Treating the root pathologies of neurological disorders with Axonis

Developing therapies to treat neurological disorders with Axonis

At Tachyon, we are particularly interested in identifying and supporting companies with discovery platforms that address an entire class of diseases. Axonis, our most recent investment, has a novel approach for developing neuro-restorative, neuro-protective, and neuro-regenerative therapies.

This approach includes early innovation using CRISPR-AAV to discover novel targets in vivo and a world-class scientific network in the field of neuroscience. These two factors, along with impressive results in animal models of spinal cord injury, have been fundamental in our decision to invest in Axonis.

The burden of CNS disorders

Central nervous system (CNS) disorders are a broad category of neurological diseases, many of which have few or no therapeutic treatment options. Globally, stroke, Alzheimer's, Parkinson's, and other dementias are amongst the top 15 conditions with the most substantial increase in health burden (in terms of deaths and years lived with disability) over the past decade. Because many neurological diseases strike in mid-to-late life, the incidence of diseases such as Alzheimer's and Parkinson's is soaring as life expectancy increases. As a result, the development of effective treatments for CNS diseases has become a global health priority.

The greatest obstacle to meaningful progress in patient care and outcomes for these pathologies is the lack of disease-modifying therapies. Few therapies today affect the disease processes of CNS disorders directly. For instance, the current standard of care for diseases such as Parkinson's and Alzheimer's involves approved drugs that provide symptomatic relief but do not halt or slow disease progression. Other diseases, such as Huntington's, have no approved therapies or treatments at all.

Axonis is determined to address this gap in treatment options for neurological disorders through the development of breakthrough, first-in-class molecules to treat the molecular basis of disease progression.

Axonis' inception: a cutting-edge AAV-CRISPR screen

In 2018 Dr. Zhigang He from Harvard / Boston Children's Hospital, Joanna Stanicka (now Axonis' CEO), and Shane Hegarty (Axonis' CSO) led an unprecedented, in vivo AAV-CRISPR screen for neuroprotection in a mouse model of CNS neurodegeneration. This technique broadly consists of deleting each of a set of genes in animal models of neurological disorders and assessing the physiological effect of each deletion to identify novel therapeutic targets. After screening over 2,000 individual genes (tested one-by-one) in vivo, the team discovered several assets. This high level of throughput was unprecedented and formed the cornerstone of Axonis' core technology and their approach to drug discovery. Alongside this screen, Axonis forged a deep network of scientific advisors whose research contributed to establishing the company's primary pipeline of assets.

Following this discovery model, Axonis was created to develop a pipeline of small-molecule, disease-modifying therapeutics for CNS disorders with the goal of restoring, regenerating, and reviving neurons. Axonis' approach targets the three underlying core pathologies of neurons: 1) imbalances in neuro excitation/inhibition, 2) neurodegeneration, and 3) failure to regenerate. Each of these dysfunctions is associated with a multitude of diseases, allowing Axonisto target a variety of neurological indications in an unprecedented way:

• Excitation/Inhibition (E/I) imbalance occurs when dysfunctional circuits alter neuron activity. This imbalance contributes to diseases such as epilepsy, spinal cord injuries, bipolar disorder, Rett syndrome, chronic pain, and schizophrenia.
• Neurodegeneration: The progressive degeneration of neurons underpins diseases such as Parkinson's, Alzheimer's, Huntington's, dementias, retinal degeneration, and Amyotrophic Lateral Sclerosis (ALS).
• Failure of regeneration: Damaged/diseased neurons do not regenerate, which leads to a permanent loss of neuron connections. This manifests in stroke, spinal cord injuries, and brain injuries, and is why neurodegenerative diseases progress irreversibly, as the lost neurons cannot be substituted.

Axonis' platform and programs

In response to these three major types of neuronal dysfunction, Axonis has developed three programs that form the core of their platform:

1. A neuron rebalancing pipeline capable of re-activating neurons with dysfunctional activity, which forms Axonis' lead program. Axonis' lead program aims to restore function and reduce pain and spasticity in patients with spinal cord injuries. A key fact that is not well known by the general public is that most human spinal cord injuries have spared, undamaged tissue (they are "anatomically incomplete") but nevertheless, result in complete paralysis. This is principally due to dysfunctional circuits that result in an excitation/inhibition imbalance, which alters neuron activity. By rebalancing spared neurons in the undamaged tissue, Axonis aims to restore some function to patients paralyzed by spinal cord injuries. For paralyzed patients, even a partial recovery of function allowing them to change positions and improve spinal alignment, or re-shuffle while sitting to avoid ulcers, would substantially improve their quality of life.
2. A pipeline focused on enabling the intrinsic ability of neurons to resist degeneration - for which Axonis is in the in vitro stages of selecting their lead candidate. Their second program aims to protect neurons from degeneration. In many instances of disease, patients with neurodegenerative disorders have already lost a significant portion (50%-70%) of their neurons at the time of diagnosis - yet, these patients still retain the majority of their body functions. This suggests that protecting the remaining, undamaged neurons from degeneration would help patients preserve their body functions - a life-changing alternative that could save patients from what is a dreaded and severe disease progression for indications such as Parkinson's. Through extensive screening, Axonis was able to uncover candidate targets that play a significant role in mediating the degeneration of neurons. Inhibiting these targets has a neuroprotective effect that helps neurons resist degradation. Currently, Axonis has two small-molecule candidate series that are inhibitors for two of their discovery targets. These stealth targets can result in therapies for the indications of Parkinson's, glaucoma, Alzheimer's, ALS, stroke, and diabetic retinopathy.
3. A pipeline aimed at regenerating lost neurons, still in early phases. Finally, in the realm of regeneration, Axonis is still in the early stages of research, with proprietary neuroregeneration targets that have yet to advance through in vitro studies. The overarching goal of these programs is to enable the regeneration of neurons lost in diseases such as stroke to actively restore lost brain connections and functions. Successfully bringing therapies to patients would potentially be life-changing for millions of patients currently struggling to manage a neurodegenerative disease.

A front-row seat into the future of neuro-therapeutics

When we first met Joanna, Axonis' CEO, a few months ago, we were struck by her scientific knowledge, energy, infectious enthusiasm, and earnest presence. Together with Shane, she has shown great aptitude for growing Axonis as a business, selecting promising strategies, and developing their pipelines effectively. Joanna and Shane are not alone: Axonis boasts a strong scientific team of advisors and co-founders with decades of experience in top institutions and deep relationships in the fields of neuroscience and CNS disease. At Tachyon we look to invest in the top teams in their respective fields, and Axonis is the perfect example.

While the need for relief from life-debilitating symptoms such as chronic pain and spasticity has driven global sales of prescription and over-the-counter CNS disease-related drugs to $86 billion in 2019, there is a great need for innovation in a market that is growing in size but limited in options, and Axonis' current pipelines of assets are able to act as both complements or substitutes for the current standard of care.

We could not be more excited to have joined Axonis in their journey. Find out more about them here.

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