Key opinion leaders (KOL) interviewed by GlobalData have indicated that a one-drug-treats-all strategy may not be effective to treat a multifactorial disease such as non-alcoholic steatohepatitis (NASH). Drug combinations with complementary mechanisms of action (MOA) would likely be the best approach.
GlobalData believes that the ideal NASH regimen should be a combination of three types of drugs:
- A drug targeting the fat deposition and the metabolic syndrome
- An anti-inflammatory drug
- An anti-fibrotic drug
Most of the drugs currently in late-stage development (Phase IIb and Phase III) for NASH can be grouped into these different categories (see Figure 1 below).
Major Drug Targets and Late-Stage Pipeline Candidates for NASH Treatment
The rationale for this treatment paradigm stems from the multiple hits pathway of NASH pathogenesis. According to this theory, the first hit is the excessive (and reversible) build-up of fat in the liver, which leads to hyperinsulinemia. This leaves the patient susceptible to a series of second hits, which increase oxidative stress in the liver and result in inflammation.
A third hit has also been proposed, where the liver is unable to reconstitute normal tissue function by replacing hepatocytes that die as a result of the inflammation. This significantly reduces liver function.
Given this reasoning, a triple combination of drugs to target all three pathophysiological mechanisms would be an ideal strategy to combat all aspects of the disease and improve clinical outcomes.
In terms of the treatment duration, GlobalData believes that although all three drugs could be administered simultaneously, the anti-fibrotic agent would likely have to be used for a shorter term in comparison to the other two drug categories. Since fibrosis is an essential component of wound repair, any anti-fibrotic therapy for NASH would have to demonstrate minimal off-target effects.