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1. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Author

Salloway, Stephen, Farlow, Martin, McDade, Eric, Clifford, David B., Wang, Guoqiao, Llibre-Guerra, Jorge J., Hitchcock, Janice M., Mills, Susan L., Santacruz, Anna M., Aschenbrenner, Andrew J., Hassenstab, Jason, Benzinger, Tammie L. S., Gordon, Brian A., Fagan, Anne M., Coalier, Kelley A., Cruchaga, Carlos, Goate, Alison A., Perrin, Richard J., Xiong, Chengjie, Li, Yan, Morris, John C., Snider, B. Joy, Mummery, Catherine, Surti, G. Mustafa, Hannequin, Didier, Wallon, David, Berman, Sarah B., Lah, James J., Jimenez-Velazquez, Ivonne Z., Roberson, Erik D., van Dyck, Christopher H., Honig, Lawrence S., Sánchez-Valle, Raquel, Brooks, William S., Gauthier, Serge, Galasko, Douglas R., Masters, Colin L., Brosch, Jared R., Hsiung, Ging-Yuek Robin, Jayadev, Suman, Formaglio, Maité, Masellis, Mario, Clarnette, Roger, Pariente, Jérémie, Dubois, Bruno, Pasquier, Florence, Jack, Jr, Clifford R., Koeppe, Robert, Snyder, Peter J., Aisen, Paul S., Thomas, Ronald G., Berry, Scott M., Wendelberger, Barbara A., Andersen, Scott W., Holdridge, Karen C., Mintun, Mark A., Yaari, Roy, Sims, John R., Baudler, Monika, Delmar, Paul, Doody, Rachelle S., Fontoura, Paulo, Giacobino, Caroline, Kerchner, Geoffrey A., and Bateman, Randall J.

Published
2021
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4. Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial

Author

Wagemann, Olivia, Liu, Haiyan, Wang, Guoqiao, Shi, Xinyu, Bittner, Tobias, Scelsi, Marzia A., Farlow, Martin R., Clifford, David B., Supnet-Bell, Charlene, Santacruz, Anna M., Aschenbrenner, Andrew J., Hassenstab, Jason J., Benzinger, Tammie L. S., Gordon, Brian A., Coalier, Kelley A., Cruchaga, Carlos, Ibanez, Laura, Perrin, Richard J., Xiong, Chengjie, Li, Yan, Morris, John C., Lah, James J., Berman, Sarah B., Roberson, Erik D., van Dyck, Christopher H., Galasko, Douglas, Gauthier, Serge, Hsiung, Ging-Yuek R., Brooks, William S., Pariente, Jérémie, Mummery, Catherine J., Day, Gregory S., Ringman, John M., Mendez, Patricio Chrem, St. George-Hyslop, Peter, Fox, Nick C., Suzuki, Kazushi, Okhravi, Hamid R., Chhatwal, Jasmeer, Levin, Johannes, Jucker, Mathias, Sims, John R., Holdridge, Karen C., Proctor, Nicholas K., Yaari, Roy, Andersen, Scott W., Mancini, Michele, Llibre-Guerra, Jorge, Bateman, Randall J., and McDade, Eric

Abstract

IMPORTANCE: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). OBJECTIVE: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. DESIGN, SETTING, AND PARTICIPANTS: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. INTERVENTIONS: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. MAIN OUTCOMES AND MEASURES: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. RESULTS: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04623242

Published
2024
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5. APOE ε4's impact on response to amyloid therapies in early symptomatic Alzheimer's disease: Analyses from multiple clinical trials.

Author

Evans, Cynthia D., Sparks, JonDavid, Andersen, Scott W., Brooks, Dawn A., Hauck, Paula M., Mintun, Mark A., and Sims, John R.

Abstract

INTRODUCTION: Apolipoprotein E (APOE) ε4 may interact with response to amyloid‐targeting therapies. METHODS: Aggregate data from trials enrolling participants with amyloid‐positive, early symptomatic Alzheimer's disease (AD) were analyzed for disease progression. RESULTS: Pooled analysis of potentially efficacious antibodies lecanemab, aducanumab, solanezumab, and donanemab shows slightly better efficacy in APOE ε4 carriers than in non‐carriers. Carrier and non‐carrier mean (95% confidence interval) differences from placebo using Clinical Dementia Rating Scale–Sum of Boxes (CDR‐SB) were –0.30 (–0.478, –0.106) and –0.20 (–0.435, 0.042) and AD Assessment Scale–Cognitive subscale (ADAS‐Cog) values were –1.01 (–1.577, –0.456) and –0.80 (–1.627, 0.018), respectively. Decline in the APOE ε4 non‐carrier placebo group was equal to or greater than that in carriers across multiple scales. Probability of study success increases as the representation of the carrier population increases. DISCUSSION: We hypothesize that APOE ε4 carriers have same or better response than non‐carriers to amyloid‐targeting therapies and similar or less disease progression with placebo in amyloid‐positive trials. HIGHLIGHTS: Amyloid‐targeting therapies had slightly greater efficacy in apolipoprotein E (APOE) ε4 carriers.Clinical decline is the same/slightly faster in amyloid‐positive APOE ε4 non‐carriers.Prevalence of non‐carriers in trial populations could impact outcomes. [ABSTRACT FROM AUTHOR]

Published
2023
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11. Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer’s Disease: A Phase I Clinical Trial

Author

Willis, Brian A., Lo, Albert C., Dage, Jeffrey L., Shcherbinin, Sergey, Chinchen, Louise, Andersen, Scott W., LaBell, Elizabeth S., Perahia, David G.S., Hauck, Paula M., and Lowe, Stephen L.

Abstract

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer’s disease (AD).Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD.Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks.Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration.Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed. Clinicaltrials.gov: NCT03019536

Published
2023
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12. Donanemab in Early Alzheimer’s Disease

Author

Mintun, Mark A., primary, Lo, Albert C., additional, Duggan Evans, Cynthia, additional, Wessels, Alette M., additional, Ardayfio, Paul A., additional, Andersen, Scott W., additional, Shcherbinin, Sergey, additional, Sparks, JonDavid, additional, Sims, John R., additional, Brys, Miroslaw, additional, Apostolova, Liana G., additional, Salloway, Stephen P., additional, and Skovronsky, Daniel M., additional

Published
2021
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14. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer's disease

Author

Zimmer, Jennifer A., primary, Shcherbinin, Sergey, additional, Devous, Michael D., additional, Bragg, Sonja M., additional, Selzler, Katherine J., additional, Wessels, Alette M., additional, Shering, Craig, additional, Mullen, Jamie, additional, Landry, John, additional, Andersen, Scott W., additional, Downing, AnnCatherine M., additional, Fleisher, Adam S., additional, Svaldi, Diana Otero, additional, and Sims, John R., additional

Published
2021
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16. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease

Author

Wessels, Alette M., primary, Lines, Christopher, additional, Stern, Robert A., additional, Kost, James, additional, Voss, Tiffini, additional, Mozley, Lyn Harper, additional, Furtek, Christine, additional, Mukai, Yuki, additional, Aisen, Paul S., additional, Cummings, Jeffrey L., additional, Tariot, Pierre N., additional, Vellas, Bruno, additional, Dupre, Nicole, additional, Randolph, Christopher, additional, Michelson, David, additional, Andersen, Scott W., additional, Shering, Craig, additional, Sims, John R., additional, and Egan, Michael F., additional

Published
2020
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17. Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease

Author

Wessels, Alette M., primary, Tariot, Pierre N., additional, Zimmer, Jennifer A., additional, Selzler, Katherine J., additional, Bragg, Sonja M., additional, Andersen, Scott W., additional, Landry, John, additional, Krull, James H., additional, Downing, AnnCatherine M., additional, Willis, Brian A., additional, Shcherbinin, Sergey, additional, Mullen, Jamie, additional, Barker, Peter, additional, Schumi, Jennifer, additional, Shering, Craig, additional, Matthews, Brandy R., additional, Stern, Robert A., additional, Vellas, Bruno, additional, Cohen, Sharon, additional, MacSweeney, Emer, additional, Boada, Mercè, additional, and Sims, John R., additional

Published
2020
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24. Clinically Negligible Pharmacokinetic and Pharmacodynamic Interactions Between Lanabecestat and Dabigatran Etexilate, a Prototypical P-gp Substrate.

Author

Monk, Scott A., Kugler, Alan R., Andersen, Scott W., Ayan-Oshodi, Mosun A., James, Douglas E., Mullen, Jamie, Zimmer, Jennifer A., and Willis, Brian A.

Subjects
ALZHEIMER'S disease, BENZIMIDAZOLES, DRUG interactions, ELECTROCARDIOGRAPHY, ENZYME inhibitors, EYE examination, GLYCOPROTEINS, INTESTINAL mucosa, PATIENT safety, PYRIDINE, SKIN tests, THROMBIN, VITAL signs, DESCRIPTIVE statistics, CHEMICAL inhibitors, PHARMACODYNAMICS
Abstract

Lanabecestat, a novel ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor evaluated for Alzheimer treatment, inhibits P-glycoprotein (P-gp) activity in vitro. After oral 50-mg lanabecestat administration, gastric fluid lanabecestat concentrations exceed half-maximal inhibitory concentration (IC50), suggesting P-gp inhibition at the intestinal wall. Plasma drug concentrations following 50 mg lanabecestat administered once daily are <10% of IC50, suggesting minimal systemic P-gp interaction. Dabigatran etexilate (DE) is the prodrug of dabigatran, a thrombin inhibitor and P-gp substrate, making dabigatran exposure an intestinal P-gp activity indicator. This study (NCT02568397) was conducted in 60 healthy subjects receiving a single dose of 150 mg DE alone or during a lanabecestat treatment regimen. On day 16, lanabecestat and DE were coadministered; on day 20, DE was dosed 4 hours after lanabecestat. Safety was assessed using clinical labs, electrocardiogram, vital signs, Columbia Suicide Severity Rating Scale scores, adverse events, and eye and skin examinations. Pharmacokinetic/pharmacodynamic samples were collected up to 36 hours postdose. Geometric mean plasma dabigatran area under the curve from time 0 to infinity (AUC0-∞) and the maximum plasma drug concentration (Cmax) increased by 15% and 17%, respectively, when coadministered with lanabecestat. When DE was dosed 4 hours after lanabecestat, there was no effect on plasma dabigatran AUC0-∞, Cmax, or thrombin time. DE had no effect on lanabecestat's AUC0-∞ and Cmax at steady state (day 16) versus lanabecestat alone (day 15). No clinically relevant safety concerns were observed. Lanabecestat has no clinically meaningful effect on dabigatran exposure or on P-gp activity at the intestinal wall. [ABSTRACT FROM AUTHOR]

Published
2020
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27. DT‐01‐04: LANABECESTAT: BASELINE CHARACTERISTICS OF PARTICIPANTS RANDOMIZED IN THE PHASE 2/3 AMARANTH STUDY

Author

Sims, John R., primary, Downing, AnnCatherine M., additional, Andersen, Scott W., additional, Wessels, Alette M., additional, Zimmer, Jennifer A., additional, Mullen, Jamie, additional, Schumi, Jennifer, additional, Stern, Robert A., additional, Vellas, Bruno, additional, Boada, Mercè, additional, Cohen, Sharon, additional, MacSweeney, Emer, additional, and Tariot, Pierre N., additional

Published
2018
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29. Derivation of cutoffs for the Elecsys ® amyloid β (1–42) assay in Alzheimer's disease

Author

Shaw, Leslie M., primary, Waligorska, Teresa, additional, Fields, Leona, additional, Korecka, Magdalena, additional, Figurski, Michal, additional, Trojanowski, John Q., additional, Eichenlaub, Udo, additional, Wahl, Simone, additional, Quan, Marian, additional, Pontecorvo, Michael J., additional, Lachno, D. Richard, additional, Talbot, Jayne A., additional, Andersen, Scott W., additional, Siemers, Eric R., additional, and Dean, Robert A., additional

Published
2018
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32. [P4–155]: DERIVING A CUT‐OFF FOR THE ELECSYS® β‐AMYLOID (1–42) IMMUNOASSAY FOR USE IN CLINICAL TRIALS SUPPORTED BY ELI LILLY FOR PATIENTS WITH CLINICALLY DEFINED ALZHEIMER's DISEASE (AD)

Author

Shaw, Leslie M., primary, Waligorska, Teresa, additional, Fields, Leona, additional, Korecka, Magdalena, additional, Figurski, Michal J., additional, Trojanowski, John Q., additional, Eichenlaub, Udo, additional, Wahl, Simone, additional, Quan, Marian, additional, Lachno, David Richard, additional, Talbot, Jayne A., additional, Andersen, Scott W., additional, Siemers, Eric R., additional, and Dean, Robert A., additional

Published
2017
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33. Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat.

Author

Willis, Brian A., Andersen, Scott W., Ayan‐Oshodi, Mosun, James, Douglas E., Liffick, Emily, Hillgren, Kathleen, Guo, Yingying, and Monk, Scott A.

Subjects
*BREAST tumors, *CARRIER proteins, *DOSE-response relationship in biochemistry, *DRUG interactions, *ENZYME inhibitors, *GENETIC polymorphisms, *TIME, *WHITE people, *PHENOTYPES, *DESCRIPTIVE statistics, *ROSUVASTATIN, *MEMBRANE transport proteins, *GENOTYPES, *PHARMACODYNAMICS
Abstract

Lanabecestat is a human β‐site amyloid precursor protein‐cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (Cmax), area under the rosuvastatin concentration‐versus‐time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8‐1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P <.05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment‐emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary. [ABSTRACT FROM AUTHOR]

Published
2020
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40. Disease Modification in Alzheimer’s Disease: Current Thinking

Author

Liu-Seifert, Hong, Schumi, Jennifer, Miao, Xiaopeng, Tian, Ying, Rabbia, Michael, Andersen, Scott W., Wilson, Steve, Li, Wen, and Entsuah, Richard

Abstract

Alzheimer’s disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression. This paper reviews the most up-to-date regulatory guidance on how to demonstrate disease modification and provides an overview of available methodologies and applications to clinical trials. The intent is to assist the field with future clinical trials designed to demonstrate disease-modifying effect in AD. The methodologies may be generalizable to broader neurodegenerative diseases.

Published
2024
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46. P4-076: INCLUSION OF PATIENTS WITH ALZHEIMER'S DISEASE PATHOLOGY IN SOLANEZUMAB EXPEDITION 3 USING FLORBETAPIR PET IMAGING OR INNO-BIA ALZBIO3 CSF Aβ1-42

Author

Dean, Robert, primary, Shaw, Leslie M., additional, Waligorska, Teresa W., additional, Korecka, Magdalena, additional, Figurski, Michal, additional, Trojanowski, John Q., additional, Sundell, Karen, additional, Andersen, Scott W., additional, Holdridge, Karen, additional, Lachno, D. Richard, additional, Talbot, Jayne, additional, and Siemers, Eric, additional

Published
2014
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