Enanta Stumbles In Trying To Show Better FXR Agonist Profile In NASH
Executive Summary
Enanta hoped its Phase II study would indicate a better efficacy and/or tolerability profile for EDP-305 compared to other FXR agonists for NASH, including Intercept’s OCA. Despite the inconclusive data, it plans a longer Phase IIb study.
Enanta Pharmaceuticals Inc. is one of at least six companies working to develop a farnesoid X receptor (FXR) agonist for non-alcoholic steatohepatitis that might offer a better overall risk/benefit profile than Intercept Pharmaceuticals Inc.’s obeticholic acid (OCA) – likely to be the first drug approved for NASH – but data from its Phase IIa ARGON-1 study don’t offer a conclusive case on efficacy or tolerability.
The Boston-based infectious disease specialist unveiled data on 25 September testing 2.5mg and 1mg doses of EDP-305 in NASH patients that hit a primary endpoint for ALT reduction at 12 weeks along with a secondary endpoint of liver fat reduction. But a high rate of pruritus and of patients exiting the study due to that adverse event has investors questioning the drug’s profile. Pruritus has also been an issue for Intercept’s drug. (Also see "Intercept's OCA Data Bolster NASH Efficacy, But Pruritus Worries Worsen" - Scrip, 11 Apr, 2019.)
Fifty-one percent of patients receiving the 2.5mg dose of EDP-305 reported at least mild-to-moderate pruritus, compared to 10% of patients who received the 1mg dose. Unfortunately for Enanta, it was also the higher dose that showed a statistically significant reduction in the liver enzyme ALT at 12 weeks – 28 u/L versus -16 u/L for placebo (p=0.049).
Likewise, for hepatic fat reduction, 45% of patients who got the 2.5mg dose were responders (30% fat reduction from baseline or greater) as measured by MRI-PDFF (magnetic resonance imaging-proton density fat fraction), a non-invasive method many NASH studies are using to measure markers of disease. (Also see "NASH News & Notes From The European Liver Meeting" - Scrip, 16 Apr, 2019.)
Numerically higher reductions of ALT and liver fat compared to baseline also were seen with the 1mg dose, Enanta chief medical officer Nathalie Adda told a 25 September investor call, but neither finding met statistical significance.
Meanwhile, 20.8% (11/51) of subjects in the 2.5mg arm discontinued treatment due to pruritus. There also was a treatment discontinuation due to rash in that arm. In the 1mg dosing cohort, fewer than 10% of patients reported pruritus and the related discontinuation rate was 1.8%.
Pruritus Effects Of Second-Generation FXR Agonists
In a statistical comparison of NASH trials testing FXR agonists, also released by Enanta on 25 September, 23% of patients receiving a 25mg dose of OCA in Intercept’s Phase II FLINT study reported pruritus at week 72. In its 18-month Phase III REGENERATE study, 51% getting the 25mg dose and 28% who received a 10mg dose of OCA reported pruritus. The comparison also showed, however, that a 10mg dose of Gilead Sciences Inc.’s cilofexor and a 90ucg dose of Novartis AG’s tropifexor – both second-generation FXR agonists like EDP-305 – yielded much lower rates of pruritus. Cilofexor posted a 14% rate of pruritus at 24 weeks, while the Novartis candidate had an 8% rate of pruritus at 12 weeks.
On the investor call, Enanta CEO Jay Luly said the company had not expected high rates of pruritus in Phase II for either dose of EDP-305 based on results seen in a two-week Phase I study of the drug. “But it appears that many of the effects of EDP-305, both efficacy and tolerability signals, occurred at lower doses in ARGON-1, likely due to the higher exposures that we observed in this NASH population,” he added.
JMP Securities analyst Liisa Bayko noted that the six companies trying to come up with a better FXR agonist than OCA – a list that includes Poxel SA’s Phase II PXL007 as well as Metacrine Inc.’s MET409 and Terns Pharmaceuticals Inc.’s TERN-101, both in Phase I – likely need to show superiority on pruritus and/or on LDL cholesterol. Increased LDL rates in some trial subjects have created another headwind for Intercept’s NASH ambitions with OCA, which already is approved to treat primary biliary cholangitis under the brand name Ocaliva. (Also see "Intercept Hopes Statin Trial Will Lessen Ocaliva's Perceived CV Risk" - Scrip, 22 Mar, 2017.)
In a 26 September note, Bayko wrote that because EDP-305 showed an incidence of pruritus similar to what Intercept reported in its Phase III trial, Enanta will need to try a lower dose – an effort that will be complicated by the unspectacular efficacy showing for the 1mg dose of EDP-305 in Phase II.
Luly said Enanta plans to initiate ARGON-2, a 72-week, Phase IIb study testing two doses of EDP-305 during the first half of 2020. “Dose 1, to be determined, will be designed to push for maximal efficacy in terms of histologic improvement, and based on ARGON-1, we expect to see some pruritus at this dose,” he explained. “But we also expect it to be manageable on the majority of these patients. Dose 2, to be determined, will be designed to offer a balanced profile in terms of efficacy and tolerability. And, as such, we believe it could also be a potential dose to explore in combinations for NASH therapy while ARGON-2 is ongoing.”
Bayko maintained a 60% likelihood of approval for EDP-305 in NASH coming out of ARGON-1, saying a deeper dive into the dataset should reveal hints for how to get better results in the next study. “Enanta still has work here and we think there may be a ‘Goldilocks’ dose, but threading the needle between efficacy and safety is a difficult task,” she wrote.
Enanta Shows Promising Fat-Reduction Capability
One factor in Enanta’s favor, Bayko added, is that EDP-305’s fat-reducing ability outstrips anything seen with other candidates in its class.
“We were hoping for a similar profile to OCA, but with less pruritus,” the JMP analyst said. “Rather, while ALT, a biomarker of liver damage was in line, liver fat reduction was best in class thus far. The reduction in liver fat doesn’t appear to be driven by changes in body weight (BW) with a comparable [approximate] 2kg drop in BW across all study arms. However, after just 12 weeks we are cautiously optimistic but wait to see this observation confirmed in larger, longer clinical studies.”
Meanwhile, EDP-305 showed only modest increases in LDL, much lower than seen in Intercept’s Phase II and Phase III studies of OCA. LDL cholesterol was up 6% with the 2.5mg dose and 5% with the 1mg dose in ARGON-1, compared with a 20% increase seen with the 25mg dose of OCA in Intercept’s Phase III study.
Enanta’s investors seem more concerned about EDP-305’s tolerability profile than enthused about its therapeutic potential, however. The firm’s stock finished the trading day on 26 September down 15% to $60.51 per share.
In June, Enanta reported successful Phase IIa data for N-protein inhibitor EDP-938 in respiratory syncytial virus (RSV), but faces a consensus view that real-world testing will illustrate the drug’s potential more fully. (Also see "Enanta Hopes To Succeed In RSV With N-Protein Inhibition Approach" - Scrip, 14 Jun, 2019.)