genetics

Uzma Chohan-Weber 11/20/2019

Drug Therapies for Alzheimer’s Disease (Carlson and Birkett, 2017)

Individuals affected with Alzheimer’s Disease experience a buildup of amyloid plaques in the brain, which consist of the dense protein beta-amyloid, created by the beta-secretase enzyme. Additionally, these individuals have neurofibrillary tangles which are composed of dying neurons that contain intracellular accumulations of twisted filaments tau protein. This buildup of beta-amyloid and tau contribute to the degeneration of the brain. As a result of these factors, drug therapies that affect beta-amyloid and tau proteins present the best areas of research to treat the cause of the disease or slow its progression.

Beta-Amyloid – Posiphen (Lahiri et al., 2006)

Posiphen is one of the drugs currently being studied that focuses on lowering of beta-amyloid, which is a protein present in abnormally high levels in the brain of people with Alzheimer’s disease. In this study, posiphen was tested in vitro using cultured human neuroblastoma cells and in vivo using a mouse animal model. The goal of the study was to investigate if posiphen (Figure 1) would lower both beta-amyloid (Aβ) and beta-amyloid precursor protein (APP) over different dose levels.

Figure 1, Chemical structure of posiphen

Beta-Amyloid – Atabecestat (Timmers et al., 2018)

Atabecestat (JNJ-54861911) is one of the drugs currently being studied that focuses on inhibiting the beta-secretase enzyme from making beta-amyloid. This enzyme is what creates beta-amyloid. Inhibition of this enzyme is a key factor in the treatment and prevention of Alzheimer’s Disease. In this study, atabecestat (Figure 2) was tested in an in vivo clinical trial using human patients with early phase Alzheimer’s Disease. The goal of the study was to investigate the pharmacodynamics activity as a proof of mechanism of atabecestat to inhibit beta-secretase in patients with mild cognitive impairment due to Alzheimer’s Disease.

Figure 2, Chemical structure of atabecestat

Tau Protein – AADvac1 (Novak et al., 2018)

AADvac1 is a vaccine being studied that focuses on targeting tau proteins through immunotherapy. Tau proteins are the main component of tangles, which is an abnormality in the brain of patients with Alzheimer’s disease. In this study, AADvac1 (Axon Peptide 108) was tested in an in vivo clinical trial using human patients with mild to moderate Alzheimer’s disease who had completed a preceding phase 1 study. The goal of the study was to prove long-term safety of AADvac1 and analyzing the performance of the vaccine.

Results – Posiphen (Lahiri et al., 2006)

This graph shows the effects of posiphen on beta-amyloid precursor protein (APP) and beta-amyloid (Aβ) in vitro in human SK-N-SH cells. The data shows that posiphen both dose and time dependently lowered both APP and Aβ levels by reducing the synthesis rate. All dose levels reduced both APP (graph A) and Aβ (graph B) as compared with controls. A different drug pheneserine was also investigated as part of the study, also showing reduction compared to controls.

This graph shows the effects of posiphen on beta-amyloid precursor protein (APP) and beta-amyloid (Aβ) in vivo in mice. The data shows that posiphen dose dependently lowered both APP and Aβ levels by reducing the synthesis rate, similar to the in vitro results. All dose levels reduced both APP and Aβ as compared with controls. A different drug pheneserine was also investigated as part of the study, also showing reduction compared to controls.

The authors concluded that posiphen, like phenserine, can lower beta amyloid and represents a drug candidate for Alzheimer’s disease treatment.

Results – Atabecestat (Timmers et al., 2018)

The above charts show the percent change from baseline in cerebrospinal fluid (CSF) and plasma amyloid-β 1–40 (Aβ1–40) at day 28 for both treatment groups (Caucasian patients with early AD and Japanese patients with preclinical AD). Both the atabecestat 10 mg and 50 mg dose groups showed reductions in beta amyloid levels from baseline in the CSF and Aβ1–40 levels and other Aβ fragments as compared to placebo in both treatment groups.

Results – AADvac1 (Novak et al., 2018)

This graph shows the antibody response to AADvac1 over 96 weeks of treatment. The values show the 95% confidence interval of the mean titres. Bold weeks indicate the points of AADvac1 vaccine treatment. The light gray shows the values obtained in the first in-human study and the white shows the sustained antibody response in the follow up study.

The authors concluded that a more frequent booster dose regimen of AADvac1 was needed. Slower brain atrophy in the MRI data and a reduction in cognitive assessment decline was observed in patients with high titres. The conclusion of the study was that additional clinical trials were required to establish proof of clinical efficacy. The follow up ADAMANT Phase II study for AADvac1 was recently completed (un-published), confirming the safety profile and a statistically significant impact on neurodegeneration.

References:

Carlson N, Birkett M (2017) Physiology of Behavior. Boston, MA: Pearson.

Lahiri DK, Chen D, Maloney B, Holloway HW, Yu QS, Utsuki T, Giordano T, et al. (2006) The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice. J Pharmacol Exp Ther. 320(1):386-96. doi:10.1124/jpet.106.112102

Timmers M, Streffer JR, Russu A, Tominaga Y, Shimizu H, Shiraishi A, Tatikola K, et al. (2018) Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study. Alzheimers Res Ther. 10(1):85. doi:10.1186/s13195-018-0415-6.

Novak P, Schmidt R, Kontsekova E, Kovacech B, Smolek T, Katina S, Fialova L, et al. (2018) FUNDAMANT: an interventional 72-week phase 1 follow-up study of AADvac1, an active immunotherapy against tau protein pathology in Alzheimer's disease. Alzheimers Res Ther. 10(1):108. doi: 10.1186/s13195-018-0436-1.

Axon announces positive results from Phase II ADAMANT trial for AADvac1 in Alzheimer’s Disease. (n.d.) Axon Neuroscience. Retrieved on 11/20/2019 from: http://www.axon-neuroscience.eu/docs/press_release_Axon_announces_positive_result_9-9-2019.pdf