Publications – AL-S PHARMA

ALS is a progressive neurodegenerative disease that leads to loss of independence and a shortened lifespan

ALS and Misfolded SOD1

Despite the heterogeneity of amyotrophic lateral sclerosis (ALS), many patients share common downstream disease processes involving axonal injury, inflammation, and protein misfolding.

Misfolded SOD1 represents an important therapeutic target because toxic SOD1 aggregates can injure motor neurons and may contribute to disease progression.

What is ALS?

Amyotrophic lateral sclerosis (ALS) is a relentless and progressive neurodegenerative disease that affects the motor neurons of the brain and spinal cord. Symptoms vary from person to person. Some forms begin with limb weakness, while others start with bulbar symptoms affecting speech or swallowing. All forms ultimately lead to loss of independence and a markedly shortened lifespan. Median survival remains three-to-five years, and diagnosis is often delayed.

What is SOD1?

Superoxide dismutase 1 (SOD1) is a protective enzyme that helps cells manage oxidative stress. In ALS, structural changes can cause SOD1 to lose its proper function and misfold, taking on toxic conformations that disrupt cellular function.

Why does misfolded SOD1 matter in ALS?

Misfolded SOD1 can injure motor neurons, damage mitochondria, and impair axonal transport. Misfolded SOD1 pathology may also spread through seeding mechanisms, helping propagate toxic protein conformations across the nervous system. Across different presentations of ALS, misfolded SOD1 can amplify axonal injury and accelerate disease progression, making it an important target for intervention.

How AP-101 fits this biology

AP-101 is designed to selectively bind the misfolded, toxic form of SOD1 and support the body’s immune system in clearing these harmful proteins. This approach aims to slow the spread of misfolded SOD1 pathology while focusing on the toxic conformations associated with ALS.

AP-101 binds selectively to the misfolded, toxic form of SOD1 and helps the body’s immune system clear these harmful proteins.

Scientific literature highlighting misfolded SOD1 as a clinically validated target

1993:

Mutations in SOD1 cause ALS
Rosen, et al.

2008:

Misfolded SOD1 seeds further aggregation
Chattopadhyay, et al.

2010:

Misfolded SOD1 detected in sporadic ALS patients
Bosco, et al.

2011:

Cell-to-cell spreading of SOD1 pathology
Münch, et al.

2012:

Misfolding of wtSOD1 causes ALS-like symptoms
Graffmo, et al.

2012:

SOD1 misfolding triggered by TDP43 & FUS
Pokrishevsky, et al.

2014:

Transmission of misfolded SOD1 aggregates in mice
Ayers, et al.

2018:

AP-101 reduces SOD1 pathology & extends survival in preclinical ALS models
Maier, et al.

2019:

Initiation of AP-101 Phase 1 study in sporadic ALS & SOD1-ALS; Presence of misfolded SOD1 confirmed in sporadic ALS CSF samples

2023:

Tofersen has been approved by both the FDA and EMA for the treatment of SOD1-ALS specifically targeting the SOD1 gene mutation, with ongoing Phase 3 trials confirming its therapeutic benefit

2024:

Presence of SOD1 seeds confirmed in sporadic ALS, recombinant SOD1 mAb abolishes seeding in vitro
Mielke, et al.

2025:

Topline Phase 2 AP-101 results show clinically meaningful changes related to survival and non-invasive ventilation in ALS patients

2025:

The potential role of misfolded wild-type SOD1 protein in sporadic ALS: a review of evidence
Marlow, et al.

2026:

Insmed ARMOR trial

2026:

Tofersen in Non-SOD1 ALS

2026:

wt-SOD1 and mutant SOD1 form identical filaments and share common fibrillation pathway
Baek et al.

1993:

Mutations in SOD1 cause ALS

2008:

Misfolded SOD1 seeds further aggregation

2010:

Misfolded SOD1 detected in sporadic ALS patients

2011:

Cell-to-cell spreading of SOD1 pathology

2012:

Misfolding of wtSOD1 causes ALS-like symptoms

2012:

SOD1 misfolding triggered by TDP43 & FUS

2014:

Transmission of misfolded SOD1 aggregates in mice

2018:

AP-101 reduces SOD1 pathology & extends survival in preclinical ALS models

2019:

Initiation of AP-101 Phase 1 study in sporadic ALS & SOD1-ALS; Presence of misfolded SOD1 confirmed in sporadic ALS CSF samples

2023:

Tofersen has been approved by both the FDA and EMA for the treatment of SOD1-ALS specifically targeting the SOD1 gene mutation, with ongoing Phase 3 trials confirming its therapeutic benefit

2024:

Presence of SOD1 seeds confirmed in sporadic ALS, recombinant SOD1 mAb abolishes seeding in vitro

2025:

The potential role of misfolded wild-type SOD1 protein in sporadic ALS: a review of evidence

2025:

Topline Phase 2 AP-101 results show clinically meaningful changes related to survival and non-invasive ventilation in ALS patients

2026:

Insmed ARMOR trial

2026:

Tofersen in Non-SOD1 ALS

2026:

wt-SOD1 and mutant SOD1 form identical filaments and share common fibrillation pathway
Baek et al.

Science Translational Medicine – 2018

A human-derived antibody targets misfolded SOD1 and
ameliorates motor symptoms in mouse models of amyotrophic
lateral sclerosis.

«Our understanding of ALS has evolved significantly, and misfolded SOD1 species are now recognized as central drivers in patients with and without hereditary ALS. AP-101 represents a scientifically validated approach to target this pathology.»

Peter M. Andersen, MD, DPhil
AP-101 Phase 2 Clinical Trial Investigator