A 2025 rodent in vivo / human cell ex vivo study investigated effects of a Nrf2 activator on ALS rodent models and ALS human nervous system cells:

“M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. Apart from the recent promising emergence of tofersen as a disease modifying therapy for the 2% of ALS patients who harbor mutations in the SOD1 gene, other approved drugs have only marginal effects on life expectancy (riluzole) or indices of disease progression (edaravone).

Data from disease model systems and from human biosamples provide strong evidence for a role of redox imbalance, inflammation, mitochondrial dysfunction, and altered proteostasis, including autophagy and mitophagy, as four key drivers in the pathobiology of ALS. We demonstrate that M102 is a dual activator of NRF2 and HSF1 transcription factor pathways, two upstream master regulators of neuroprotective mechanisms, with the potential to modulate all four of these key drivers of neurodegeneration and with excellent penetration across the blood brain barrier.

Stress response of the KEAP1-Nrf2-ARE system is stronger in astrocytes compared to neurons. A body of evidence from in vitro and in vivo model systems and from post-mortem CNS tissue from ALS patients has indicated that the NRF2 response is impaired in ALS, and has also been shown to decline with age.

HSF1 is a stress-inducible transcription factor that is the key driver for expression of multiple heat shock proteins which act as chaperones responsible for correct folding of newly synthesized proteins, refolding of denatured proteins, and prevention of aggregation of misfolded proteins. However, to date, many small molecule activators of HSF-1 have shown undesirable properties e.g. by acting as Hsp90 inhibitors or by exerting direct proteotoxic effects.

M102 (S-apomorphine hydrochloride hemihydrate) is a proprietary new chemical entity (NCE) and the S-enantiomer of the marketed R-apomorphine (Apokyn®; pure R-enantiomer). The R-enantiomer is a dopamine agonist administered subcutaneously for management of advanced Parkinson’s disease. M102 is a very weak dopamine antagonist and does not show the adverse effects associated with dopamine agonism.

M102 treatment rescues motor neuron (MN) survival in co-cultures with C9, SOD1 and sporadic ALS patient-derived astrocytes. Other NRF2 activators have been investigated in clinical trials or have been approved for medical use. These include dimethylfumarate (DMF) (Tecfidera®, Biogen) and omaveloxolone (Reata, Biogen).

• DMF was originally approved for the treatment of psoriasis (Fumaderm®) and was later repurposed for the treatment of relapsing-remitting multiple sclerosis (Tecfidera®). A phase 2 trial of DMF in ALS provided Class 1 evidence of safety at a dose of 480 mg/day and lack of disease-modifying efficacy. DMF treatment is associated with dose-limiting lymphopenia and flushing (Tecfidera® Prescribing Information).
• Omaveloxolone (Skyclarys®) is a potent NRF2 activator that has been approved by the FDA and EMA for the treatment of Friedreich’s ataxia. By activating the NRF2 pathway, omaveloxolone ameliorates oxidative stress and improves mitochondrial function. As a potent NRF2 activator, omaveloxolone exhibited significant liver toxicity with elevated AST/ALT levels in 37% of patients exposed to a dose of 150 mg.
• Toxicity has also been reported with other potent NRF2 activators, such as bardoxolone methyl (EC50: 53 nM) which showed significant heart, liver, and renal toxicity in humans.

In contrast, our preclinical toxicological studies indicate that M102 has a much higher safety margin in relation to liver toxicity. M102 has the potential to modulate multiple key drivers of neurodegeneration, increasing the chances of achieving impactful neuroprotection and disease modifying effects in ALS.

This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.”

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-025-00908-y “M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis”