Innovation

Blade is developing innovative approaches to understand the underlying disease and treat fibrosis.

Uncontrolled, progressive fibrosis is a driving factor in or hallmark of many debilitating disease states, afflicting millions of individuals in the United States and worldwide. Fibrosis-related diseases can affect organs including the kidney, liver, lungs, skin, and eye, leading to organ dysfunction and failure, and potentially death.

While the underlying pathophysiology of fibrosis is complex, research continues to enhance our understanding of this disease process. Key components of one of the primary biological pathway are known, as represented below; however, there is a pressing need to identify and develop new therapies against additional novel targets and pathways.

Blade Therapeutics’ foundational programs are based on cutting edge research licensed from Hal Dietz, M.D., and his team at Johns Hopkins University. We are leveraging insights from this research to discover new therapeutic approaches that can broadly modulate fibrosis, and thereby contribute to diverse diseases.

FIBROSIS-RELATED DISEASES

Diseases characterized by uncontrolled, progressive fibrosis include diabetic nephropathy (DN), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and corneal fibrosis.

Non-Alcoholic Steatohepatitis (NASH)

It is estimated that up to one-third of the populations in the US and Europe have a condition termed non-alcoholic fatty liver disease (NAFLD), which is characterized by steatosis, or excessive accumulation of fat in the liver (Wree, 2013; Blachier, 2013). Many of these individuals, for reasons not totally understood, subsequently develop liver inflammation, or steatohepatitis. This condition, called non-alcoholic steatohepatitis, or NASH, develops in roughly 10 - 20% of NAFLD patients, accounting for approximately 10 - 20 million individuals in the US (Schattenburg, 2011). Individuals experiencing chronic liver inflammation often develop liver fibrosis, with eventual risks of cirrhosis, hepatocellular carcinoma, and liver failure. Based on current projections, NASH is predicted to become the leading cause of liver transplantation by 2020 (Wree, 2013). Unfortunately, there are no therapies available to prevent or treat liver fibrosis

Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a rare, highly debilitating, and poorly understood disease. Most commonly affecting individuals over 50 years old, IPF is characterized by interstitial pneumonia and chronic progressive lung fibrosis. Over the course of the disease, healthy lung tissue is replaced with fibrotic tissue, causing a continuous decline in lung function. Disease progression is unpredictable and is often rapid, with many patients progressing to lung failure and potentially death within 2 - 3 years. Unfortunately, the disease’s early genesis is unknown, and there are no tests to identify patients that are at greatest risk of developing IPF. Members of Blade’s own team were instrumental in the pioneering work at InterMune that led to the approval of pirfenidone to treat IPF; however, there remains a pressing need for effective therapies for this serious and as-of-yet incurable disease.

Diabetic Nephropathy (DN)

Diabetic nephropathy (DN), or diabetic kidney disease, is a progressive disorder associated high morbidity and mortality. It is estimated to afflict approximately 20 - 30% of diabetes patients, accounting for approximately 700,000 individuals in the US (Schlipak, 2011; Duran-Salgado, 2014; US Renal Data System). Chronic high blood sugar levels, which are often associated with both Type 1 and Type 2 diabetes, can lead to damage of renal glomeruli, the capillary networks within the kidneys. Chronic inflammation within renal tissue can induce scarring and glomerulosclerosis and ultimately renal failure. In fact, diabetic nephropathy remains the leading cause of end-stage renal disease (ESRD). Strategies to delay disease progression and extend kidney function typically entail glycemic control and management of hypertension, but no curative therapies for DN exist, and there is a clear need for disease-modifying therapies. Furthermore, with increasing rates of diabetes and CDC predictions of 1 in 3 Americans having diabetes by 2050 (Stanton, 2016), this need will continue to grow.

Systemic Sclerosis (SSc)

Systemic sclerosis (SSc), or scleroderma (which translates to hardening of the skin), is a rare, chronic autoimmune disease characterized by fibrotic and vascular abnormalities. Most individuals with SSc exhibit some degree of skin fibrosis, although many patients also progress to develop fibrosis within internal organs, potentially leading to severe complications and organ failure. Disease progression is highly variable in SSc, with some patients remaining stable for years and others developing severe complications relatively rapidly. The underlying biology in SSc is complicated and poorly understood, which has hampered efforts to develop effective and curative therapies. Disease management is predominantly through patient-specific symptomatic interventions and systemic immunosuppression, neither of which are curative. An effective anti-fibrotic therapy could prolong organ function and offer tremendous benefit for SSc patients.

Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis (PSC) is a rare, chronic, progressive disease characterized by inflammation and subsequent destruction of intra- and extrahepatic bile ducts. Over time, patients develop liver fibrosis and cirrhosis, which ultimately can lead to liver failure. PSC is also associated with increased rates of colorectal, hepatobiliary, and gallbladder cancer (Kumar, 2016). Epidemiology studies indicate that there may be up to 50,000 individuals afflicted with PSC in the US (Ali, 2015), although prevalence rates are generally presumed to be underestimated due to the difficulty of correctly diagnosing asymptomatic patients (Eksteen, 2014). Disease management primarily entails symptomatic treatment (for example, of pruritus and fatigue), but there are no FDA-approved agents to treat PSC, and no therapies have been shown to consistently slow disease progression. An anti-fibrotic agent that effectively delays disease progression would be of tremendous benefit to individuals with PSC.

REFERENCES

Wree et al. 2013. Nat. Rev. Gastroenterol. Hepatol. 10: 627–636.
Blachier et al. 2012. J. Hepatol. 58: 593-608.
Schattenburg et al. 2011. Curr Opin Lipidol. 22:479-488.
Schlipak. 2011. Am Family Physician. 83(6):739-740.
Duran-Salgado et al. 2014. World J Diabetes. 5(3):393-398.
US Renal Data System: https://www.usrds.org/
Stanton, 2016. Am J Kidney Dis. 63(2)(suppl 2):S3-S21
Kumar et al., 2016. Clin Med Insights Gastroenterol. 9:25-29.
Ali et al., 2015. Intractable Rare Dis Res. 4(1):1-6.
Eksteen, 2014. Br Med Bull. 110(1):89-98.