In addition to the long-term liver damage caused by PSC, patients with the disease experience many near-term symptoms and side effects. These include fatigue, jaundice (or a yellowing of the skin or whites of the eyes), abdominal pain, depression, severe itching (also known as pruritus) and poor liver function. Patients also experience sudden ‘cholangitis attacks,’ which are a type of infection caused by bile duct blockages that require urgent medical attention and sometimes hospitalization.
A Rare Disease with Serious Unmet Need
Primary sclerosing cholangitis, or PSC, is a rare disease that irreparably damages the bile ducts, leading to bile acid dysregulation, which ultimately can result in end-stage liver disease, liver failure and bile duct cancer. Currently, there are no approved therapies for PSC. NGM is advancing aldafermin as a potential treatment to address the root cause of this disease.
1 Similar patient prevalence in the US and EU5; Patient prevalence in PSC, as is common for rare diseases with no approved therapies may be underestimated.
Source: Cooper et al. 2023; De Vries et al. 2018; Horsely-Silve et al 2017; Tabibian et al. 2018
A Progressive, Severe Disease of the Bile Duct and Liver
Bile is a digestive fluid produced by the liver. Its primary job is to help our bodies digest the fats that we eat by breaking them down so they can be absorbed through the digestive tract.
Bile ducts carry bile from the liver to the small intestine. But, in people with PSC, inflammation (known as ‘cholangitis’) leads to fibrosis, or scarring (sclerosing), of the bile duct walls, which in turn obstructs the normal flow of bile. As a result, bile acids build up in the liver, leading to permanent liver damage and scarring.
A progressive, severe disease, people with PSC typically develop end-stage liver disease and liver failure within five to ten years of diagnosis, requiring a liver transplant. PSC patients are also at a significantly increased risk of developing bile duct cancer.
A Spectrum of Near-Term Symptoms and Side Effects
NGM’s Opportunity to Treat PSC: Targeting the Root Cause of Disease
Aldafermin, discovered by NGM scientists through the company’s Biologics Discovery Engine, is the first and only drug candidate engineered to be an analog of the human hormone FGF19, which plays a key role in regulating bile acid levels in the body.
FGF19 impacts two separate receptor complexes, resulting in a novel mechanism of action with both anti-inflammatory and anti-fibrotic effects and a unique opportunity to treat people impacted by PSC.
By addressing bile acid overproduction via the FGFR4/KLB receptor, aldafermin may reduce inflammation associated with PSC, including mitigating pruritus. By simultaneously addressing components of metabolic dysregulation via the FGFR1c/KLB receptor, aldafermin may also improve liver function and health in PSC patients.
Supportive Clinical Data and Development Status
Prior clinical studies with aldafermin, including a completed Phase 2 trial of aldafermin in PSC patients, have demonstrated significant reductions in biomarkers of hepatic injury and fibrosis, as well as bile acid synthesis and serum bile acids, and a reduction in pruritus. Aldafermin has been found to be generally well-tolerated in over 800 subjects to date.
NGM received orphan drug designation from both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency and has agreed with the FDA on a plan to use biomarker (surrogate) endpoints for potential accelerated approval. NGM is currently planning for a registration trial of aldafermin in PSC.