Slowing down Alzheimer’s disease by combining an anti-oxidant drug, GV1001, with donepezil
Original author: Koh, SH., Kwon, H.S., Choi, S.H., et al. (2021) (DOI: 10.1186/s13195-021-00803-w)
Content writer – Clinical
October 25, 2022
Alzheimer’s disease (AD) is a neurodegenerative disease that impairs short-term memory and affects the judgment and behavior of the patient. Brain cells continue to die as time passes and the patient eventually becomes dependent on round-the-clock care to perform basic tasks of everyday life such as bathing and changing clothes. In 2022, over 55 million people are living with dementia. Being the most common type of dementia, AD has become a global healthcare challenge of the 21st century.
Currently, there is no disease-modifying treatment for AD. The symptoms are being managed using drugs such as donepezil, rivastigmine, and galantamine. These drugs have extensive side effects and do not stop the progression of AD. Efforts to develop an effective treatment for AD have failed to bear any fruit. One reason for disappointing results can be that most of the new drugs are targeting only the amyloid plaques – the extracellular deposits of the amyloid beta protein. Amyloid plaques are thought to play a central role in the disease's development and progression, but the pathophysiology of AD is multifaceted including inflammation and oxidative stress among other factors. Therefore, any effort to slow down or reverse AD should target inflammation and oxidative stress as well.
The authors of this journal article conducted a phase 2 clinical trial to evaluate the safety and efficacy of a drug named GV1001. It is a 16-amino-acid peptide that corresponds to a portion of the human enzyme telomerase reverse transcriptase (TERT). GV1001 was originally developed as an anticancer drug but failed to show any efficacy in that regard. Later on, it was shown to have anti-inflammatory and antioxidant activity, as well as an ability to reduce the toxic effects of amyloid plaques which indicated its potential use in AD.
It is a phase 2 clinical trial with a parallel design. The masking status was double-blind. A total of 109 participants were assessed for eligibility and 96 were enrolled in the trial. All 96 participants had probable AD as confirmed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association criteria and the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Furthermore, the patients had a Korean Mini-Mental State Examination (K-MMSE) score of at least 19 at the screening visit and a Global Deterioration Scale (GDS) score of 5 to 6. The participants were also receiving stable doses of donepezil (10 mg) for more than 3 months before the screening visit. Magnetic resonance imaging (MRI) and computed tomography (CT) were performed to exclude patients who were suspected to have other types of dementia and psychotic conditions.
The clinical trial included a screening visit, a double-blind treatment period of about 6 months, and an end-of-study visit. The participants were randomly assigned to receive a subcutaneous injection of 0.56 mg or 1.12 mg of GV1001 or a placebo every week for 4 weeks. This was followed by subcutaneous injections once every 2 weeks for 24 weeks. So, the overall injection count was 14 injections (4+10). The efficacy was evaluated at baseline, week 12, and week 24.
Results & discussion
The primary outcome was the difference in the Severe Impairment Battery (SIB) score of the participants between the start of the trial to week 24. Whereas, the secondary outcome was Clinical Interview-Based Impression of Change, Clinician Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), MMSE, and GDS scores. And finally, the safety of the drug was evaluated by considering adverse events (AEs), laboratory test results, vital signs, electrocardiogram findings, and physical examination.
The SIB difference between the placebo group and GV1001 1.12 mg was 6.6 in the full set analysis (FAS) (p = 0.027) and 7.1 in the per-protocol set (PPS) (p = 0.018). This difference was lower between the placebo group and GV1001 0.56 mg. Among the secondary parameters, only NPI showed variation among the groups. It was found to be better in the group receiving GV1001 1.12 mg. The safety of GV1001 was found to be the same as the placebo.
GV1001 protects neurons from the harmful effects of sustained inflammation. The above-mentioned results indicate that the antioxidant activity of GV1001 is beneficial to AD patients already receiving the standard donepezil therapy. GV1001 reduced the SIB decline at a dose of 1.12 mg in this phase 2 clinical trial. These results warrant a phase 3 clinical trial with a larger and more diverse sample.
Impact of the research
GV1001 provides another option to target the multifaceted pathophysiology of AD. It can potentially be combined with AD drugs to achieve better outcomes. This clinical trial provides evidence that GV1001 is safe and effective in slowing down AD. A phase 3 clinical trial is required to confirm this finding in a larger sample size.