trial of GV-971 finished with positive results, and it is on its way to the market in China (Table 2).”
"Perspective
AD, like the aging population, has increasingly become a medical and social concern. There are currently four clinically used drugs (a total of five therapies, the fifth one of which is a combination of two drugs) that have been approved by the FDA, but they only treat the symptoms and have no significant effect on the progression of AD. Based on this retrospective review of AD and the lessons learned, we propose that fluoxetine,402 a selective serotonin reuptake inhibitor (SSRI), may have strong potential for the treatment of AD (Fig. 7).”
"Furthermore, fluoxetine has been reported to bind and inhibit NMDA receptors directly in the CNS,416 and this can reduce the inhibition of a-secretase and thus prevent the production of Aß.203,417 Fluoxetine also inhibits ?-secretase activity and reduces the production of toxic amyloid Aß by activating MEK-ERK signaling.371,372 In addition, fluoxetine can bind to the endoplasmic reticulum protein sigma-1 receptor.418 Sigma-1 receptor ligands can enhance acetylcholine secretion.419,420 The sigma-1 receptor activator Anavex 2–73 has entered a phase III clinical trial after it was granted fast-track status by the FDA because of the promising results in phase II. The sigma-1 receptor is located in the mitochondrion-associated ER membrane so that the activation of the sigma-1 receptor can prolong Ca2+ signaling in mitochondria.421 Consequently, the local and specific elevation of [Ca2+] in the mitochondrial matrix can enhance ATP synthesis,422,423 which ameliorates hypometabolism."
"The most interesting and challenging phenomena regarding fluoxetine is that fluoxetine is clinically more effective in women than in men440 and that the prevalence of AD and other dementias is higher in women than in men441; meanwhile, women live significantly longer than men.442 These phenomena suggest that there are interplays or trade-offs between AD and longevity. In particular, APOE is the strongest genetic risk factor for AD18,19,20,21 and is the only gene associated with longevity that achieves genome-wide significance (P?<?5?×?10–8).443 APOE4 is associated with a risk of AD that declines after the age of 70; the OR for APOE4 heterozygotes remains above unity at almost all ages; surprisingly, however, the OR for APOE4 homozygotes dips below unity after the age of 89.444 There may be genetic and nongenetic factors that interact with APOE4, lead to shorter survival in more aggressive form of AD, or promote longevity in an age-dependent manner.11 Uncovering the puzzle of APOE4 and the mystery of longevity may provide insights for AD prevention."
Received
28 March 2019
Revised
07 July 2019
Accepted
17 July 2019
Published
23 August 2019
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