Potential of Preclinical Program in Mental Fatigue

• Chronic fatigue treatment market worth US$1.2 billion in 2024, rising to c.US$2.3bn by 20331
• Recent Nature article indicates extent of mental fatigue problem2
• Low levels of dopamine in the brain are linked to mental and cognitive fatigue
• TheraCryf's dopamine modulator (DAT) offers a potential treatment for chronic fatigue
• Asset at late preclinical stage with published data demonstrating effectiveness at alleviating fatigue in established models

Alderley Park, 18 December 2025 - TheraCryf plc (AIM: TCF), the clinical stage drug development company focussing on brain disorders, notes a recent Nature article2 which discusses the extent of the issue of mental fatigue and highlights the commercial opportunity provided by its second pre-clinical programme, DAT, which has the potential to treat fatigue.

Central nervous system fatigue is associated with diseases such as multiple sclerosis (MS), myalgic encephalomyelitis (ME), long COVID and chemotherapy treatment. More than 80% of patients with multiple sclerosis suffer from fatigue and report it as the most common and debilitating symptom3. This overwhelming cognitive exhaustion, which is not simply being 'tired', severely impacts daily life. Currently there are no approved treatments for fatigue in these patients.

The potential market opportunity for treating chronic fatigue was estimated at US$1.2 billion in 2024 with the market expected to reach US$2.3 billion by 20331.

Growing scientific interest in the origins of mental fatigue is underscored by the recent Nature article2 by Lynne Peeples which highlights the research being undertaken to discover the roots of mental fatigue which could point to treatments for these debilitating disorders. Dopamine plays a major role in alertness and motivation with low levels being linked to fatigue states4.

Current treatments include stimulants, such as amphetamines, which produce a rapid rise in dopamine, however, they are associated with significant side effects and a high potential for abuse because of the 'rush'-like feelings they produce.

TheraCryf's DAT asset is differentiated by its ability to gradually increase levels of brain dopamine without the 'rush'-like profile, potentially providing a treatment that alleviates mental fatigue without abuse liability.

Elevating dopamine levels can also lead to increased wakefulness and the DAT asset has demonstrated positive preclinical proof of concept in connection with this, in models of drug-induced fatigue, MS fatigue and narcolepsy. The narcolepsy treatment market alone was valued at US$3.48 billion in 2024 and is expected to reach US$7.73 billion by 20325.

Dr Huw Jones, CEO of TheraCryf commented:

"Disease and treatment-related fatigue is a very serious issue for patients who are already severely affected by several underlying conditions. A therapeutic that could target these symptoms is clearly needed and the increase in research efforts and the associated market value related to fatigue make this a very attractive path to pursue.

"Our dopamine modulator is differentiated and highly selective, with strong potential in the large and growing area of central nervous system fatigue. While we progress our lead Ox-1 orexin blocker programme, we continue to explore the significant potential of the DAT programme for future development or licensing."

• Market Size and Trends: Chronic Fatigue Treatment Market: https://www.marketsizeandtrends.com/report/chronic-fatigue-syndrome-treatment-market/
• Is your brain tired? Researchers are discovering the roots of mental fatigue, Nature 10 December 2025 [https://www.nature.com/articles/d41586-025-03974-w]
• Dobryakova: Dopamine Imbalance Hypothesis: https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2015.00052/full
• Neural and computational mechanisms of momentary fatigue and persistence in effort-based choice, Nature July 2021 12(1):4593
• Data Bridge Market Research: https://www.databridgemarketresearch.com/reports/global-narcolepsy-treatment-market