The Science

Calming the Inflammation That Drives Neurodegeneration

Neurodegenerative diseases share a common thread — chronic inflammation in the brain. Alsonex follows that thread to a single, well-understood target, and to a molecule designed to switch off the damaging inflammatory signal.

The challenge

A Common Thread in the Brain

For all their differences, the neurodegenerative diseases — Motor Neuron Disease (MND), sometimes referred to as Amyotrophic Lateral Sclerosis (ALS), along with Parkinson's, Alzheimer's and Huntington's disease — share a striking feature. In each, nervous system cells in the brain and spinal cord begin to deteriorate, function abnormally and ultimately die. And neurons, unlike most cells in the body, do not reproduce or replace themselves: once they are lost, they are lost for good. Symptoms that begin mildly become progressively worse, and these diseases are ultimately fatal.

Inflammation within the brain occurs in all neurodegenerative diseases. Inflammation is meant to protect the body. It is the immune system's normal response to injury or infection, and in healthy tissue acute inflammation is a key component of repair. But inflammation that becomes chronic turns destructive, as inflammatory cells release reactive oxygen species and proteases that damage the very tissue they were meant to defend. In the brain, the body is largely unable to repair this damage, and the cascade of events creates further damage. MND is a disease where chronic neuronal inflammation is well documented. The thread that runs through neurodegeneration, then, is chronic neuroinflammation — and it is that, that Alsonex set out to address.

Chronic neuroinflammation and progressive neuron loss A healthy neuron, with an intact cell body and branching processes, deteriorates under chronic neuroinflammation. Symptoms that begin mildly become progressively worse: the neuron's processes retract and it is ultimately lost. Neurons do not replace themselves, so once lost they are lost for good. progressive, irreversible loss over time Healthy Inflamed Lost not replaced
Figure: A healthy neuron deteriorates under chronic neuroinflammation — mild, then progressive, then lost.
The complement system

The Body's Inflammatory Tripwire

A key part of the inflammatory response is a suite of proteins known as the complement system. Complement is part of innate immunity — the body's first line of defence — and is made up of distinct plasma proteins that react with one another to recognise threats and trigger an inflammatory response to fight infection. Ordinarily, these precursor proteins circulate harmlessly throughout the body; at a site of infection, they are activated locally and set off a chain of potent inflammatory events.

Complement works as a triggered-enzyme cascade. One activated complement protein cleaves the next, which cleaves the next again, so that a small initial signal is rapidly and hugely amplified into a large response. It can be set off through three distinct activation pathways — the classical pathway, triggered by antibody or by C1q binding directly to a target; the MB-lectin pathway, triggered by mannan-binding lectin; and the alternative pathway, triggered directly on the target surface. The three pathways begin differently but converge on the same point: the cleavage of complement component C3, and then of C5, generating the same set of effector molecules.

The complement cascade Three initiation pathways — classical (antibody and C1q), MB-lectin (mannan-binding lectin) and alternative (pathogen surfaces) — converge on the C3 convertase, which cleaves C3. This forms the C5 convertase, which cleaves C5 into two fragments: C5a, the potent inflammatory signal, and C5b, which assembles with C6 to C9 into the membrane-attack complex. INITIATION PATHWAYS Classical Antibody–antigen complexes · C1q MB-lectin Mannan-binding lectin (MBL) Alternative Pathogen surfaces C3 convertase pathways converge here C3 C5 convertase cleaves C5 C5 splits into two fragments C5a inflammatory signal C5b + C6–C9 → MAC membrane-attack complex
Figure: Three initiation pathways converge on C3, then C5 — generating C5a, the potent inflammatory signal.

Powerful systems need brakes, and complement has many regulatory mechanisms to prevent it running unchecked. The trouble in neurodegenerative disease is that, in the brain, those brakes fail to hold — and the cascade continues to produce its most potent inflammatory signals.

C5a, the crux

C5a — The Signal at the Centre

When the cascade reaches its terminal step, the C5 convertase cleaves C5 into two fragments: C5b and C5a. C5a is a potent anaphylatoxin and the centrepiece of the complement cascade — the most stable of the small complement fragments and the one with the highest specific biological activity. It is a major effector of all the complement activation pathways: it recruits and activates inflammatory cells, increases vascular permeability and amplifies inflammation wherever it is produced.

Critically, C5a is also produced locally within the central nervous system — and the C5a1 receptor through which it acts is present on neurons and glia, the brain's own cells. C5a signals by binding to the C5a1 receptor. In a healthy brain that signalling is measured and controlled and often beneficial. In neurodegenerative disease it is not: excess C5a, acting through the C5a1 receptor on neurons and glia, drives the chronic neuroinflammation that damages and destroys neurons.

C5a drives neuroinflammation In the central nervous system, the inflammatory signal C5a binds the C5a1 receptor present on neurons and glia, including microglia. This signalling activates those cells and drives chronic neuroinflammation, which in turn damages and destroys neurons. C5a the trigger binds NEURONS & GLIA (incl. MICROGLIA) cell membrane C5a1 receptor cell activated microglial activation, gliosis, inflammatory mediators released Chronic neuro- inflammation Neuronal damage & loss In a healthy brain this signalling is measured and controlled. In neurodegeneration, excess C5a drives the damage.
Figure: C5a binds the C5a1 receptor on neurons and glia, driving microglial activation, gliosis and neuron loss.

The fingerprints of this process are visible in patients. In MND there is a significant contribution of immune and inflammatory components to the disease. Activation fragments of the complement system are increased in the plasma and cerebrospinal fluid of MND patients, and are localised to glia in the spinal cord and the motor cortex. C5a itself is elevated within leukocytes from ALS patients, suggesting heightened C5a receptor interaction. These findings point to enhanced complement terminal-pathway activation in MND that likely plays an important role in the disease process. C5a, in short, is the signal at the centre of the damage — and the best place to intervene.

ALS-205, the answer

ALS-205 — Switching the Signal Off

If excess C5a signalling drives the damage, then blocking that signal should calm it. A highly targeted, centrally active, inhibitor of the C5a–C5aR1 axis should, at least in principle, dampen the inflammation, return the brain toward a more normal homeostatic state and prevent further damage. ALS-205 is such an inhibitor and does just that in models of human disease.

ALS-205 is a potent and selective blocker of the human C5a1 receptor. Rather than shutting down the whole complement system — which the body needs to fight infection — it blocks C5a precisely where it does its harm, at the C5a1 receptor on neurons and glia, while leaving the rest of innate immunity to function. Where most attempts to target complement have used antibodies — large proteins that do not readily cross into the brain and must be given by injection — ALS-205 is a small molecule, and that matters: small enough and sufficiently lipophilic to be taken orally and to cross readily into the central nervous system, where neurodegenerative disease takes hold.

ALS-205 blocks the C5a1 receptor ALS-205, a small-molecule antagonist, occupies the C5a1 receptor on neurons and glia. With the receptor blocked, C5a can no longer bind or signal, so the inflammatory signalling is switched off and neuroinflammation is calmed — while the rest of innate immunity keeps working. C5a cannot signal NEURONS & GLIA cell membrane ALS-205 occupies the receptor cell quiet no C5a signalling, no inflammatory activation Inflammation calmed A potent, selective antagonist of the human C5a1 receptor — blocking C5a precisely where it does harm, while the rest of innate immunity keeps working.
Figure: ALS-205 occupies the C5a1 receptor so C5a can no longer signal — and the inflammation quietens.

A small molecule, not an antibody: oral, brain-penetrant, selective. ALS-205 is Alsonex's lead compound, and it has already moved from this rationale into disease models and into the clinic — with improved survival in animal studies of MND and safe target engagement in patients.

See the evidence behind ALS-205