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PRDS vs ENTA phase-2 dosing:
https://twitter.com/DewDiligence/status/1570156764741632000
EDP-235 as possible treatment for long COVID?
A Key to Long Covid Is Virus Lingering in the Body, Scientists Say
Virus remaining in some people’s bodies for a long time may be causing longer-term complications, recent research suggests
Yes, that's an additional opportunity for EDP-235.
EDP-235 as possible treatment for long COVID?
A Key to Long Covid Is Virus Lingering in the Body, Scientists Say
Virus remaining in some people’s bodies for a long time may be causing longer-term complications, recent research suggests
Sept. 8, 2022 12:01 am ET
The virus that causes Covid-19 can remain in some people’s bodies for a long time. A growing number of scientists think that lingering virus is a root cause of long Covid.
New research has found the spike protein of the SARS-CoV-2 virus in the blood of long Covid patients up to a year after infection but not in people who have fully recovered from Covid. Virus has also been found in tissues including the brain, lungs, and lining of the gut, according to scientists and studies
The findings suggest that leftover reservoirs of virus could be provoking the immune system in some people, causing complications such as blood clots and inflammation, which may fuel certain long Covid symptoms, scientists say.
A group of scientists and doctors are joining forces to focus research on viral persistence and aim to raise $100 million to further the search for treatments. Called the Long Covid Research Initiative, the group is run by the PolyBio Research Foundation, a Mercer Island, Wash., based nonprofit focused on complex chronic inflammatory diseases.
“We really want to understand what’s at the root of [long Covid] and we want to focus on that,” says Amy Proal, a microbiologist at PolyBio and the initiative’s chief scientific officer. Dr. Proal has devoted her career to researching chronic infections after developing myalgic encephalomyelitis/chronic fatigue syndrome, an illness that shares similar symptoms with long Covid, in her 20s.
Three long Covid patients, frustrated at the lack of answers and treatments, have helped connect researchers.
“Long Covid is this really incredible emergency,” says Henry Scott-Green, one of the patients, a 28-year-old in London who says brain fog, extreme fatigue and other debilitating long Covid symptoms prevented him from resuming full-time work as a product manager, though he plans to return soon. “We’re really trying to run really efficiently and cut out as many layers of bureaucracy as possible.”
So far, the group says it has received a pledge of $15 million from Balvi, an investment and direct giving fund established by Vitalik Buterin, the co-creator of the cryptocurrency platform Ethereum.
Among the strongest evidence of viral persistence in long Covid patients is a new study by Harvard researchers published Friday in the journal of Clinical Infectious Diseases. Researchers detected the spike protein of the SARS-CoV-2 virus in a large majority of 37 long Covid patients in the study and found it in none of 26 patients in a control group.
Patients’ blood was analyzed up to a year after initial infection, says David R. Walt, a professor of pathology at Brigham and Women’s Hospital in Boston and Harvard Medical School and lead researcher of the study. Dr. Walt isn’t currently involved with the long Covid initiative.
A year after infection, some patients had levels of viral spike protein that were as high as they did earlier in their illness, Dr. Walt says. Such levels long after initial infection suggest that a reservoir of active virus is continuing to produce the spike protein because the spike protein typically doesn’t have a long lifetime, he adds.
Dr. Walt plans to test antivirals such as Paxlovid or remdesivir to see if the drugs help clear the virus and eliminate spike protein from the blood. He says it’s possible that for some people, the normal course of medication isn’t enough to clear the virus. Such cases may require “a much longer exposure to these antivirals to fully clear,” says Dr. Walt.
One of the research group’s goals is to find a way for people to identify whether they continue to have the virus in their bodies. There is no easy way to determine this now.
New studies offer clues about who may be more susceptible to long Covid, a term for lingering Covid-19 symptoms. WSJ breaks down the science of long Covid and the state of treatment. Illustration: Jacob Reynolds for The Wall Street Journal
Long Covid patients experience such a wide range of long-term symptoms that scientists think there is likely more than one cause, however. Some cases may be fueled by organ damage, for instance.
Yet consensus is growing around the idea that lingering virus plays a significant role in long Covid. Preliminary research from immunologist Akiko Iwasaki’s laboratory at Yale University documented T or B cell activity in long Covid patients’ blood, suggesting that patients’ immune systems are continuing to react to virus in their bodies. Dr. Iwasaki is a member of the new initiative.
In a 58-person study published in the Annals of Neurology in March, University of California, San Francisco researchers also found SARS-CoV-2 proteins circulating in particles in long Covid patients’ blood, especially in those with symptoms such as fatigue and trouble concentrating.
Now, the group is completing a study using imaging techniques and tissue biopsies to detect persistent virus or reactivation of other viruses in tissue. It also is looking at T-cell immune responses in tissues and whether they correlate with symptoms.
Some people may harbor the virus and don’t have long-term symptoms, says Timothy Henrich, an associate professor of medicine at UCSF involved with the study and a member of the long Covid initiative. For others, lingering virus may produce problems.
“I think there’s a real amount of mounting evidence that really suggests that there is persistent virus in some people,” says Dr. Henrich.
Write to Sumathi Reddy at Sumathi.Reddy@wsj.com
https://ir.enanta.com/news-releases/news-release-details/new-preclinical-data-edp-235-enantas-oral-coronavirus-protease
For me this seems one more step validating EDP-325. As J.Luly Enanta CEO addressed some of the potential differences between the Enanta antiviral and it's Pfizer competitor Paxlovid we may soon see some of those differences quantified in a medical conference in about 6 weeks.
willyw,
Thanks for that excellent post.
I've seen a few articles that make it seem that the USA wants to try harder to be ahead of the curve with covid (and or other possible emerging health threats) The CDC has recently spoken to reorganizing, in part based on perceived past failures in covid.
And Fauci really never stopped lamenting our covid response;
https://www.aol.com/fauci-u-covid-response-theres-140731132.html
When I factor in that both Joe and Jill Biden experienced covid/paxlovid viral breakthroughs I have to wonder if EDP-325 might experience a more rapid green lighting of the EDP-325 approval process. Exactly how common is breakthrough? J.Luly Enanta CEO in the recent August earnings report gave a few reasons as to how EDP-325 could be superior to Paxlovid.
EUA? Rolling approval? Some grant or other assistance?
I feel the current climate is that they are not going to make the world wait for a better covid antiviral.
Enanta CEO J.Luly has mentioned that the phase 2 work should be within Enanta's capacity without outside partnership.
The ATM aspect may reassure investors, the government or potential partners that the Phase 2 (or 2/3) IS going forward. This itself could streamline the work of setting up the next stages of trial work.
In gaining a partner to potentially take the trials to phase 3, larger enrollment and world wide to be in a superior bargaining position Enanta may almost need to demonstrate that they don't need a partner. The ATM could ensure Enanta a stronger bargaining position in order to achieve a more lucrative financial agreement with a potential partner.
A final point worth noting is that potentially the patent issue with Pfizer could be decided- either in an legal decision or a settlement.
IF Enanta saw an encouraging legal patent decision the potential EDP-325 collaboration could become even more attractive.
Whether they touch the ATM or not, it seemed responsible to me to make sure that they can move forward in the approval and de-risking process of EDP-325.
I concur. If ENTA inks a partnership deal for EDP-235, the ATM will probably not get used.
ENTA had ~$330M of pro forma cash at 6/30/22 (#msg-169621212), so the ATM looks like a backup contingency in case ENTA decides to conduct the phase-2(/3) EDP-235 trial without a partner.
ENTA opens $100M ATM with Jefferies:
https://www.sec.gov/Archives/edgar/data/0001177648/000119312522231299/d396056d424b5.htm
ENTA had ~$330M of pro forma cash at 6/30/22 (#msg-169621212), so the ATM looks like a backup contingency in case ENTA decides to conduct the phase-2(/3) EDP-235 trial without a partner.
p.s. ENTA has never raised capital as a public company apart from its 2013 IPO. HCV milestones and royalties from ABBV have been sufficient to fund ENTA's operations.
There are two ways of looking at this from ENTA’s perspective. The bearish take is that COVID antivirals aren’t needed in adults under age 65 lacking major risk factors, limiting the addressable market for EDP-235. The bullish viewpoint is that Paxlovid isn’t potent enough to help low-risk patients, but a superior drug such as EDP-235 could find an opening where Paxlovid has been shown to be ineffective.
The market seems to agree with the bearish take, as least for today.
Reason for today’s ENTA selloff: #msg-169786228.
FDA wants PFE to_test Paxlovid in_relapse_cases:
https://finance.yahoo.com/news/1-fda-asks-pfizer-test-201939904.html
The U.S. Food and Drug Administration (FDA) has ordered Pfizer Inc to test the effects of an additional course of its antiviral Paxlovid among people who experience a rebound in COVID-19 after treatment, the regulator said on Friday.
Before moving to the financials, I want to address briefly our ongoing patent litigation in which we are seeking damages for Pfizer's infringement of our issued 953 patent in the manufacture, use and sale of its COVID-19 antiviral paxlobid.
We recognize the importance of paxlovid's availability for patients and we do not intend to seek an injunction or take other action in this litigation to impede the production, sale or distribution of paxlovid. And finally, in this lawsuit, we are taking steps to ensure that we will be fairly compensated for our intellectual property. Importantly, our 953 patent is completely separate from the patent estate covering our discovery of EDP-235 and our ongoing antiviral discovery work for coronaviruses. Indeed, we have a growing 3CL protease inhibitor patent estate, including several issued U.S. patents, one of which covers EDP-235. These patents describe compounds built on an independent and distinct chemical scaffold from the one described in the 953 patent and in Pfizer's patents for paxlovid.
Re: EDP-235 clinical-trial plans
On yesterday’s CC, Jay Luly may have slipped up by inadvertently revealing that ENTA is seeking to conduct a phase-2/3 trial for EDP-235 (rather than separate phase-2 and phase-3 trials). From the CC transcript:
https://www.fool.com/earnings/call-transcripts/2022/08/09/enanta-pharmaceuticals-enta-q3-2022-earnings-call/
“…generally speaking, the concept on the phase 2 piece would be fairly small and then we would head in to the larger [i.e. phase 3] portion, which would be registrational, obviously.”
ENTA might be able to commercialize without a partner in RSV, but I doubt they would attempt to do so in HBV, where a large proportion of the addressable market is ex-US.
ENTA's EV at the current share price ($71.27) is approximately $1.4B, based on the numbers in #msg-169621216 and #msg-169621212.
ENTA’s fully-diluted share count @6/30/22=24.7M—unchanged since 3/31/22 (#msg-168831164).
The 24.7M figure above consists of: 20.7M basic shares on the 6/30/22 balance sheet (https://www.sec.gov/ix?doc=/Archives/edgar/data/0001177648/000095017022015515/enta-20220630.htm#consolidated_balance_sheets ); and 4.0M options outstanding at 6/30/22 (whether or not exercisable) (ibid, p.12).
ENTA’s pro forma cash @6/30/22=$329.4M—a decrease of $23.9M since 3/31/22 (#msg-168831159).
The $329.4 figure above consists of: $290.0M of net current assets on the 6/30/22 balance sheet (https://www.sec.gov/ix?doc=/Archives/edgar/data/0001177648/000095017022015515/enta-20220630.htm#consolidated_balance_sheets ); and $39.4M of marketable securities on the 6/30/22 balance sheet designated as long-term (e.g. bonds with a time to maturity greater than one year).
Note: Net current assets on the 6/30/22 balance sheet include the $28.7M receivable from the IRS (#msg-169620450).
Does this mean ENTA is thinking of going it alone down the line with perhaps with the RSV or HBV drugs?
ENTA hires CMO with Big Pharma credentials:
https://ir.enanta.com/news-releases/news-release-details/enanta-pharmaceuticals-appoints-scott-t-rottinghaus-md-senior
ENTA is due a $28.7M tax refund from the IRS relating to NOL carrybacks allowed by the 2020 Cares Act.
ENTA hires CMO with Big Pharma credentials:
https://ir.enanta.com/news-releases/news-release-details/enanta-pharmaceuticals-appoints-scott-t-rottinghaus-md-senior
Dr. Rottinghaus brings over 20 years of clinical experience in drug development, with expertise in a variety of therapeutic areas including rare disease, hematology, nephrology, neurology, dermatology, rheumatology, and infectious diseases.
Prior to joining Enanta, Dr. Rottinghaus was Vice President and Head of Clinical Development for Hematology and Nephrology at Alexion, AstraZeneca Rare Disease, where he led clinical development for several assets, including ravulizumab, a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome.
Before his time at Alexion, Dr. Rottinghaus was a senior director at Pfizer, driving the advancement of several drug programs such as tofacitinib in rheumatology and dermatology, as well as tigecycline, voriconazole, and anidulafungin in the infectious disease field. Earlier in his Pfizer career, he worked as a clinician on early stage clinical trials for influenza vaccine development. Dr. Rottinghaus’ experience includes multiple NDA and MAA submissions and FDA Advisory Committee participation.
During his industry career, Dr. Rottinghaus continued to practice as an attending physician and assistant clinical professor in infectious diseases at Yale School of Medicine. He has co-authored more than 30 scientific publications. Dr. Rottinghaus holds an M.D. from Mayo Medical School, an M.Sc. in Biology from the University of Cambridge where he studied as a Marshall Scholar, and a B.S. in Biology as well as a B.A. in Latin and Greek from Kansas State University.
ENTA FY3Q22* financials—royalty_revenue=$19.5M—6/30/22_cash=$292.7M (down from $322.5M at 3/31/22):
https://ir.enanta.com/news-releases/news-release-details/enanta-pharmaceuticals-reports-financial-results-its-fiscal-32
FY3Q22 R&D expenses were $39.1M, inline with prior guidance of $150-170M for FY2022; FY2Q22 SG&A expenses were $12.9M, higher than the annualized run rate of the prior guidance of $35-41M for FY2022 (#msg-166871344) due to an increase in headcount.
--
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).
*ENTA’s fiscal year ends on September 30.
Elaborating on #msg-169566734, the MoA of EDP-235 could not be simpler: EDP-235 stops SARS-CoV-2 viral replication. If the next EDP-235 trial (either phase-2 or phase2/3—see #msg-169566784) has a well-chosen endpoint and an appropriate patient pool (e.g. rate of hospitalization, compared to placebo, in high-risk patients), EDP-235 is a big favorite to show meaningful efficacy. To put it another way, ENTA (and a potential partner) would have to screw up royally for EDP-235 to not be successful in the next trial.
p.s. The above may not be entirely clear to investors who are unfamiliar with clinical development of antiviral drugs. This is probably why ENTA’s recent 40% pop occurred over the course of a week rather than in a single day.
So do we know for certain that the MOA of ENTAs drug identical?
Thank you Vin and Willy. - this makes sense “the MOA of Covid protease inhibitors is well defined”
So do we know for certain that the MOA of ENTAs drug identical?
Crazy good call.
I actually bought a little more last Thursday at 48. Wish I bought more than I did.
Crazy good call. I actually bought a little more last Thursday at 48. Wish I bought more than I did.
ENTA is up over $3 today. I figured the rise over the release of the safety data on friday would continue this week. The questions remaining in my mind are how many days in a row will the stock price rise, and will it get to the mid $60s or, dare I say it, get back to $70 before the earnings report is released?
willyw, sorry I didn't see your response before I posted. Nice job.
Was the risk any different for their RSV drug?
respiratory syncytial virus did not meet the primary endpoint in a Phase 2b clinical trial. The therapy did not reduce symptoms when compared to placebo;
From Enanta;
"Antiviral treatment for RSV, including EDP-938, has the greatest potential to show optimal efficacy in high-risk populations, as these patients have reduced RSV immunity which manifests in a longer duration of viral shedding and greater disease severity, allowing a bigger window to realize the full potential of EDP-938. Moving forward, our broad clinical development plan will focus on evaluating EDP-938’s potential in populations with the greatest unmet need, namely those who are at high-risk for severe disease, including pediatric patients, immune compromised, and a high-risk adult population."
---------------------------
Think of covid. Where is the business - what population group? The high risk.
Let me reframe "did not meet the primary endpoint in a Phase 2b clinical trial" as
failed to differentiate the treated group (those intentionally infected) to other healthy.
I think that it's because the normal healthy group recovered so quickly that there was little differentiation between the two groups.
The real question is whether the Enanta RSV drug (EDP-938) will create a differentiated response in the higher risk groups with weakened immune response and more attenuated recoveries.
Look at Paxlovid and covid.
What if you attempted to prove Paxlovid worked by comparing it to groups of covid infected "healthies" who were asympotmatic and who recovered quickly? You could easily conclude that Paxlovid didn't work due to the lack of differentiation.
Here is what the trial did show;
"Final data available from all high-risk patients enrolled in EPIC-HR study (n= 2,246) confirmed prior results of interim analysis showing PAXLOVID™ (nirmatrelvir [PF-07321332] tablets and ritonavir tablets) reduced risk of hospitalization or death by 89% (within three days of symptom onset) and 88% (within five days of symptom onset) compared to placebo; no deaths compared to placebo in non-hospitalized, high-risk adults with COVID-19"
That's the way that I interpreted it.
Enanta took data where they could get it, but by no means was it going to be a trial that was going to be where the bulk of their business would be or on a group that would see the most benefit.
That's my quick take on it and there are many here far more sharp than I am.
I could be wrong. But I have to wonder if many on twitter who called the trial results a whiff or a failure are reading it right. Like you, I'm curious myself of other's interpretation of the results.
https://clinicaltrials.gov/ct2/show/NCT03691623?term=EDP-938&cond=RSV&draw=2&rank=2
Was the risk any different for their RSV drug?
respiratory syncytial virus did not meet the primary endpoint in a Phase 2b clinical trial. The therapy did not reduce symptoms when compared to placebo;
Appreciate the input??
How many drugs get thru phase 1 with that type of data and never get approved or take a few years at minimum to get approved.
How many drugs get thru phase 1 with that type of data and never get approved or take a few years at minimum to get approved. There is still a fairly high degree of risk.
If Luly can provide some color on what the approval process is it would be great.
I will probably miss out on a lot of ENTA gains or maybe never have a chance to get in because I’m waiting for some patient results that show the drug works.
Thanks dew. Seen that info on twitter and didn’t check into much because I’m in Belize diving.
Wishing ENTA well. I will probably miss out on a lot of ENTA gains or maybe never have a chance to get in because I’m waiting for some patient results that show the drug works.
It would be nice to see this drug work. While I’m here I found out my daughter who has trisomy 21, OCD and Autism got Covid. She has been vaccinated and boosted but she is also in the high risk group. Kept her away from Covid for 2 years literally the dayI leave she tested positive. Trying to get Pax for her.
R
I hope you are right. You sure nailed the other call; up $5.50 last Friday and up $4.50 today. 10 bucks in two days and 7 more days to go till earnings.
Biden is still positive for covid.
The rebound may be getting more attention than it would have a month or two earlier.
It may create a sense of urgency in tracking what the ideal dosing period is.
I hate to say.... or I have to say carefully---- It is good that they will have another decent or better antiviral to test against the Paxlovid benchmark. They are bound to learn a lot.
If Luly can provide some color on what the approval process is it would be great.
By no means do they seem to have this pandemic under control.
ENTA is up over $3 today. I figured the rise over the release of the safety data on friday would continue this week. The questions remaining in my mind are how many days in a row will the stock price rise, and will it get to the mid $60s or, dare I say it, get back to $70 before the earnings report is released?
Shionogi’s S-217622 has some issues:
#msg-168536263 teratogenicity
#msg-169462279 efficacy not proven
More info on S-217622 than you probably wanted to know:
https://www.biorxiv.org/content/10.1101/2022.01.26.477782v1.full
Conclusions
• Data presented in Ph1 first-in-human study indicate that S-217622 was well tolerated in healthy individuals, and the pharmacokinetics evaluations highlighted the potential for once-daily administration
• In Ph2a, treatment with 5-day oral administration of S-217622 demonstrated a rapid clearance of SARS-CoV-2 and was well tolerated in patients with mild-to- moderate or asymptomatic infection
• The results support further clinical development of S-217622 through large-scale clinical studies for the treatment of mild-to-moderate or asymptomatic SARS- CoV-2 infection
https://www.shionogi.com/content/dam/shionogi/global/investors/ir-library/presentation/2022/ECCMID%20Ph1_2a%20presentation%20final2.1.pdf
What if Enanta did a 6 day versus 5 day (or 5 and 6 day cohorts) and there were no rebounds, even in a larger pool?
So both Fauci and now Biden have rebounded. I agree that it may not be a serious problem, but it may pose an opportunity.
Getting to your second point- an approved drug that doesn't use Ritonavir may be more likely to be approved immediately by a doctor or pharmacist- thereby treating more immediately, having lower viral loads, less secondary immune/inflammation reactions, a quicker and more complete recovery. That may be more true for the older or more immune compromised or those with other co-morbidities. That's where we are really seeing the serious health consequences.
In short- there looks like there is a lot of need and potential upside to EDP-235.
I don't think the viral rebound phenomenon is that common or too much of a problem. EDP-235 may have even less of a problem with rebound given its high potency and long half-life.
The biggest advantage for EDP-235 is indeed that it doesn't use ritonavir, and that advantage will be greatest in older patients since they are at higher risk for Covid and more likely to be taking other drugs.
Covid isn't going anywhere.
It also seems that problems with viral rebound are happening (Paxlovid -too weak or too short a duration??)
Recent virus strains are evading vaccines.
Many doctors are hesitating to prescribe due to the complicated nature of drug interactions w/ Ritonavir.
The last thing on the sheet I really liked?
"Select third mechanism for HBV combination regimen with EDP-514" (in 2022)
I believe that Enanta has reinforced confidence in their capabilities with antivirals.
If they can come up with a third compound for HBV......
[Slide #31]: "Select third mechanism for HBV combination regimen with EDP-514" (in 2022)…
Yesterday was a great day for Enanta.
I'm sure that the Earnings call will shed more light on the covid development plan.
Covid isn't going anywhere. Covid is evading vaccines, and other troubling issues like reinfection, long covid and additive damages from reinfections suggests we need a better antiviral.
It also seems that problems with viral rebound are happening (Paxlovid -too weak or too short a duration??)
Recent virus strains are evading vaccines.
Many doctors are hesitating to prescribe due to the complicated nature of drug interactions w/ Ritonavir.
So the emergency isn't really quite over- infections are once again rising.
There is a need for a faster pathway to approval for EDP- 235
The last thing on the sheet I really liked?
"Select third mechanism for HBV combination regimen with EDP-514" (in 2022)
I believe that Enanta has reinforced confidence in their capabilities with antivirals.
If they can come up with a third compound for HBV......
ENTA’s updated corporate slide set—(including new EDP-235 info):
https://ir.enanta.com/static-files/fb5db89a-b15b-4820-9e77-b8c5b087f869
Slides 17-21 pertain to EDP-235. Slide 20 shows comparative potency vs other agents.
Agreed. EDP-235 is plainly more potent than Paxlovid. And without the manifold drug-drug interactions consequent to ritonavir, EDP-235 should be considerably safer than Paxlovid too.
The clean safety profile of EDP-235 is the biggest news in today's dataset. That's because the MoA of EDP-235 is well understood, so efficacy at the doses selected for phase-2 is almost a fait accompli.
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