NASH: The silent killer

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.

Hepatitis drugs are effective and ever-cheaper. Yet the disease still kills.

There are plenty of good news stories around hepatitis. Effective, and ever-cheaper treatments are available for both hepatitis B (HBV) and C (HCV), two common strains of this viral condition. HCV can be cured almost completely, thanks to the therapy revolution brought about by Gilead’s Sovaldi (sofosbuvir) starting in 2014. The A and B strains of the disease can be prevented with vaccination.  

Sovaldi’s success – the drug sold $10 billion in its first full year on the market – was also a good news story for Gilead’s shareholders. The company pulled in more than $50 billion from its hepatitis franchise between 2014 and 2017. Sovaldi famously cost $1000 per pill, or $84,000 per typical treatment course in the US.

That particular party did not last long: competition forced down prices, while market demand started to reduce as patients were effectively treated. Competition provided much-needed good news for payers, however, clobbered with astronomical bills during 2014 and 2015 but in a strong position to negotiate thereafter. That, in turn, meant more good news for patients, not all of whom had been able to access the cure at its starting price. Competition also brought more convenient, shorter treatment regimens, covering a wider range of virus genotypes. Latecomer AbbVie scooped in a not-unreasonable $3.44 billion in 2018 from HCV drug Mavyret, whose list price is 60% lower than Sovaldi’s was. Those Mavyret sales were worth more than Gilead’s entire HCV franchise that year.

Large price cuts for HCV medicines in the Western world have come alongside lower HBV treatment costs, including through generic versions of the antivirals entecavir and tenofovir, according to the World Health Organization.

Yet, despite this, 300 million people across the world are still living with hepatitis, many of them in low and middle income countries, says the World Hepatitis Alliance. Hepatitis can trigger acute and chronic infections and, in some cases, liver cirrhosis and even a need for transplant. But symptoms do not always appear, especially in the early stages. About half of people suffering with HCV don’t know they have it.

The remaining challenges are awareness and diagnosis. Don’t rely too heavily on pharmaceutical companies for that – most are losing interest in what is, for most, a declining franchise. Gilead, struggling to fill the gap left by its once-booming HCV franchise, is moving into a very crowded, and challenging hematology space, and seeking to address other kinds of liver conditions such as non-alcoholic steatohepatitis (NASH – another crowding space). Johnson & Johnson and Merck are among those to have dis-continued HCV pipeline regimens. And Mavyret won’t plug the $20 billion hole that AbbVie will face when Humira goes generic in 2023, either – hence AbbVie’s $63 billion offer to buy Allergan.

Access to adequate testing facilities and affordable diagnostic tools is the main barrier to eliminating viral hepatitis by 2030 – a goal which all countries signed up to, but which only a dozen countries are currently on track to achieve, according to the World Hepatitis Alliance.  Sovaldi brought about a treatment revolution in HCV. Another revolution is required to ensure all those who need that treatment actually receive it.