In medicine, the phrase “tipping point” is generally used by epidemiologists to describe the dramatic spread of infectious diseases from a small node of infected people. Think Zika, Dengue fever, or even AIDS.
However, more recently, the concept of an epidemiologic tipping point has broadened to include diseases such as obesity and diabetes, and more recently non-alcoholic steatohepatitis, or NASH—which is highly correlated with both obesity and diabetes.
A growing risk
NASH is now more prevalent than diabetes and much harder to detect before advanced stages. Earlier this year, Newsweek called NASH, “the looming 21st century public health threat,” citing the fact that most of the 25 million people who have NASH don’t know it—and 20% of those people will end up developing stage 4 NASH, or cirrhosis.
Peter Traber, CEO and chief medical officer of Galectin Therapeutics, has watched as the prevalence of NASH has exploded. “Fatty liver disease is truly a hidden epidemic and has become a major global problem. The percentage of patients with NASH on the liver transplant waiting list is growing by 15% per year,” he said.
A tipping point in NASH drug development
By 2020, NASH is expected to replace hepatitis C as the main cause of liver transplantation. Hopefully, given the current R&D environment, there could be at least one, and possible several, new drugs available to treat NASH by then. There is currently no cure of treatment.
NASH R&D has become a hotbed for pharma innovation and ambition. Large pharma companies, as well as smaller start-ups and mid-sized biotechs, have created clinical development programs devoted to NASH therapies across a variety of targets. The programs are in different phases of development, but each of the companies hopes to launch a NASH drug within the next five years.
Intercept’s NASH drug obeticholic acid and Genfit’s Elafibranor are both moving into Phase 3 development. Conatus’ caspase protease inhibitor, emricasan, is in Phase 2b.
Other big pharma names are hot on their heels. Shire, which is partnered with Lumena, is moving its LUM002 into phase 2.
Gilead, already dominant in hepatitis C, is in late stage 1 with a drug it acquired in April from Nimbus Pharmaceuticals, while Boehringer Ingelheim is in Phase 1 development with a small-molecule drug that it acquired from Pharmaxis a year ago for $250 million.
Although big pharma has a stake in the development of NASH therapeutics, much of the discovery and early development work is taking place among smaller companies. While some of these companies are forging connections with larger companies, others are independently staking a claim in the NASH market.
Galectin Therapeutics, based in Norcross, GA, is one of those companies. Galactin is developing GR-MD-02, a complex carbohydrate drug that targets galactin-3, which is implicated in the pathogenesis of fatty liver diseases and fibrosis.
According to Traber, “Treating fibrosis has become the holy grail of medicine. The key to addressing NASH is by being able to prevent and reverse fibrosis.”
In preclinical studies, Galectin tested GR-MD-02, which is made from apple pectin, in the liver, lungs, kidneys and heart. The goal was to determine whether treatment with this drug would reduce fibrosis in different organs.
“We found that if you inhibit galactin-3, you prevent and reverse fibrosis,” Traber explained. Considering the fact that 45% of all deaths in the US are related to some type of fibrosis—cirrhosis, heart failure, chronic kidney disease and pulmonary arterial hypertension for example—the implications of this connection are potentially far-reaching.
Fast-track clinical development
Galectin began the investigational new drug process with the FDA at the beginning of 2014 and received fast-track designation that summer. An early phase 1 study in normal volunteers confirmed that GR-MD-02 had no drug-drug interactions, which is critical since patients with NASH usually have hypertension, diabetes or other co-morbidities.
A subsequent placebo-controlled, blinded study in stage 3 NASH patients confirmed safety and demonstrated evidence of pharmacodynamic effect at higher doses.
Galectin has just completed recruitment for a placebo-controlled trial in 30 biopsy-confirmed patients with stage 3 NASH, which is considered advanced disease. Results from this proof-of-efficacy trial are expected in September.
Analysts have predicted the NASH market will be worth $35 billion to $40 billion by 2025, with $25 billion of that coming from the US. While there are numerous contenders developing drugs with an eye towards launching a NASH drug within the next five years, the companies are taking different approaches to treating the condition.
Most NASH drugs in development are orally active and intended to treat early stage NASH before it advances towards cirrhosis. By contrast, Galectin’s drug is intended to treat late-stage NASH. Since GR-MD-02 is a carbohydrate, it is significantly less expensive to manufacture.
“We feel our drug is differentiated because of its ability to reverse fibrosis,” Traber said. “However, a good treatment strategy may end up being a combination therapy approach, similar to other chronic diseases.”
Addressing payers’ concerns
The ability to reverse fibrosis could be viewed positively by payers, including state governments and private payers.
“Someone with NASH fibrosis or cirrhosis is going to have high levels of healthcare utilization and may even need a liver transplant,” Traber said. “If we are able to reverse fibrosis, then the patient’s clock is reset and they end up dying of something else. In the process, a lot of costs are averted.”
There is also the issue of when to treat NASH. “Payers will be concerned about the best timing for intervention in patients with NASH. Among early-stage patients, you don’t know who will progress. Early treatment, along with weight loss and lifestyle changes, could potentially eliminate NASH before it progresses,” Traber said.
But Galectin could have a tough rival in Intercept. Intercept’s obeticholic acid, or Ocaliva, recently won unanimous support from a FDA advisory committee for treatment of primary biliary cirrhosis and the company already has a stage 3 trial underway to support an application for Ocaliva in NASH. A breakthrough designation from the FDA last year could help accelerate its development for this indication.
While the treatment options for NASH are currently sparse, the next five years could see a much more competitive market.