Clinical Trial Landscape in NASH This recent publication by leading KOL’s is a good summary of just about everything one needs to know regarding NASH drug developments and the challenges. It is worth mentioning there is only few phase3 trials and those drugs if approved most likely will not be effective for all NASH patients. As a result combo therapies will ultimately will be the optimal treatment for the condition ideally a drug “with significant metabolic effect”, like Tesamorelin and its metabolic benefits. Another issue with current trials are exclusion of “patients with
multiple chronic conditions or elderly population” as we know HIV patients are also excluded from current trials resulting in label restrictions of these drugs among others also PLWH, not only because of lack of proven efficacy but also safety concerns (more about it below)as a result of drug to drug interactions between to be approved NASH drugs and antivirals. Again THTX’s NASH protocol does include HIV patients who have higher prevalence of NASH compared to general population. Another important factor mentioned was concerns about safety and tolerability of the NASH drug’s candidates and potential “drug-induced liver injury” due to the fact that fluctuation of liver enzymes are common among NASH patients. Tesamorelin has been prescribed to tens of thousands HIV patients for years safely with no interactions with antivirals, no liver toxicity generally well tolerated with very few side effects none of which are serious. In summary some of the mentioned NASH drug development’s challenges will not apply to Tesamorelin which also be an ideal candidate to be used with other drugs if and when approved.
“Considering the complexity of NASH pathophysiology, it is likely that a single drug will not be potent enough to reverse the disease, and combination therapies may be needed. The ideal combination would target multiple steps on the pathogenesis, starting with energy balance to fibrogenesis and should include drugs with significant metabolic effects in addition to liver directed therapy.
As a mitigation, the FDA requires and encourages analysis of effectiveness and safety data in demographic and other specific subgroups (elderly, chronic kidney disease, and others). Ultimately, this issue of representation leads to restriction of drug labels, which may lead to restriction of NASH treatment, leaving apart a non-negligible portion of the population suffering from NASH. An important additional challenge of drug development also is the assessment of drug safety and tolerability to ensure protection of the population from rare and severe adverse reactions. Drug-induced liver injury (DILI) has been a major concern in drug development for decades, sometimes even resulting in withdrawal or halt of a marketed drug in candidate-drug development. Despite several initiatives and tools to assess the potential liver toxicity, this safety assessment, has limitations especially in the NAFLD/NASH population in which fluctuation of liver enzymes is common.”