Abstract
Background and Purpose
The efficacy and safety of GV1001 have been demonstrated in patients with moderate-to-severe Alzheimer’s disease (AD). In this study, we aimed to further demonstrate the effectiveness of GV1001 using subscales of the Severe Impairment Battery (SIB), which is a validated measure to assess cognitive function in patients with moderate-to-severe AD.
Methods
We performed a post hoc analysis of data from a 6 month, multicenter, phase 2, randomized, double-blind, placebo-controlled trial with GV1001 (ClinicalTrials.gov, NCT03184467). Patients were randomized to receive either GV1001 or a placebo for 24 weeks. In the current study, nine subscales of SIB—social interaction, memory, orientation, language, attention, praxis, visuospatial ability, construction, and orientation to name— were compared between the treatment (GV1001 1.12 mg) and placebo groups at weeks 12 and 24. The safety endpoints for these patients were also determined based on adverse events.
Results
In addition to the considerable beneficial effect of GV1001 on the SIB total score, GV1001 1.12 mg showed the most significant effect on language function at 24 weeks compared to placebo in both the full analysis set (FAS) and per-protocol set (PPS) (p=0.017 and p=0.011, respectively). The rate of adverse events did not differ significantly between the 2 groups.
Conclusions
Patients with moderate-to-severe AD receiving GV1001 had greater language benefits than those receiving placebo, as measured using the SIB language subscale.
Keywords: GV1001, Efficacy, Alzheimer’s Disease, Language
INTRODUCTION
Alzheimer’s disease (AD) is the most common cause of dementia, and its prevalence is increasing worldwide.1,2 Acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantine have been approved for the symptomatic treatment of AD.3 Although the effects of these medications may last long, they are not considered to delay the progression of the disease.4 Recently, anti-amyloid agents (aducanumab and lecanemab) have shown efficacy in treating the pathological change of early AD, and the United States Food and Drug Administration has approved them for the treatment of early AD.5 However, treatment options for patients with moderate-to-severe AD are limited, leading to a significant unmet need.
GV1001 has been suggested to have diverse mode of action against AD, including anti-apoptotic, anti-inflammatory, anti-aging, anti-oxidant, and mitochondrial stabilizing effects.6,7 The efficacy and safety of GV1001 1.12 mg in patients with moderate-to-severe AD was shown in phase 2 randomized clinical trial by analyzing the change in Severe Impairment Battery (SIB) scores over a duration of 24 weeks.2 The SIB score is a reliable measure of cognitive function and disease progression in patients with moderate-to-severe AD, who may exhibit a “floor effect”.8,9 It consists of 9 subscales: social interaction, memory, orientation, language, attention, praxis, visuospatial ability, construction, and orientation to name. Among these subscales, the SIB-Language (SIB-L) subscale has the greatest proportion of items (24 of 51 total items), because of the importance of language.10 These subscales, including SIB-L, have been used to evaluate the efficacy of acetylcholinesterase inhibitors and memantine in patients with moderate-to-severe AD in large prospective clinical trials.11,12,13,14
In the current study, our objective was to further demonstrate the efficacy of subcutaneous injection of GV1001 1.12 mg in moderate-to-severe AD, using SIB subscales. We conducted a post hoc analysis of our recent multicenter, randomized, double-blind clinical trial with GV1001.2
METHODS
Study design and post hoc analysis population
The clinical design and detailed methods used in the original clinical trial have been previously described.2 In brief, this 24 week, multicenter, randomized, double-blind, placebo-controlled, prospective clinical trial included patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] ≤ 19, Global Deterioration Scale [GDS] score of 5−6, and receiving stable doses of donepezil at 10 mg/day ≥ 3 months before the screening visit). The primary efficacy endpoint was the change in SIB score from baseline to week 24. Patients with a GDS score of 7 were not assessed for eligibility, because due to the loss of linguistic and fundamental motor abilities, such as walking, they were unable to perform cognitive tests and follow the clinical trial protocol. Eligible patients were enrolled and randomly assigned in 1:1:1 ratios to GV1001 0.56 mg, GV1001 1.12 mg, and placebo (normal saline) groups. The study treatment was administered by subcutaneous (SC) injection every week for 4 weeks (4 times), followed by SC administration every 2 weeks until week 24 (10 times), for a total of 14 SC injections. Current post hoc analysis was performed in patients assigned to the GV1001 1.12 mg or placebo groups in both the full analysis set (FAS) and the per-protocol set (PPS).
Analysis of the effects on the subscales of SIB
The SIB includes 51 questions with scores ranging (0 to 100). It is divided into nine subscales (maximum score): social interaction (6), memory (14), orientation (6), language (46), attention (6), praxis (8), visuospatial ability (8), construction (4), and orientation to name (2). Safety endpoints were determined based on adverse events, laboratory test results, vital signs, and other safety-related observations. The χ2 test and analysis of variance were used to assess baseline characteristics. Changes from baseline to weeks 12 and 24 in the SIB subscale scores for the GV1001 and placebo groups were analyzed using a mixed effects model for repeated measures (MMRM) analysis. For each endpoint, the least squares (LS) mean for each treatment group was calculated, along with the treatment-placebo differences (GV1001 vs. placebo), 95% confidence intervals (CIs) for differences, and the p-values for treatment-placebo differences. Comparisons between groups were performed using a 2-sided significance level of 0.05. All statistical analyses were performed using Stata version 18.0 (StataCorp LLC, College Station, TX, USA).
Ethics statement
The study protocol was approved by the independent Institutional Review Boards of Hanyang University of Guri Hospital (2017-03-019) and each participating center. The process was performed according to Good Clinical Practice guidelines and the Declaration of Helsinki. All participants provided written informed consent.
RESULTS
A total of 96 participants were randomized between September 2017 and September 2019. In the current study, 28 participants assigned to the 1.12 mg GV1001 group, and 27 participants assigned to the placebo group were included and analyzed using FAS (Fig. 1). The PPS consisted of 25 participants in the GV1001 group, and 26 participants in the placebo group.
Fig. 1. Study profile.
Disposition of participants throughout the trial.
IP: investigational product, FAS: full analysis set, PPS: per-protocol set.
*One participant was excluded due to multiple reasons.
Baseline characteristics, including age, sex, age at AD diagnosis, years since diagnosis of AD, and total SIB, Korean version of MMSE, Clinical Dementia Rating-Sum of Boxes, Neuropsychiatric Inventory, GDS, Alzheimer’s Disease Cooperative Study-Activities of Daily Living, and Clinician Interview-based Impression of Severity scores, were similar between the GV1001 and placebo groups (Table 1).
Table 1. Demographic and baseline characteristics.
| Characteristics | GV1001 1.12 mg (n=32) | Placebo (n=31) | Overall (n=63) | p-value | |
|---|---|---|---|---|---|
| Age (yr) | 0.764* | ||||
| Mean ± SD | 71.6±8.4 | 70.9±8.9 | 71.3±8.6 | ||
| Median | 75 | 72 | 74 | ||
| Min, Max | 56.0, 82.0 | 56.0, 84.0 | 56.0, 84.0 | ||
| Sex | 0.513† | ||||
| Male | 15 (46.9) | 12 (38.7) | 27 (42.9) | ||
| Female | 17 (53.1) | 19 (61.3) | 36 (57.1) | ||
| Age at AD diagnosis (yr) | 0.943* | ||||
| Mean ± SD | 67.8±8.4 | 67.9±8.6 | 67.9±8.4 | ||
| Median | 70 | 68 | 68 | ||
| Min, Max | 50.0, 80.0 | 54.0, 82.0 | 50.0, 82.0 | ||
| Years since diagnosis of AD | 0.194* | ||||
| Mean ± SD | 4.4±2.6 | 3.6±1.7 | 4.0±2.2 | ||
| Median | 4 | 3 | 4 | ||
| Min, Max | 1.0, 10.0 | 1.0, 8.0 | 0.0, 10.0 | ||
| SIB, total | 0.840* | ||||
| Mean ± SD | 76.9±20.1 | 75.9±16.5 | 76.4±18.2 | ||
| Median | 84 | 81 | 82 | ||
| Min, Max | 15.0, 96.0 | 39.0, 97.0 | 15.0, 97.0 | ||
| K-MMSE | 0.552* | ||||
| Mean ± SD | 12.6±5.1 | 11.9±4.9 | 12.3±5.0 | ||
| Median | 13 | 12 | 13 | ||
| Min, Max | 1.0, 19.0 | 4.0, 19.0 | 1.0, 19.0 | ||
| CDR-SOB | 0.979* | ||||
| Mean ± SD | 10.1±4.1 | 10.1±4.1 | 10.1±4.1 | ||
| Median | 10 | 10 | 10 | ||
| Min, Max | 5.0, 23.0 | 4.0, 18.0 | 4.0, 23.0 | ||
| NPI | 0.370* | ||||
| Mean ± SD | 22.6±16.7 | 18.8±14.4 | 20.9±15.7 | ||
| Median | 18 | 14 | 16.5 | ||
| Min, Max | 4.0, 68.0 | 1.0, 63.0 | 1.0, 68.0 | ||
| GDS | 0.726* | ||||
| Mean ± SD | 5.3±0.5 | 5.4±0.5 | 5.4±0.5 | ||
| Median | 5 | 5 | 5 | ||
| Min, Max | 5.0, 6.0 | 5.0, 6.0 | 5.0, 6.0 | ||
| ADCS-ADL | 0.839* | ||||
| Mean ± SD | 35.8±10.3 | 32.9±9.9 | 34.3±10.1 | ||
| Median | 35.5 | 33 | 34 | ||
| Min, Max | 14.0, 51.0 | 12.0, 54.0 | 12.0, 54.0 | ||
| CIBIS | 0.739* | ||||
| Mean ± SD | 4.8±0.8 | 4.7±0.9 | 4.8±0.8 | ||
| Median | 5 | 5 | 5 | ||
| Min, Max | 3.0, 6.0 | 3.0, 6.0 | 3.0, 6.0 | ||
p-value for the differences between the GV1001 and placebo groups. Values are presented as number (%) not otherwise specified.
SD: standard deviation, AD: Alzheimer’s disease, SIB: Severe Impairment Battery, K-MMSE, Korean version of Mini-Mental State Examination, CDR-SOB: Clinical Dementia Rating Scale-Sum of Boxes, NPI: Neuropsychiatric Inventory, GDS: Global Deterioration Scale, ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of Daily Living, CIBIS: Clinician Interview-based Impression of Severity.
*Analysis of variance and †χ2 test were used.
Regarding the total SIB score, Table 2 demonstrates the significant benefit of GV1001 compared to placebo, in the FAS, at weeks 12 and 24 (p=0.031 and p=0.026, respectively), by comparing the LS mean change from baseline. This difference was statistically significant in the PPS (p=0.016 at week 12, and p=0.017 at week 24). Among the SIB subscales, language (p=0.017) and praxis (p=0.047) showed significant benefits for the mean change in LS from baseline in the FAS at week 24 (Table 2, Fig. 2). In PPS, this benefit was demonstrated only for language (p=0.011). At week 12, the mean change in LS from baseline, for memory, was significantly different between the GV1001 and placebo groups in FAS and PPS (p=0.037 and p=0.047, respectively).
Table 2. Effects of GV1001 on the total score of SIB and subscales in FAS and PPS.
| Variable | Week | LS mean of CFB (± SE) | |||||
|---|---|---|---|---|---|---|---|
| FAS | PPS | ||||||
| GV1001 1.12 mg (n=28) | Placebo (n=27) | p-value | GV1001 1.12 mg (n=25) | Placebo (n=26) | p-value | ||
| SIB, total | 12 | 0.74±1.42 | −3.65±1.45* | 0.031 | 1.00±1.49 | −4.04±1.47* | 0.016 |
| 24 | −0.33±2.11 | −6.93±2.09* | 0.026 | −0.12±2.13 | −7.23±2.09* | 0.017 | |
| Social interaction | 12 | −0.29±0.15 | −0.25±0.16 | 0.865 | −0.11±0.16 | 0.11±0.15 | 0.317 |
| 24 | −0.1±0.22 | −0.42±0.22 | 0.314 | 0.05±0.18 | 0.18±0.18 | 0.603 | |
| Memory | 12 | 0.55±0.47 | −0.85±0.48* | 0.037 | 0.55±0.51 | −0.88±0.5* | 0.047 |
| 24 | 0.24±0.53 | −0.70±0.53 | 0.210 | 0.23±0.54 | −0.72±0.53 | 0.210 | |
| Orientation | 12 | −0.02±0.18 | −0.35±0.18 | 0.199 | −0.01±0,19 | −0.33±0.19 | 0.245 |
| 24 | 0.14±0.22 | −0.42±0.21 | 0.067 | 0.15±0.22 | −0.41±0.22 | 0.074 | |
| Language | 12 | 0.37±0.74 | −1.31±0.75 | 0.111 | 0.48±0.79 | −1.53±0.77 | 0.069 |
| 24 | 0.04±0.98 | −3.26±0.97* | 0.017 | 0.12±1.00 | −3.42±0.98* | 0.011 | |
| Attention | 12 | 0.04±0.25 | −0.2±0.25 | 0.503 | 0.09±0.26 | −0.28±0.25 | 0.304 |
| 24 | −0.34±0.28 | −0.26±0.28 | 0.823 | −0.31±0.28 | −0.32±0.28 | 0.976 | |
| Praxis | 12 | 0.09±0.2 | −0.38±0.20 | 0.101 | 0.09±0.21 | −0.36±0.2 | 0.121 |
| 24 | −0.19±0.27 | −0.95±0.27* | 0.047 | −0.19±0.27 | −0.93±0.27 | 0.050 | |
| Visuospatial ability | 12 | −0.01±0.26 | −0.17±0.27 | 0.672 | −0.01±0.29 | −0.14±0.29 | 0.757 |
| 24 | 0.19±0.38 | −0.77±0.38 | 0.074 | 0.19±0.39 | −0.76±0.38 | 0.083 | |
| Construction | 12 | −0.02±0.17 | −0.08±0.17 | 0.792 | −0.03±0.19 | −0.12±0.18 | 0.740 |
| 24 | −0.19±0.18 | −0.1±0.17 | 0.735 | −0.19±0.18 | −0.12±0.18 | 0.770 | |
| Orientation to name | 12 | 0.04±0.06 | −0.08±0.06 | 0.140 | 0.04±0.06 | −0.08±0.06 | 0.150 |
| 24 | −0.08±0.07 | −0.08±0.07 | 0.964 | −0.08±0.07 | −0.08±0.07 | 0.959 | |
p-value for the differences between the GV1001 and placebo groups. The differences between the treatment and placebo groups were assessed using the mixed-effects model for repeated measures analysis.
SIB: Severe Impairment Battery, FAS: full analysis set, PPS: per-protocol set, LS: least square, CFB: change from baseline, SE: standard error.
*p<0.05.
Fig. 2. Effects of GV1001 on the total SIB and SIB-L scores.
In both FAS (A) and PPS (C), the patients assigned to the 1.12 mg GV1001 group demonstrated a significantly better mean change in the total SIB scores from baseline at weeks 12 and 24, compared to the placebo group. Among the subscales, the SIB−L scale showed a significant benefit in the GV1001 group compared to the placebo group at week 24 (B and D). Error bars indicate the standard error.
SIB: Severe Impairment Battery, SIB-L: Severe Impairment Battery-Language, FAS: full analysis set, PPS: per-protocol set.
*p<0.05 (GV1001 vs. placebo).
Table 3 describes the number of treatment-emergent adverse events (TEAEs) in the study participants. There were no significant differences in TEAEs between the groups (Table 3). No severe TEAE was noted in the GV1001 1.12 mg group.
Table 3. Overall summary of TEAEs by severity: safety set population.
| All TEAEs | Placebo (n=31) | GV1001 1.12 mg (n=32) | Overall (n=63) | p-value* | p-value† | |||
|---|---|---|---|---|---|---|---|---|
| No. (%)* | Events† | No. (%)* | Events† | No. (%) | Events | |||
| Mild | 12 (38.7) | 32 | 10 (31.3) | 34 | 22 (34.9) | 66 | 0.122 | 0.179 |
| Moderate | 2 (6.5) | 4 | 5 (15.6) | 10 | 7 (11.1) | 14 | ||
| Severe | 2 (6.5) | 2 | 0 (0.0) | 0 | 2 (3.2) | 2 | ||
The differences between the treatment group and placebo group were assessed using the χ2 test.
TEAE: treatment-emergent adverse event.
*p-value for the differences in the number of patients between the GV1001 and placebo groups.
†p-value for the differences in the number of events between the GV1001 and placebo groups.
DISCUSSION
In this post hoc analysis, the significant beneficial effect of GV1001 on language in patients with moderate-to-severe AD was demonstrated using an SIB-L subscale. The benefits were evident in both FAS and PPS. The GV1001 1.12 mg treatment group showed either an improvement or no change in language function after 24 weeks. Among the patients in the GV1001 1.12 mg treatment group, only one patient showed more than 3.7 points decrement in the SIB-L score, which is considered a clinically relevant change.12
Language dysfunction is one of the most noticeable and problematic manifestations of AD.15 As the stage of AD increases, the patient’s language ability decreases. This causes enormous distress and burden for both patients and their caregivers, as they cannot communicate adequately and understand each other’s needs.16 Language also plays an important role in maintaining emotional connection between the patient and their caregivers, including family.10 Mortality was associated with lower verbal fluency,17 and diverse neuropsychiatric symptoms (i.e., depression, agitation, and aggression) were caused by communication problems.15 Language dysfunction also disturbs appropriate palliative care, including pain control.18 These neuropsychiatric symptoms and uncontrolled pain can worsen the cognition and daily life activities of patients.15,19 Therefore, treatment that can improve language function might reduce the problematic neuropsychiatric symptoms, and adequate pain control might lead to substantial improvement of quality of life for both the patients and their caregivers.10,15
Although a decrement in language function is evident and important in patients with moderate-to-severe AD, it is often difficult to evaluate changes in these symptoms. One of the reasons is that the assessment tools that are available are limited. To overcome this limitation, SIB-L was developed as a reliable measurement to evaluate the effects of treatment on language function.10 SIB-L comprises the largest proportion of SIB, which is a scale to evaluate cognitive function in patients with moderate-to-severe AD who may have floor effect.20 Using the SIB-L score, the benefits of donepezil 23 mg/day versus donepezil 10 mg/day for language function was demonstrated in patients with moderate-to-severe AD.11 Like the GV1001 1.12 mg group in our study, the donepezil 23 mg/day treatment group showed an improvement in language function above baseline. The beneficial effect of memantine compared to placebo, on language function in patients with moderate-to-severe AD, was also reported using the SIB-L score.12 However, no improvement was found in the SIB-L score. The effect of galantamine treatment in patients with severe AD was analyzed using SIB, but failed to show a beneficial effect on language functions.21 Rivastigmine was evaluated among patients with mild-to-moderate AD using the Alzheimer’s Disease Assessment Scale-Cognitive subscale, but the benefits for language function are conflicting.22,23
The reasons for GV1001 showing a better effect on language function than placebo were not investigated in the current study. It is possible that the diverse neuroprotective effects of GV1001, such as anti-apoptotic, anti-inflammatory, anti-aging, antioxidant, and mitochondrial-stabilizing effects, which have been previously reported,6,7 may have influenced these results. Additional in vitro and in vivo studies are required to further investigate the underlying mechanisms of GV1001.
This study had several limitations. First, the enrolled patients were of a single ethnicity, and the number of patients was relatively small. However, showing the benefits of GV1001 in language function in this population is meaningful, and warrants a clinical trial with a multiethnic and larger number of patients. Second, the results of the current study may have been underpowered to detect the significant efficacy of GV1001 in some subgroups.
In conclusion, this analysis suggests that GV1001 1.12 mg is safe, and may be beneficial for language function in patients with moderate-to-severe AD as measured by the SIB-L scale. These findings indicate that GV1001 may support communication in patients with advanced AD whose language function is critical to improving their quality of life.
Footnotes
Funding: This research was supported by grants from the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (HI20C0253, HU21C0113, and HU21C0007), and GemVax & Kael Co., Ltd.
Conflict of Interest: KSJ is an employer of GemVax & Kael Co., Ltd. and holds equity in the company. Other authors have no conflicts of interest to declare.
- Conceptualization: Koh SH, Kim S.
- Formal analysis: Kim S.
- Funding acquisition: Koh SH, Kim S.
- Investigation: Kwon HS, Koh SH, Choi SH, Jeong JH, Na HR, Lee CN, Yang Y, Lee AY, Lee JH, Park KW, Han HJ, Kim BC, Park J, Lee JY, Lee KY.
- Supervision: Choi SH, Jeong JH, Na HR, Lee CN, Yang Y, Lee AY, Lee JH, Park KW, Han HJ, Kim BC, Park J, Lee JY, Lee KY.
- Visualization: Kwon HS.
- Writing - original draft: Kwon HS.
- Writing - review & editing: Koh SH, Kim S.
AVAILABILITY OF DATA AND MATERIAL
Access to participant-level data from this study will not be made available, while GV1001 is in clinical trials for Alzheimer’s disease and waiting for approval from the US Food and Drug Administration. Thereafter, all data supporting this study will be shared by qualified academic researchers after obtaining the consent of researchers.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Access to participant-level data from this study will not be made available, while GV1001 is in clinical trials for Alzheimer’s disease and waiting for approval from the US Food and Drug Administration. Thereafter, all data supporting this study will be shared by qualified academic researchers after obtaining the consent of researchers.