muscle soreness is obviously common, but it sounds to me like you got the shot too high in the shoulder - that kind of injury is not that rare and in fact happened to my mom who years later has shoulder pain. Glad you are feeling better but just an FYI for future that it may be the administration and not what's in the vaccine

I don’t have a strong view but I think nvax is still directed at jn1 while mrna vaccines have been updated to kp2 which is the predominant strain now. I recently got flu and pfe same day (nvax wasn’t an option) fwiw

agree totally - probably feel like crap with that amount of adjuvant

references for ark bio peds data
(and apologies for typos in the post I am responding to I was mobile and dictating)

phase 2 data set from Ark bio's fusion inhibitor (N=80, 73 completed trial, N=49 for randomized part of trial with 3 dose levels tested so overall N in the go forward dose for phase 3 quite small so data will have a lot of noise):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368966/

PR on the phase 3 data with N=300 and change:

https://arkbiosciences.com/en_2022n/112

note that 1 log reduction is 90% reduction, 2 log 99%, 3 log 99.9% etc. so this is c/w what ENTA has said was a .6 log reduction in their phase 3 on virology (The full results are surely available if someone wants to dig them up but google just spit out the company PR)

Again the best benchmark there is for the upcoming peds phase 2 data as far as I know

Hard to say because there is a paucity of data in this setting amd it’s a small trial that is not powered on synptoms and other clinical endpoints. If they get a log delta and trend on any clinical endpoints that’s good. Less than half a log not good. The ark bio chinese trial had .6 log and got on clonical endponts in phase 3 but only had robust effects in the youngest age groups IIRC. those of the rough benchmarks I have in my head but the arc biodata is a different mechanism of action also and otherwise there’s really nothing else to go on as a frame of reference as far as I know

To be clear I think this kind of a line is typically meaningless, but it just so happens management probably has seen some of the data from the peds phase 2 and this is new language for them. I am reading tea leaves here. You can make an argument that negative data and scrapping the RSV program will cause the stock to rise since there is negative value right now on the program. Spending money on a phase 3 with meh data is the real bear case actually if you ask me

I listened and agree she is a good speaker. The story remains the same. The only thing worth emphasizing is that the cash runway factors in a phase 3 for the lead RSV drug and also phase 1 for the Kit inhibitor. She also mentioned they are "planning for success" for the peds trial with some "early start up activities" which of course doesn't mean the phase 2 data will be positive, but at this point the company probably has seen at least the antiviral data from the trial since it completed enrolling 6+ weeks ago

covid antivirals in development have negative value period. This might change with how the FDA handles ensitrelvir

Yes regulators require it (and it does have value to see antiviral effect in humans and some dose ranging too)

It's a challenge study where healthy volunteers are inoculated with virus and randomized to drug vs placebo. You should expect good results it is a very potent molecule. I would say the baseline expectation is the EDP-938 data:

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

I don't think it is a market moving event because in this setting you start drug as soon as infection sets in, whereas in the real world you at best can get drug on board 2 days post symptoms. EDP-938 failed in standard risk even with good challenge study results in healthy adults because the placebo arm was already getting better by the first dose. It is a right of passage though to move into a real world setting

it already has safe and effective subq dosing, but it is 2 shots
GSK partnered with HALO for their long acting to try and get beyond Q2 month dosing (they have other strategies but HALO tech is one of them)

Yes - especially given how much covid is around you would think the covid vaccine market would meet or exceed expectations, so the downward revenue revision does seem like it is coming from the RSV vaccine

among the programs cut is the infant RSV vaccine

Glp-1 drugs may be the backbone therapy fr weight loss but I continue to think over time the companies that can edge ahead on efficacy and safety with combinations will likely come out on top. That’s not so easy to predict. This kind of data from a drug with a different MOA is a reminder of that

GSK

long acting IL-5 (dosed Q6 months) was successful in asthma, data just presented is on par with shorter acting agents like GSK's nucala (dosed monthly) and AZN's fasenra (dosed Q2 months)

https://www.gsk.com/en-gb/media/press-releases/depemokimab-late-breaking-data-presented-at-ers-show-a-54-reduction-in-severe-asthma-exacerbations/

Nucala is the market leader in this class, but Fasenra is close behind due to Q2 months dosing
Both drugs also compete against dupixent in severe asthma
GSK's long maligned pipeline is showing some signs of life

you know I am bullish but i will present the bear case
1. they will burn money so the floor of 20 will go down with time
2. other RSV drugs with positive challenge data have failed in real world setting, including 938 in low risk people
3. the largest market is in peds, and there is a very effective antibody therapy for passive immunity (and a maternal vaccine) which cuts into the market opportunity
4. the lawsuit is a crapshoot and may favor PFE actually since the molecule predates the pandemic
5. they are starting to ramp up spending in immunology and the lead candidate/ indication is behind 2 other competitors already

1. I personally think they will exercise discipline
2. their RSV candidate has a different MOA as a replication inhibitor, has shown a hint of real world efficacy in the terminated stem cell trial
3. the peds market will remain large because passive immunity wanes and these kids will eventually have a first RSV infection that is often severe. The adult market could end up being sizeable as well and vaccine uptake is low and there are always breakthrough infections still
4. crapshoot could go their way too
5. again financial discipline, the opportunity is huge so room for more than one player

Also do you know of symptoms other than mucus that will have to improve?

Clinical endpoints will be related to lower respiratory tract disease (pneumonia) , then other endpoints like oxygen needs, ventilation, hospitalization, etc. mucus won’t be an endpoint

“How common is it that the viral load is significantly reduced and symptoms do not get better? “

I can’t say but there are certainly examples where virology and symptoms are not correlated - in both directions. Ensitrelvir just hit on viral endpoints but not symptoms in Covid. Remdesivir on the other hand hit on symptoms without virology (as did Edp-235 for that matter). I’m sure there are other examples amd there is probably rich data sets in flu.
In RSV specifically GILDs drug missed in both virologic and symptom endpoints in a similar stem cell transplant population. Even in a tiny sample size it’s hard to imagine a 5 log difference in the terminated trial happening by chance. In peds ark bio hit on both in a chinese trial. ENTA’s peds data is primarily looking at VL and ark bio had about a .6 log difference relative to placebo and hit on the clinical endpoints.

The only data in HR is from this terminated study that had enrollment issues bc masking post Covid reduced cases hugely. The entry was updated to include results a couple months ago but N is very small

https://clinicaltrials.gov/study/NCT04633187?term=Edp-938&rank=9&tab=results

GSK succeeds in COPD

https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-phase-iii-trial-of-nucala-mepolizumab-in-copd/

Full data will be presented soon. The primary competition is going to be Dupixent so will be interesting to compare the data sets. GSK has a nearly identical drug but with PK that enables Q6 month dosing which already had positive phase 3 readouts in other indications and could provide a nice competitive edge down the road
This is a large opportunity

The only parties that are in a good position to handicap the lawsuit ARE PFE and ENTA! (although rulings for summary judgement are expected by year end so they would have a better sense after that)
PFE would also know how their next gen covid asset is faring (Shionogi has a next gen compound behind ensitrelvir without the DDI issues so there is potential competition for paxlovid down the road). PFE would also know how their RSV asset is doing. So of the universe of potential suitors PFE is in the best position to evaluate ENTA. ENTA however probably wants to see the results of both phase 2s before making any major decision (and see the lawsuit through).
I would prefer ENTA partner the RSV drugs though and then let them play around with the high risk high reward stuff in immunology with a better cash position and lower burn. That could happen sooner than later bc they do have the peds data in hand already which is the larger of the markets

I find there is rarely new news at investor conferences, but always a possibility I guess
These small bios yo yo all the time and day to day is usually meaningless

I think their hep B program is a long shot and I am more bearish on that than the street, but they do have the patent suits over the LNP used in the covid vaccines which is a wild card so perhaps related to that??

I enjoyed this article thanks. Worth emphasizing:

“there is no A.I. replacement for expensive and painstaking clinical trials”

Also:


“You always have to cross your fingers the first time you put a drug in people,” Derek Lowe, a pharmaceutical researcher and a blogger for Science, told me. “All kinds of crazy shit can happen.”


But the ability to find drug candidates using AI is very much a reality it seems

I would imagine results as least as good as 938/zelicapavir
I don’t think this is a market moving event. Investors and potential partners want to see real world data especially in light of the failed phase 2 in low risk adults
It will be interesting to compare with the Shionogi challenge results due by year end.
The bigger news is the peds trial in q4 IMO

got it appreciate the color Kiwi

I'm not informed enough to assess the valuation bc I just don't know the competitive landscape well. If you believe GSk is fizzling and PFE may have some difficult simply going to 30+ bc they have had some drop off in immune response as they increased valency in the past IIRC then you could justify the valuation pretty easily. The flip side is that if 38 or 40 is the magic number of serotypes where you essentially get about as much coverage as you need and someone else gets there first you are toast. I feel like right now the market is more or less baking in very high probability of a successful phase 3 and 1 maybe 2 competitors with similar offerings at similar time tables

the distribution of the benefit is also important - I only read the times piece not the paper, but if you have a sizeable minority who got much more than 77 days that is important to know too when making this kind of decision

I'm impressed at how quickly they were able to move forward the 31 valent program
GSK bought a program but they have yet to advance it and the 30+ still appears to be preclinical (unless they are in ultra stealth mode)
I'm not sure where PFE is w their program, and at what serotype number there starts to be serious diminishing returns (i.e. 31 might get you up to 85-90% coverage ). I honestly haven't followed the space closely, but PCVX has exceeded my expectations particularly on speed unless MRK/PFE/GSK are all tight lipped for competitive reasons

True and I don't have fist had knowledge, but I just feel 77 days is not trivial it was 770 versus 693 then? Can I read on my phone and watch something w headphones? Can't you go down to twice weekly and still get much of the benefit?

Don't you find this odd?

77 days longer life over 3 years is not trivial IMO. I would do that even given the rigors of dialysis. The time commitment is real but these days with phones tablets etc it is not utterly unproductive time. If a cancer drug extended life by 77 days it would get universally adopted.

post hoc data mining

I am guessing PFE raises guidance for paxlovid further as well as comirnaty given what is going on right now w covid

They can try and take some share from GSK I guess, but I largely agree w you. There could also be some IP advantages too
Prep is underpenetrated, so room to grow there, but that is a much smaller market than treatment

I think you are right amd may just be referring to vaccines

The ensitrelvir “HR” study was loaded with low risk patients and there is real world data showing improvement in high risk patients recently although not as robust as the original paxlovid data so I think reasonable to use it still
Shionogi got a type c vs type d meeting w fda which means the fda is open to discussing the totality of data and not just narrow focus so regulators may come around after all. The problem for Shionogi is that even on the 6 symptom subset the improvement while stat sig may not be clinically significant at less than a day improvement. (I would have to go back to the data but something like 15-20 hours)

It’s probably smart to see how the FDA handles ensitrelvir after missing on the primary endpoint but hitting (weakly) on a smaller predefined symptom scale and possibly some data on long Covid (6 month data hasn’t been disclosed)

“Is there a lot of doubt about success in phase 3?”

This seems to be the reason. See recent results from the Shionogi drug ensitrelvir. Regulators are using a symptom scale on the primary endpoint that is tough to beat in an immune experienced population

PFE bought a fusion inhibitor that was pretty far along and an N (protease) that was preclinical and got halted. Then their fusion peds trial got terminated (bad taste?) and is being reformulated. Their adult trial is ongoing AFAIK but other fusion inhibitors have failed so reason fr some skepticism. ENTA feels that while fusion inhibitors do fine in challenge studies by definition in real world setting infection is further along and fusion inhibitors can’t address already infected cells only helping to block new cells from infection. So they feel their N stands a much better chance. There is a fusion Inhibitor by a chinese company that succeeded in phase 3 though in peds.
The closest replication inhibitor is Shionogi with an L (polymerase) inhibitor. It is due to report challenge study results one quarter after ENTa. Preclinically it is a bit less potent than ENTA polymerase (EC 50 .35-.76 versus .1-.2) but not sure that will matter clinically as both plenty potent. In fact ENTA N-inhibitor probably enough for most infections and farther along although you can in theory combine the 2 for difficult t treat cases
So Shionogi farther behind but the bigger threat IMO and ENTA the clear front runner

PFE said it can be a 1.5 B market or more when they bought reviral