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AT-HOME ADMINISTRATION OF GANTENERUMAB BY CARE PARTNERS TO PEOPLE WITH EARLY ALZHEIMER’S DISEASE: FEASIBILITY, SAFETY AND PHARMACODYNAMIC IMPACT

 

F.G. Boess1, M.A. Scelsi2, T. Grimmer3, R.J. Perry4, M. Tonietto5, G. Klein5, C. Hofmann5, M. Salami1, J. Wojtowicz1, C.J. Lansdall1, C. Lane2, G.A. Kerchner5, J. Smith2, R.S. Doody1,6, for the GRADUATION Investigators and the gantenerumab study group

 

1. F. Hoffmann-La Roche Ltd, Basel, Switzerland; 2. Roche Products Ltd, Welwyn Garden City, UK; 3. Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; 4. Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK; 5. Pharma Research and Early Development, F. Hoffmann-La Roche, Ltd., Basel, Switzerland; 6. Genentech, Inc., South San Francisco, CA, USA

Corresponding Author: Frank G. Boess, Ph.D., F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland, E-mail: frank.boess@roche.com

J Prev Alz Dis 2024;
Published online March 19, 2024, http://dx.doi.org/10.14283/jpad.2024.60

 


Abstract

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer’s disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes), development of gantenerumab in sporadic Alzheimer’s disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies.
OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners.
DESIGN: Phase 2, open-label, single arm study.
SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023.
PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer’s disease (mild cognitive impairment/mild dementia due to Alzheimer’s disease), and evidence of amyloid positron emission tomography positivity.
INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners.
MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety.
RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6–15.8; n=149) and -35.48 centiloids (range: -63.2–-7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners.
CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer’s disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer’s disease. Although gantenerumab’s development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer’s disease and their families.

Key words: Amyloid PET, subcutaneous home administration by care partner, gantenerumab, Alzheimer’s disease.


 

 

Introduction

Monoclonal antibodies targeting different amyloid-beta (Aβ) protein species such as intravenously administered aducanumab, donanemab, and lecanemab, can remove amyloid plaques as measured by amyloid positron emission tomography (PET), slow cognitive and functional decline, and impact downstream disease pathology in early Alzheimer’s disease (AD) (1-4).
Gantenerumab is a subcutaneously administered fully-human, anti-Aβ immunoglobulin G1 monoclonal antibody with highest affinity for aggregated Aβ, including oligomers, fibrils, and plaques (5-6). It removes Aβ via microglia-mediated phagocytosis, promotes amyloid plaque clearance, and has previously shown downstream effects on biomarkers of AD pathology and neurodegeneration (7-8).
Two multicenter, randomized, double-blind, placebo-controlled phase 3 trials (GRADUATE I [NCT03444870] and GRADUATE II [NCT03443973) assessed the clinical and biological efficacy and safety of subcutaneous (SC) gantenerumab, administered by a healthcare professional (HCP), in early symptomatic AD (mild cognitive impairment due to AD or mild dementia due to AD) using a dose of 510 mg every 2 weeks (Q2W) (9). In these studies, the primary endpoint assessing change from baseline in Clinical Dementia Rating – Sum of Boxes (CDR-SB) in gantenerumab versus placebo groups was not met, while a significant (but lower than expected) effect on amyloid reduction was observed (10). As a consequence, development of gantenerumab in sporadic Alzheimer’s Disease (AD) was stopped and all ongoing trials were terminated early due to sponsor decision.
Subcutaneous administration of therapies including monoclonal antibodies by non-healthcare-professional [non-HCP] caregivers (e.g. care partners, parents or patients) is well established in populations of diverse age ranges across a number of disease areas, including rheumatoid arthritis (11), multiple sclerosis (12), hemophilia A (13), and diabetes (14). A subcutaneous administration at home by care partners could help address significant and increasing capacity constraints across healthcare systems (15) and simplify care for people living with AD by offering additional flexibility and convenience and reducing the burden of frequent clinic visits or visits by an HCP. Receiving and administering a treatment injection at home may be a new experience for many people living with AD and their families. In this study we assessed care partner and participant (patient) satisfaction with and convenience of home administration, as well as the ease and confidence in their ability to give an injection from a care partner’s point of view.
The multicenter, single-arm, open-label GRADUATION trial (NCT04592341) evaluated the pharmacodynamic effect on brain amyloid load of a once-weekly (Q1W) subcutaneous administration of gantenerumab (255 mg) in participants with early symptomatic AD. The GRADUATION trial allowed home dosing by a non-HCP care partner, if they were willing and deemed able to administer gantenerumab by the study investigator after a standardized training. Secondary objectives included the assessment of gantenerumab administration by the care partner in the home setting using a home administration questionnaire (HAQ), safety, and gantenerumab plasma concentrations. The GRADUATION study is the first trial that investigated subcutaneous home administration by a non-HCP care partner in an Alzheimer’s disease population. Interim data from this study examining at home administration by care partners can provide guidance to future drug development programs.

 

Methods

Trial Design

GRADUATION was a phase 2, multicenter, open-label, single arm, pharmacodynamic (PD) study in participants with mild cognitive impairment due to AD or mild AD dementia. Participants were recruited from 33 centers in 8 countries. Following screening, eligible participants entered open-label treatment for up to 104 weeks (due to early study termination, none of the subjects entered the optional extension to 208 weeks), with a 16 week follow-up after the last dose. Additional details on the study design are provided in Supplemental Figure S1.

Trial Oversight

The GRADUATION study was conducted in accordance with the International Conference on Harmonization E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, and the laws and regulations of the countries in which the research was conducted. The protocol and any subsequent amendments were approved by the relevant Institutional Review Board/Ethics Committee and regulatory authorities. All trial participants and their study partners (care partners) provided written informed consent. The study was designed and funded by the sponsor F. Hoffmann-La Roche, who provided the study drug, analyzed the data in collaboration with academic authors, and funded professional writing assistance in developing this manuscript.

Eligibility Criteria

The study included participants aged 50 to 90 years, with mild cognitive impairment due to Alzheimer’s disease or probable Alzheimer’s disease dementia of mild severity, according to National Institute on Aging/Alzheimer’s Association (NIA-AA) diagnostic criteria (16, 17). Participants with a Clinical Dementia Rating – Global Score (CDR-GS) (18) of 0.5 or 1.0, abnormal memory (CDR memory domain score ≥0.5) and a Mini Mental State Examination (MMSE) (19) score ≥ 22) were eligible. All enrolled participants had evidence of amyloid pathology confirmed by an amyloid PET binary visual read consistent with the FDA/EU label (20, 21) for [18F]florbetaben performed by two expert central readers. In case of disagreement, a third central reader was used to obtain a majority final result. Participants were eligible whether or not they were receiving stable standard-of-care symptomatic medications for AD at baseline (cholinesterase inhibitors or memantine). All participants needed a study partner/non-HCP care partner with sufficient cognitive and physical capacity (as determined by the investigator), who was willing and capable of administering SC injections. Participants were excluded if they were taking anticoagulants, or had clinically significant findings in an MRI at screening that could cause or contribute to cognitive impairment, presence of ARIA-edema (ARIA-E) or >5 combined microbleeds and areas of leptomeningeal hemosiderosis (cumulative ARIA-H), >2 lacunar infarcts or any white matter lesion that corresponds to an overall Fazekas score of 3 (22). Detailed eligibility criteria are shown in the Supplemental Methodology Section.

Dosing

All eligible participants received gantenerumab, administered at the study site or at home by a nurse or a non-HCP care partner. The gantenerumab dose was up-titrated over a 36-week period to a target of 255 mg once-weekly (compared to the target dose of 510 mg every two weeks evaluated in the GRADUATE studies), regardless of apolipoprotein E ε4 (APOE ε4) genotype or weight. Initially, participants received a minimum of 3 doses of 120 mg every 4 weeks (Q4W) and underwent brain magnetic resonance imaging (MRI) to confirm eligibility for the next dosage level. This was followed by a minimum of 3 doses of 255 mg Q4W, 6 doses of 255 mg every 2 weeks (Q2W), and a final up-titration to the target dose of 255 mg once-weekly, with an MRI prior to each up-titration and at pre-specified intervals throughout the study. Additional details are provided in Supplemental Figure S1. Non-HCP care partners willing and capable of administering SC injections received training and observed dose administration by qualified study staff at the first three dosing visits. At the next four dosing visits, care partners administered injections under staff supervision. All care partners received a manual with detailed instructions (see supplementary methods section: “Gantenerumab administration manual for study partners”). A vial adapter (an aid device to reduce the risk of needlestick injuries) manufactured by West Pharma was used to withdraw the medication from the vial into a disposable syringe (optional step for health care professionals and required for care partners). After supervised dosing at the clinic, subsequent dosing could be by the care partner at home except for doses that coincided with a clinic visit required to complete in-person assessments (e.g. Weeks 36, 52, 64, and 76). At site visits, the care partner was asked to administer the injection under study staff supervision. If at any time the investigator or care partner determined that home administration by care partner was no longer suitable, study drug had to be administered at home or in the clinic by a home nurse (contracted by the sponsor) or study staff. Injections were administered as one 0.8-mL (120-mg) dose for the first three injections by site staff or one 1.7-mL (255-mg) dose (all subsequent injections including care partner administrations) subcutaneously to the abdomen. Full instructions for the subcutaneous administration of gantenerumab were provided through training at site and a manual (see supplementary materials) that detailed each of the steps required including storage, preparation of supplies, and the injection process. The injection process, using the vial adapter for withdrawing the medicine, could be completed in less than 5 minutes. The care partner was instructed to remain with the participant for an observation period of at least one hour and to call an emergency number provided by the investigator in case of a severe reaction at the injection site or symptoms of a serious allergic reaction. The treatment period was initially planned for up to 104 weeks, with an optional extension up to 208 weeks. Since the pivotal GRADUATE trials did not meet the primary endpoint (and thus did not provide evidence of clinical benefit of gantenerumab), GRADUATION was terminated early by the sponsor.

Primary Outcome – Amyloid PET

The primary objective of the study was to evaluate the PD effect of a once-weekly dosing regimen of gantenerumab on brain amyloid load with change from baseline to week 52 and 104 in amyloid PET Centiloid (CL) levels as the corresponding endpoint. Amyloid [18F]florbetaben PET was collected at baseline, at week 52, and 104. Each participant at each visit underwent a total of 20 minutes (4×5 minute acquisition) of serial PET imaging starting 90 minutes (± 1 minute) post intravenous injection of 300MBq (± 20%) of [18F]florbetaben. PET images were processed in PMOD (PMOD Technologies, Zurich, Switzerland) according to the following steps: motion correction, time averaging, smoothing to reach a common resolution of 7.0 mm (in-plane) and 8.0 mm (axial), coregistration to a time matched MRI. For each amyloid PET image, a standardized uptake value ratio (SUVR) value was calculated in a neocortical composite region (composed of frontal, parietal, temporal and cingulate cortex) using the whole cerebellum as reference region. This SUVR value was then mapped into a CL value using the following equation: CL=175.6 * SUVR – 174.2. The time window for the Week 52 and Week 104 PET was defined as ± 84 days of the study day corresponding to Week 52 or Week 104, respectively.

Secondary Outcome – Home Administration Questionnaire

The secondary objective and corresponding endpoint of the study was to evaluate care partner overall satisfaction and confidence with home administration based on care partner responses to the home administration questionnaire up to Week 52 and Week 104. The home administration questionnaire (HAQ) was completed at site visits Week 36, Week 52 (interim analysis), Week 76, and Week 104 (primary analysis) or early termination. The HAQ included four items to be completed by the care partner to assess confidence, convenience, ease of use, and overall satisfaction with administration in the home setting. Each item was rated on a 4-point verbal Likert scale and respondents were asked to consider their most recent at-home administration. The questionnaire consisted of the following items (and response options): 1. “How confident were you in your ability to give the injection?” (Not at all confident, somewhat confident, confident, very confident). 2. “How easy was it to give the injection?” (Not at all easy, somewhat easy, easy, very easy). 3. “Overall, how satisfied were you with giving an injection at home?” (Not at all satisfied, somewhat satisfied, satisfied, very satisfied). 4. “Overall, how convenient was it for you to administer the medication at home?” (Not at all convenient, somewhat convenient, convenient, very convenient). This study-specific measure was developed based on existing validated treatment satisfaction questionnaires (23). Questions 5 and 6 were answered by the participant, and included as an exploratory outcome: 5. “How convenient was it for you to receive the medication at home?” (Not at all convenient, somewhat convenient, convenient, very convenient). 6. “How satisfied were you with receiving an injection at home?” (Not at all satisfied, somewhat satisfied, satisfied, very satisfied).

Pharmacokinetic Samples

Blood samples for PK analysis were collected at study Day 1, Day 4, Week 24, Week 36, Week 52, Week 76, Week 104 and at Follow-up. Plasma samples were analyzed for gantenerumab concentrations using specific, target binding competent and validated enzyme-linked immunosorbent assay (ELISA) methods.

Safety Assessments

Safety outcomes encompassed the assessment of incidence, nature, severity and timing of adverse events (AEs), serious adverse events, amyloid-related imaging abnormalities – ARIA-E and ARIA-H as reported by a central neuroradiologist, and injection site reactions, physical examinations, vital signs, blood tests, electrocardiograms, and Columbia-Suicide Severity Rating Scale (C-SSRS) scores. Participants underwent brain MRI prior to each dosage increase during up-titration, as well as on target dose at weeks 48, 60, 76, 104, or early termination.

Statistical Analysis

Sample size was determined as the number of participants needed for the estimated change from baseline to Week 104 in amyloid-PET load to fall into a 10 CL confidence interval (CI) around its true value. With an expected standard deviation of 25.67 CL and drop-out rate of 35% at Week 104, 150 participants were required to fulfill this criterion. The standard deviation of amyloid reduction at Week 104 was estimated using amyloid PET data from the SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) studies Open Label Extensions (based on a cutoff date of 14 October 2019), yielding a value of 25.67 CL.
The following analysis sets were defined: Intent-to-treat (ITT): all enrolled participants, whether or not the participant received the assigned treatment; Safety-evaluable (SE): all participants enrolled who received at least one dose of study treatment, whether prematurely withdrawn from the study or not; Opportunity for home dosing safety-evaluable (OH-SE): all participants in the SE analysis set who did not discontinue study drug before week 26; Home dosing by care partner safety-evaluable (H-SE): all participants in the SE analysis set who received at least one dose of study treatment administered at home by care partner.

Statistical analysis of the primary endpoint

Descriptive summary statistics (mean, standard deviation, median, and minimum and maximum) for the brain amyloid CL load at baseline, Week 52 and Week 104, as well as the change from baseline to Week 52 and Week 104 were produced. A Mixed Model for Repeated Measures (MMRM) analysis was used to estimate the mean change in CL from baseline to Week 52 and Week 104 on the ITT analysis set. The model included the change from baseline in CL as the dependent variable, while adjusting for visit (as categorical), apolipoprotein E allele ε4 (APOE ε4) status (as categorical; carrier vs non-carrier), baseline CL, and baseline CL-by-visit. Visit was treated as the repeated variable within a participant. An unstructured variance-covariance matrix was applied to model the within-participant errors; in the case of non-convergence, compound symmetry was used, together with a robust estimator of standard error (“sandwich” estimator). Data acquired after the intercurrent event “Substantial reduction in drug exposure due to the COVID-19 pandemic” (defined as four or more missed dose-months due to pandemic-related reason) or more than 56 days from date of last dose were excluded from the analysis and treated as missing for the primary analysis purposes. There was no data imputation for missing data. However, the MMRM model provides unbiased estimates and valid inference in the presence of missing data, under the missing at random assumption. The statistical package used was SAS 9.4..

Statistical analysis of the secondary endpoint

Descriptive summaries were generated separately for each of the 4 items of the care partner portion of the HAQ on the H-SE analysis set. Responses to each item are considered ordinal data: for each item at each visit, the number of available responses as well as the number and percentage for each response category were reported. No imputation of missing data was performed. The same approach was followed for the 2 items included in the participant portion of the HAQ. Additionally, descriptive tables summarize the number of home administrations by care partner per participant as well as the reasons for the care partner not performing home-administrations.

Statistical analysis of the safety data

Descriptive summary statistics were generated for MRI safety findings ARIA-E and ARIA-H, ISRs, and other AEs including serious AEs and treatment discontinuations due to AE.

 

Results

Trial Population

From 506 screened participants, 192 were enrolled in the study and received at least one dose of study drug. At the time of study termination by sponsor, no participants had completed Week 104, 106 participants (55.2%) had completed Week 76 and 164 participants (85.4%) had completed Week 52. Full disposition data are presented in the supplemental material (Supplemental Figures S2 and S3). Participant baseline characteristics are presented in Table 1. Mean age of participants was 70.5 years and 50.5% were female. The majority were white (91%) and educated for > 12 years (67%). More participants with MCI due to AD (56%) than mild AD dementia (44%) were enrolled and 51% received AD medication at baseline. The majority of care partners were female (64.2%), living with the participant (71.1%) and had no prior experience with administration of subcutaneous injections (58.4%; Table 2). All participants who received study drug after week 26 were considered part of the “opportunity for home dosing” (OH-SE) data set. Twenty-three participants from the OH-SE dataset did not receive any home administration doses by their care partner: Three participants received several supervised injections on-site by care partner, but did not continue with home dosing because of treatment interruption due to AE, withdrawal of treatment due to ARIA-H or subject withdrawal; the remaining twenty participants received home administration by a HCP (sponsor-provided home nurse). Reasons stated for not receiving home administration by care partner in this group were “study partner decision” (n=13), “other” (n=5), “subject decision” (n=1) or missing (n=1). Review of free-text indicated that “other” was mostly due to care partner availability to provide administrations on a weekly basis. Participants without home dosing by care partner tended to be older and a higher proportion had a diagnosis of mild AD dementia (61%) (Table 1). In the subgroup of care partners who did not administer study drug at home, fewer were living with the participant, on average, care partners spent less time with the participant per week, and a higher proportion were employed compared to the group of care partners who were able to administer study drug (Table 2). Per protocol, the first possible home administration was Week 26. Of the 163 participants with home administration by care partner, the majority received their first home administration by Week 28 (Week 26: 49.7%; Week 28: 23.9%; Supplemental Table S1). The median percentage of home administrations that were administered by care partner (out of the maximum possible number of home administrations for a given participant) was 94.1%, and the median number of administrations was 38.0. The reasons reported for “missed” possible home care-partner administrations, included “study partner decision” (52.6%), “other” (41.8%), “training [related to home administration] in progress or additional training required” (4.1%), and participant decision (1.5%). Review of free-text indicated that “other” was mostly due to unavailability of care partner or administration by home nurse. The proportion of participants receiving home administration by care partner continued to remain high over the period studied until the termination of the study (Figure 1a,b and Supplemental Table S2).

Table 1. Participant Baseline Characteristics

* During a study period with per protocol home administration. Participants who did not reach this stage (n=6) are not included in this subpopulation.

Table 2. Care Partner Demographic Data

* During a study period with per protocol home administration. Care partners of participants that did not reach this stage are not included in this subpopulation. The number of care partners is higher than the number of participants, since care partner changes were possible during the study.

Figure 1. Percentage of Home Administration by Care Partner Over Time in Participants Who Received ≥ 1 Home Administration by Care Partner

Percentage is calculated for each visit as number of participants treated at home by care partner/total number of all participants treated (among all participants who received any home administration by care partner during the course of the study). Protocol-mandated on-site visits occurred at Weeks 36, 52, 64, 76 and 88 and on these visits participants received injections by their care partners at site under site-staff supervision.

 

Primary Outcome – Amyloid PET

Mean amyloid burden at baseline was 101.8 CL (range: 28.1–178.4; n=192; Supplemental Table S3). For the 149 participants with a valid Week 52 PET, the mean amyloid burden at baseline was 101.2 CL, and reduced to 75.0 CL (range: 5.5–141.8) at Week 52. The mean change from baseline to Week 52 was -26.2 CL, (range: -75.6–15.8). As the study was terminated early by sponsor, only 12 participants had early termination PET assessments within the pre-defined time window for Week 104 (±85 days of Week 104 and ≤56 days since last dose). For these participants, the mean amyloid burden at baseline was 92.4 CL (range: 32.0–141.4), and reduced to 56.9 CL (range: 24.5–125.4) at Week 104 (actual mean PET assessment date was Week 96, i.e. 8 weeks prior to the planned date). The mean change from baseline to Week 104 was -35.5 CL (range: -63.2–-7.0). None of the values were below the amyloid positivity threshold (24 CL) at Week 104. Findings were corroborated by the MMRM analysis, for which the adjusted mean change in amyloid burden from baseline to Week 52 was -26.0 CL (95% CI: -28.6–-23.4), and from baseline to Week 104 was -42.9 CL (95% CI: -54.8–-30.9). Baseline, Week 52 and Week 104 amyloid PET data in the participants with and without home administration by care partner are presented in Supplemental Table S4.

Secondary Outcome – Home Administration Questionnaire

Of the 148 care partners who responded to the home administration questionnaire (HAQ) at Week 52, the majority found home administration of study drug both easy (easy: 30.4%; very easy: 57.4%) and convenient (convenient: 25.7%; very convenient: 70.9%). Most care partners reported feeling confident in (confident: 31.1%; very confident: 62.2%) and satisfied with (satisfied: 29.7%; very satisfied: 64.9%) administering the injection at home. Of the 154 participants who responded to the HAQ at Week 52, the majority found home administration convenient (convenient: 17.5%; very convenient: 76.6%) and were satisfied with receiving the injection at home (satisfied: 22.1%; very satisfied: 74.0%) (Figure 2, Supplemental Table S5). These findings were supported by HAQ responses at Week 36, Week 76 and Week 104 data (Figure 2, Supplemental Tables S2 and S5).

Figure 2. Responses to Home Administration Questionnaire by Care Partners and Participants at Week 52

 

Care partners with multiple HAQ assessments (n=139) in general remained somewhat satisfied (n=1), satisfied (n=26) or very satisfied (n=72) with giving injections at home throughout the study. For care partners reporting changes in satisfaction from the first to the last assessment, twenty increased from satisfied to very satisfied, three changed from somewhat satisfied to satisfied or very satisfied, and one from not at all satisfied to very satisfied. Fifteen care partners indicated decreases from very satisfied at first to satisfied at the last assessment and one from satisfied to somewhat satisfied.

Pharmacokinetics

Average plasma concentrations increased during the up-titration phase, with the highest concentrations observed at Week 52 (mean plasma concentration at week 52 (SD)=78.7 (33.8) ug/mL, n=129). Samples taken at Day 4, Week 24, Week 36, Week 52 and Week 76 confirmed that plasma concentrations after weekly administration of gantenerumab 255 mg for both the total study population and the subgroup with home administration by care partner were in the expected range (supplemental table S6). The PK-model derived mean (CV%) Cmax and mean (CV%) Cmin at steady-state were 74.4 (37.8) and 53.3 (42.5) ug/mL, respectively.

Adverse Events

In the safety-evaluable population, 92.7% of participants had at least 1 adverse event. The most frequently reported adverse events (>10%) were COVID-19 (25.5%); injection site reaction (ISR) (22.9%); ARIA-E (20.8%); headache (16.7%); and fall (12.0%) (Table 3). Seventeen participants (8.9%) experienced an AE that led to withdrawal from study drug, predominantly driven by protocol-specified ARIA-H discontinuation criteria (n=10 for exceeding the stipulated cumulative ARIA-H counts; see supplemental methodology section for ARIA-H discontinuation rules). Two instances of withdrawal from study drug were due to ARIA-E. None of the other AEs that led to withdrawals were related to gantenerumab or associated with medication errors. Serious adverse events were reported in 26 (13.5%) participants. Four participants (2.1%) experienced SAEs considered related to study treatment by the investigator: one participant experienced a serious related event of generalized tonic-clonic seizure (temporally associated with ARIA-E); two participants experienced serious related events of ARIA-E; and one participant concurrently experienced serious related events of ARIA-E, ARIA-H, and partial seizures. As of Last Patient, Last Visit (LPLV), all the SAEs considered related to study treatment by the investigator had resolved or were considered resolving by the investigator. There was one fatal event of endocarditis, considered as unrelated to study drug and related to concurrent illness according to the investigator. A summary of AEs in the participants with and without home administration by care partner in the OH-SE analysis set is presented in supplemental table S7.

Table 3. Summary of Adverse Events

* Most frequently reported AEs by MedDRA preferred term (>1 participant) leading to discontinuation are ARIA-H and ARIA-E. Discontinued treatment due to AEs was predominantly driven by protocol-specified discontinuation criteria, which was the accumulation of more than 15 ARIA-H or more than 3 focal areas of leptomeningeal hemosiderosis (including baseline findings) during the study. † considered unrelated to study treatment by PI and sponsor. ‡ All ISRs were non-serious and mild or moderate. § ARIA events were reported as AEs if they resulted in a change in study treatment, were considered clinically significant by the investigator, or were temporally associated with CNS symptoms (ARIA-E only). ¶ Management rules for ARIA are provided in Supplemental methodology section. ** Symptomatic ARIA-E is defined as ARIA-E temporally associated with CNS symptoms. †† ARIA-E associated with CNS symptoms where the ARIA-E AE and/or the CNS symptom adverse event was reported as a serious AE. ‡‡ As of LPLV, all SAEs considered related to study treatment by the investigator had resolved or were considered resolving by the investigator. §§ BGTS ≥4 is the threshold for dosing suspension, dosing could continue if ARIA-E event BGTS <4 and asymptomatic. *** AEs are selected using a Basket of Preferred Terms. AE, adverse event; ARIA-E, amyloid related imaging abnormalities – edema; ARIA-H, amyloid related imaging abnormalities – hemosiderosis; BGTS, Barkhof Grand Total Scale; CNS, central nervous system; ISR, injection site reaction; MRI, magnetic resonance imaging; PET, positron emission tomography; PI, principal investigator; SD, standard deviation.

 

ARIA MRI findings

Per the study protocol, ARIA events were to be reported as AEs if they resulted in a change in study treatment, were considered clinically significant by the investigator, or were temporally associated with CNS symptoms. Table 3 includes all ARIA detected by the central MRI reader, regardless of whether they were reported as an AE. The overall incidence of ARIA-E MRI findings was 44 (22.9%). Most ARIA-E were asymptomatic; 7.8% of participants experienced ARIA-E temporally associated with CNS symptoms; 13 participants (6.8%) experienced recurrent ARIA-E. The mean (SD) time to radiological resolution for ARIA-E was 11.02 (6.91) weeks; 44 participants (22.9%) had at least one new ARIA-H MRI finding; 29 participants (15.1%) had ARIA-E with concurrent ARIA-H.

 

Discussion

The administration of gantenerumab as a single subcutaneous injection of 255 mg once-weekly (Q1W) at home was investigated in the single-arm open-label trial (NCT04592341, GRADUATION), as an alternative to receiving two 255 mg (510 mg) injections every second week (Q2W) at the target dose by a HCP (dosing regimen used in the placebo-controlled Phase 3 trials NCT03444870, GRADUATE I and NCT03443973, GRADUATE II). GRADUATION evaluated the feasibility of home administration by non-HCP care partners, following appropriate training by the investigator and qualified study staff, to simplify the dosing regimen for people living with Alzheimer’s disease and their families and provide additional flexibility and convenience.
The baseline demographics and disease characteristics of the enrolled population in the GRADUATION study were similar to the participants enrolled in the pivotal GRADUATE studies (10). The similarity of baseline characteristics is important since GRADUATION is an open-label, single arm study and it was our intention to compare the pharmacodynamic properties and safety and tolerability of the weekly administration schedule of SC gantenerumab (255 mg) by care partner in the home environment in GRADUATION with the administration of SC gantenerumab (510 mg) every 2 weeks by HCP as in the placebo-controlled GRADUATE studies (10).
In the GRADUATION study, mean amyloid burden at baseline was 101.80 CL, which was slightly higher than the values of 94.44 and 95.62 CL reported for the treatment arms in the amyloid PET substudies of the GRADUATE I and II trials (10). The mean change from baseline to Week 52 using the alternative dose regimen in GRADUATION was -26.19 CL, similar to the changes of -24.01 and –21.17 CL observed in the amyloid PET substudies of the GRADUATE I and II trials (10). For the participants with an early termination PET assessment within the pre-defined time window for Week 104 (after the study was terminated early due to lack of efficacy in the pivotal trials), the mean change from baseline to Week 104 was -35.5 CL (range: -63.2–-7.0) (n=12). Due to the small number of participants who had Week 104 PET assessments, most of which were acquired prior to the actual Week 104 after treatment start and due to the fact that all participants had stopped dosing prior to Week 104, these data should only be considered supportive of further amyloid reduction with continued once-weekly dosing, while the absolute value at Week 104 needs to be interpreted with caution. It is important to note that at the time of the Week 52 PET, participants had received the target dose of 255 mg/week only for 3 months, due to the length of the uptitration period (34 weeks, see supplemental figure S1). While the total gantenerumab dose administered in one month is the same in the GRADUATE and GRADUATION studies, the dosing frequency and overall regimen start to diverge at week 24 (see supplemental figure S1).
The PK samples taken at pre-specified visits confirmed that plasma concentrations after once-weekly administration of gantenerumab 255 mg were in the expected range, and consistent with the model-derived Cmax and Cmin values at steady-state determined in an integrated population PK analysis across multiple gantenerumab studies (24).
The acceptance of home administration of subcutaneous gantenerumab by care partners was high and sustained over time in the GRADUATION study, despite the lack of prior experience in performing injections for most of the care partners. The care partners who performed home administration were more likely to live with the participant and less likely to be full-time or part-time employed compared to those care partners that did not perform home administration.
Of the 148 care partners who completed the home administration questionnaires at the week 52 visit, 93.3% were “confident” or “very confident” in their ability to give the injection, 87.8% reported that home administration of study drug was “easy” or “very easy”, 96.6% considered home administration “convenient” or “very convenient” and 94.6% were “satisfied” or “very satisfied” with giving an injection at home. The high levels of convenience and satisfaction with home administration reported by the care partners were also evident in the responses provided by the participants.
Gantenerumab was safe and well tolerated, including in the setting of home administration by a non-HCP care partner, and gantenerumab’s safety profile, including for ARIA and ISRs, was similar to that observed in the pivotal GRADUATE trials (10). The ARIA-E MRI findings were mostly asymptomatic, manageable with the protocol-stipulated ARIA management rules, and resolved. No new safety findings were identified with either the novel once-weekly regimen of gantenerumab or with home injections by non-HCP care partners.
Since the GRADUATION study was a single-arm study without placebo arm, no conclusions regarding clinical efficacy can be drawn. An important limitation of the current study is that there is less than expected PET data after week 52. This is because the phase 2 GRADUATION study was terminated early by sponsor, after the pivotal phase 3 GRADUATE trials did not meet their primary endpoint of change from baseline at week 116 in CDR-SB in participants with early symptomatic AD. As such, there are limited data available to evaluate the PK–PD relationship of the once-weekly target dose of 255 mg, compared with the 510 mg Q2W regimen used in the GRADUATE studies. Only 12 participants in GRADUATION had an early termination PET within the pre-defined time range of Week 104. Comparisons of the GRADUATION PK–PD (up to week 52) and safety results (over the whole course of the study) with the GRADUATE trials are relevant, since the study populations, and the study design (other than the changes in dose regimen and care partner administration) are largely similar. Another limitation is that the assignment of participants to home administration by care partner was not at random, but based on participant or care partner preference and physician decision regarding the ability of the care partner to correctly and safely administer gantenerumab at home after receiving adequate training. We may therefore see higher satisfaction and convenience rates for home administration due to the enrollment of a subset of care partners that agreed to home administration and were considered able by an HCP. The intent of this approach was to mirror a clinical practice situation, whereby home administration by care partner would be dependent on patient, care partner and physician judgment.
In summary, once-weekly SC administrations of 255 mg gantenerumab with home administration by care partners resulted in similar levels of amyloid reduction at week 52 and a similar safety and tolerability profile as the Q2W SC administration of 510 mg gantenerumab by an HCP in the GRADUATE studies.
Home administration of subcutaneous gantenerumab by a care partner was safe and feasible and may be a convenient option for other anti-Aβ antibodies to reduce the number of hospital visits necessary for treatment and increase flexibility for people living with Alzheimer’s disease and their families.

 

Funding: This study was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Acknowledgments: We would like to thank all the participants, study partners and their families, the investigators and site staff, and the entire study team for their time and commitment to the GRADUATION study. We also thank the early developers and supporters of the gantenerumab program, the gantenerumab steering committee and gratefully acknowledge the contribution to this study from the members of the cross functional study teams at F. Hoffmann-La Roche, and Genentech, Inc. Medical writing support for the development of this manuscript was provided by Steven Duckett, PhD, Nucleus Global, funded by F. Hoffmann-La Roche.

Conflict of interest: Frank Boess is an employee of and owns stocks or stock options in F. Hoffmann-La Roche Ltd. Marzia A. Scelsi is an employee of Roche Products Ltd. Timo Grimmer received consulting fees from AbbVie, Alector, Anavex, Biogen, Cogthera, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Janssen, Noselab, Novo Nordisk, NuiCare, Orphanzyme, Roche Diagnostics, Roche Pharma, UCB, and Vivoryon; lecture fees from Biogen, Eisai, Grifols, Medical Tribune, Novo Nordisk, Roche Pharma, Schwabe, and Synlab; and has received grants to his institution from Biogen, Eisai, and Roche Diagnostics. Richard J. Perry has received consulting fees from Roche, Eli Lilly, Biogen, Merck Sharp & Dohme, and Eisai. He has received research support from GE. Matteo Tonietto is an employee of F. Hoffmann-La Roche Ltd. Gregory Klein is an employee of and shareholder in F. Hoffmann-La Roche Ltd. Carsten Hofmann is an employee of and owns stocks or stock options in F. Hoffmann-La Roche Ltd. Mahtab Salami is an employee of F. Hoffmann-La Roche Ltd. Jakub Wojtowicz is an employee of and owns stocks or stock options in F. Hoffmann-La Roche Ltd. Claire J. Lansdall is an employee of and owns stocks or stock options in F. Hoffmann-La Roche Ltd. Christopher Lane is an employee of Roche Products Ltd and owns stock/stock options/shares in F. Hoffmann-La Roche Ltd. Geoffrey A. Kerchner is an employee of and owns stocks or stock options in F. Hoffmann-La Roche Ltd. Janice Smith is an employee of Roche Products Ltd and owns stock or stock options in F. Hoffmann-La Roche Ltd. Rachelle S. Doody is an employee of F. Hoffmann-La Roche Ltd and Genentech Inc., part of F. Hoffmann-La Roche Ltd. Doody is a shareholder in F. Hoffmann-La Roche Ltd.

Data availability: For eligible studies qualified researchers may request access to individual participant-level clinical data through a data request platform. At the time of writing this request platform is Vivli (https://vivli.org/ourmember/roche/). For up-to-date details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://go.roche.com/data_sharing. Anonymized records for individual participants across more than one data source external to Roche cannot, and should not, be linked due to a potential increase in risk of patient re-identification.

 

SUPPLEMENTARY MATERIAL

 

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