Despite the best efforts of the British weather to hamper proceedings, the 2018 edition of the Global NASH Congress took place in a snowy London on the 27th and 28th of February. With a handful of therapies in Phase III trials, and industry focus on the disease at an all-time high, we are within touching distance of the first approvals of therapies for the treatment of NASH. As previously discussed1, there is no precedent for regulatory bodies reviewing or approving novel NASH therapies, and as such robust guidance for industry is needed to help design late-stage trials in order to provide sufficient data to support these initial filings. With both the EMA and FDA giving fantastic presentations at this year’s event, looking at the importance of various aspects of late-phase NASH trials, there is now increased insight on what regulatory agencies view as important for these pivotal trials.
In the first presentation of Monday’s afternoon session, the EMA’s Dr. Peter Mol discussed the importance of cardiovascular outcomes in the treatment of NASH. With the high CV risk in the NASH population (with patients frequently presenting with comorbid obesity, diabetes, and hypercholesterolemia) and the subsequent high level of background CV events, in addition to progressive nature of the disease likely necessitating long-term drug treatment, positive CV outcomes are something the EMA are keen to see with novel NASH therapies. In the current ongoing Phase III trials, endpoints are typically focused on surrogate measures (something Dr Mol discussed both the positive and negative aspects of – “…there is no surrogate for safety!”), including histological resolution of NASH and fibrosis (with the latter being the only endpoint linked to positive outcomes). Only elafibranor’s Phase III trial has a specific secondary endpoint measuring cardiovascular events (likely driven by Phase II results showing elafibranor’s effects on positive effects on plasma lipids2), with Intercept, Allergan and Gilead only measuring all-cause mortality. With Dr. Mol’s comments in mind, it could be likely that positive CV outcomes, in addition to demonstrated efficacy, becomes a prerequisite for novel NASH therapies in a similar way to that seen with diabetes and obesity treatments.
In the subsequent afternoon session, the FDA’s Dr. Stephanie O. Omokaro discussed the agency’s regulatory considerations for NASH trial endpoints – like Dr. Mol, Dr. Omokaro also highlighted the importance of surrogate endpoints in NASH trials in order for novel therapies to gain accelerated approval and address the major unmet need for lacking pharmacotherapies. Again, she also highlighted the pitfalls of use of surrogate endpoints, especially focused on the risk of detecting undiscovered risks associated with long term drug treatment in a more diverse, real-world population. However, unlike the EMA, the FDA seem more concerned regarding hepatotoxicity of new NASH therapies, rather than the ability to show positive CV outcomes (the FDA’s Robert Temple was quoted during the presentation as saying “Hepatotoxicity has been the most common single adverse effect causing major drug problems, including withdrawals and refusals to approve”). Continuing on a similar theme as many of the other presenters at the congress, Dr. Omokaro also called for validation and standardization of non-invasive biomarkers/diagnostics, in order to facilitate the frequency of endpoint measurement in NASH trials
With no examples on previous NASH approvals to draw from, it’s perhaps unsurprising that there is are some differences between the EMA and FDA’s views on endpoints and outcomes for emerging NASH therapies (although it could be noted that previous examples of this disparity exist e.g. the FDA approving Qsymia for obesity (albeit with a mandated CV outcomes trials), whilst the EMA refusing to approve, due to the lack of evidence on CV safety). Ultimately, any NASH therapy that can show additional positive CV outcomes are likely to be a major hit with physicians, as has been seen with drugs for other metabolic diseases, such as the GLP-1 receptor agonists in obesity and diabetes.
For other highlights of the Global Engage NASH 2018 Congress, take a look at my colleague Tim Blackstock’s thoughts here .
For DRG’s assessment of the NASH market, please click here.
- Genfit, Research and Development Pipeline (http://www.genfit.com/pipeline/elafibranor/; accessed March 19, 2018)