Yearly Archives: 2023

Hope on the Horizon: Breakthrough Investigational Treatments for Neurodegenerative Diseases

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Clinical neurodegenerative research is at an exciting crossroads. Scientists and pharmaceutical companies are focusing on a variety of innovative approaches to better understand and treat theses complex diseases, including Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD). Emerging trials are exploring novel therapies targeting not only symptom management but also disease origination.

At the heart of AriBio’s AR1001 investigational drug’s potential lies its groundbreaking mechanism of action. The oral drug seeks to target the underlying factors responsible for AD, in hopes of slowing down or even halting disease progression. Although first established for erectile dysfunction, AR1001 appears to reduce amyloid b (Ab) protein and increase blood flow in the brain. It’s accomplished via a selective phosphodiesterase 5 inhibitor preventing degradation of secondary messengers (cAMP and cGMP) regulating cellular functioning. By reducing neuroinflammation, promoting neural regeneration, and mitigating the toxic Ab plaque build-up in the brain, AR1001 represents a potential leap forward in AD treatment.

Cognito Therapeutics’ CA-0011 trial showcases a novel route to combat AD. It combines elements of neuroinflammation reduction, neural regeneration promotion, and the mitigation of Ab plaques in the brain. Their innovative investigational device utilizes non-invasive neuromodulation techniques to target specific brain regions associated with cognitive function, achieved by delivering 40Hz gamma stimulation through a self-administered glasses headset. By providing precisely tuned electrical currents, the device aims to modulate neural activity, enhance synaptic plasticity, and promote neural connectivity in a region-specific manner. This neuromodulation approach is designed to optimize brain function and potentially ameliorate cognitive deficits. The device’s non-invasive mechanism of action represents a promising avenue in the quest for effective treatments and cognitive improvements for patients suffering from AD.

Eli Lilly continues to produce evermore promising monoclonal antibodies targeting AD, with one of the newest being Remternetug. These antibodies bind to Ab plaques in the brain, initiating immune cells, or microglia, to clear them. Following in the footsteps of Donanemab, this investigational drug also targets the pyroglutamated structure of Ab in plaque form, but it’s given as a simple injection rather than an IV-infusion. When Remternetug was given to AD patients for 6 months, around 75% resulted in Ab plaque clearance. That took Donanemab 18 months to do, suggesting Remternetug may be a more sufficient therapeutic.

Neflamapimod, developed by EIP Pharma, is a small molecule investigational drug showing promise for a multitude of neurodegenerative diseases. It’s designed to inhibit the enzyme p38 MAP kinase targeting the cholinergic system, believed to be involved in the inflammation and cell dysfunction and death associated with PD, LBD, and AD. By targeting these pathways Neflamapimod’s goal is to reduce neuroinflammation, alleviate some motor symptoms, and potentially slow down cognitive decline. It appears to work best in those with low baseline ptau181 levels and less extensive cortical neurodegeneration. When tested in AD patients, those with ptau181 levels below 2.2 ng/mL resulted in substantial benefits to attention, dementia severity, motor functional mobility, and memory compared to those with higher levels of the biomarker. A similar pattern is seen with DLB patients with normal ptau181 levels improving compared to those with abnormally elevated levels. Based on these findings, a criterion limiting those with higher ptau181 levels could uncover a greater efficacy for those on Neflamipimod to treat DLB. A phase IIb clinical trial, RewinD-LB, is ongoing to evaluate its safety and efficacy, offering optimism for a new therapeutic approach for DLB.

These promising developments bring new hope for improved care and potentially disease-modifying treatments. While there is still much to learn and discover, the field of neurodegenerative disease research is advancing, inching closer to a future with effective interventions and even potential cures. If you, or anyone you know, may be interested in taking part in a clinical trial involving any of the above discussed investigational therapeutics, please reach out to us at 503-548-0908.

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Sources:

Alam, John, et al. “Association of Plasma Phosphorylated Tau with the Response to Neflamapimod Treatment in Patients with Dementia with Lewy Bodies.” Neurology, 1 Sept. 2023, pp. 10.1212/WNL.0000000000207755–10.1212/WNL.0000000000207755, https://doi.org/10.1212/wnl.0000000000207755. Accessed 31 Oct. 2023.

“AR1001 | ALZFORUM.” Www.alzforum.org, 10 Mar. 2023, www.alzforum.org/therapeutics/ar1001. Accessed 31 Oct. 2023.

Beaney, Abigail. “First Patient Dosed in Phase IIb RewinD-LB Trial for DLB.” Clinical Trials Arena, 14 Aug. 2023, www.clinicaltrialsarena.com/news/neflamapimod-trial-dementia-lewy-bodies/?cf-view. Accessed 31 Oct. 2023.

Benussi, Alberto, et al. “Exposure to Gamma TACS in Alzheimer’s Disease: A Randomized, Double-Blind, Sham-Controlled, Crossover, Pilot Study.” Brain Stimulation, vol. 14, no. 3, May 2021, pp. 531–540, https://doi.org/10.1016/j.brs.2021.03.007.

“Cognito Therapeutics Announces Proprietary Gamma Sensory Stimulation for 6-Months Reduces White Matter Atrophy in Alzheimer’s Disease Patients.” Www.businesswire.com, 1 Aug. 2022, www.businesswire.com/news/home/20220801005207/en/Cognito-Therapeutics-Announces-Proprietary-Gamma-Sensory-Stimulation-for-6-Months-Reduces-White-Matter-Atrophy-in-Alzheimer%E2%80%99s-Disease-Patients.

Senior, Emily Craig. “Another Alzheimer’s Drug Could Be Better than Donanemab.” Mail Online, 19 July 2023, www.dailymail.co.uk/health/article-12314599/Another-Alzheimers-drug-pipeline-looks-better-donanemab.html. Accessed 31 Oct. 2023.

“Treatment Effect of Neflamapimod Enriched When Excluding High P-Tau181 Level Patients.” Neurology Live, 11 Sept. 2023, www.neurologylive.com/view/treatment-effect-neflamapimod-enriched-excluding-high-p-tau181-level-patients. Accessed 31 Oct. 2023.

Psychedelics May Help Treat Neurodegenerative Disorders

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The hallmark features of AD include neuroinflammation, dendritic atrophy, and loss of synapse density in cortical regions controlling cognition, memory, and mood. Recent research has pointed to a potentially groundbreaking therapy using psilocybin, a naturally occurring compound found in certain mushrooms known for its hallucinogenic properties. While some current treatments carry significant risk for adverse side effects, psilocybin and other psychedelics are relatively low risk. This blog discusses the emerging evidence suggesting that psilocybin may hold promise as a treatment for AD due to its ability to promote neuronal growth and modulate neuroinflammation.

Recent studies have demonstrated that psychedelics like psilocybin can stimulate 5-HT2A receptors, promoting cortical neuron growth, activation of neuronal survival mechanisms, and modulation of the immune system. Activation of these receptors induces the expression of immediate early genes (IEGs), which are known to be involved in neuroplasticity. Moreover, psychedelics have been shown to activate signaling pathways that promote neurotrophic factor release, particularly brain-derived neurotrophic factor (BDNF), which plays a crucial role in neuronal growth and survival. BDNF is often reduced in AD, contributing to the progressive loss of spines and synapses associated with dementia. In both human and animal studies, psychedelics like psilocybin increased BDNF expression in the cortex, increasing neuronal growth. These structural changes are accompanied by functional changes, such as an increase in spontaneous excitatory postsynaptic currents (sEPSCs), which indicate improved synaptic activity.

Neuroinflammation is increasingly recognized as a critical component of AD pathophysiology. Psychedelics have shown potential in modulating the immune system and reducing inflammation. By promoting cortical neuron growth and modulating neuroinflammation, psilocybin may have the potential to simultaneously address two significant components of AD pathophysiology.

One of the most promising aspects of psychedelic medicine is the long-lasting therapeutic effects observed after a single administration. Clinical trials and preclinical studies have demonstrated that psychedelic-assisted therapy can elicit therapeutic responses lasting for months. In some cases, this effect has been associated with increased neuroplasticity. In addition to promoting neuronal growth and modulating neuroinflammation, using psilocybin to activate 5-HT2A receptors has been shown to improve mitochondrial function. Mitochondrial dysfunction and oxidative stress are common features of neurodegenerative diseases like AD. By enhancing mitochondrial function, psilocybin may further contribute to its therapeutic potential for AD.

 While the evidence supporting the use of psilocybin for treating neurodegenerative disorders like AD is still limited, the emerging research is promising. The unique ability of psychedelics to promote both structural and functional neuroplasticity through the activation of 5-HT2A receptors makes them an intriguing candidate for further exploration as a potential treatment for AD. As we continue to investigate the therapeutic potential of psychedelics, it is crucial to conduct further research to better understand their mechanisms of action and assess their safety and efficacy for treating neurodegenerative diseases. Collaborative efforts between researchers, medical professionals, and therapeutic facilitators will be essential to unlock the full potential of psychedelic medicine and offer hope to those affected by devastating neurological disorders like AD.

Reference: Saeger, H. N., & Olson, D. E. (2022). Psychedelic-inspired approaches for treating neurodegenerative disorders. Journal of Neurochemistry, 162, 109–127. 

Rationale for Amyloid-Beta Targeting Therapies for Early AD Treatment

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Recent translational studies have led to a model of Alzheimer’s disease (AD) pathophysiology that focuses on the accumulation of amyloid-beta (Aβ) plaques between 20-30 years prior to the spread of tau, neuronal loss, and appearance of clinical symptoms. These findings have enabled the current research landscape to evolve to include preclinical stages of AD, when treatment success is predicted to be higher. There are a number of contributing factors that lead to a person developing AD. However, the multifactorial nature of AD largely plays into the reasoning researchers are focusing on Aβ accumulation for potential therapeutic interventions for early AD.

As discussed in previous blogs, Aβ is an enzymatic product of the amyloid precursor protein (APP) gene. An imbalance of Aβ production in the brain and extra-cellular clearance precedes Aβ protein misfolding and aggregation into brain plaques in AD. Mutations in APP can make enzymes involved in processing it bind more tightly to it, causing more of these misfolded Aβ protein fragments to be produced. Additionally, the APP gene can be processed by 3 main proteases: β-secretase and gamma-secretase promote toxic Aβ production, whereas A-secretase produces healthy, soluble Aβ. Dysregulation in these secretases can result in Aβ over production. Although an excess of Aβ proves detrimental, Aβ protein is necessary for normal neurotransmission and synaptic plasticity, so knocking out the APP gene altogether is not a viable solution. Large-scale genome-wide association studies have identified over 50 additional genetic risk factors for AD, and while they do not denote the exact cause of the disease, most are involved in maintaining Aβ homeostasis. For instance, those with early-onset AD often have mutations in at least one of three genes: APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN 2), and have increased Aβ due to genetic driven-dysregulation. This is compared to those with late-onset AD, with Aβ plaques largely attributed to reduced cellular quality control.
Another well-known genetic association with Aβ metabolism and homeostasis is an individual’s apolipoprotein (APOE) genotype. In-vitro and mouse models have shown that APOE moderates the activity of specific enzymes and downstream Aβ production. Those with an APOE E4 genotype were found to have significantly higher Aβ secretion, and those with two copies resulted in a 5-13-fold increase in AD incidence. Although our genes can be important in determining health status, sometimes it’s the downstream events, after protein production, that can initiate dysfunction. These post-translational, or epigenetic, changes further modify gene expression and protein production and degradation, continuing to alter Aβ levels.
In an attempt to protect the brain from Aβ plaques, microglia activate to prevent Aβ plaque spread, help with Aβ clearance, and attempt to limit Aβ accumulation. A dysregulation in these microglia, or a normal regulation under Aβ conditions, can further induce Aβ aggregation in the brain. Transforming growth factor-beta1 (TGFβ-1) is a neuroprotective, anti-inflammatory growth factor that stimulates Aβ clearance. In those with early AD, this growth factor is selectively impaired. The presence of Aβ can induce detrimental microglia activity, causing the release of pro-inflammatory cytokines and interfering with anti-inflammatory cytokine synthesis. For example, the cytokine tumor necrosis factor-alpha (TNF-α) results in increased synthesis of Aβ peptides, and its presence perpetuates more TNF- α in a vicious cycle. Studies have found that TNF-α levels are elevated in both mild cognitive impairment (MCI) and AD. Therefore, Aβ is again a common factor in the culmination of events that can lead to disease progression. Since microglia have both beneficial and detrimental effects on the brain when associated with Aβ, an undiscovered temporal factor may be at play, indicating that only at certain stages can microglia constructively intervene. More research is needed to elucidate this further.

Toxicity within the Aβ pathway is believed to play a crucial role in the progression of AD. Studies have suggested a temporal progression of Aβ pathophysiology from the spread of Aβ aggregation to the formation of plaques in the brain. While the causal effect is not fully established, evidence suggests that Aβ aggregation may facilitate and have a synergistic effect on other pathophysiological pathways, triggering downstream effects such as tau misfolding, tangle formation, and eventual neurodegeneration. Understanding this relationship is crucial for unraveling the pathogenesis of AD.

In summary, the central role of Aβ in AD pathophysiology demonstrates why it is a viable target for early treatment options. Aβ accumulation during preclinical stages presents a critical time period for intervention. Imbalances in Aβ production and clearance contribute to plaque formation, while genetic risk factors can trigger further disruption of Aβ homeostasis. When microglia fail to effectively limit Aβ accumulation, Aβ aggregation is accelerated. The resulting toxicity is thought to start a cascade of events, causing disease progression. Continued research holds potential for the development of effective therapies targeting Aβ in the early stages of AD, potentially improving treatment outcomes for individuals affected by this devastating disease.

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Reference:

The Amyloid-β Pathway in Alzheimer’s Disease

Hampel H; Hardy J; Blennow K; Chen C; Perry G; Kim SH; Villemagne VL; Aisen P; Vendruscolo M; Iwatsubo T; Masters CL; Cho M; Lannfelt L; Cummings JL; Vergallo A

https://pubmed.ncbi.nlm.nih.gov/34456336/