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Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
Several agents have been developed to decrease the formation of Ab42 by blocking β- or γ-secretase, the enzymes believed responsible for cleaving APP into Ab42. The nonselective γ-secretase inhibitor semagacestat not only failed in clinical trials but also worsened symptoms in some subjects, perhaps because it inhibited the important Notch receptor (Imbimbo & Giardina, 2011). Active clinical trials are currently testing several new agents. An alternate approach to inhibiting the action of γ-secretase would be to modify its action sufficiently to lower Ab42 production. Tarenflurbil is an allosteric modulator of γ-secretase that shifts APP cleavage away from producing the toxic Ab42 and instead to producing less toxic protein fragments such as Ab38. It was the first selective Ab42 lowering agent in clinical trials but failed to show significant benefit for AD patients in a large Phase III trial (Imbimbo & Giardina, 2011).
Brain insulin resistance: role in neurodegenerative disease and potential for targeting
Published in Expert Opinion on Investigational Drugs, 2020
Inhibition of gamma-secretase was not a successful strategy either. Semagacestat (LY-450,139) was tested in a phase III trial. 1500 patients were treated for 21 months. In 2010, the trial was halted as it showed a worsening of dementia in patients compared to placebo controls [194]. Inhibitor of beta-secretase (BACE1) did not fare any better. In June 2018, Lilly and AstraZeneca stopped a Phase 2/3 trial of 2,219 people with AD testing the BACE1 inhibitor Lanabecestat. In July 2018, Janssen stopped a Phase 2b/3 trial and a Phase 2 trial of its inhibitor Atabecestat due to liver toxicity. Nov 2018: Merck announced that in a Phase 3 trial, people with AD who took the inhibitor verubecestat scored worse on cognitive tests than those on placebo. Novartis/Amgen’s BACE inhibitor CNP520 (Umibecestat) was tested in two Phase 2/3 trials. In July 2019 the company announced that the trials have been stopped due to patients getting worse. Participants taking umibecestat declined in the RBANS cognitive composite tests, had more brain atrophy, and lost more weight than people on placebo did. In September 2019, BIOGEN and Eisai halted two phase 3 trials on the basis of safety concerns caused by their drug Elenbecestat. For details on these trials please see [195].
Investigational BACE inhibitors for the treatment of Alzheimer’s disease
Published in Expert Opinion on Investigational Drugs, 2019
Bruno P. Imbimbo, Mark Watling
Detrimental effects on cognition and clinical global status have been observed not only with BACE1 inhibitors but also with other anti-Aβ drugs. An 18-month, double-blind, placebo-controlled study with the γ-secretase inhibitor semagacestat (100 and 140 mg/day) in 1,537 mild-to-moderate AD was discontinued prematurely because of deterioration in patient cognition [37]. Patients receiving the highest dose (140 mg/day) performed significantly worse than placebo-treated patients for cognition (as assessed with MMSE), functionality (as assessed with ADCS-ADL), psychiatric symptoms (as assessed with NPI) and clinical global performance (as assessed with CDR-SB). This dose of semagacestat had been shown to significantly decreased the production of CNS Aβ by 52% in a previous study [38]. Avagacestat, another γ-secretase inhibitor, worsened cognition (MMSE) compared to placebo in a 6-month study involving 209 mild-to-moderate AD patients [39]. Tarenflurbil, a γ-secretase modulator, significantly worsened CDR-SB compared to placebo in an 18-month study involving 1,684 mild AD patients [40]. CAD106, an active anti-Aβ vaccine, tended to worsen MMSE compared to placebo (p = 0.052) in a 90-week study involving 121 patients with mild AD [41]. Another Aβ antigen, AD02, worsened cognition (ADAS-Cog) and clinical global status (CDR-SB) versus control treatment in an 18-month study involving 332 patients with early AD [42]. Scyllo-inositol, an Aβ aggregation inhibitor, dose-dependently increased mortality in an 18-month study involving 353 mild-to-moderate AD patients [43].
Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease?
Published in Expert Review of Neurotherapeutics, 2019
Francesco Panza, Madia Lozupone, Mark Watling, Bruno Pietro Imbimbo
Negative effects of BACE inhibitors on cognition, functionality and clinical global performance were also observed in trials of other anti-Aβ drugs. Higher mortality rate on semagacestat (a γ-secretase inhibitor) was reported in a Phase III trial involving 1,537 mild-to-moderate AD patients [15]. This trial was discontinued prematurely because of deterioration in patient cognition. At the time of trial termination, 10.2%, 23.9% and 27.3% of patients on placebo, semagacestat 100 mg and semagacestat 140 mg daily, respectively, had withdrawn from the study because of adverse events. There were six deaths on placebo (1.2%), 11 deaths on 100 mg (2.2%), and 15 deaths on 140 mg (2.8%). A previous study has shown that the doses of semagacestat used in the Phase III trial (100 and 140 mg/day) significantly decreased the production of CNS Aβ by 47% and 52%, respectively [16]. Avagacestat, a γ-secretase inhibitor, worsened cognition in both prodromal [17] and in mild-to-moderate AD patients [18]. Tarenflurbil, a γ-secretase modulator, significantly worsened CDR-SB compared to placebo in mild AD patients, although it did not affect CSF Aβ levels [19]. CAD106, an active anti-Aβ vaccine, tended to worsen MMSE compared to placebo in patients with mild AD [20]. Another Aβ antigen, AD02, worsened cognition and functionality in patients with early AD [21]. Scyllo-inositol, an Aβ aggregation inhibitor, dose-dependently increased mortality in mild-to-moderate AD patients [22].