61% Relapse Rate and Treatment Challenges for Millions of Lupus 'Brain Fog' Patients: EginLife's EG-501 Paves the Way Forward

As the subway doors opened, 32-year-old Ms. Chen suddenly froze in place, forgetting which station she was headed to. The laptop bag in her hand seemed unfamiliar, and the station names on the app appeared like garbled code. She struggled to recall but felt as though she were groping through a thick, hazy fog. In the end, all she could do was send a WeChat message to her boss: "Sorry, I may need to take a leave." This was not the most severe episode, nor would it be the last.

Ms. Chen suffers from Neuropsychiatric Systemic Lupus Erythematosus (NPSLE), a core central nervous system manifestation of an autoimmune disease. Cognitive Impairment (CI) — commonly known as"Brain Fog"——is its most typical symptom, affecting 57% to 80% of NPSLE patients.¹. Symptoms include short-term memory loss, speech disorders, lack of concentration, and may be accompanied by migraines, visual flashes, or mood swings. These are not simply "work stress," but rather the result of increased autoimmune antibodies causing neuroinflammation, microinfarctions, and interfering with the functions of the cerebral cortex and nervous system.²。

When cognitive impairment strikes aWomen in their 30s, their impactWill affect simultaneouslyThree main lines: health, career, and family. Research shows,NPSLE Patients Face Twice the Unemployment Risk of Healthy IndividualsFacing within 5-10 years20% to 30% Increased Risk of Dementia³。A UK study on brain fogQualitative research indicates that patients often experience "memory fragmentation and attention dispersion."Resulting in issues such as slow decision-making and errors at work, they are forced to switch from full-time to part-time or work from home, or even lose their jobs, creating "invisible loss of productivity."

"Brain fog" is not only a dilemma that hinders patients' physical and mental health and daily life. Due to its insidious onset, atypical clinical manifestations, lack of gold-standard assessment methods, and scarcity of specific therapeutic drugs, the clinical diagnosis and treatment of NPSLE seem to be shrouded in a "fog," urgently awaiting a breakthrough.

According to the "Chinese Expert Consensus on the Application of Biologics in Systemic Lupus Erythematosus (2024 Edition)," China bears the highest global burden of SLE, with a total patient population of approximately 1 million and about 126,000 newly diagnosed patients annually. Based on analyses from the National Medical Insurance Database and the Chinese Rheumatism Data Center (CRDC), the incidence rate in China is approximately 14.09 per 100,000, significantly higher than the global incidence rate of 1.4~11.0 per 100,000.Among them,The incidence rate of NPSLE is 20% to 75%.⁴，The subset of cognitive impairment is estimated to be around 100,000 to 200,000 cases, presenting a vast blue ocean market.

Further analysis reveals that clinical studies have found cognitive impairment can occur in SLE patients even before the condition progresses to NPSLE. Approximately 56% of SLE patients may experience cognitive impairment within a year. This suggests that cognitive impairment is not an exclusive symptom of NPSLE patients; rather, it represents a significant clinical gap faced by the much larger population of SLE patients.

NPSLE has diverse and heterogeneous clinical manifestations, typically with complex conditions and significant individual variability, posing severe challenges for diagnosis and treatment.The clinical assessment criteria for NPSLE are not uniform, mainly reflected in the differences between the MoCA and ACR evaluation systems, causing diagnostic challenges for doctors. The "Chinese Systemic Lupus Erythematosus Diagnosis and Treatment Guidelines (2025 Edition)" points out that the average diagnostic delay for SLE patients in China is 10.8 months, with delayed diagnosis closely related to higher disease activity and organ damage.

As cognitive impairment progressively develops into irreversible organic damage to the nervous system, NPSLE not only affects patients' daily work and life but also leads to severe risks of disability and mortality.A retrospective study analyzing 9,538 SLE patients in China from 2002 to 2022 showed that NPSLE accounted for 11.47% of the total deaths in SLE cases.⁵Another study pointed out,The mortality rate of NPSLE patients is 11 to 14 times that of the general population.⁶

The study suggests that cognitive impairment is reversible and fluctuating, and early assessment, diagnosis, management, and treatment can help improve patients' quality of life.This means that highly efficient solutions and novel mechanism drugs are expected to reverse early cognitive impairment and clinical manifestations and organic lesions in NPSLE patients, helping them retain work capacity, reproductive function, and quality of life, thereby improving the poor prognosis associated with high disability and mortality rates.

Currently, there are no drugs available globally for treating cognitive impairment associated with lupus erythematosus.Traditional treatments mainly involve broad-target anti-inflammatory and immunosuppressive drugs, including antimalarials, glucocorticoids, and immunosuppressants.

"Expert Consensus on Clinical Practice for Central Nervous System Neuropsychiatric Lupus in Chinese Adults (2024 Edition)" proposes that the treatment principle for central nervous system NPSLE is early, multidisciplinary, and personalized management, formulating reasonable immunosuppressive therapy and antiplatelet anticoagulation treatment plans, with regular follow-ups. The short-term goal of treatment is to control the condition and achieve clinical remission or low disease activity; the long-term goal is to prevent recurrence and central nervous system damage, improve prognosis, and enhance quality of life.

As aHighly heterogeneousCentral Nervous System (CNS）Disease,NPSLEInvolvedFrom Mild "Brain Fog"Until cerebrovascular disease,EpilepsyDiverse clinical manifestations.Traditional therapies struggle to address the core pathology and haveBlood-brain barrier (BBB) Poor penetration, mismatched mechanisms, and significant side effects, which fail to truly address the dilemma of cognitive impairment.However, biologics targeting refractory NPSLE also struggle to meet the medication needs of patients with mild to moderate "brain fog," with limited patient accessibility and adherence.

"Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus (2025 Edition)" recommend that patients with confirmed active NPSLE should be treated with glucocorticoids combined with immunosuppressive agents (commonly cyclophosphamide CTX). However, the current standard of care (SoC) has significant shortcomings:

First, the natural dense structure and poor permeability of the blood-brain barrier make it difficult for most drugs to enter the brain, resulting in limited efficacy.Most classical immunosuppressants have physicochemical properties that result in extremely low peripheral-central permeability, far below the concentration required to suppress neuroinflammation or clear autoantibodies; even if high-dose intravenous infusion is used to increase the concentration, the active efflux mechanism makes it difficult for the drug to maintain an effective steady state within the brain parenchyma. This leads to the prolonged persistence of cognitive symptoms such as "brain fog," becoming a key bottleneck for treatment response rates being lower in lupus damage compared to other organs.

Secondly, glucocorticoids + immunosuppressantsShort-term ContainmentThe combination presents high drug toxicity and side effects, significantly reducing the long-term quality of life for patients.The most commonly used CTX tends to cause liver damage, bone marrow suppression, and reproductive toxicity, increasing the risk of tumor development. On the other hand,The application of medium to high doses of glucocorticoids exacerbates the decline in bone density, increasing the incidence of osteoporosis and fractures; furthermore, hormone-induced lymphocyte apoptosis and suppression of macrophage function elevate the risk of infections and complications.

Finally, the classical scheme mechanismContinuing the SLE treatment concept, which is to control short-term immune storms targeting systemic inflammation, butNot Targeting the Core Pathological Mechanism of "Brain Fog"——Excitotoxicity of Glutamate,Expression of antibodies and glutamate transporters that have infiltrated the brain parenchymaLack of direct repair effect，Unable to restore synaptic function.

In fact, the limitations of SoC treatment have long been evident in clinical settings — the 5-year survival rate of SLE patients in China has reached 94%, yet the standardized mortality rate remains significantly higher than that of the general population. Relapse is a prominent clinical characteristic of SLE. Previous studies have shown that the 5-year cumulative relapse rate of SLE patients under SoC treatment is 61%. Coupled with the impact of adverse drug reactions, nearly 60% of patients experience organ damage progression within 5 years.⁷。ClinicalContinuousSeeking alternative strategies with lower toxicity and better central targeting.

In recent years, emerging biologics such as rituximab have brought new options for refractory NPSLE. The "Expert Consensus on Clinical Practice for Adult Central Nervous System Lupus in China (2025 Edition)" points out that rituximab can rapidly improve central nervous system symptoms in patients with refractory NPSLE, alleviate cognitive impairment, neurological symptoms, and epilepsy, and improve related imaging manifestations.However, in practical applications, biologics are still "absent" in mild to moderate cognitive impairment indications:

First, the SLE indication has not been officially approved, limited to a narrow indication space for severe/refractory SLE (such as lupus nephritis).Rituximab was first approved for the treatment of lymphoma. Since its clinical trial for SLE did not meet the primary endpoint, it has not been officially approved for the SLE indication. The recommendations in domestic and international diagnosis and treatment guidelines are mostly based on its superior outcomes in severe refractory SLE, but both the cognitive evidence and the scope of indications are limited. This has led to itsLow clinical application rate makes it difficult to directly reach patients with early, mild, and moderate cognitive impairment.。

Secondly, as an anti-CD20 monoclonal antibody, it does not directly target the mechanism of glutamate receptor overactivation, which may result in significant fluctuations in efficacy.Rituximab recognizes onlyCD20 on B cell surface does not directly act on glutamate excitotoxicityThe NMDA/AMPA receptors. Moreover, local inflammation in the central nervous system is mainly characterized by microvasculitis and antibody deposition, possibly lacking sufficient B-cell infiltration, which limits the therapeutic efficacy. Additionally, the asynchrony between the peripheral and central systems, along with temporal differences in immune reconstitution among different subpopulations, leads to delayed improvement in synaptic function.

Thirdly, the medication must be administered via injection at the hospital, with a high unit price, resulting in a heavy financial burden for patients who pay out-of-pocket. This leads to low patient accessibility and compliance.RituximabIt needs to be administered via intravenous infusion and must be completed in a hospital with emergency rescue capabilities. The standard infusion time is 3-6 hours, and even specific rapid protocols require at least 60/90 minutes.⁸The time cost is high. After the medical insurance negotiation and the special procurement of anti-cancer drugs, the average winning bid prices for Roche's original Rituximab in 2018 were 2,326.47 yuan/bottle and 7,958.35 yuan/bottle, respectively.⁹。

In addition, the guidelines recommend that biologics should be used in combination with SoC. Especially for recurrent patients, if hormone, immunosuppressants, and biologics are sequentially administered, the annual total out-of-pocket burden is high, which may lead to forced prolongation of the dosing interval or abandonment of maintenance therapy, subsequently forming a vicious cycle of disease recurrence and a surge in subsequent hospitalization costs.

Therefore, patients with "brain fog" are in urgent needConvenient oral administration, excellent blood-brain barrier penetration, targeting pathology (Glutamic AcidExcitotoxicity）A brand-new drug to break free from the vicious cycle of hormone dependence and recurrence.

On October 26, Evergreen Therapeutics will publicly disclose for the first time itsUS Phase II Clinical Data of Original Class 1 New Drug EG-501.

It is reported that the indication for EG-501 isNeuropsychiatric Systemic Lupus Erythematosus (NPSLE) Cognitive Impairment，Will provide patients with a new treatment option. EG-501 is aOral Small Molecule TabletsIts mechanism of action is through targeted receptor antagonism, effectively reducing neuroinflammation in the brain and providing neuroprotective effects. This innovative therapy is expected to break through the limitations of traditional treatments, offering patients a beacon of hope. Dr. Tao Du, founder and chairman of Evergreen Therapeutics and former senior reviewer at the FDA, stated, "The Phase II data of EG-501 validates its efficacy in improving cognitive function and demonstrates good safety. We believe it has the potential to become the world's first approved drug for the effective treatment of cognitive impairment in NPSLE. At the same time, these results fully confirm the practical value of Evergreen's self-developed AI platform in drug development."

Notably, EG-501 was "born" from Evergreen Therapeutics' Miaowu AI platform, which was established for the development of highly efficient and precise therapeutic drugs. Relying on AI modeling, whole-genome atlases, and desensitized medical case databases, Evergreen Therapeutics...Tens of MillionsPhenotype-gene association data identified 12 disease dimensions highly correlated with the target; after multi-dimensional evaluation of market capacity, unmet clinical needs, and commercial accessibility, SLE cognitive impairment was ultimately selected as the lead indication for EG-501 Phase II trials.

At the same time, the upcoming Phase II clinical data of EG-501 will, for the first time, achieve the end-to-end closed-loop validation of the Miaowu AI platform "from drug discovery to obtaining positive clinical signals." More significantly, its clinical data will prove —AI-designed molecules can truly cross the "valley of death" and reproduce predicted efficacy in the human body.

References:

1.Popescu, A., & Kao, A. H. (2011). Neuropsychiatric systemic lupus erythematosus. Current neuropharmacology

2.Diamond B et al. (2009). Curr Opin Neurol.

3.Jolly M et al. (2025). Lupus.

4.Hanly JG (2021). Arthritis Rheumatol.

5.Dong F et al. (2024). Lupus 33(12):1389-1398.

6.Jayasinghe M, et al. Cureus. 2025;17(2):e79569.

7.Chinese Expert Consensus on the Application of Biologics in Systemic Lupus Erythematosus (2024 Edition)

8. Chinese Expert Consensus on Rapid Intravenous Infusion of Rituximab (2020 Edition)

9. VCBeat - $29 Billion! The Birth of China's First Biosimilar, 16 Companies Rushing In, Can Roche Withstand the Challenge?