AstronauTx investment analysis

October 17, 2023

This is not investment advice. We used AI and automated software tools for most of this research. We did some fact checking but cannot guarantee the accuracy of everything in the article. We do not have a position in or a relationship with the company.

Overview

AstronauTx is a London-based biotech firm developing novel treatments for Alzheimer's disease and other neurodegenerative disorders. Founded by the Dementia Discovery Fund in 2019, the company focuses on correcting brain physiology, specifically enhancing the support role of astrocytes, the brain's most common cell type.

The company raised a £48 million ($61 million) Series A in October 2023. Novartis Venture Fund led the round, along with Brandon Capital, Bristol Myers Squibb, EQT Life Sciences (investing from the LSP Dementia Fund), and MPM Capital. The Dementia Discovery Fund, which played a role in the company's inception, also participated in this round. AstronauTx's foundation was additionally supported by seed funding from the UCL Technology Fund and the UK Future Fund.

In neurodegenerative diseases like Alzheimer’s and Parkinson’s, harmful proteins like β-amyloid, tau, and α-synuclein accumulate, disrupting brain function. AstronauTx seeks to strengthen the brain's natural night-time processes that clear these toxins and solidify memories. As the disease progresses, these processes weaken, increasing cognitive deficits. AstronauTx's approach emphasizes:

• Enhancing nighttime toxin clearance and memory consolidation to reduce harmful protein buildup
• Boosting daytime neural support to maintain overall brain health and improve function

AstronauTx has not disclosed the targets they are working on or any specific programs. This analysis will discuss the scientific rationale of their approach, summarize the risks and opportunity in Alzheimer's and neurodegenerative disease, and speculate on which targets the company might be pursuing.

Highlights and risks

Valuation

Given the lack of details about AstronauTx's programs, we did not perform a valuation analysis.

Qualitatively, the company could be a candidate for a crossover round upon identifying a development candidate and / or initiating clinical studies, and the company could be an IPO candidate if preclinical and / or early clinical data are compelling. However, given how tight the IPO market is as of the time of this writing, AstronauTx may require the market to loosen a bit before it can IPO.

Scientific background

Overview of astrocytes

Astrocytes are a subtype of glial cells widely distributed throughout the central nervous system and play a multitude of roles in maintaining brain health and function:

• Support & Nutrition: Astrocytes provide structural and nutritional support to neurons. They have processes that wrap around neuronal synapses and blood vessels, where they help form the blood-brain barrier (BBB) and regulate blood flow.
• Ion Homeostasis: They play a role in potassium buffering, helping to maintain the extracellular ion balance which is crucial for neuronal signaling.
• Neurotransmitter Uptake: Astrocytes help in the uptake and recycling of neurotransmitters like glutamate, preventing excitotoxicity.
• Synaptic Modulation: They release gliotransmitters (like ATP, D-serine) that can modulate synaptic activity.
• Blood-Brain Barrier Maintenance: Astrocytes' end-feet encase blood vessels and contribute to the maintenance and integrity of the blood-brain barrier.
• Immune Response: They are involved in the brain's immune responses, releasing inflammatory or anti-inflammatory factors, depending on the context.

Role in Alzheimer's and other neurodegenerative diseases

• Aβ Accumulation: The accumulation of beta-amyloid (Aβ) peptides is a hallmark of Alzheimer's. Astrocytes are known to take up and degrade Aβ; however, they can become dysfunctional and contribute to Aβ accumulation over time.
• Inflammation: Chronic activation of astrocytes (known as astrogliosis) in neurodegenerative conditions can result in the prolonged release of pro-inflammatory molecules, potentially exacerbating neuronal damage.
• Tau Pathology: In addition to Aβ, the accumulation of hyperphosphorylated tau is another characteristic of Alzheimer's. Astrocytes can take up tau, and in some cases, tau pathology has been observed within astrocytes.
• Glutamate Toxicity: Dysfunctional astrocytes can lead to reduced uptake of the neurotransmitter glutamate, resulting in its accumulation in the synaptic cleft. This can cause excitotoxicity, damaging neurons.
• Neurovascular Dysfunction: Alzheimer's and other neurodegenerative diseases often show compromised blood-brain barrier integrity. Given astrocytes' role in maintaining the BBB, their dysfunction can contribute to these neurovascular abnormalities.
• Metabolic Support: Astrocytes provide metabolic substrates to neurons, especially during high-demand situations. Their dysfunction can compromise this support, potentially starving neurons.

Therapeutic potential

As shown above, there are many potential therapeutic strategies targeting astrocytes for Alzheimer's disease. AstronauTx has not disclosed their targets or programs, but we can speculate on the strategies they may be pursuing.

Please note that the below is just speculation, as AstronauTx has not disclosed any specific programs.

Based on the experience of AstronauTx's founders, collaboration with Saniona (a biotech with expertise in ion channel drug discovery and development), and the company description, it appears that AstronauTx is pursuing ion channel targets (they may also be pursuing other targets).

Ion channels expressed by astrocytes that play roles in toxin-clearance, memory consolidation, or other protective brain mechanisms might be prime candidates. Examples include Kir4.1 potassium channels, aquaporin-4 channels, and possibly certain calcium channels involved in astrocytic calcium signaling. Further, the astrocyte-specific GABA transporter (GAT3/4) has been studied by the company's scientific founder, although their research suggests this target is not a high priority.

Here's an overview of the potential categories of astrocytic ion channel targets:

Potential target	Rationale	Drawbacks	Experience in other indications
Aquaporins	While not an ion channel in the traditional sense, AQP4 is a water channel prominently expressed in astrocytes and is crucial for water homeostasis in the brain. It is also involved in the glymphatic system, which facilitates waste clearance from the brain. Dysregulation of the glymphatic system has been suggested in Alzheimer's disease, and there's evidence suggesting that efficient functioning of the glymphatic system during sleep might be involved in memory consolidation.	Overactivation might risk excessive water movement, leading to cerebral edema. The specificity of drugs targeting AQP4 might be challenging, as AQP4 is also present in other organs.	While there are no approved drugs that directly target AQP4, the presence of anti-AQP4 autoantibodies in neuromyelitis optica (NMO) has led to treatments aimed at mitigating their harmful effects. The role and potential of AQP4 as a drug target in Alzheimer's disease remains under investigation.
Inwardly rectifying potassium channels (Kir)	Essential for potassium buffering. Dysregulation of potassium homeostasis in the brain has been implicated in various neurological disorders, including Alzheimer's. Modulating these channels might help restore potassium homeostasis. Proper potassium homeostasis is crucial for maintaining the overall excitability of the brain, which in turn influences processes like memory consolidation.	Overinhibition might impair potassium buffering, leading to increased neuronal excitability and potential excitotoxicity. Non-specific modulation could affect other potassium channels and disrupt various physiological processes.	Drugs that modulate potassium channels, including Kir channels, have been developed for various indications, primarily cardiovascular diseases. However, their potential role in neurological disorders is still an area of active research, and direct targeting of astrocytic Kir channels for neurodegenerative diseases remains relatively unexplored.
Calcium Channels	Since calcium dysregulation is a prominent feature in neurodegenerative diseases, modulating calcium-permeable channels on astrocytes might be a viable strategy. Transient Receptor Potential (TRP) channels and store-operated channels could be targets to influence calcium-mediated processes in astrocytes. Astrocytes do not generate action potentials like neurons, but they have intracellular calcium (Ca2+) oscillations and waves that play essential roles in astrocyte-neuron communication. Such calcium signaling can influence neurotransmitter release, synaptic plasticity, and, potentially, memory processes.	Calcium signaling is complex and ubiquitous in various cell types; non-specific modulation could lead to unintended consequences. Overmodulation could disrupt intracellular calcium homeostasis, potentially leading to cell death.	TRP Channels: Various TRP channel modulators have been developed for indications ranging from pain to respiratory conditions. Some of these modulators have also been investigated in the context of neurodegenerative and neurological disorders. Store-operated channels: These channels are indirect targets for immunosuppressants like tacrolimus and cyclosporine. Their role in neurodegenerative diseases remains an area of active research.
Gap Junction Channels & Hemichannels	These channels allow for communication between astrocytes and also with the extracellular environment. Given their role in gliotransmission and astrocytic network activity, they could be relevant. Dysregulated gliotransmission might contribute to neurodegenerative pathology, so modulating these channels might be beneficial.	Non-specific modulation could disrupt cell-to-cell communication, as connexin hemichannels contribute to gap junctions. Overactivation might lead to excessive gliotransmitter release, potentially harming neurons.	Gap junction inhibitors, such as carbenoxolone, have been studied in various conditions like inflammatory disorders and certain cancers. The role of gap junction inhibitors in neurodegenerative diseases continues to be an area of research interest.
Purinergic Receptors	While these are technically receptors, some subtypes are ion channels that are permeable to calcium and other cations. Particularly, channels like P2X7 that are involved in gliotransmission and are responsive to extracellular ATP might be relevant. ATP release and purinergic signaling are involved in various physiological and pathological processes in the brain, and modulating these channels might have protective effects. These channels allow for the release of gliotransmitters from astrocytes, which can modulate synaptic activity and plasticity. Gliotransmitters include glutamate, D-serine, and ATP, among others, and their release can influence neuronal excitability and synaptic strength, potentially impacting memory processes.	These receptors are diverse and found on multiple cell types; non-specific targeting might result in off-target effects. Chronic modulation in astrocytes could disrupt essential brain functions given their roles in inflammation, neurotransmission, and vascular regulation.	P2X7 receptor antagonists have been explored mainly for inflammatory conditions, given the receptor's role in inflammation. Some investigations have looked into the potential of P2X7 antagonists in neurodegenerative diseases, given the role of inflammation in these conditions.

AQP4 appears promising, especially given the recent interest in the glymphatic system's role in neurodegenerative diseases. However, the potential for off-target effects in other organs and the risk of cerebral edema make drug development challenging.

Kir4.1 channels have been directly implicated in astrocyte dysfunction in neurological diseases, making them an attractive target. However, the challenge lies in the specificity of modulation.

Calcium channels have widespread roles, and while they're crucial for astrocyte function, targeting them might lead to broad and potentially detrimental effects unless drugs are designed with high specificity.

Connexin and pannexin channels provide an exciting avenue, given their role in gliotransmission. Yet, non-specific modulation might have broad implications for brain function.

Unmet need in Alzheimer's

Alzheimer's disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The primary neuropathological hallmarks of AD include the accumulation of extracellular β-amyloid plaques and intracellular tau tangles, leading to neuronal loss and brain atrophy. Despite decades of research, there remains a significant unmet need in the treatment of AD. Current treatments primarily address symptoms, with limited effects on disease progression. This unmet need is accentuated by the debilitating nature of these diseases and the emotional and financial burden they place on patients, caregivers, and healthcare systems.

Market size

In the U.S., it's estimated that over 6 million people suffer from Alzheimer's alone, making it the 6th leading cause of death. As the aging population grows, these numbers are expected to increase.

Approximately 10 million people suffer from AD and PD in the EU. Similar to the U.S., the aging population in Europe is set to increase the prevalence of these diseases.

The global prevalence of AD is estimated at around 50 million, and it's expected to triple by 2050. The combined prevalence of all neurodegenerative diseases is much higher.

Pricing

The pricing of therapies for neurodegenerative diseases is a complex issue. Given the significant unmet need and the potential for disease-modifying treatments to offer substantial value to patients, caregivers, and healthcare systems, there's a willingness-to-pay for effective therapies.

Novel treatments with proven efficacy in halting or reversing disease progression can command high prices. For example, Aduhelm, a recently approved Alzheimer's drug in the U.S., launched with a list price of around $56,000 per year. However, this price was viewed as controversial in light of the debatable clinical benefit provided by the drug, leading to challenges with reimbursement and disappointing launch.

Leqembi (lecanemab), another amyloid-beta targeting antibody that was approved in July 2023, may have a more promising commercial future. Leqembi has a lower list price of around $26,500 and stronger clinical data than Aduhelm (aducanumab), although there were some safety issues.