Enanta Pharmaceuticals Inc (ENTA)

[vinmantoo]

What technical details?

[DewDiligence]

It seems to me that @Biohazard3737 (“Sheep of Wall Street”) is drawing a negative inference about EDP-235 based on the technical details of the potency assays used by ENTA without his considering alternative explanations for the way the assays were conducted. Only people inside ENTA would know the rationale for these details, as far as I can tell.

Regarding RSV, @Biohazard3737 evidently does not understand that the MoA of EDP-938 (an N-protein inhibitor) is intended to work later in the course of an infection than a fusion inhibitor. Of course, the RSVP trial might fail to meet its primary endpoint, but if that happens it won’t be for the reason cited by @Biohazard3737.

[vinmantoo]

I read the guy’s dismissal of EDP-235 and it doesn’t make sense. He doesn’t state why it wouldn’t be an important drug if approved. Obviously we need efficacy data in Covid patients after safety data comes in this quarter. However, EDP-235 advantages would be significant as it would be only one pill a day and no need for a second drug to maintain Paxlovid levels high, and the drawbacks that has regarding other drugs.

[DewDiligence]

My two replies (one re RSV and one re EDP-235) are within the same thread.

[JK2016]

And what were your replies to those comments?

[DewDiligence]

Tweet thread from a short:

https://twitter.com/Biohazard3737/status/1519372523892363266?ref_src=twsrc%5Etfw%7Ctwcamp%5Etweetembed%7Ctwterm%5E1519372523892363266%7Ctwgr%5E%7Ctwcon%5Es1_&ref_url=https%3A%2F%2Fpublish.twitter.com%2F%3Fquery%3Dhttps3A2F2Ftwitter.com2FBiohazard37372Fstatus2F1519372523892363266widget%3DTweet

I replied to two of the tweets in the thread.

[DewDiligence]

Shionogi PR re COVID antiviral fails to mention teratogenicity!

https://www.businesswire.com/news/home/20220423005001/en

Shionogi is evidently acting like MRK did with Molnupiravir—i.e. pretending that a safety issue does not exist. In MRK’s case, the result was a product with essentially no demand because the FDA EUA restricts usage to patients “for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate” (#msg-167236732).

[vinmantoo]

Wow, ENTA has been a roller coaster recently. I look forward to the rebound tomorrow.

[DewDiligence]

Some_patients_may_need_longer_treatment_course_of Paxlovid, according_ to_anecdotal_info:

https://www.bostonglobe.com/2022/04/21/metro/puzzling-phenomenon-patients-report-rebound-covid-19-symptoms-after-taking-antiviral-paxlovid/

The FDA EUA specifies a 5-day treatment course because that’s what PFE tested in its clinical trials.

[DewDiligence]

Ascletis’ ASC11 could be a serious competitor to EDP-235 based on the in vitro assays of potency described in the PR (https://finance.yahoo.com/news/ascletis-announces-3clpro-inhibitor-asc11-085000053.html ). However, the most consequential differentiators among agents from this drug class are safety and pharmacokinetics, and Ascletis’ PR is silent on these points. We’ll have to wait for Ascletis’ phase-1 data in late 2022 (or early 2023) to know how their drug actually stacks up.

[JK2016]

Thoughts on the news from ASCLF today on a possible best in class competitor?

[DewDiligence]

XBI was -4.8%, so today’s selloff was not ENTA-specific.

[JK2016]

Why the purge today? Yikes.

[DewDiligence]

One fewer serious competitor for EDP-235.

[willyw]

https://www.bloomberg.com/news/articles/2022-04-13/shionogi-falls-most-in-decade-on-birth-defect-risk-of-covid-pill

"The pill’s [shionogi's covid antiviral] chance of commercial success fell to 5% from 50% after the report tying it to birth defects, which may make it less competitive, said Stephen Baker, an equities analyst at Jefferies & Co."

also

" Demand for drugs to treat Covid is fierce as the world transitions to an endemic state and the focus shifts to easy-to-take medications."

--------------
Enanta's covid candidate EDP-325 is expected to finish it's Phase 1 MAD and SAD dosing in the 2nd quarter and commence phase 2 in Q3

[DewDiligence]

ENTA’s EDP-235 presentation slides and poster at the ASBMB* annual meeting:

https://www.enanta.com/wp-content/uploads/2022/04/Enanta_EDP-235-ASBMB-Annual-Meeting-Seminar_Final.pdf

https://www.enanta.com/wp-content/uploads/2022/04/EDP-235-2022-ASBMB-Annual-Meeting-Poster-Final.pdf

*American Society for Biochemistry and Molecular Biology.

[DewDiligence]

(ENTA)—PFE acquires private RSV-therapeutics company for undisclosed up-front and $525 biobucks:

https://www.businesswire.com/news/home/20220407005081/en/

https://www.evaluate.com/vantage/articles/news/deals-snippets/pfizer-doubles-down-respiratory-syncytial-virus

Reviral (the private company being acquired) has an RSV fusion inhibitor, Sisunatovir, in phase-2 trials for hospitalized infants (https://www.businesswire.com/news/home/20210616005103/en ) and immune-comprised adults, with data from both expected in 2H23. Reviral also has an N-protein inhibitor in phase-1.

As ENTA’s Jay Luly has mentioned on many occasions, RSV fusion inhibitors, which seek to prevent the virus from entering cells, haven’t worked especially well for patients who have a high viral load at treatment start. That’s why ENTA’s lead RSV compound is the N-protein inhibitor, EDP-938. ENTA expects to report phase-2b (‘RSVP’) data for EDP-938 during 2Q22; the phase-2a data were recently published in NEJM (#msg-167916018).

ENTA also has a second RSV compound, EDP-323, an L-protein inhibitor; this is an MoA no other company is pursuing (yet), as far as I know.

[DewDiligence]

PFE hits_goal_of_shipping_6M_courses*_of Paxlovid during_1Q22:

https://finance.yahoo.com/news/1-pfizer-made-6-mln-214629742.html

The company's targets for 2Q22 and full-year 2022 are 24M and 100M courses, respectively. Demand is not an issue—PFE does not expect to have any problem whatsoever in selling as many courses as it can produce.

*Each course of treatment consists of 20 tablets of Paxlovid and 10 tablets of ritonavir.

[rwwine]

New Covid Variant XE Found In UK, More Transmissible Than Omicron: WHO
https://www.ndtv.com/world-news/new-covid-variant-xe-found-in-uk-more-transmissible-than-omicron-who-2858643

Continued need for ENTA’s anti-viral candidate.

[DewDiligence]

ENTA’s EDP-235 featured in C&EN:

https://cen.acs.org/business/next-generation-COVID-19-antivirals/100/i11

[DewDiligence]

I will feel a lot better when ENTA gets one or more of its other HBV candidates into safety trials.

Indeed. Meanwhile, the number of HBV candidates from other companies (e.g. ALGS, ASMB, ABUS) keeps falling.

[vinmantoo]

ALGS discontinues another HBV candidate:

Thanks Dew! I will feel a lot better when ENTA gets one or more of its other HBV candidates into safety trials.

I am also anxiously awaiting the EDP-235 the phase I safety trial so it can get into Covid patients for the phase 2/3 trial. The reemergence of Covid in many countries makes it clear that more drugs are needed.

[DewDiligence]

ALGS discontinues another HBV candidate:

https://finance.yahoo.com/news/aligos-discontinues-development-antisense-oligonucleotide-120000830.html

Aligos Therapeutics…today announced that it has discontinued development of its drug candidate, ALG-020572, which was being studied in subjects with chronic hepatitis B (CHB).

Dosing in the first CHB cohort of Study ALG-020572-401 (NCT05001022) was stopped after one subject experienced a serious adverse event (SAE) with significant increase in alanine aminotransferase (ALT) following multiple dosing of 210 mg ALG-020572 that resulted in a brief hospitalization. This is one of four CHB subjects in this first cohort who experienced potentially drug-related ALT flares…

Please see #msg-167924816 for related info.

[DewDiligence]

After the SOTU last night it seemed to me that addressing covid was still very much an interest by the Biden administration.

No question. Note that PFE is up sharply today.

p.s. I referenced your post here on iHub’s PFE board (#msg-168063575).

[willyw]

There are many possibilities, much depending upon the trajectory of covid, new variants and abilities for vaccines to adapt to new strains.

I'm hopeful that speed to approval is maintained. IF Enanta does indeed have a best in class PI antiviral a speedy approval via EUA should be a plus.

After the SOTU last night it seemed to me that addressing covid was still very much an interest by the Biden administration.

[DewDiligence]

True on both counts.

[vinmantoo]

Maybe, but sales to the government for free distribution to patients generally come with substantial price concessions.

Maybe so, but a hell of a lot of pills need to be stockpiled, and PFE can't come close to covering that amount.

[DewDiligence]

Maybe, but sales to the government for free distribution to patients generally come with substantial price concessions.

[willyw]

I think Joe Biden's SOTU address last night may influence Enanta. Joe said that Paxlovid reduced (from memory) hospitalizations 90% and that he was going to make it available free and immediately after a positive covid DX. (availability will presumably continue to ramp up)

1) One could infer that the next best in class antiviral might see the same treatment- such as Enanta's covid antiviral (EDP-325).

2) We might also assume that since Joe's presidency hinges (in part) on getting past covid that the EUA use may be prolonged long enough for Enanta to get a more rapid approval in order to provide a non-RTV boosted once daily covid theraputic.

3) Joe also mentioned that being a part of the international community meant making our superior vaccines available- and one could extrapolate if we had a best in class approved antiviral that it could even be construed as an excellent means to reinforce our diplomatic relations with other countries as well as the right thing to do.

4) Joe Biden -- whether you are dem or republican, love him or hate him - is still president for approximately 3 more years and policies may extend beyond presidencies.

What I heard last night seemed positive for covid biotech- perhaps especially for Enanta.
It's a hypothesis - but based somewhat in the context of what Biden referred to last night at the SOTU as well as in Obama's pandemic preparedness systems.

A strong covid response could be a part of Biden's legacy and potentially aid the world in covid recovery.

[vinmantoo]

So....how long will it be till the Pfizer is replaced by a non-boosted one? A once a day antiviral instead of a twice a day?
I guess the market thinks covid is departing. But is it?

If EDP-235 turns out to be the real deal, it will be the choice over Paxlovid. Governments will want a stockpile to be ready if Covid surges again, and that is a huge market.

[willyw]

(written but not posted Valentines day Monday 2/14)
I know that the posts are merely observing that money is moving out of covid; Molnupiravir, Moderna, Pfizer, Novamax. I guess that Mr. Market has spoken and the market is always right. : )
I have to wonder if covid is over. I have to wonder if this is an opportunity.
The news with Molnupiravir shows us that a superior antiviral will beat out an inferior one. So....how long will it be till the Pfizer is replaced by a non-boosted one? A once a day antiviral instead of a twice a day?
I guess the market thinks covid is departing. But is it?

Even without a new variant, there is no reason to think that Delta or Omicron will magically leave. They will stay and still have lots of un vaxxed and unboosted to infect.
https://www.mayoclinic.org/coronavirus-covid-19/vaccine-tracker

So I wouldn't celebrate too fast.
And we are seeing that boosting only lasts so long.
Covid can revisit the past infected, the un vaxxed and underboosted.
So for me, it looks like a time to bet that it isn't ending, that it will continue. Is the USA still populated with the old, the overweight? Diabetics? People with multiple co-morbidities? Cancer patients/ people w/ compromised immune systems? People who eschew vaccinations, boosters, masks and mandates?

Were I to guess we may have a series of descending waves- but we are FAR from over. Perhaps the tremendous years Pfizer has had may be decreasing, but I have a sense of optimism about the next best in class antivirals.

Finally..... what if there is yet another variant?

And it appears that there IS yet another variant.
Even as many proclaim that the pandemic is over.
Right or wrong I have been adding as the share price dropped.

[JK2016]

A new drug shows promise against respiratory virus, study shows
By Brenda Goodman, CNN

Updated 1:39 PM ET, Thu February 17, 2022
A 3-year-old patient in the hospital receives medication via an inhalation mask to treat Respiratory Syncytial Virus (RSV).
A 3-year-old patient in the hospital receives medication via an inhalation mask to treat Respiratory Syncytial Virus (RSV).
(CNN)A new antiviral medication against respiratory syncytial virus, or RSV, appears to be safe and lowered viral levels and symptoms significantly more than a placebo, according to the results of a study published Wednesday in The New England Journal of Medicine.

The study is unusual in that it is based on a two-part human challenge trial, where researchers purposefully infect people with a pathogen to test a new therapy. Challenge studies speed up research because scientists don't have to wait for their study participants to get sick out in the real world. They can also enroll fewer people, knowing that participants will inevitably catch a germ. But they're also risky and only considered ethical when the need for a new treatment or therapy is thought to outweigh the potential risks to study participants.

[DewDiligence]

Comments on ALGS' ALGS-097111: #msg-167924816.

[DewDiligence]

ENTA’s PR on NEJM article:

https://www.enanta.com/investors/news-releases/press-release/2022/Enanta-Pharmaceuticals-Announces-Publication-in-The-New-England-Journal-of-Medicine-of-Data-from-the-Phase-2a-Human-Challenge-Study-of-EDP-938-for-the-Treatment-of-Respiratory-Syncytial-Virus-RSV/default.aspx

[DewDiligence]

ENTA’s phase-2a RSV trial published in NEJM:

https://www.nejm.org/doi/full/10.1056/NEJMoa2108903

[JK2016]

And the dosing begins with expected read out Q2.

[DewDiligence]

ENTA’s fully-diluted share count @12/31/21=24.7M—an increase of 0.3M since 9/30/21 (#msg-166903176).

The 24.7M figure above consists of: 20.5M basic shares on the 12/31/21 balance sheet (https://www.sec.gov/ix?doc=/Archives/edgar/data/0001177648/000095017022001018/enta-20211231.htm p.2 ); and 4.2M options outstanding at 12/31/21 (whether or not exercisable) (ibid, p.11).

[DewDiligence]

ENTA’s pro forma cash @12/31/21=$377.7M—a decrease of $13.6M since 9/30/21 (#msg-166903163).

The $377.7M figure above consists of: $289.1M of net current assets on the 12/31/21 balance sheet (https://www.sec.gov/ix?doc=/Archives/edgar/data/0001177648/000095017022001018/enta-20211231.htm p.2); and $88.7M of marketable securities on the 12/31/21 balance sheet designated as long-term (e.g. bonds with a time to maturity greater than one year).

[willyw]

Dang; BMY's Daclatasvir

[willyw]

Yes, thanks for the transcript Dew. I sometimes have trouble hearing and need the transcripts to affirm what I thought I heard.

So far as some derisking - both the RSV and Covid phase 1 data at the 54:25 minute mark Luly mentioned both will be complete next Q.
EDP-325 phase 2/3 covid should start in the 2nd half.

RE: EDP 514, it almost appears that Enanta is in no hurry to partner with sub-optimal HBV compounds that stand lesser chances of success.

Gilead's HCV program succeeded due to several shrewd acts;
1) They were willing to pay more than anyone for the best nuke.
2) They partnered, then abandoned Merck'sDaclatasvir as a second combination agent (with their own in house NS5a Ledipasvir), thus retaining 100% of the HCV sales from the start.

I have to suspect that this is what Enanta would like to do with HBV. I'd guess that they are trying hard to find another/create another MOA or agent to combine EDP-514 with. That act of not partnering may show some confidence in what they have (EDP-514) and -perhaps- confidence that they can create a 2nd compound in house.

IMHO, this also rather explains also WHY the L- inhibitor in RSV.
IF Enanta can have a total lock on RSV from the get go they may reduce the enticement for others to follow in with vaccines or anti-virals.
SURE- many tried with HCV.... but how many succeeded? Still trying? Few- very few.

Time will tell if that could repeat with RSV and HBV.

[vinmantoo]

Thanks Dew. Good to hear that EDP-235 will begin phase I trials this month. Plenty of room for and money to be made with a best-in-class Covid protease inhibitor.

I will feel even better when another HepB drug is chosen for trials for future combination with EDP-514.

[DewDiligence]

ENTA FY1Q22 CC transcript:

https://www.fool.com/earnings/call-transcripts/2022/02/09/enanta-pharmaceuticals-enta-q1-2022-earnings-call/

[DewDiligence]

Phase-1 for EDP-235 (qD SARS-CoV-2 protease inhibitor WITHOUT ritonavir boosting) will stat during Febuary:

https://www.sec.gov/Archives/edgar/data/0001177648/000095017022000875/enta-ex99_1.htm

[DewDiligence]

ENTA FY1Q22* financials—royalty_revenue=$27.6M—12/31/21_cash=$347.7M—(down_from_$352.4M_@9/30/21):

https://www.sec.gov/Archives/edgar/data/0001177648/000095017022000875/enta-ex99_1.htm

FY1Q22 R&D expenses were $48.5M, slightly high relative to prior guidance of $150-170M for the full FY2022; FY1Q22 SG&A expenses were $9.5M, inline with prior guidance of $35-41M for full fiscal FY2022 (#msg-166871344).

--
How ENTA’s Mavyret royalty is calculated

ENTA’s royalty rate on Mavyret sales from ABBV is tiered, as shown in the table in #msg-142808661. The royalty rate is applied to the 50% Glecaprevir component of Mavyret (a 2-drug combination). The royalty tiers reset at the start of each calendar year (like tax brackets), so ENTA’s royalty rate is highest in the fourth calendar quarter (ENTA’s fiscal* Q1) and is lowest during the first calendar quarter (ENTA’s fiscal* Q2).

During calendar 4Q21 (ENTA’s FY1Q22*), ABBV sold $427M of Mavyret (#msg-167727290), noting that HCV new-patient starts were still below pre-pandemic levels. ABBV issued calendar-2022 guidance for Mavyret sales of $1.7B, unchanged from the calendar-2021 number (#msg-167728327).

*ENTA’s fiscal year ends on September 30.

[willyw]

As it pertains to Enants's Covid program
https://www.marketwatch.com/story/shionogi-aims-to-begin-global-phase-3-trial-of-covid-19-pill-late-february-271643611039

"Currently, Shionogi is conducting what it calls a Phase 2b/3 trial in Japan and some other countries but not in the U.S. That trial is expected to end by late July this year, it said. Separately, it said it is talking to the Food and Drug Administration and the European Medicines Agency about a global Phase 3 trial that it targets to begin in late February."
---------

It appears that Shionogi's covid program entered phase 1 the end of July- 6 months ago. Which may help gauge the speed of Entanta's program.
As the Pfizer covid antiviral will be first to market it should see huge demand, but it will not likely be best in class and could soon yield to an unboosted antiviral- such as Shionogi's.

As recently as 3 weeks ago at the JP Morgan healthcare conference J Luly reiterated that there will be a shortage of covid antiviral product and that Enanta could have potentially a best in class protease inhibitor.
Enanta's drug will commence Phase 1 clinic in Febuary 2022.

[willyw]

What I'm kicking around is the trajectory of covid, the possible extended use of EUA which could greatly benefit ENTA, and the failures or weaknesses of Enanta's covid competitors. (MRK, AVIR, PRDS?--maybe ultimately PFE)

IF both Enanta and Shionogi did well with their covid theraputic protease inhibitors it's hard to see Paxlovid being a long term preferred med.
The question is how effective will they be? Will one be better? How quickly can they get US/EU approval?

It seems that the worst case covid investing scenario for Enanta would have been a short pandemic- like traditional influenza.

But instead the reverse happened; Alpha, then Delta, now Omicron, and there may be more resistant variants on the way.
There is still a lot of vaccine hesitancy. It seems obvious that a sizeable un-vaccinated (or under boosted) pool will remain and face both the current covid and future resistant strains. A prolonged pandemic with elusive cures may encourage the continued use of EUA.

Equally interesting as it pertains to VIR you can see that support can quickly be withdrawn. Can they scale up quick enough if the target keeps shifting? The antivirals look good there.

RE: HBV Enanta hasn't rushed into other collaborations. It makes me think that they prefer in-house. There truly may not be much out there worthy of a collaboration. Enanta can carefully tailor two Enanta compounds to work together instead of bolting together random parts available thru collaboration.
--Although the RNA destabilzer didn't work out they still may have some worthwhile data that helps with the next compound. Enanta has combined 514 with a nuke so they must have an idea of what they need for the next piece. I'm not sure the competition has that.

[vinmantoo]

A large number of biotech stocks are at or close to their 52 week lows now. I bought a small amount of several today including ABBV, ENTA, SGEN,IMGN and even CDMO. I was toying with opening a position in VIR as their monoclonal antibody is the only one that works with omicron and they are now scaling up production. One caveat is their HepB program doesn't look stellar to me but that is down the road.

[willyw]

LOL: Idenix. That's one I hadn't heard in a longer while. : )

IF I had thought there was potential for Zepatier level success I might have tripled my SMALL position.

Meanwhile I'm out 10-20 bucks for being impetuous.

[DewDiligence]

Zepatier—that's a name I hadn't heard in a while, LOL.

[willyw]

I purchased a small amount a few weeks ago to force my attention- which worked.
I had thought; well, what if it became a Zepatier?
But the more I investigated the less attractive it looked. That ended yesterday when I sold.

It was never just one thing, but a number of things- and that disquieting number only grew.