Focus

Blade’s focus is identifying targets that are critical to the fibrotic process and advancing them into drug discovery and development.

Uncontrolled fibrosis is a driving factor in several debilitating disease states. Progressive fibrosis leads to organ dysfunction and failure, and potentially death. In the U.S., many millions of Americans are afflicted with a fibrosis-related disease, which may affect organs including the kidney, liver, lungs, skin, and eye.

The underlying pathophysiology of fibrosis is complex and incompletely understood. As a result, there is a pressing need to identify novel targets that are critical to the fibrotic process. Key diseases characterized by uncontrolled fibrosis include diabetic nephropathy (DN), idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), systemic sclerosis (SSc), and corneal fibrosis.

Our foundational programs are based on cutting edge research licensed from Hal Dietz, M.D. and his team at Johns Hopkins University. We are applying these meaningful insights to discover disease-modifying drugs that broadly modulate fibrotic disease, and may ultimately be of benefit to and change outcomes for millions of patients.

Non-Alcoholic Steatohepatitis (NASH)

It is estimated that up to a third of the US and European populations have a condition called non-alcoholic fatty liver disease (NAFLD), a disease 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, or approximately 10 – 20 M individuals in the US (Schattenburg, 2011). Subjects experiencing chronic liver inflammation often develop liver fibrosis, with eventual risks of cirrhosis, hepatocellular carcinoma, and liver failure. Furthermore, NASH is predicted to become the leading cause of liver transplantation by 2020 (Wree, 2013). Despite these epidemic trends, there are no therapies available to prevent or treat liver fibrosis.

Idiopathic Pulmonary Fibrosis (IPF)

IPF is a rare, yet debilitating disease that is poorly understood. It is characterized by the onset of interstitial pneumonia, chronic progressive lung fibrosis, and ultimately lung failure and most commonly afflicts individuals over 50 years old. Unfortunately, its origin is unknown and doctors are not yet able to identify patients that are at greatest risk of developing IPF. 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. While our own team was instrumental in the pioneering work at InterMune that led to the approval of pirfenidone to treat IPF, there remains a pressing need for effective therapies for this serious and as-of-yet incurable disease.

Diabetic Nephropathy (DN)

Diabetic nephropathy, or diabetic kidney disease, is a progressive disorder associated high morbidity and mortality and is estimated to afflict approximately 20 – 30% of diabetes patients (Schlipak, 2011; Duran-Salgado, 2014). Chronic levels of high blood sugar, often associated with both Type 1 and Type 2 diabetes, can lead to damage of renal glomeruli, or capillary networks within the kidneys. Chronic inflammation within renal tissue can induce scarring and glomerulosclerosis and ultimately renal failure. Strategies to delay disease progression and prolong kidney function typically entail glycemic control and management of hypertension, but no curative therapies exist. Given that diabetic nephropathy remains the leading cause of end-stage renal disease, itself afflicting approximately 700 K individuals in the US (US Renal Data System), 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 progress to develop fibrosis within additional organs, 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 efforts and 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 the intra- and extrahepatic bile ducts. Over time, patients develop liver fibrosis, cirrhosis, and ultimately 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, pruritus and fatigue), but there are no FDA-approved agents in PSC and no therapies have been consistently proven to slow disease progression. An anti-fibrotic that effectively delays disease progression would be of tremendous benefit to individuals afflicted 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/
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.