TISA-818
TISA-818，A new mechanism drug
Multi-indication strategy was developed for TISA-818 as a multi-pathway immunomodulation to show its advantages:
（1）TISA-818 shows anti-inflammation function in acute stage without immune suppression, which can be used in infectious period. ARDS patients with infection were recruited in the phase II clinical trial.
（2）TISA-818 combines tissue repairing with anti-inflammation and anti-oxidative stress functions. Clinical trial on the prevention and therapy of radiation induced oral mucositis is in the progression. In the future it is worth to develop 818 into inhalation for COPD.
（3）TISA-818 could be effective on anti-fibrosis. Phase I healthy volunteer study of IPF has completed in Sweden.
Acute Respiratory Distress Syndrome (ARDS)
Unmet clinical needs of ARDS
TISA-818 therapy for ARDS: phase I study in healthy volunteers
Good safety and tolerability with a plasma half-life of approximately 6 hours
Overall Design: Single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) phase I study.
Primary Objectives: to evaluate the safety and tolerability of 818 injection after single and multiple intravenous injection in healthy volunteers.
Second Objective: to evaluate the PK profile of 818 injection after single and multiple intravenous injection in healthy volunteers.
Clinical Research Site/Investigators: Phase I Clinical Research Center, Huashan Hospital Affiliated to Fudan University / Jing Zhang and Guoying Cao.
Favorable safety and tolerability: Only mild adverse reactions observed following single and multiple intravenous infusions of TISA-818 injection. No serious adverse events (SAEs) reported. No treatment discontinuations due to drug-related effects.
Dose-proportional exposure observed post intravenous infusion. Linear pharmacokinetic relationship demonstrated. No accumulation detected after 7-day repeated dosing across 0.1-12 mg dose range.
TISA-818 therapy for ARDS: phase II study --- Study Design
A Randomized, Double-blind, Placebo-Controlled Phase II Clinical Study to Evaluate Safety and Preliminary Efficacy of TISA-818-Inj in Patients with Acute Respiratory Distress Syndrome. Study was designed based on the New Global Definition of ARDS in 2023.
Primary Objective: To assess the safety of TISA-818-Inj in adult ARDS patients ---AEs, SAEs, and examinations.
Secondary objectives:
- To evaluate the preliminary efficacy of TISA-818-Inj in patients with ARDS ---Ventilator-free days; Oxygenation index change; Length of stay; Clinical improvement; All cause of mortality; Biomarker exploration; long term SF-36 and lung function.
- To evaluate the population pharmacokinetic (Pop PK) characteristics of TISA-818-Inj in patients with ARDS ---PK.
- To evaluate the PK characteristics of TISA-818 in alveolar lavage fluid ---PK.
TISA-818 therapy for ARDS: clear signal of the efficacy
Good safety：
TISA-818 Exhibited a good safety and tolerability profile.
Clear signal of clinical benefit：
The therapy at 6 mg BID for NIV/HFNO patients, not only provided an improvement in oxygenation from early stage but also translated to superior clinical outcomes, including more ventilator-free days at Day 28 (18.7 vs 13.4), higher survival and off ventilator rate at Day 21 (100% vs 66.7%), higher rate of clinical improvement (77.8% vs 44.4%) and less length of ICU stay at Day 28 (8.7 vs 12.2). Impressively, 100% patient in 6 mg BID NIV/HFNO set were off ventilator by Day 21 and showed clinical improvement by Day 28.
Good Data concordance：
The efficacy profile of TISA-818 is highly consistent, with correlated benefits observed across key endpoints, including improved oxygenation (P/F ratio), prolonged ventilator-free days, and increased survival and off ventilator rates. These benefits contributed to a higher rate of clinical improvement and shorter ICU & hospital stays.
A high degree of overlap was observed among the patients who demonstrated a positive treatment response across these individual endpoints.
Similar positive trends were observed across subgroups, regardless of ventilation type (IMV vs. NIV/HFNO), baseline P/F ratio (<150 vs. >150), or disease severity (mild-to-moderate vs. moderate-to-severe).
Acute Lung Injury (ALI)
What is ALI？
ALI is a continuum of clinical and radiographic changes affecting the lungs, characterised by acute onset severe hypoxaemia, not related to left atrial hypertension, occurring at any age. At the severe end of this spectrum lies Acute Respiratory Distress Syndrome (ARDS).
A wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. The clinical syndrome of acute onset respiratory distress, dyspnea, and bilateral infiltrates is referred to as acute respiratory distress syndrome. The histologic counterpart of acute respiratory distress syndrome is diffuse alveolar damage, classically characterized by hyaline membranes. Other histologic features of acute lung injury include intraalveolar fibrin, organization, interstitial edema, and reactive pneumocytes. Diffuse alveolar damage and other histologic features of acute lung injury are nonspecific as to etiology, and once identified require the pathologist to search the biopsy for further features that may help identify a specific etiology. ( Cheung OY, Graziano P, Smith ML. Acute Lung Injury. Practical Pulmonary Pathology: A Diagnostic Approach. 2018:125–146.e3. doi: 10.1016/B978-0-323-44284-8.00006-5. Epub 2017 Nov 5. PMCID: PMC7152358.)
The Etiology of ALI
There are over 50 different causes of ARDS (see Table 1), with sepsis and pulmonary aspiration being the most common. The pathophysiology of ARDS is complex, but its hallmarks include lung endothelial and alveolar epithelial injury with a consequent increase in membrane permeability and the accumulation of protein-rich debris in the alveolar air space. Injury to the epithelium and endothelium is largely caused by a complex and exaggerated production of many inflammatory mediators (for example TNF-α, IL-6). These host processes are likely responsible for the high rates of morbidity and mortality of this illness.
Table 1 Examples of causes of acute lung injury inhumans
Current treatment
Treatment of acute lung injury is based in both ventilatory and nonventilatory strategies. To date, the most significant advances in the supportive care of lung injury patients have been associated with improved ventilator management. Several clinical trials have shown that a large number of pharmacologic strategies have not been effective in reducing mortality. (Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 2010 Aug;23(4):243-52. doi: 10.1089/jamp.2009.0775. PMID: 20073554; PMCID: PMC3133560.)
Approach of Enlitisa to ALI
Enlitisa is currently developing a novel broad-spectrum anti-inflammatory and anti-fibrotic drug （UP-818）with intended use for treating acute lung injury and IPF.
We have conducted animal experiments using LPS induced acute lung injury in rats. UP-818 could significantly reduce the total leukocytes and neutrophils in lung lavage fluid. Its efficacy was equivalent to that of dexamethasone. The total protein content in the lavage was also significantly reduced in UP-818 treated groups. It indicated that UP-818 could reduce the damage of epithelia barrier in lung.
Severe Oral Mucositis（SOM）
What is SOM ?
Radiotherapy-Induced Oral Mucositis is an acute inflammatory injury of the oral mucosa caused by ionizing radiation disrupting the normal renewal of epithelial cells during radiotherapy for head and neck cancers. It manifests as mucosal erythema, erosion, ulcers, and fibrosis, accompanied by localized pain, dry mouth, dysphagia, and taste dysfunction; severe cases may lead to systemic symptoms like fever and fatigue, with increased infection risks. Over 90% of head and neck radiotherapy patients develop RIOM, with severity linked to radiation dose, treatment fields, and concurrent chemotherapy. RIOM significantly impairs quality of life and may result in malnutrition or treatment interruption.
Project Introduction and Innovative Advantages
This drug is a novel structural compound with anti-inflammatory, analgesic, tissue-repair-promoting, and anti-fibrotic properties. Currently, there are no specific therapeutics for the prevention or treatment of radiotherapy-induced mucositis (RIM). Clinical management primarily focuses on symptom relief and complication mitigation, including nutritional support, pain control, and prevention/treatment of secondary infections.
Key advantages include:
（1）Anti-inflammatory efficacy: Effectively inhibits excessive neutrophil aggregation in the lungs, reducing alveolar-capillary barrier damage.
（2）Anti-oxidative stress: Significantly suppresses heat shock protein (HSP) expression, demonstrating robust antioxidative effects.
（3）Tissue repair modulation: Promotes wound healing by modulating the interaction between TGFβ and its receptors.
In an acetic acid-induced oral mucositis rat model, the drug exhibited exceptional analgesic effects comparable to topically applied lidocaine. These findings suggest its potential for comprehensive prevention of RIM, attenuation of mucosal injury severity, pain relief, and accelerated tissue repair. Currently in clinical trials, this project represents a breakthrough that could elevate China's R&D capabilities in this field, with profound societal implications.
Chronic Obstructive Pulmonary Disease（COPD）
What is COPD ?
Chronic Obstructive Pulmonary Disease (COPD) is a chronic respiratory disorder characterized by persistent and irreversible airflow limitation, primarily caused by abnormal inflammatory responses to long-term exposure to noxious particles (e.g., tobacco smoke, air pollutants). Its pathological basis includes chronic bronchitis (airway mucus hypersecretion, wall thickening) and emphysema (alveolar destruction), clinically manifesting as progressive dyspnea, chronic cough, sputum production, and reduced exercise tolerance. Acute exacerbations, often triggered by infections, worsen symptoms with wheezing and fever. Diagnosis relies on spirometry (e.g., FEV1/FVC < 0.70) and imaging. Treatment focuses on bronchodilators, corticosteroids, oxygen therapy, and pulmonary rehabilitation, while smoking cessation is critical to slow progression. As the third leading cause of death globally, COPD severely impacts quality of life and is strongly linked to complications like cardiovascular diseases and lung cancer.
TISA-818: Extend to chronic obstructive pulmonary disease, COPD
Unmet Clinical Needs: Key limitations exist in current treatment approaches:
- Limited anti-inflammatory options beyond ICS, which show poor efficacy against neutrophil-dominant inflammation.
- Weak anti-inflammatory effects of oral PDE4 inhibitors with suboptimal clinical outcomes.
- Lack of disease-modifying effects - even the PDE3/4 dual inhibitor ensifentrine, while building upon PDE4 inhibition with additional PDE3 targeting, shows no mechanistic evidence of inhibiting airway remodeling.
Therapeutic breakthrough requirement: A drug combining both bronchodilator and anti-inflammatory effects represents the key solution to address these clinical needs. TISA-818 gets this potential possibility.
TISA-818, an inhaled therapeutic candidate for COPD, acts via multiple pathways to provide bronchodilation, reduce inflammation, enhance lung function, and mitigate airflow obstruction.
chronic diabetic foot ulcers (DFUs)
What is DFU?
Diabetic Foot ulceration (DFU) is a major complication of diabetes mellitus and is associated with high levels of morbidity and mortality, as well as significant financial costs. The lifetime incidence rate of diabetic foot ulceration is 19-34%, with a yearly incidence rate of 2% (4). After successful healing the recurrence rates of diabetic foot ulcers (DFU) are 40% within a year and 65% within 3 years. Therefore, the prevention of DFU is paramount to reduce the risks to the patient and the resultant economic burden to society.
Key risk factors
Diabetic Foot ulceration (DFU) is a major complication of diabetes mellitus and is associated with high levels of morbidity and mortality, as well as significant financial costs. The lifetime incidence rate of diabetic foot ulceration is 19-34%, with a yearly incidence rate of 2% (4). After successful healing the recurrence rates of diabetic foot ulcers (DFU) are 40% within a year and 65% within 3 years. Therefore, the prevention of DFU is paramount to reduce the risks to the patient and the resultant economic burden to society.
Key risk factors
Not all patients with diabetes are at-risk for ulceration. Key risk factors include: a loss of protective sensation (LOPS), peripheral artery disease (PAD) and foot deformity. Additionally, a history of foot ulceration and any level of lower extremity amputation further increase risk for ulceration.
Pathogenesis
Diabetic foot ulcers are pathologically complex mostly because the ulceration is undermined by the existence of multiple risk factors, such as poor patient adherence to treatment, severity of the ulcer, ulcer location and duration, vascular condition, control of glycated hemoglobin (HbA1c) levels, smoking habits, and kidney dysfunction.
Principles of ulcer treatment
1.Pressure offloading and ulcer protection
2.Restoration of tissue perfusion
3.Treatment of infection
4.Metabolic control and treatment of co-morbidities
5.Local ulcer care
6.Education for patient and relatives
For more information，visit Home - IWGDF Guidelines
Unmet clinical needs
Approximately 80% of lower limb amputations are preceded by chronic diabetic foot ulcers (DFUs), resulting in a heavy burden of medical care and expenditure. The current treatment for DFUs in clinical practice focuses primarily on local wound care, including debridement, off-loading, infection control, and maintaining a moist environment with dressings, whereas adjunctive therapies such as the use of growth factors, tissue engineering products, hyperbaric oxygen, and negative pressure wound therapies are applied if the DFUs worsen. Although current treatments featuring tissue repair or the use of anti-inflammatory agents might help in closing or controlling the progression of DFUs, most of these treatments are not well supported by clinical evidence or are not recommended for routine care by the International Working Group on the Diabetic Foot. In addition, the annual increase in amputations also suggests that treatment improvement is needed. These factors impose a significant clinical need for novel and effective interventions to tackle this life-debilitating and life-threatening disease. Refer to DOI: 10.1001/jamanetworkopen.2021.22607
Our Strategy
UP-611-NA sodium is a powerful selective cysteinyl leukotriene receptor-1 (CysLT1) receptor antagonist, which can competitively inhibit the interaction between leukotriene D4 (LTD4) and CysLT1, reduce the expression of vascular endothelial growth factor, thereby regulating vascular permeability, inhibiting the aggregation of inflammatory cells and degranulation of mast cells, and down regulating the expression of inflammatory factors. UP-611-NA sodium can also promote the proliferation of vascular endothelial cells, accelerate the formation and maturation of new blood vessels, promote the deposition of extracellular matrix and the growth of granulation tissue, accelerate wound healing, and ultimately achieve the effects of anti-inflammatory, anti-edema, repair tissue damage, and promote wound healing.
The UP-611-NA sodium gel, which was first developed by our company, is used as a local drug delivery agent for diabetic foot ulcer patients. The local drug exposure is much higher than the system exposure, which will effectively promote the healing of ulcer wounds and reduce the safety risk of system administration. It is estimated that UP-611-NA sodium gel has good safety and effectiveness in diabetic foot ulcer patients, and may become an effective drug for treating diabetic foot ulcer in the future. It will provide a new treatment option for diabetic foot ulcer patients.
Burns wound
What is it?
A burn wound, the most common type of wound, is an injury to the flesh caused by heat, chemicals, friction, or electricity.
Burns are classified according to the depth of the burn wound and extent of affected burned body surface area. In deep second degree and higher grade burns the epidermis and skin appendages are destroyed so that healing can only take place with severe scarring. In these cases, necrectomy and skin grafting are recommended. Extensive and deep burns should be treated at specialized centers and more precise criteria for this are laid down in the guidelines. Emergency room treatment protocols have improved the quality of admission and treatment. Concomitant injuries need to be diagnosed and treated early. In addition to the damage to the skin the subsequent burn disease with massive accumulation of interstitial fluid determines the prognosis. The circulation is stabilized and the risk of infection is controlled by intensive fluid management, early necrectomy and split thickness skin grafting. Modern sedation and ventilation management allows a more rapid convalescence.
Epidemiology
Globally in 2004, the incidence of burns severe enough to require medical attention was nearly 11 million people and ranked fourth in all injuries, higher than the combined incidence of tuberculosis and HIV infections. Fortunately, although burns and fires account for over 300,000 deaths each year throughout the world, the vast
majority of burns are not fatal[1]. Risk factors for burns include those related to socioeconomic status, race and ethnicity, age, and gender, as well as those factors pertaining to region of residence, intent of injury, and comorbidity.
[1]Michael D Peck. Epidemiology of burns throughout the world. Part I: Distribution and risk factors. Burns, 2011 Nov;37(7):1087-100.
Standard Care Considerations for Burns
Standard care for serious burns includes careful attention to the following parameters:
• Hemodynamic resuscitation
• Management of co-morbidities
• Timely burn debridement and excision
• Wound closure
• Management of wound infection
• Pain control
• Nutritional support
• Measures to inhibit excessive scar formation
• Rehabilitation, including passive range of motion when burns overlie joints
Unmet clinical needs
The treatment of burn wound plays critical role in the whole procedure of burn therapy. Complicated pathophysiology status in the patients after burn are mainly caused by the burn wound and cure with the wound closure. Proper wound treatment is vital to the success of burn therapy, so clinical has been concerned. The main purpose of burn wound treatment is to protect and clean the wound, reduce infection, close the wound as soon as possible, and maximize the recovery of function and appearance.
According to the current wound treatment, no ideal topical agent - one that would adapt to all wounds at all times—has yet been identified.
Burn injuries are often slow to heal, leading to lengthy hospitalization time, increased health care costs, and lower quality of life, especially in deep second degree and higher grade burns is likely to leave hypertrophic scar or cicatricial keloid/ contracture, which affect the cosmetic aspects of quality of healing (cosmesis) or impair functional abilities.
Our Strategy
Montelukast sodium is a powerful selective cysteinyl leukotriene receptor-1 (CysLT1) receptor antagonist, which can competitively inhibit the interaction between leukotriene D4 (LTD4) and CysLT1, reduce the expression of vascular endothelial growth factor, thereby regulating vascular permeability, inhibiting the aggregation of inflammatory cells and degranulation of mast cells, and down regulating the expression of inflammatory factors. Montelukast sodium can also promote the proliferation of vascular endothelial cells, accelerate the formation and maturation of new blood vessels, promote the deposition of extracellular matrix and the growth of granulation tissue, accelerate wound healing, and ultimately achieve the effects of anti-inflammatory, anti-edema, repair tissue damage, and promote wound healing.
The montelukast sodium gel, which was first developed by our company, was used for the first time in burn wounds as a topical product. It is expected to alleviate edema, pain, bleeding and promote wound healing by inhibiting inflammatory cell infiltration, reducing capillary permeability, and inhibiting oxidative stress, which eventually accelerate wound closure, inhibit scar formation, and facilitate function and appearance recovery.
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