Replies to post #2882 on Enanta Pharmaceuticals Inc (ENTA)

[dewophile]

There is probably room for both. Assuming safety equivalent milder cases go for an easier to take oral agent more severe an injection. The sweet spot is obviously a more efficacious oral drug which is the opportunity enanta sees. Safety will be paramount the first oral kit drug for CSU was pulled for liver tox. That’s why phase 1 is actually going to be an important inflection point for this drug (along w the fact you can check bio markers to confirm target engagement even in healthy volunteers )

[dewophile]

THRD had a presentation yesterday by the way. They reiterated a few things that ENTA mentioned:

1. the biology is very much mast cell mediated, and kit inhibitors are really the master regulators of mast cells. So all the other mechanisms may hit upstream or downstream, but you simply don't get the immediate inactivation of resident mast cells (followed by decrease in mast cells) with other mechanisms, so this is likely why you see such high efficacy
2. ENTA had mentioned that you can use a biomarker (tryptase) in phase 1, but THRD emphasized this point. They said there is now enough efficacy data in the indication linked to tryptase that the efficacy curves and tryptase curves "sit on top of one another". So it is a VERY good biomarker of efficacy that you can employ in phase 1. And you can drive tryptase levels down to undetectable levels with Kit inhibition
3. As for safety it (and efficacy) following the CLDX gives good insight, and it seems the more data there is the more reassuring the safety profile (e.g. the neutropenia and other on target effects don't seem to be that significant at all).
4. reiterated ENTA's take to a tee - that if you can get efficacy even close to an antibody for KIT w an oral drug it is a clearly attractive profile (they used psoriasis as a model where oral drugs are given first line most often even when efficacy is even lower than parenteral drugs/biologics)
5. They had 2 cases of DILI (drug induced liver injury) in their first 3 patients! They think they have identified the metabolite causing this and are hopeful. In total 5 patients were enrolled but they never made it past the lowest dose and even at that lowest dose they found significant tryptase inhibition
6. They mentioned they are still doing preclinical work on follow on compounds in addition to this second generation compound that should enter the clinic mid year. This tells me even they think there is room for better potency, selectivity, or both. Hopefully ENTA can come up with a compound that can compete or exceed because they will be at least 6-12 months behind (THLD ended up with a nearly 2 year delay when their first gen compound ran into liver issues)
7. The second indication they will be looking at is asthma. Even though plenty of biologics from GSK, REGN, etc., no new oral drugs for 25 or so years here. I don't need to tell you that would be a massive opportunity, but first things first!
I'm getting more excited about this area for ENTA if they can get a good compound. Liver tox is tough to predict preclinically (THLD acknowledged this), so the phase 1 next year is going to be quite meaningful (especially with a good biomarker of activity to go along w safety)