Nonalcholic steatohepatitis (NASH) is a common, hard to diagnose liver disease, characterised by the presence of steatosis, or fatty liver, as well as liver inflammation and damage.
Despite the fact that if NASH is left untreated it can lead to liver fibrosis, in some cases developing to liver cirrhosis, and can in some cases progress to hepatocellular carcinoma there are no approved therapies for NASH and current first line of treatment is lifestyle modifications including diet and exercise followed by off-label generic drugs, such as Vitamin E, pioglitazone and pentoxifylline. There is, however, no clinical proof that these options work.
Seizing the opportunities in the NASH 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鈥檚 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 , Gilead and , to smaller companies like Genfit and Viking.
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By GlobalData鈥淭he expected arrival of the first NASH-targeting therapies鈥� combined with 鈥渢he large number of patients with NASH… [and] increased awareness of NASH by patients and physicians鈥� 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 鈥済ain familiarity with physicians, patients, and payers.鈥�
Who is the front runner in the race to market?
The general consensus is that Intercept Pharmaceuticals鈥� Ocalavia (obeticholic acid) is the front runner in the race to market. This is because 鈥渋t is furthest ahead in terms of clinical development鈥� and its 鈥淯SP is its strong efficacy and oral formulation,鈥� 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鈥檚 (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 鈥淸the] higher dose of Ocalavia shows higher efficacy, however, also shows tolerability issues,鈥� 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鈥檚 elafibranor.
However, Dharmarajan did note: 鈥淭he NASH space has a history of late-stage failures, so while Ocalavia鈥檚 prospects look bright at the moment, it鈥檚 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.鈥�
Other drugs seeking to pip Ocalavia to victory
There is still hope for other companies wanting to be the first to launch a NASH drug. Elafibranor was underlined by GlobalData鈥檚 senior director of infectious diseases and respiratory Christopher Pace as Ocalavia鈥檚 main competitor. The drug is currently being evaluated in a pivotal Phase III trial with preliminary data expected in the second half of this year.
Genfit鈥檚 drug has previously been evaluated in Phase II studies, which showed that it was both efficacious and safe. This good safety profile was confirmed when Genfit announced in May this year that a Data Safety Monitoring Board (DSMB) had issued a positive recommendation for the continuation of the Phase III RESOLVE-IT trial; this comes 36 months after the initiation of the study.
Genfit deputy chief medical officer Dr Pascal Birman said: 鈥淭his sixth positive DSMB review continues to support GENFIT鈥檚 development of elafibranor in NASH.
鈥淚n addition, the safety profile gives us further confidence as we explore elafibranor in the clinical setting, specifically for pediatric NASH 鈥� a na茂ve patient population and a trial we expect to begin enrolling shortly.鈥�
Another notable drug is Gilead鈥檚 selonsertib. However, Pace notes its 鈥渓aunch has been pushed back.鈥� This is due to the drug鈥檚 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.
Optimism for companies who fail to win the race
Importantly, failure to win the race to market is 鈥渦nlikely鈥� to lock companies out of the NASH market until the drug loses its patent and can become a generic, according to Dharmarajan.
This is mainly because different companies are focusing on variant patient populations – Intercept鈥檚 Ocalavia and Gilead鈥檚 selonsertib focus on NASH patients with cirrhosis, whereas Genfit鈥檚 elafibranor and Novartis鈥� emricasan are indicated for patients without cirrhosis 鈥� and the drug currently engaged in the race have a variety of different mechanisms of action.
Dharmarajan explains: 鈥淭he 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.鈥�
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 鈥渂etter design [of] clinical trials鈥�. 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.
