Enanta Pharmaceuticals Inc (ENTA)

[dewophile]

Sure
Here is a sampling:

1. Ziresovir (fusion inhibitor) difference in VL vs placebo of .6 log on day 5 and they also hit on the primary clinical endpoint of brochiolitis score. This was in hospitalized infants.

https://www.nejm.org/doi/full/10.1056/NEJMoa2313551

2. ALX-0171 also targeting the fusion protein given as a nebulized / inhaled product which hit on virology in hospitalized infants - cleared virus about twice as fast as placebo but missed on clinical endpoints.

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30320-9/abstract

3. Lumicitabine which is a polymerase inhibitor like ENTA’s second drug (although it is a nuke acting at the active site versus EDP-323). This missed on both virology and clinical endpoints.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10355467/#pone.0288271.ref015

This is not exhaustive but covers a nice range of outcomes. The company has emphasized the advantage of a replication inhibitor versus fusion inhibitors w the latter only able to inhibit vital entry and not already infected cells. Enta feels this is important because in the real world unlike challenge studies infection has set in longer before dosing so being able to target already infected cells could be that much more important in a real world setting.
Lumicitabine is the only non fusion inhibitor I’m aware of with phase 2 data in real world settings including the pediatric setting. It had good challenge data (almost identical to 938 in fact ), has high barrier to resistance, replication inhibitor so also goes after cells that are infected. So that’s the hardest one to explain away IMO. While the study I linked to was sizable the single dose cohorts never got to therapeutic levels and the second study was halted and only 4 patients got study drug w 3 in the highest dose cohort. So that leaves the MAD cohort and only 13 evaluable patients were dosed at the high dose cohort. So this miss could easily be due to lack of power. The drug also has to be converted into the active triphosphate while EDP-938 and 323 don’t. (323 while also a polymerase inhibitor inhibits the L at an inactive site ). This makes modeling difficult amd in peds in particular in addition to using challenge data the company also had to incorporate a non human primate model to check levels of conversion into the active form in lungs (infants especially hospitalized have largely progressed from upper to lower respiratory tract infection. From the discussion in the linked paper.

“The pediatric PK model was coupled with a semi-mechanistic pediatric lung model from monkeys, which estimated the formation of the pulmonary ALS-008112 and NTP at a given plasma exposure.”

So while blood levels in these 13 patients were at least as high or higher than the adults in the challenge study you don’t know if the active drug levels in infant lungs were at therapeutic level. Edp-938 has no need for conversion to be active so easier to model effective doses from pk/pd models in adults.

Two other points of potential differentiation. Lumicitabine (like many other nukes) had neutropenia as a side effect. Not exactly great when you have a population fighting an infection. Also we don’t know when in the course of infection the 13 evaluable patients first got study drug , but the median time to dosing in the entire trial was 4 days. Enta will presumable have a larger data set with the 96 patients enrolled so they can look at data in patients who got as little as 3 days (and up to 5). There are examples of other antivirals for respiratory infection like tamiflu that only showed efficacy when given within 3 days of symptom onset. So the 13 could be down to a handful that got it within 3 days which leaves you even more underpowered to show a difference w placebo

Longer post than I intended sorry