Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial

Abstract

Background: Our previous studies showed that GV1001 has various protective effects against β-amyloid and other stressors. Based on these findings, we hypothesized that GV1001 might have beneficial effects in patients with Alzheimer's disease (AD).

Methods: A phase 2, double-blind, parallel-group, placebo-controlled, 6-month randomized clinical trial was performed to evaluate the safety and efficacy of subcutaneously administered GV1001. Between September 2017 and September 2019, 13 centers in South Korea recruited participants. A total of 106 patients were screened, and 96 patients with moderate-to-severe AD were randomized 1:1:1 to the placebo (group 1, n = 31), GV1001 0.56 mg (group 2, n = 33), and 1.12 mg (group 3, n = 32) groups. GV1001 was administered every week for 4 weeks (4 times), followed by every 2 weeks until week 24 (10 times). The primary endpoint was the change in the Severe Impairment Battery (SIB) score from baseline to week 24. The key secondary efficacy endpoints were the change in the Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, and Global Deterioration Scale scores. The safety endpoints were also assessed based on adverse events, laboratory test results, vital signs, and other observations related to safety.

Results: Group 3 showed less decrease in the SIB score at 12 and 24 weeks compared with group 1 (P < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups.

Conclusions: The results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial.

Trial registration: ClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.

Keywords: Alzheimer’s disease; Clinical trial; Efficacy; GV1001; Safety.

Conflict of interest statement

KSJ is an employer of GemVax & Kael Co., Ltd. and holds equity in the company. Other authors declare no competing interests.

Figures

Fig. 1

Study design. Overall study design of the present clinical trial

Fig. 2

Patient disposition. Participant flow throughout the trial. aOther medical conditions include renal dysfunction (n = 1), hepatic dysfunction (n = 2), and condition that in the opinion of the investigator can interfere with the interpretation of the study result (n = 1). bOne participant was excluded according to multiple reasons. cParticipants from a single center were excluded after the administration of the first study treatment, as mandatory clinical data, including baseline clinical data and the results of neurological examination performed at corresponding time points, were not uploaded to the central web-based system and the investigator of this center could not verify the source of these data. Abbreviations: MMSE Mini-Mental State Examination, I/E inclusion/exclusion, IP investigational product, FAS full analysis set, PPS per-protocol set

Fig. 3

Effects of GV1001 on SIB, ADCS-ADL, and CDR-SOB scores in patients with AD with moderate-to-severe dementia. The change in the SIB score from baseline to 24 weeks was considered the primary endpoint. In the FAS and PPS, the patients assigned 1.12 mg of GV1001 had significantly better mean change from the baseline scores than the placebo group at weeks 12 and 24 (a and b, respectively). Among the secondary endpoints, ADCS-ADL (c, d) and CDR-SOB (e, f) scores showed a similar pattern to the SIB scores; however, statistical significance was not achieved in the FAS and PPS. LS indicates least squares. Error bars indicate standard error. *P < 0.05 (group 2 vs. group 3). Abbreviations: SIB Severe Impairment Battery, ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living, CDR-SOB Clinical Dementia Rating Scale-Sum of Boxes, AD Alzheimer’s disease, FAS full analysis set, PPS per-protocol set, LS least square