The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
Carsten Hofmann - One of the best experts on this subject based on the ideXlab platform.
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a phase i study to assess the effect of speed of injection on pain tolerability and pharmacokinetics after high volume subcutaneous administration of Gantenerumab in healthy volunteers
Clinical Therapeutics, 2020Co-Authors: Agnes Portron, Paul Jordan, Kristy Draper, Christopher Muenzer, Daniel Dickerson, Thijs Van Iersel, Carsten HofmannAbstract:Abstract Purpose Gantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of Gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous Gantenerumab. Methods This randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior Gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC Gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated. Findings Immediately after the subcutaneous Gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous Gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous Gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, Gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups. Implications Subcutaneous Gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009 .
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Gantenerumab reduces amyloid β plaques in patients with prodromal to moderate alzheimer s disease a pet substudy interim analysis
Alzheimer's Research & Therapy, 2019Co-Authors: Gregory Klein, Carsten Hofmann, Guoqiao Wang, Paul Delmar, Danielle Abisaab, Nicola Voyle, Sunita Rehal, Mirjana Andjelkovic, Smiljana Ristic, Randall J BatemanAbstract:We previously investigated low doses (105 or 225 mg) of Gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of Gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD). A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target Gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold. Results from this exploratory interim analysis of the PET substudy suggest that Gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).
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correction to a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2018Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten Hofmann, Paul DelmarAbstract:Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows:
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higher dose Gantenerumab leads to significant reduction in amyloid plaque burden results for the marguerite and scarlet road open label extension studies s2 005
Neurology, 2018Co-Authors: Gregory Klein, Carsten Hofmann, Paul Delmar, Mirjana Adjelkovic, Danielle Abisaab, Smiljana Milosavljevicristic, Monika Baudler, Paulo Fontura, Rachelle DoodyAbstract:Objective: To evaluate the efficacy of Gantenerumab on amyloid burden assessed longitudinally with florbetapir PET. Background: Scarlet RoAD (SR, NCT01224106) and Marguerite RoAD (MR, NCT02051608) were phase 3 studies to assess the efficacy and safety of Gantenerumab in prodromal and mild AD. Following a pre-planned futility analysis with low likelihood to meet the primary endpoint with 105 mg and 225 mg Gantenerumab sc monthly, both trials were converted to open label extension studies (OLE) to evaluate safety and efficacy of higher doses of Gantenerumab up to 1200 mg sc monthly. Here we report the PET results. Design/Methods: Patients enrolled in SR and MR double-blind (DB) trials were eligible to enter OLE studies. Patients were assigned to one of six titration schedules (ranging from 2 to 6 months), all with a target dose of 1200 mg sc monthly. Change in amyloid burden was assessed by comparing florbetapir PET at OLE baseline and week 52. Results: Among 81 patients enrolled in the OLE PET substudies, 40 (14 in MR-Placebo, 17 in MR-Gantenerumab, 9 in SR) met the criteria for high dose analysis (cutoff date: August 31, 2017). Mean (SD) change in absolute SUVR units seen in the three groups were −0.24 (0.21), −0.27 (0.14), −0.13 (0.16), up to three times the 2-year change seen at 225 mg dose in the DB SR study. Overall, approximately one third of patients had amyloid levels below the cut point for amyloid positivity at week 52. Conclusions: This study showed significantly higher reductions of amyloid plaque with 1200 mg Gantenerumab dosing regimen compared to 105 or 225 mg dosing. Results in this ongoing study confirmed the amyloid plaque removal component of the Gantenerumab mechanisms of action, and showed that within a 6–9 month higher-dose treatment period, approximately one third of subjects achieved below threshold PET SUVR signals based on quantitative measures. Disclosure: Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Delmar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Hofmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Adjelkovic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Abi-Saab has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Milosavljevic-Ristic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Baudler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Fontoura has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann La-Roche Ltd. Dr. Fontoura holds stock and/or stock options in F. Hoffmann La-Roche Ltd., which sponsored research in which Dr. Fontoura was involved as an investigator. Dr. Doody has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche.
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optimizing the Gantenerumab phase 3 dosing regimen through pk pd modeling and clinical trial simulations p6 179
Neurology, 2018Co-Authors: Carsten Hofmann, Sylvie Retout, Paul Delmar, Smiljana Milosavljevicristic, Nicola Voyle, Ronald Gieschke, Daniel SerafinAbstract:Objective: To combine available internal and external information and generate additional clinical safety data to confirm prior modeling assumptions. Background: Following a futility assessment of one Gantenerumab Phase 3 study (Scarlet RoAD) in 2015 a strategy to select a potentially efficacious and safe dosing regimen for Gantenerumab had to be developed. Design/Methods: Mathematical PK/PD models for PET (surrogate for efficacy) and ARIA (safety) were developed to create a hypothesis for an optimal dosing regimen in patients. Subsequently, several dosing regimens were tested in open-label-extension parts of former Phase 3 studies to assess the safety of higher doses and to inform the PK/PD models. The updated models were used to simulate different Phase 3 titration regimens with the aim to find a safe, potentially efficacious and simple dosing regimen for all patients, irrespective of the ApoE4 genotype status. Results: Actual clinical data from the OLEs and PK/PD modeling data indicated that a slow up-titration regimen delivers the best benefit/risk ratio. Patients are very sensitive to amyloid plaque clearing agents at the beginning of treatment and a slow up-titration will therefore help mitigating ARIA-E events. The mitigation of ARIA-E events pays off long-term as treatment will be paused in less patients until ARIA-E resolution. Clinical trial simulations indicated that doubling the dose every three months until the final dose is reached provides the best results in terms of benefit, risk and simplicity. Conclusions: The holistic approach of combining available internal and external data through PK/PD modeling and generating new clinical data to confirm the model assumption allowed the team to develop an optimized dosing regimen for the new Gantenerumab Phase 3 studies in a very short period of time. Disclosure: Dr. Hofmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Gieschke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Retout has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Milosavljevic-Ristic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Voyle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Delmar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Serafin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG.
Sylvie Retout - One of the best experts on this subject based on the ideXlab platform.
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correction to a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2018Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten Hofmann, Paul DelmarAbstract:Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows:
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optimizing the Gantenerumab phase 3 dosing regimen through pk pd modeling and clinical trial simulations p6 179
Neurology, 2018Co-Authors: Carsten Hofmann, Sylvie Retout, Paul Delmar, Smiljana Milosavljevicristic, Nicola Voyle, Ronald Gieschke, Daniel SerafinAbstract:Objective: To combine available internal and external information and generate additional clinical safety data to confirm prior modeling assumptions. Background: Following a futility assessment of one Gantenerumab Phase 3 study (Scarlet RoAD) in 2015 a strategy to select a potentially efficacious and safe dosing regimen for Gantenerumab had to be developed. Design/Methods: Mathematical PK/PD models for PET (surrogate for efficacy) and ARIA (safety) were developed to create a hypothesis for an optimal dosing regimen in patients. Subsequently, several dosing regimens were tested in open-label-extension parts of former Phase 3 studies to assess the safety of higher doses and to inform the PK/PD models. The updated models were used to simulate different Phase 3 titration regimens with the aim to find a safe, potentially efficacious and simple dosing regimen for all patients, irrespective of the ApoE4 genotype status. Results: Actual clinical data from the OLEs and PK/PD modeling data indicated that a slow up-titration regimen delivers the best benefit/risk ratio. Patients are very sensitive to amyloid plaque clearing agents at the beginning of treatment and a slow up-titration will therefore help mitigating ARIA-E events. The mitigation of ARIA-E events pays off long-term as treatment will be paused in less patients until ARIA-E resolution. Clinical trial simulations indicated that doubling the dose every three months until the final dose is reached provides the best results in terms of benefit, risk and simplicity. Conclusions: The holistic approach of combining available internal and external data through PK/PD modeling and generating new clinical data to confirm the model assumption allowed the team to develop an optimized dosing regimen for the new Gantenerumab Phase 3 studies in a very short period of time. Disclosure: Dr. Hofmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Gieschke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Retout has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Milosavljevic-Ristic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Voyle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Delmar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Serafin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG.
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a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2017Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten HofmannAbstract:Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of Gantenerumab in prodromal Alzheimer’s disease (AD). In this randomized, double-blind, placebo-controlled phase III study, we investigated Gantenerumab over 2 years. Patients were randomized to Gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, Gantenerumab 105 mg, and Gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE e4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with Gantenerumab may be necessary to achieve clinical efficacy. ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
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efficacy safety and biomarker data from scarlet road a global phase 3 study of Gantenerumab in patients with prodromal ad s1 002
Neurology, 2016Co-Authors: Robert Lasser, Philip Scheltens, Tania Nikolcheva, Sylvie Retout, Bruno Dubois, Dietmar Volz, Csoboth Csilla, Merce BoadaAbstract:Objective: SCarlet RoAD (NCT01224106; WN25203) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year study testing the efficacy and safety of Gantenerumab in prodromal AD. Background: Gantenerumab is a human, anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ. Methods: Patients were 50-85 years old with MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 pg/mL, Innotest®), with cognition and functional performance largely preserved—excluding a diagnosis of AD dementia. 799 patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg Gantenerumab, depending on APOEe4 allele status (APOEe4 homozygotes received 105 mg or placebo). 114 patients were enrolled in a PET sub-study. Results: Gantenerumab and placebo treatment groups were not different in the primary endpoint (CDR-SB scores over 2 years). An exposure-dependent trend was shown for clinical benefit in patients predicted to have a faster progression rate. Serious adverse events were reported in 19.5[percnt], 17.3[percnt] and 16.9[percnt] of patients in the placebo, 105 mg and 225 mg Gantenerumab arms, respectively. ARIA were dose- and APOEe4 allele-dependent. Amyloid-PET standardized uptake value (SUVr), using mean cerebellar gray as reference region, showed a dose-dependent reduction from baseline. CSF analyses found dose-dependent reductions in CSF p-Tau and t-Tau, but no changes in Aβ42 levels. Conclusions: Gantenerumab was well tolerated by patients with prodromal AD. Although no significant differences in primary efficacy endpoints between treatment arms were observed, Gantenerumab was associated with an exposure-dependent clinical benefit in patients predicted to progress faster, and dose-dependent reductions in brain Aβ SUVr and CSF p-Tau and t-Tau. These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration. Study Supported by: F. Hoffmann-La Roche Disclosure: Mr. Lasser has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Scheltens has received research support from Merck, GE Healthcare, and Piramal. Dr. Dubois has received personal compensation for activities with Eli Lilly and Boehringer-Ingelheim as a consultant. Dr. Nikolcheva has received personal compensation for activities with F. Hoffman-La Roche. Dr. Retout has received personal compensation for activities with Hoffman-La Roche. Dr. Volz has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Csoboth has received personal compensation for activities with Genentech, Inc., as an employee. Dr. Boada has received research support from Lilly.
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resultats d efficacite de tolerance et des biomarqueurs de scarlet road une etude de phase 3 internationale du Gantenerumab chez des patients atteints d une maladie d alzheimer ma a la phase prodromale
Revue Neurologique, 2016Co-Authors: Bruno Dubois, Robert Lasser, Tania Nikolcheva, Sylvie Retout, Merce Boada, Philippe Scheltens, Dietmar VolzAbstract:Introduction Gantenerumab (G), un anticorps monoclonal anti-Aβ, humain, se lie avec une grande affinite aux agregats d’Aβ. Le traitement a ete interrompu en decembre 2014 apres une analyse de futilite pre-planifiee. Le suivi des patients continue. Objectifs SCarlet RoAD ( NCT01224106 ) est une etude de phase 3, multicentrique, randomisee, en double-insu vs placebo sur 2 ans, concue pour evaluer l’efficacite et la tolerance du G dans la MA a la phase prodromale. Patients et methodes Des injections sous-cutanees mensuelles de placebo ou G 105 mg ou 225 mg (si non homozygotes APOEe4) ont ete administrees a 799 patients randomises âges de 50–85 ans ; score MMSE ≥ 24, score CDR global de 0,5 (scores memoire 0,5 ou 1,0), dosage d’Aβ42 dans le LCR Resultats Pas de difference du score CDR-SB sur 2 ans (critere principal) pour G et placebo. Tendance au benefice clinique dependant de l’exposition, si progression rapide attendue. Evenements indesirables graves : 19,5 %, 17,3 % et 16,9 % des patients placebo et G 105/225 mg respectivement. ARIA dependantes de dose et allele APOEɛ4. Diminution dose-dependante de SUVr sur substance grise cerebelleuse au TEP amyloide. Diminution dose-dependante de p-Tau et t-Tau sans modification des taux de l’Aβ42 dans LCR. Discussion G a ete bien tolere chez les patients ayant une MA a la phase prodromale. Bien qu’aucune difference sur les criteres principaux d’efficacite n’ait ete observee, G a ete associe a des reductions dose-dependantes de Aβ SUVr cerebrale et de p-Tau et t-Tau dans le LCR. Conclusion Ces resultats sont coherents avec une clairance de l’amyloide cerebrale et un effet sur les marqueurs de la neurodegenerescence.
Robert Lasser - One of the best experts on this subject based on the ideXlab platform.
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correction to a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2018Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten Hofmann, Paul DelmarAbstract:Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows:
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a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2017Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten HofmannAbstract:Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of Gantenerumab in prodromal Alzheimer’s disease (AD). In this randomized, double-blind, placebo-controlled phase III study, we investigated Gantenerumab over 2 years. Patients were randomized to Gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, Gantenerumab 105 mg, and Gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE e4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with Gantenerumab may be necessary to achieve clinical efficacy. ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.
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efficacy safety and biomarker data from scarlet road a global phase 3 study of Gantenerumab in patients with prodromal ad s1 002
Neurology, 2016Co-Authors: Robert Lasser, Philip Scheltens, Tania Nikolcheva, Sylvie Retout, Bruno Dubois, Dietmar Volz, Csoboth Csilla, Merce BoadaAbstract:Objective: SCarlet RoAD (NCT01224106; WN25203) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year study testing the efficacy and safety of Gantenerumab in prodromal AD. Background: Gantenerumab is a human, anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ. Methods: Patients were 50-85 years old with MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 pg/mL, Innotest®), with cognition and functional performance largely preserved—excluding a diagnosis of AD dementia. 799 patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg Gantenerumab, depending on APOEe4 allele status (APOEe4 homozygotes received 105 mg or placebo). 114 patients were enrolled in a PET sub-study. Results: Gantenerumab and placebo treatment groups were not different in the primary endpoint (CDR-SB scores over 2 years). An exposure-dependent trend was shown for clinical benefit in patients predicted to have a faster progression rate. Serious adverse events were reported in 19.5[percnt], 17.3[percnt] and 16.9[percnt] of patients in the placebo, 105 mg and 225 mg Gantenerumab arms, respectively. ARIA were dose- and APOEe4 allele-dependent. Amyloid-PET standardized uptake value (SUVr), using mean cerebellar gray as reference region, showed a dose-dependent reduction from baseline. CSF analyses found dose-dependent reductions in CSF p-Tau and t-Tau, but no changes in Aβ42 levels. Conclusions: Gantenerumab was well tolerated by patients with prodromal AD. Although no significant differences in primary efficacy endpoints between treatment arms were observed, Gantenerumab was associated with an exposure-dependent clinical benefit in patients predicted to progress faster, and dose-dependent reductions in brain Aβ SUVr and CSF p-Tau and t-Tau. These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration. Study Supported by: F. Hoffmann-La Roche Disclosure: Mr. Lasser has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Scheltens has received research support from Merck, GE Healthcare, and Piramal. Dr. Dubois has received personal compensation for activities with Eli Lilly and Boehringer-Ingelheim as a consultant. Dr. Nikolcheva has received personal compensation for activities with F. Hoffman-La Roche. Dr. Retout has received personal compensation for activities with Hoffman-La Roche. Dr. Volz has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Csoboth has received personal compensation for activities with Genentech, Inc., as an employee. Dr. Boada has received research support from Lilly.
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resultats d efficacite de tolerance et des biomarqueurs de scarlet road une etude de phase 3 internationale du Gantenerumab chez des patients atteints d une maladie d alzheimer ma a la phase prodromale
Revue Neurologique, 2016Co-Authors: Bruno Dubois, Robert Lasser, Tania Nikolcheva, Sylvie Retout, Merce Boada, Philippe Scheltens, Dietmar VolzAbstract:Introduction Gantenerumab (G), un anticorps monoclonal anti-Aβ, humain, se lie avec une grande affinite aux agregats d’Aβ. Le traitement a ete interrompu en decembre 2014 apres une analyse de futilite pre-planifiee. Le suivi des patients continue. Objectifs SCarlet RoAD ( NCT01224106 ) est une etude de phase 3, multicentrique, randomisee, en double-insu vs placebo sur 2 ans, concue pour evaluer l’efficacite et la tolerance du G dans la MA a la phase prodromale. Patients et methodes Des injections sous-cutanees mensuelles de placebo ou G 105 mg ou 225 mg (si non homozygotes APOEe4) ont ete administrees a 799 patients randomises âges de 50–85 ans ; score MMSE ≥ 24, score CDR global de 0,5 (scores memoire 0,5 ou 1,0), dosage d’Aβ42 dans le LCR Resultats Pas de difference du score CDR-SB sur 2 ans (critere principal) pour G et placebo. Tendance au benefice clinique dependant de l’exposition, si progression rapide attendue. Evenements indesirables graves : 19,5 %, 17,3 % et 16,9 % des patients placebo et G 105/225 mg respectivement. ARIA dependantes de dose et allele APOEɛ4. Diminution dose-dependante de SUVr sur substance grise cerebelleuse au TEP amyloide. Diminution dose-dependante de p-Tau et t-Tau sans modification des taux de l’Aβ42 dans LCR. Discussion G a ete bien tolere chez les patients ayant une MA a la phase prodromale. Bien qu’aucune difference sur les criteres principaux d’efficacite n’ait ete observee, G a ete associe a des reductions dose-dependantes de Aβ SUVr cerebrale et de p-Tau et t-Tau dans le LCR. Conclusion Ces resultats sont coherents avec une clairance de l’amyloide cerebrale et un effet sur les marqueurs de la neurodegenerescence.
Paul Delmar - One of the best experts on this subject based on the ideXlab platform.
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Gantenerumab reduces amyloid β plaques in patients with prodromal to moderate alzheimer s disease a pet substudy interim analysis
Alzheimer's Research & Therapy, 2019Co-Authors: Gregory Klein, Carsten Hofmann, Guoqiao Wang, Paul Delmar, Danielle Abisaab, Nicola Voyle, Sunita Rehal, Mirjana Andjelkovic, Smiljana Ristic, Randall J BatemanAbstract:We previously investigated low doses (105 or 225 mg) of Gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of Gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD). A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target Gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold. Results from this exploratory interim analysis of the PET substudy suggest that Gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).
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correction to a phase iii randomized trial of Gantenerumab in prodromal alzheimer s disease
Alzheimer's Research & Therapy, 2018Co-Authors: Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, Tania Nikolcheva, Elizabeth Ashford, Sylvie Retout, Carsten Hofmann, Paul DelmarAbstract:Following publication of the original article [1], the author reported errors in the formatting of the table. The details of the errors are as follows:
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higher dose Gantenerumab leads to significant reduction in amyloid plaque burden results for the marguerite and scarlet road open label extension studies s2 005
Neurology, 2018Co-Authors: Gregory Klein, Carsten Hofmann, Paul Delmar, Mirjana Adjelkovic, Danielle Abisaab, Smiljana Milosavljevicristic, Monika Baudler, Paulo Fontura, Rachelle DoodyAbstract:Objective: To evaluate the efficacy of Gantenerumab on amyloid burden assessed longitudinally with florbetapir PET. Background: Scarlet RoAD (SR, NCT01224106) and Marguerite RoAD (MR, NCT02051608) were phase 3 studies to assess the efficacy and safety of Gantenerumab in prodromal and mild AD. Following a pre-planned futility analysis with low likelihood to meet the primary endpoint with 105 mg and 225 mg Gantenerumab sc monthly, both trials were converted to open label extension studies (OLE) to evaluate safety and efficacy of higher doses of Gantenerumab up to 1200 mg sc monthly. Here we report the PET results. Design/Methods: Patients enrolled in SR and MR double-blind (DB) trials were eligible to enter OLE studies. Patients were assigned to one of six titration schedules (ranging from 2 to 6 months), all with a target dose of 1200 mg sc monthly. Change in amyloid burden was assessed by comparing florbetapir PET at OLE baseline and week 52. Results: Among 81 patients enrolled in the OLE PET substudies, 40 (14 in MR-Placebo, 17 in MR-Gantenerumab, 9 in SR) met the criteria for high dose analysis (cutoff date: August 31, 2017). Mean (SD) change in absolute SUVR units seen in the three groups were −0.24 (0.21), −0.27 (0.14), −0.13 (0.16), up to three times the 2-year change seen at 225 mg dose in the DB SR study. Overall, approximately one third of patients had amyloid levels below the cut point for amyloid positivity at week 52. Conclusions: This study showed significantly higher reductions of amyloid plaque with 1200 mg Gantenerumab dosing regimen compared to 105 or 225 mg dosing. Results in this ongoing study confirmed the amyloid plaque removal component of the Gantenerumab mechanisms of action, and showed that within a 6–9 month higher-dose treatment period, approximately one third of subjects achieved below threshold PET SUVR signals based on quantitative measures. Disclosure: Dr. Klein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Delmar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Hofmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Adjelkovic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Abi-Saab has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Milosavljevic-Ristic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Baudler has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche. Dr. Fontoura has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann La-Roche Ltd. Dr. Fontoura holds stock and/or stock options in F. Hoffmann La-Roche Ltd., which sponsored research in which Dr. Fontoura was involved as an investigator. Dr. Doody has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche.
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optimizing the Gantenerumab phase 3 dosing regimen through pk pd modeling and clinical trial simulations p6 179
Neurology, 2018Co-Authors: Carsten Hofmann, Sylvie Retout, Paul Delmar, Smiljana Milosavljevicristic, Nicola Voyle, Ronald Gieschke, Daniel SerafinAbstract:Objective: To combine available internal and external information and generate additional clinical safety data to confirm prior modeling assumptions. Background: Following a futility assessment of one Gantenerumab Phase 3 study (Scarlet RoAD) in 2015 a strategy to select a potentially efficacious and safe dosing regimen for Gantenerumab had to be developed. Design/Methods: Mathematical PK/PD models for PET (surrogate for efficacy) and ARIA (safety) were developed to create a hypothesis for an optimal dosing regimen in patients. Subsequently, several dosing regimens were tested in open-label-extension parts of former Phase 3 studies to assess the safety of higher doses and to inform the PK/PD models. The updated models were used to simulate different Phase 3 titration regimens with the aim to find a safe, potentially efficacious and simple dosing regimen for all patients, irrespective of the ApoE4 genotype status. Results: Actual clinical data from the OLEs and PK/PD modeling data indicated that a slow up-titration regimen delivers the best benefit/risk ratio. Patients are very sensitive to amyloid plaque clearing agents at the beginning of treatment and a slow up-titration will therefore help mitigating ARIA-E events. The mitigation of ARIA-E events pays off long-term as treatment will be paused in less patients until ARIA-E resolution. Clinical trial simulations indicated that doubling the dose every three months until the final dose is reached provides the best results in terms of benefit, risk and simplicity. Conclusions: The holistic approach of combining available internal and external data through PK/PD modeling and generating new clinical data to confirm the model assumption allowed the team to develop an optimized dosing regimen for the new Gantenerumab Phase 3 studies in a very short period of time. Disclosure: Dr. Hofmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Gieschke has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Retout has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Milosavljevic-Ristic has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Voyle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Delmar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG. Dr. Serafin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche AG.
Merce Boada - One of the best experts on this subject based on the ideXlab platform.
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efficacy safety and biomarker data from scarlet road a global phase 3 study of Gantenerumab in patients with prodromal ad s1 002
Neurology, 2016Co-Authors: Robert Lasser, Philip Scheltens, Tania Nikolcheva, Sylvie Retout, Bruno Dubois, Dietmar Volz, Csoboth Csilla, Merce BoadaAbstract:Objective: SCarlet RoAD (NCT01224106; WN25203) was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-year study testing the efficacy and safety of Gantenerumab in prodromal AD. Background: Gantenerumab is a human, anti-Aβ monoclonal antibody that binds with high affinity to aggregated Aβ. Methods: Patients were 50-85 years old with MMSE scores ≥24, CDR-Global scores of 0.5 (memory box scores of 0.5 or 1.0) and evidence of amyloid pathology (CSF Aβ42 <600 pg/mL, Innotest®), with cognition and functional performance largely preserved—excluding a diagnosis of AD dementia. 799 patients were randomized to monthly subcutaneous injections of placebo, or 105 mg or 225 mg Gantenerumab, depending on APOEe4 allele status (APOEe4 homozygotes received 105 mg or placebo). 114 patients were enrolled in a PET sub-study. Results: Gantenerumab and placebo treatment groups were not different in the primary endpoint (CDR-SB scores over 2 years). An exposure-dependent trend was shown for clinical benefit in patients predicted to have a faster progression rate. Serious adverse events were reported in 19.5[percnt], 17.3[percnt] and 16.9[percnt] of patients in the placebo, 105 mg and 225 mg Gantenerumab arms, respectively. ARIA were dose- and APOEe4 allele-dependent. Amyloid-PET standardized uptake value (SUVr), using mean cerebellar gray as reference region, showed a dose-dependent reduction from baseline. CSF analyses found dose-dependent reductions in CSF p-Tau and t-Tau, but no changes in Aβ42 levels. Conclusions: Gantenerumab was well tolerated by patients with prodromal AD. Although no significant differences in primary efficacy endpoints between treatment arms were observed, Gantenerumab was associated with an exposure-dependent clinical benefit in patients predicted to progress faster, and dose-dependent reductions in brain Aβ SUVr and CSF p-Tau and t-Tau. These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration. Study Supported by: F. Hoffmann-La Roche Disclosure: Mr. Lasser has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Scheltens has received research support from Merck, GE Healthcare, and Piramal. Dr. Dubois has received personal compensation for activities with Eli Lilly and Boehringer-Ingelheim as a consultant. Dr. Nikolcheva has received personal compensation for activities with F. Hoffman-La Roche. Dr. Retout has received personal compensation for activities with Hoffman-La Roche. Dr. Volz has received personal compensation for activities with F. Hoffmann-La Roche as an employee. Dr. Csoboth has received personal compensation for activities with Genentech, Inc., as an employee. Dr. Boada has received research support from Lilly.
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resultats d efficacite de tolerance et des biomarqueurs de scarlet road une etude de phase 3 internationale du Gantenerumab chez des patients atteints d une maladie d alzheimer ma a la phase prodromale
Revue Neurologique, 2016Co-Authors: Bruno Dubois, Robert Lasser, Tania Nikolcheva, Sylvie Retout, Merce Boada, Philippe Scheltens, Dietmar VolzAbstract:Introduction Gantenerumab (G), un anticorps monoclonal anti-Aβ, humain, se lie avec une grande affinite aux agregats d’Aβ. Le traitement a ete interrompu en decembre 2014 apres une analyse de futilite pre-planifiee. Le suivi des patients continue. Objectifs SCarlet RoAD ( NCT01224106 ) est une etude de phase 3, multicentrique, randomisee, en double-insu vs placebo sur 2 ans, concue pour evaluer l’efficacite et la tolerance du G dans la MA a la phase prodromale. Patients et methodes Des injections sous-cutanees mensuelles de placebo ou G 105 mg ou 225 mg (si non homozygotes APOEe4) ont ete administrees a 799 patients randomises âges de 50–85 ans ; score MMSE ≥ 24, score CDR global de 0,5 (scores memoire 0,5 ou 1,0), dosage d’Aβ42 dans le LCR Resultats Pas de difference du score CDR-SB sur 2 ans (critere principal) pour G et placebo. Tendance au benefice clinique dependant de l’exposition, si progression rapide attendue. Evenements indesirables graves : 19,5 %, 17,3 % et 16,9 % des patients placebo et G 105/225 mg respectivement. ARIA dependantes de dose et allele APOEɛ4. Diminution dose-dependante de SUVr sur substance grise cerebelleuse au TEP amyloide. Diminution dose-dependante de p-Tau et t-Tau sans modification des taux de l’Aβ42 dans LCR. Discussion G a ete bien tolere chez les patients ayant une MA a la phase prodromale. Bien qu’aucune difference sur les criteres principaux d’efficacite n’ait ete observee, G a ete associe a des reductions dose-dependantes de Aβ SUVr cerebrale et de p-Tau et t-Tau dans le LCR. Conclusion Ces resultats sont coherents avec une clairance de l’amyloide cerebrale et un effet sur les marqueurs de la neurodegenerescence.
