Developing drugs for NASH: the race to market

This lack of efficacious treatments leaves a range of unmet needs in the NASH space, most notably developing new treatments for various stages of NASH towards liver cirrhosis.

To add to this, the prevalence of the liver disease across seven major markets - the US, France, Germany, Italy, Spain, the UK and Japan - is already high and is expected to grow significantly over the next few years. Part of the reason for this growth is the condition’s close connection with obesity and related co-morbidities, rates of which are rising in developed countries.

In a recent NASH-specific report, GlobalData epidemiologists predicted an annual growth rate of 0.61% over the next few years and for cases of NASH to increase by more than four million to 65.2 million.

A range of pharmaceutical companies have noticed lucrative opportunities in this market, and consequently have begun to compete in drug R&D and a race to market. Examples range from pharma giants, such as Novartis, Gilead and Novo Nordisk, to smaller companies like Genfit and Viking.

“The expected arrival of the first NASH-targeting therapies” combined with “the large number of patients with NASH... [and] increased awareness of NASH by patients and physicians” means the NASH market size is expected to reach $18bn by 2026, according to GlobalData director of immunology Lakshmi Dharmarajan.

Being the first to market will allow the pharma company to capitalize on this large market earlier than most, which as Dharmarajan points out will allow them to “gain familiarity with physicians, patients, and payers.”

The general consensus is that Intercept Pharmaceuticals’ Ocalavia (obeticholic acid) is the front runner in the race to market. This is because “it is furthest ahead in terms of clinical development” and its “USP is its strong efficacy and oral formulation,” in the words of Dharmarajan.

In April this year, Intercept presented 18 month data from its Phase III REGERNATE study of Ocalavia at the European Association for the Study of the Liver’s (EASL) International Liver Congress in Vienna.

The results showed 23.1% of patients given the higher, 25mg dose of the drug achieved the primary endpoint of at least one stage of fibrosis improvement with no worsening of NASH, compared to 11.9% of the placebo group. For the 10mg dosing group, the endpoint was also met for 17.6% of patients, but this figure was not statistically significant.

Importantly, the latest data also showed that Ocalavia improved other indicators of liver health, such as hepatocellular ballooning and lobular inflammation, as well as reducing core liver biochemistry parameters.

However, there are serious concerns about the safety profile of the drug; including reports of adverse events linked to liver toxicity and a rise in LDL cholesterol and pruritus.

This is especially concerning since “[the] higher dose of Ocalavia shows higher efficacy, however, also shows tolerability issues,” as noted by Dharmarajan. This is a particular issue since it will probably lead to low compliance by patients.

Despite these concerns, in the recent NASH report, GlobalData gave Ocalavia a positive clinical score of approximately 4.4, which was only exceeded by Genfit’s elafibranor.

However, Dharmarajan did note: “The NASH space has a history of late-stage failures, so while Ocalavia’s prospects look bright at the moment, it’s difficult to know how far ahead the company truly is until they receive regulatory approval for NASH and begin accessing patients in real-world settings.”

Genfit deputy chief medical officer Dr Pascal Birman said:“This sixth positive DSMB review continues to support GENFIT’s development of elafibranor in NASH.

“In addition, the safety profile gives us further confidence as we explore elafibranor in the clinical setting, specifically for pediatric NASH – a naïve patient population and a trial we expect to begin enrolling shortly.”

Another notable drug is Gilead’s selonsertib. However, Pace notes its “launch has been pushed back.” This is due to the drug’s failure to meet its 48 week endpoint of at least one stage improvement in liver fibrosis in the Phase III STELLAR-trial.

The study found that 9.3% patients given the 18mg dose of selonsertib 12.1% of 6mg group and 13.2% of the placebo group achieved the endpoint.

Dharmarajan explains: “The NASH space is immature, and the sheer size of the patient population combined with the fact that a game-changing clinical approach has not yet been identified means that it will likely be a market ripe with opportunity for years to come.”

Additionally, there are some advantages of competitors biding their time and observing the winner. Pace sees the main advantage as being able to learn from previous failures, which in turn means “better design [of] clinical trials”. In addition better pricing strategies may emerge from watching how the original drug performs.

Furthermore, he argues it may open up opportunities for developing combination therapies either with internal assets or in deals with other players; the cost and efficacy of which is expected to be better than monotherapies.