Title: Madrigal’s and Viking’s NASH Drugs: Who’s best in class?

Author: Peter G. Traber, MD

Two companies, Madrigal Pharmaceuticals (NASDAQ: MDGL) and Viking Therapeutics (NASDAQ: VKTX), this year reported clinical data on the activity of thyroid hormone receptor β (THR-β) agonists in the treatment of NASH, most recently on September 18, 2018 by Viking (see press release). The press release by Viking stated, “VK2809's effect on liver fat at 12 weeks appears to exceed all other oral agents currently in development for NASH, supporting our view that VK2809 has a best-in-class profile.” How does this statement hold up to scrutiny? MDGL’s widely analyzed data set (see recent corporate presentation) demonstrated a rather robust effect on NASH in a 36-week Phase 2 study, based initially on reduction in liver fat at 12 weeks as measured by MRI-PDFF. The positive findings on reduction of liver fat were maintained by week 36 and, importantly, there were improvements on liver biopsy including resolution of NASH and reduction of fibrosis.

Who’s “best in class”

The class of THR-β agonists is important in spectrum of potential therapeutic classes for treatment of pre-cirrhotic NASH. The clinical data so far provides ample encouragement to progress into late development. Declaring one of these two THR-β agonists in development as “best in class”, however, is premature and we may not even have the necessary public data to accurately opine on this comparison.

Drug Chemistry

One characteristic of “best in class” is embodied in the drug chemistry, and particularly the specificity of the agonism of THR-β versus THR-α, since THR-α activity would promote cardiovascular toxicity and osteoporosis. Madrigal provides specific statements that MGL-3196 is a highly selective THR-β agonist, unlike “earlier compounds from other companies”, and has high liver uptake. A novel functional assay developed at Roche that was used in the discovery and characterization of MGL-3196 is cited as supporting this assertion.

Viking states that VK2809 has high THR-β selectivity and is targeted primarily to liver tissue. It is unknown whether the Roche functional assay has been used to evaluate the comparative selectivity of VK2809, which was originally discovered by Metabasis Therapeutics. Both drugs are structurally different small molecules and it is not possible to validate the company statements on specificity based on structure alone. In fact, the only way to analyze the validity of these statements and compare the drugs on this very important issue is to have access to confidential and proprietary information that is always held closely in pharmaceutical companies. The THR-β agonist specificity is a critical issue in the eventual “best in class” moniker, particularly related to the potential for long-term adverse events, but this information will likely be unavailable to the general investing public. I would note that Madrigal has a follow-on THR-β agonist in its pipeline which presumably has enhanced chemical properties, which may be an important additional asset.

Clinical Trial Results

Another characteristic of “best in class” is, of course, the relative efficacy and safety in clinical trials. 83.3% of NASH subjects treated with VK2809 (combined two doses) had a ≥ 30% reduction in liver fat at 12 weeks. In contrast, 60.3% of total subjects and 75% of high-exposure subjects treated with MGL-3196 had a ≥ 30% reduction in liver fat at week 12.

Is this enough evidence to suggest that VK2809 is “better” than MGL-3196 in reducing liver fat? In my view, it is too early to make such a determination. First, it is not reliable to compare two different studies to determine whether the numerical difference between 83.3% and 60.3%/75% is actually different from a statistical perspective. Second, it appears there were only ~30 patients treated with VK2809 in the study versus 78 treated with MGL-3196 and the press release and subsequent call did not review detailed information, saving it for presentation at the upcoming AASLD meeting. Finally, there is more data available, for up to 36 weeks of treatment, from the MGL-3196 trial showing improvement in liver injury markers (AST and ALT), fibrosis biomarkers (ELF and Pro-C3), liver MRI imaging (multi-parametric MRI), and most importantly liver histology including reduction in fibrosis score and resolution of NASH. Will the marginally higher proportion of patients with improvement in MRI-PDFF with VK2809 at 12 weeks translate to better improvement in liver fat after longer treatment and in better efficacy on liver histology and other parameters? Possibly, but there are no data to assess.

The other critical clinical area is safety, which must be pristine for therapy of pre-cirrhotic NASH with all its associated disorders and concomitant disease. More than 180 human subjects in phase 1 and 150 patients in phase 2 have been treated with MGL-3196 for up to 9 months without a significant safety signal reported. In contrast, there are fewer patients treated with VK2809 for a shorter duration. While VK2809 appears safe so far, the number of patients and the time of exposure is significantly lower.

The Leader in Development

While the jury is out on “best in class” for THR-β agonists, and may be for some time, the drug leading clinical development is clear. Madrigal will be initiating a pivotal phase 3/4 trial in 4Q18 to 1Q19 and appears to have enough cash to fund such a trial. As Viking stated in their business call, they will likely need to complete a phase 2 study with liver histology, which is the only way to collect a registration endpoint acceptable to regulatory agencies, before entering phase 3. While there may be creative ways to accelerate the development program, I estimate that Viking is at least 1-2 years behind Madrigal.

It is exciting for the NASH therapy space that there are two very promising THR-β agonists in development for pre-cirrhotic NASH. Both companies should be congratulated on the progress of their drugs in clinical development. Madrigal leads in development and it is too premature to discuss which of the two drugs are “best in class”. However, the uncertainties of drug development require a cautious view of “lead” and “best” as these descriptors may change very quickly. Finally, it should not escape attention that this class has some ideal characteristics for combination therapy with other classes in NASH development with complimentary mechanisms of action.

As a disclaimer, this article did not consider the position of THR-β agonists in relationship to multiple other drugs that are in development for NASH, several which have relatively near-term phase 3 data read-outs.

For more information on Peter G. Traber and how his expertise could benefit your drug development project, please click here or contact Peter at ptraber@alacrita.com.

Disclosure: From March 2011 through June 2018 the author was CEO and CMO of Galectin Therapeutics (NASDAQ: GALT), a company with a NASH development asset, and continues to hold equity in the company.

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