Previously, we reviewed the pathology and genetics of Alzheimer’s disease (AD) and discussed the two most common AD drug development targets, amyloid-beta plaques, and tau. Now, we’ll look at various novel AD drug targets and the companies forging ahead to find new treatments.
REVIVING THE BRAIN?
Loss of neurons is Alzheimer’s signature, devastating effect. What if we could jump-start the development of new brain cells? Two companies are trying to do just that.
Neuronascent (Clarksville, MD) aims to develop small molecule activators of neurogenesis. By screening large chemical libraries, the company has identified compounds promising to spark neurogenesis from adult neural stem cells in both tissue culture and mouse models.
The company’s lead compound, NNI-362, promoted the growth of new hippocampal neurons in mice. The new cells migrated to the correct location and differentiated. Moreover, they survived long enough to reverse previously observed cognitive declines. The hippocampus is one of the first regions of the brain to show damage in AD and is thought to play a role in memory formation and spatial navigation. Neuronascent completed Phase I trials of NNI-362 in 2021, showing a significant reduction of AD pathological biomarkers. Following the successful completion of Phase 1 trials, Neuronascent aims to continue toward Phase 2 proof-of-concept trials for age-related neurodegenerative indications in 2024.
Neurotrope Biosciences (New York, NY) is developing bryostatin, a drug that activates protein kinase C epsilon (PKCꞓ). This protein plays a crucial role in forming memories. In animal models of stroke, traumatic brain injury, and AD, bryostatin appears to restore deficits in synapses (connections between brain cells) and decrease cell death. These results suggest that bryostatin could help prevent neuron loss and restore synapses.
NEUROINFLAMMATION
Neuroinflammation is one of the drivers of neurodegeneration in AD, multiple sclerosis, and other brain disorders. Research suggests that the protein c1q is present at higher levels in people with Alzheimer’s disease. C1q accumulates at neuronal synapses, the key communication points between brain cells. This protein also signals other immune cells, such as macrophages—which then chomp up cellular debris in affected brains. The accumulation of c1q could account for the loss of synapses and accompanying mental decline.
South San Francisco-based Annexon is working on a promising therapy that centers on controlling inflammation in the brain. ANX005, now in Phase IIa development, is a monoclonal antibody that mops up excess c1q. The results from phase 2 indicated that the treatment involving ANX005 was typically well-received, achieved consistent target engagement, and presented clinical advancement in certain patient subsets.
Another company homing in on neuroinflammation is vTv Therapeutics (High Point, NC). Their drug, Azeliragon (TTP488), failed in Phase III clinical development. Azeliragon is a small molecule inhibitor of the receptor for advanced glycation end products (RAGE). RAGE is present in many neurological cell types. Its activation may promote amyloid-beta production and transport, tau aggregation, and chronic inflammation. Preventing any of these developments could improve Alzheimer’s symptoms.
Anavex (New York, NY ) also targets neuroinflammation with their small molecule drug ANAVEX 2-73, an activator of the sigma-1 receptor (S1R). S1R is found on the surface of microglial cells, a type of white blood cell found in the brain. Activating S1R appears to reduce neuroinflammation. ANAVEX 2-73 is in Phase III clinical testing.
IMMUNOTHERAPY
Immunotherapy—activating the patient’s immune system to fight disease—has taken the oncology world by storm. South San Francisco-based Alector is trying this approach to Alzheimer’s. Their lead Alzheimer’s candidate, ALOO2, targets and activates the TREM2 receptor, which is present in immune cells active in the brain. The idea is to activate those immune cells to clear out amyloid-beta and other potentially damaging proteins. The TREM2 target was identified based on genetic studies, which showed that patients with a dysfunctional TREM2 gene had a significantly higher risk of developing AD. In comparison, those whose mutations led to an overexpression of the receptor had a lower risk. AL002 began Phase II clinical testing in 2021 and enrolled 265 individuals with early AD for evaluating the efficacy and safety of AL002. The results of this study are expected to be released in 2023.
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SEARCHING FOR A NEW MECHANISM
Rather than target Aβ plaques directly, Yumanity Therapeutics (Cambridge, MA) tried to identify the problems they cause. Yumanity scientists have engineered yeast cells to overproduce the Aβ protein and monitor its detrimental effects, such as disrupting the action of other vital cellular proteins. Because yeast share many molecular pathways with humans, researchers can use them to screen for potential drugs that address protein disruption. Promising candidates are then tested in Alzheimer’s patient-derived cells. By tackling a completely different disease mechanism, the new compounds may achieve greater success than seen so far with drugs that act directly on amyloid beta or tau. Yumanity (now Kineta, based in Washington) is in the lead-optimization phase of preclinical development.
In partnership with Biogen (Cambridge, MA), Proteostasis Therapeutics (Cambridge, MA) targets AD-associated protein aggregates by activating proteasomes. These cellular components eliminate damaged proteins and dysfunctional protein aggregates by dismantling their chemical bonds. The protein USP14 inhibits proteasomes. Proteostasis is working on the preclinical development of a USP14 inhibitor that fully activates proteasomes in AD patients. This makes it more likely that the proteasomes will recognize and destroy amyloid plaques and tau tangles.
Oryzon Genomics (Barcelona, Spain) is taking an epigenetic approach to Alzheimer’s. Epigenetic modifications are chemical changes to gene sequences that don’t change the information content but affect how much that content is used, in other words, the amount of a particular protein the body makes. Oryzon researchers identified an enzyme, lysine-specific histone demethylase 1 (LSD1), which makes epigenetic modifications to genes that result in “turning them down,” so they produce less of the corresponding protein. LSD1 makes these changes to genes that support neuronal survival. Oryzon scientists have designed a drug, ORY-2001, that inhibits LSD1. Inhibiting LSD1 could mean that more neurons survive in AD patients, leading to improved cognitive function. ORY2001 completed the Phase IIa clinical trials in November 2020 for assessing the safety, tolerability, and preliminary efficacy in patients with mild to moderate AD.
It’s encouraging to know how many therapies are in the Alzheimer’s treatment pipeline. With more hard work and investment, perhaps one of the many introduced above will lead to a cure—or the winning therapy may include a combination of these approaches. The world awaits a winner in this all-important race.
FREQUENTLY ASK QUESTIONS
Question: Can you explain the novel drug targets Neuronascent and Neurotrope Biosciences are focusing on for Alzheimer’s disease treatment?
Neuronascent and Neurotrope Biosciences are two companies pursuing novel drug targets for Alzheimer’s disease (AD) treatment.
Neuronascent, based in Clarksville, MD, aims to address the devastating loss of neurons, which is a hallmark of Alzheimer’s disease. They are focused on developing small molecule activators of neurogenesis. By screening large chemical libraries, Neuronascent has identified compounds that show promise in sparking neurogenesis from adult neural stem cells, both in tissue culture and mouse models. Their lead compound, NNI-362, has demonstrated the ability to promote the growth of new hippocampal neurons in mice. These newly formed neurons migrated to the correct location, differentiated, and importantly, reversed previously observed cognitive declines. The hippocampus is a crucial region of the brain involved in memory formation and spatial navigation and is one of the first regions to show damage in Alzheimer’s. Neuronascent has completed Phase I trials of NNI-362 in 2021, with significant reductions in AD pathological biomarkers. The company plans to move forward to Phase 2 proof-of-concept trials for age-related neurodegenerative indications in 2024.
Neurotrope Biosciences, located in New York, NY, is working on a drug called bryostatin that activates a protein kinase C epsilon (PKCꞓ). This protein plays a vital role in memory formation. In animal models of stroke, traumatic brain injury, and Alzheimer’s disease, bryostatin has shown the potential to restore deficits in synapses (connections between brain cells) and reduce cell death. These findings suggest that bryostatin could help prevent neuron loss and restore synapses, offering a promising approach for Alzheimer’s disease treatment.
Question: How are companies like Annexon, vTv Therapeutics, and Anavex targeting neuroinflammation in Alzheimer’s disease?
Annexon, vTv Therapeutics, and Anavex are among the companies focusing on targeting neuroinflammation in Alzheimer’s disease.
Annexon, located in South San Francisco, is working on a therapy centered around controlling inflammation in the brain. Their drug candidate, ANX005, is a monoclonal antibody that targets excess c1q protein, which is associated with neuroinflammation. C1q is found at higher levels in people with Alzheimer’s disease and accumulates at neuronal synapses, the communication points between brain cells. The accumulation of c1q can lead to the loss of synapses and cognitive decline. ANX005 has shown promise in Phase 2a development, with consistent target engagement and clinical advancement in certain patient subsets.
vTv Therapeutics, based in High Point, NC, is pursuing a drug called Azeliragon (TTP488) to address neuroinflammation. Azeliragon is a small molecule inhibitor of the receptor for advanced glycation end products (RAGE), which is present in various neurological cell types. Activation of RAGE may promote amyloid-beta production, tau aggregation, and chronic inflammation, all of which contribute to Alzheimer’s symptoms. By inhibiting RAGE, Azeliragon aims to prevent these developments and potentially improve Alzheimer’s symptoms.
Anavex, headquartered in New York, NY, is targeting neuroinflammation with their small molecule drug ANAVEX 2-73. This drug is an activator of the sigma-1 receptor (S1R), which is found on the surface of microglial cells in the brain. Activating S1R appears to reduce neuroinflammation. ANAVEX 2-73 is currently undergoing Phase 3 clinical testing as a potential treatment for Alzheimer’s disease.
Question: What are some innovative approaches being explored by Alector, Yumanity Therapeutics (now Kineta), Proteostasis Therapeutics, and Oryzon Genomics for Alzheimer’s treatment?
Alector, Yumanity Therapeutics (now Kineta), Proteostasis Therapeutics, and Oryzon Genomics are exploring innovative approaches for Alzheimer’s treatment.
Alector, located in South San Francisco, is taking an immunotherapy approach to Alzheimer’s disease. Their lead candidate, ALOO2, targets and activates the TREM2 receptor, which is present in immune cells active in the brain. The aim is to activate these immune cells to clear out amyloid-beta and other potentially damaging proteins associated with Alzheimer’s disease. ALOO2 has entered Phase 2 clinical testing, and its efficacy and safety are being evaluated in individuals with early AD. Results are expected to be released in 2023.
Yumanity Therapeutics (now Kineta), based in Washington (formerly Cambridge, MA), has taken a unique approach to Alzheimer’s treatment. Instead of directly targeting amyloid-beta plaques, they have focused on identifying the problems these plaques cause. Using yeast cells engineered to overproduce the Aβ protein, they monitor its detrimental effects on other vital cellular proteins. Yeast shares many molecular pathways with humans, allowing researchers to screen for potential drugs that address protein disruption. Promising candidates are then tested in Alzheimer’s patient-derived cells. Yumanity is currently in the lead-optimization phase of preclinical development.
Proteostasis Therapeutics, located in Cambridge, MA, is working in partnership with Biogen to target AD-associated protein aggregates through the activation of proteasomes. Proteasomes are cellular components that eliminate damaged proteins and dysfunctional protein aggregates by dismantling their chemical bonds. The protein USP14 inhibits proteasomes, preventing them from clearing these aggregates effectively. Proteostasis is developing a USP14 inhibitor that fully activates proteasomes in AD patients, which would enhance the clearance of amyloid plaques and tau tangles.
Oryzon Genomics, headquartered in Barcelona, Spain, is taking an epigenetic approach to Alzheimer’s disease. They have identified an enzyme called lysine-specific histone demethylase 1 (LSD1), which makes epigenetic modifications to genes that result in u0022turning them down,u0022 leading to the production of less corresponding protein. Inhibiting LSD1 with their drug ORY-2001 could mean that more neurons survive in AD patients, potentially leading to improved cognitive function. ORY-2001 has completed Phase IIa clinical trials, assessing its safety, tolerability, and preliminary efficacy in patients with mild to moderate AD.
These innovative approaches provide hope for advancing Alzheimer’s disease treatment and finding a potential cure.
