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Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

ABSTRACT: BACKGROUND:Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (A?), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed. METHODS:In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85?years were randomized (1:1:1) to placebo or atabecestat 10 or 50?mg once daily (later reduced to 5 and 25?mg) for 6 months. Participants entered ALZ2004, a 12-month treatment extension with placebo or atabecestat 10 or 25?mg, followed by an open-label phase. Safety, changes in CSF biomarker levels, brain volume, and effects on cognitive performance were assessed. RESULTS:Of 114 participants randomized in ALZ2002, 99 (87%) completed, 90 entered the ALZ2004 double-blind phase, and 77 progressed to the open-label phase. CSF A? fragments and sAPP? were reduced dose-proportionately. Decreases in whole brain and hippocampal volumes were greater in participants with mild cognitive impairment (MCI) due to AD than in preclinical AD, but were not affected by treatment. In ALZ2004, change from baseline in RBANS trended toward worse scores for atabecestat versus placebo. Elevated liver enzyme adverse events reported in 12 participants on atabecestat resulted in dosage modification and increased frequency of safety monitoring. Treatment discontinuation normalized ALT or AST in all except one with pretreatment elevation, which remained mildly elevated. No case met ALT/AST >?3× ULN and total bilirubin >?2× ULN (Hy's law). CONCLUSION:Atabecestat was associated with trend toward declines in cognition, and elevation of liver enzymes. TRIAL REGISTRATION:ALZ2002: ClinicalTrials.gov, NCT02260674, registered October 9, 2014; ALZ2004: ClinicalTrials.gov, NCT02406027, registered April 1, 2015.

SUBMITTER: Novak G

PROVIDER: S-EPMC7227237 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

Novak Gerald G Streffer Johannes Rolf JR Timmers Maarten M Henley David D Brashear H Robert HR Bogert Jennifer J Russu Alberto A Janssens Luc L Tesseur Ina I Tritsmans Luc L Van Nueten Luc L Engelborghs Sebastiaan S

Alzheimer's research & therapy 20200514 1

<h4>Background</h4>Atabecestat, a potent brain-penetrable inhibitor of BACE1 activity that reduces CSF amyloid beta (Aβ), was developed for oral treatment for Alzheimer's disease (AD). The long-term safety and effect of atabecestat on cognitive performance in participants with predementia AD in two phase 2 studies were assessed.<h4>Methods</h4>In the placebo-controlled double-blind parent ALZ2002 study, participants aged 50 to 85 years were randomized (1:1:1) to placebo or atabecestat 10 or 50 m ...[more]

PMID: 32410694

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Project description:Backgroundβ-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia.MethodsIn two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aβ1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated.ResultsIn both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aβ1-40 reductions, respectively. The trend of the reduction was similar across the Aβ1-37, Aβ1-38, and Aβ1-42 fragments in both atabecestat dose groups, consistent with Aβ1-40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period.ConclusionsJNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults.Trial registrationALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.

Project description:IntroductionCurcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.MethodsWe performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex(®) with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.ResultsMean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex(®) was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).ConclusionsCurcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex(®) in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.Trial registrationClinicalTrials.gov Identifier: NCT00099710.

Project description:BACKGROUND:PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS:This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS:There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of >?90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. CONCLUSIONS:The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching >?50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. TRIAL REGISTRATION:Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.

Project description:BACKGROUND:Results from a phase 2a study indicated that treatment with the novel ?7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg). METHODS:The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n?=?77), ABT-126 50 mg QD (n?=?108), ABT-126 75 mg QD (n?=?73), donepezil 10 mg QD (n?=?76), or placebo (n?=?104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies. RESULTS:A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29?±?0.95; one-sided P?=?0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47?±?0.94 (P?=?0.309); ABT-126 50 mg, -0.87?±?0.85 (P?=?0.153); and ABT-126 75 mg, -1.08?±?0.94 (P?=?0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters. CONCLUSIONS:In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies. TRIAL REGISTRATION:ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).

Dataset Information

Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

Publications

Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer's disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study.

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