Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research
Abstract
:1. Introduction
2. Basic Pathophysiology and Neuropathology of AD
3. Explanations for Failures of Candidate DMTs for AD and the Consequent Shift in Current Clinical Trials
3.1. Inadequate Understanding of the Complex Pathophysiology of AD: Wrong Selection of Main Treatment Target and Inappropriate Drug Dosages
3.2. Inadequate Understanding of the Complex Pathophysiology of AD: Late Initiation of Treatments During the Course of AD Development
3.3. Novel Biomarkers of Aβ Metabolism and Aggregation
3.4. Vascular System’s Novel Biomarkers
3.5. Novel Biomarkers of Inflammation and Glial Activation
3.6. Novel Biomarkers for Synaptic Dysfunction
3.7. Novel Biomarkers for α-Synuclein Pathology
3.8. Novel Biomarkers for TDP-43 Pathology
3.9. Iron Metabolism Associated Novel Biomarkers
3.10. Oxidative Stress Biomarkers
- Biomarkers associated with damage to proteins: decreased plasma superoxide dismutase (SOD) activity accompanied with increased levels of oxidized proteins has been observed in MCI in comparison to healthy participants (HC). Plasma glutathione reductase/glutathione peroxidase (oxidized proteins) ratio (GR/GPx ratio) also showed statistically significant differences between AD and MCI in a recent study—thus is considered an accumulative biomarker in the disease progression [55].
- Biomarkers associated with lipid peroxidation: Urine, plasma and CSF 8,12-isoiPF(2alpha)-VI [56] and plasma malondialdehyde (MDA) [45] showed statistically significant differences between AD and MCI patients, and were also considered reliable biomarkers of AD progression. Additionally, some plasma lipid peroxidation compounds (PGF2α, isoprostanes, neuroprostanes, isofurans, neurofurans) showed statistically significant correlation with medial temporal atrophy in AD and MCI patients [57].
- Biomarkers associated with damage to DNA: plasma and CSF 8-hydroxy-2′-deoxyguanosine (8-OHdG) is the most studied biomarker of oxidative DNA damage. Significantly higher levels of this biomarker in AD than in healthy controls (HC) have been observed. Increased levels of 8OHdG and 8-hydroxyguanosine (8OHD) are indicative of DNA and RNA oxidation [58].
- Total antioxidant capacity determined by the ferric-reducing antioxidant power (FRAP assay) and indirect antioxidants plasma levels (vitamin E, selenium) were decreased in MCI and AD compared to HC, but not yet in a statistically significant and accumulative pattern [59].
- Others: the APO E genotype has been studied in order to correlate genetic risk factors with oxidative stress biomarkers in AD. E4 allele carriers MCI patients have significantly decreased plasma SOD activity compared to non-E4 carriers, with no further difference for other oxidative-stress biomarkers between the two groups [60].
3.11. Other Neuronal Proteins as Novel Biomarkers
3.11.1. Inadequate Understanding of the Complex Pathophysiology of AD: Combination Treatments
3.11.2. Methodological Issues
4. Discussion and Conclusions
- Although recent evidence still supports the possibility that Aβ status could predict AD risk and play a significant role in disease progression, it does query the perceived centrality of its role in the causation or definition of the disease. Consequently, we suggest that future clinical research should not always have to be approached through an Aβ lens.
- Besides Aβ biomarkers, other possible biomarkers, such as biomarkers of inflammation and glial activation, synaptic dysfunction, α-synuclein pathology, TDP-43 pathology, iron metabolism and oxidative stress must be further investigated. Selected blood and CSF biomarkers, along with imaging and elaborate memory scale measurements may be combined to generate disease signatures, and they could also be used for drug efficiency monitoring, risk classification and prognosis. Most of them are considered to be incorporated into drug development programs.
- The complex pathophysiology of AD probably demands therapeutic efforts towards multi-agent approaches. Such combination DMTs might permit efficient interventions in multiple pathways or interventions in different components of the same pathway.
- Issues with clinical trial design and methodology are also important. Indeed, new innovative study designs are applied. Adaptive randomization and interim analyses can reduce the size and duration of any trial and they may prevent advancing to phase 3 in cases that data show no clinical efficacy.
Author Contributions
Funding
Conflicts of Interest
References
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Agent | Agent Mechanism Class | Mechanism of Action | Therapeutic Purpose | N | Parameter Evaluates | Results | Reasons behind Stopping Trial |
---|---|---|---|---|---|---|---|
Semagecestat | Antiamyloid | γ-secretase inhibitor | Reduce amyloid production | 463 | ADAS-cog ADCS-ADL | No efficacy | worsening of daily function, increased rates of skin cancer and infection |
Avagacestat | Antiamyloid | γ-secretase inhibitor | Reduce amyloid production | 263 | CSF biomarkers amyloid PET ADAS-cog ADCS-ADL | No efficacy | higher progression rate of the disease, skin cancer |
Tarenflurbil | Antiamyloid | γ-secretase inhibitor | Reduce amyloid production | 1046 | ADAS-cog ADCS-ADL | No efficacy | low brain penetration |
Lanabecestat | Antiamyloid | BACE1 inhibitor | Reduce amyloid production | 1722 | ADAS-cog13 | No efficacy | futility |
Verubecestat | Antiamyloid | BACE1 inhibitor | Reduce amyloid production | 1454 | CDR-SB | No efficacy | cognition and daily function worsening |
Atabecestat | Antiamyloid | BACE1 inhibitor | Reduce amyloid production | 18 | Ab CSF and Plasma | No efficacy | - |
Bapineuzumab | Antiamyloid | Monoclonal antibody directed at plaque and oligomers | Remove amyloid | 683 ApoE4 carriers 329 non carriers | Ab and pTau in CSF | No efficacy | Brain edema or effusion, futility |
Solanezumab | Antiamyloid | Monoclonal antibody directed at plaque and oligomers | Remove amyloid | 2129 | ADAS-cog14 | No efficacy | futility |
Gammagard Liquid (IVIg) | Antiamyloid | Human normal immunoglobulin | Remove amyloid | 390 | ADAS-cog11 ADCS-ADL | No efficacy | No efficacy |
LMTM | Anti-tau | Tau protein aggregation inhibitor | Reduce neurofibrillary tangle formation | 891 | ADAS-cog | No efficacy | No efficacy |
Biomarker | Utility in AD | |
---|---|---|
Aβ metabolism and aggregation biomarkers | ||
✓ CSF Aβ38 | patient selection | |
✓ Plasma BACE1 | patient selection and prognosis | |
Vascular system biomarkers | ||
✓ hFABP (CSF, serum) | patient selection and prognosis | |
Inflammation and glial activation biomarkers | ||
✓ TREM2 | increased levels in AD | |
✓ YKL-40 (known as CHI3L1) | patient selection; prognostic marker | |
Synaptic dysfunction biomarkers | ||
✓ Neurogranin (CSF) | Disease progression; patient selection and prognosis | |
✓ CSF SNAP-25 | patient selection | |
✓ Synaptotagmin | patient selection | |
α-Synuclein pathology biomarkers | ||
✓ CSF α-synuclein | patient selection | |
TDP-43 pathology biomarkers | ||
✓ Plasma TDP-43 | associated with greater brain atrophy and cognitive impairment | |
Iron metabolism biomarkers | ||
✓ Plasma/CSF Ferritin | screening of preclinical AD and prognostic biomarker | |
Other neuronal protein biomarkers | ||
✓ CSF VILIP-1 | Early AD diagnosis; differentiating AD-MCA; prognostic biomarker | |
✓ CSF/plasma NF-L | biomarkers for prognosis | |
Oxidative biomarkers | ||
associated with damage to proteins | ✓ SOD (plasma) | differentiating MCI from HC significantly decreased in MCI E4 allele carriers compared to non-E4 carriers |
associated with damage to proteins | ✓ GR/GPx ratio (plasma) | accumulative biomarker in the disease progression |
associated with lipid peroxidation | ✓ 8,12-isoiPF(2alpha)-VI (urine, plasma and CSF) | differentiating AD-MCA; biomarkers of AD progression |
associated with lipid peroxidation | ✓ MDA (plasma) | differentiating AD-MCA; biomarkers of AD progression |
associated with damage to DNA | ✓ 8-OHdG (plasma, CSF) | differentiating AD from HC |
total antioxidant capacity | ✓ FRAP assay (plasma) | decreased in MCI and AD compared to HC |
indirect antioxidants | ✓ vitamin E, selenium (plasma) | decreased in MCI and AD compared to HC |
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Yiannopoulou, K.G.; Anastasiou, A.I.; Zachariou, V.; Pelidou, S.-H. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines 2019, 7, 97. https://doi.org/10.3390/biomedicines7040097
Yiannopoulou KG, Anastasiou AI, Zachariou V, Pelidou S-H. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines. 2019; 7(4):97. https://doi.org/10.3390/biomedicines7040097
Chicago/Turabian StyleYiannopoulou, Konstantina G., Aikaterini I. Anastasiou, Venetia Zachariou, and Sygkliti-Henrietta Pelidou. 2019. "Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research" Biomedicines 7, no. 4: 97. https://doi.org/10.3390/biomedicines7040097
APA StyleYiannopoulou, K. G., Anastasiou, A. I., Zachariou, V., & Pelidou, S. -H. (2019). Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines, 7(4), 97. https://doi.org/10.3390/biomedicines7040097