R & D

Idiopathic Pulmonary Fibrosis （IPF）

What is IPF. (I think that it should be much shorter than the original text)

Idiopathic pulmonary fibrosis (IPF) is the most common type of pulmonary fibrosis. It is a disease that causes scarring (fibrosis) of the lungs. As the scarring progresses, transfer of oxygen into the bloodstream is increasingly impaired, leading to irreversible loss of lung function as well as high morbidity and mortality rates.. Lung damage from IPF is irreversible and progressive, meaning it gets worse over time.

Patients with IPF generally have a poor prognosis with a mean survival between two to five years, and there is a high unmet medical need for safe and well-tolerated medicines that can halt, and potentially reverse, its progression

IPF is designated as an orphan disease in the U.S., with U.S. prevalence and incidence of IPF estimated to be ~115,000 and an incidence of 30,000-40,000 new cases per year , respectively. Incidence and mortality are on the rise, and prevalence is expected to increase with the aging population.

Our approach

Enlitisa is currently developing a novel broad-spectrum anti-inflammatory and antifibrotic drug （TISA-818）with intended use for treating acute lung injury and IPF.

We have conducted animal experiments using bleomycin induced lung fibrosis in rats. TISA-818 significantly improved the survival rate of the animals. The hydroxyproline was reduced in UP-818 treated lung tissues compared with that in model group. The lung tissues were sent for Transcriptomic and proteomic analysis of the lung tissues showed that αSMA, MMP2, Collagen, TGFβ1R2, integrin, fibronectin and several other well-known fibrosis related substances were down-regulated both in mRNA and protein levels, which were also confirmed by immunohistochemical study by using the lung tissue sections of IPF rats.

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.)

R & D pipeline

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. 

Radiation Proctitis (RP)

What is RP ?

Radiotherapy plays an important role in the comprehensive treatment of patients with pelvic malignant tumors, but it may lead to radiation proctitis (RP) in some patients, which affects their physical health and quality of life. RRI refers to the radiation physical damage of rectum caused by radiotherapy of pelvic malignant tumors (cervical cancer, endometrial cancer, prostate cancer, bladder cancer, rectal cancer, anal cancer, etc.). RRI can be classified into acute radiation proctitis and chronic radiation proctitis, which are usually classified by 3 months after the start of radiotherapy.

The inflammatory lesion of RP is different from the general inflammatory reaction. The inflammatory cell infiltration of intestinal mucosa is mainly neutrophils and eosinophils in the early stage, and lymphocytes and plasma cells in the late stage. The pathogenesis of RRI is relatively complex. Radiotherapy ionizing radiation will produce a large number of free radicals in irradiated tissues, leading to radiation and oxidative stress damage:

(1) directly damage DNA and cytoskeleton, leading to cell death, barrier destruction, and bacterial population displacement.

(2) The lipid (unsaturated fatty acid) on the cell membrane is peroxidized and degraded to stimulate inflammatory reaction.

(3) Vascular endothelium is damaged, permeability is increased, coagulation system is activated, thrombin activity is enhanced, chemotaxis is produced, and inflammatory reaction is induced.

(4) In the later stage, the stem cells lost, the healing was insufficient, ischemia and fibrosis occurred.

Current treatment

Acute radiation proctitis is usually self-limiting with the discontinuation of the radiation therapy. Supportive medical management is usually the only treatment required and includes hydration, antidiarrheals, and possibly steroid or 5-aminosalicylate enemas. The management of chronic proctitis can be divided into noninvasive treatments (anti-inflammatory agents, sucralfate, short-chain fatty acids, hyperbaric, antioxidants) and invasive treatments (ablation and surgery).

Currently, there is no medicine approved for treating radiation proctitis.

Approach of Enlitisa to RP

UP-611-NA sodium is reformulated as a sterile gel with new indications. It is developed by Enlitisa and the rights of development and commercialization in China has been licensed to Shanghai Pharmaceutical company (SHP). Currently, The Phase I clinical trial conducted by SHP was completed. The phase II studies will start at the end of 2022 in patients with hemorrhoid surgery and acute radiation proctitis, respectively.

Based on the following mechanisms of action of UP-611-NA sodium and the results of non clinical studies of UP-611-NA sodium gel, UP-611-NA sodium gel is intended to be used for the treatment of RP: (1) Antioxidation: inhibit oxidative stress, remove pathogenic factors, and reduce oxidative stress damage. (2) Anti inflammation: Different from the anti inflammation effect of 5-aminosalicylic acid (5-ASA), UP-611-NA sodium plays a role in the downstream of arachidonic acid, does not interfere with the synthesis of prostaglandins, only antagonizes the leukotriene receptor, inhibits the leukotriene mediated physiological effect, and inhibits the cascade inflammatory reaction caused by peroxidation. (3) Repair promotion: leukotriene is a negative feedback regulator of mesenchymal stem cell differentiation. UP-611-NA sodium inhibits the effect of leukotriene, induces mesenchymal stem cell differentiation, and promotes damage repair.

Surgical Wound of Anorectal Surgery

 Background

Hemorrhoids are the most common anorectal surgical disease, which can affect the physical and mental health and quality of life of patients to varying degrees. Surgical treatment is an effective means of treatment, but repeated pain after surgery not only leads to irritability and insomnia, but also greatly increases the incidence of perianal edema, urinary retention and other complications.

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, was used for the first time in hemorrhoid surgery wounds through local administration of anal canal. It is expected to alleviate postoperative edema, pain and bleeding and promote wound healing by inhibiting inflammatory cell infiltration, reducing capillary permeability, and inhibiting oxidative stress.

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.