NASH – non-alcoholic steatohepatitis – is an increasingly prevalent liver disease. It is characterized by a build-up of fat in the liver, plus cellular damage, often including inflammation and fibrosis. NASH typically has few noticeable symptoms until it becomes very serious. That can mean liver cancer, and/or liver failure. NASH is the fastest growing cause of liver transplant in the US.
The condition is tightly associated with metabolic disease and obesity, and already affects about one in eight of the adult population. No treatment for NASH exists – yet. But with this ‘disease of affluence’ expected to spread across more than five times as many people by 2030, representing a $20-30 billion market, drug developers are scrambling to find an answer.
It has not been an easy quest. Like its co-morbidities, obesity and diabetes, this is a complex, multi-factorial disease that likely requires an equally multi-pronged treatment approach – and behavioral change. UK guidelines recommend life-style adjustments (e.g. healthier eating and more physical activity) in the first-line setting, though in the US early pharmacological intervention is preferred. Currently, diabetes drugs such as metformin are often used to treat NASH.
Gilead – which made billions from its treatments for another kind of liver disease, Hepatitis C – saw its Phase III trial of NASH hopeful selonsertib fail earlier in 2019. But it is not giving up. In April, it joined forces with diabetes leader Novo Nordisk to take into trials a three-way combination, using two of Gilead’s other NASH development candidates plus Novo’s oral GLP-1 agonist, semaglutide. Semaglutide (branded Ozempic) has already expanded its reach from diabetes into obesity, and is in the clinic as a NASH monotherapy. The two Gilead compounds have also already, as a duo, shown promise in improving steatosis and markers of liver fibrosis.
There are many other NASH players. Madrigal Pharmaceuticals in March 2019 began a Phase 3 trial of its once daily, oral thyroid hormone receptor agonist, resmetirom. Israel’s Galmed Pharmaceuticals is planning Phase 3 trials of its fatty acid bile acid conjugate, Aramchol. This compound works by altering how fats – lipids – are metabolized in the liver. Aramchol showed beneficial effects on NASH markers, including fibrosis, in a Phase 2b study. The compound has Fast Track designation from FDA.
M&A activity in NASH has been plentiful in recent years. In 2016, Allergan acquired Tobira Therapeutics for $1.7 billion, and Gilead paid $400 million up-front (and may pay twice that in milestones) for Nimbus Apollo. (The year before, it bought a $470 million NASH program from Phenex).
Johnson & Johnson, Novartis (which bought emricasan from Conatus in December 2016) and Pfizer are among the Big Pharmas who are active in NASH. Some big players are teaming up to crack this challenge: Pfizer and Novartis joined forces in October 2018 to perform a combination study involving tropifexor (a Novartis asset) with one or more Pfizer compounds. AbbVie and Takeda are also in the mix, having acquired Allergan and Shire, respectively – each with NASH interests.
Now it is all about clinical results, as sponsors determine whether they are any closer to addressing what Galmed calls an “emerging world crisis”. With several Phase 3 NASH trials starting or reading out, developers will soon have more clues as to the most promising treatment strategies, if not a treatment itself.
Ultimately, though, the solution to NASH – like its sister conditions, obesity and diabetes – is healthier, more active lifestyles.