Re: Farmas USA
NVAX
Aviso que va a ser un mensaje largo en el que pongo las últimas conversaciones relevantes en IV (y no pongo todo)...
Sobre la cantidad de sujetos que se necesitarían para hacer la fase 3 con garantías:
given the low attack rate, I'm curious how heavily the trial would have had to be powered to contend with what actually happened.
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I calculate 20,000 in the placebo arm and 20,000 in the vaccine arm to show 30% efficacy - and that too with the tiniest margin of safety.
You also have to also watch confounding variables like a hawk because you are going to get lots of noise from diabetics, patients with heart disease, new cancer diagnosis, those with autoimmune diseases, etc
They should really talk to Pfizer and ask about patient monitoring during the last big Prevnar trial. I fear NVAX does not get how noise scales with study size (independent of attack rates). It is really, really hard to contend with noise when attack rates are low.
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Sobre la serología que se mostró en Argentina:
This is exactly what we have been talking about. Can you post a link or was this a screen grab? Assuming this is valid, we can now compare PH II and PH III MN results at 28 days.
Refer to cklau52 post 10323,
Geometric mean rise in neutralizing titers as interpolated from the graph PH II elderly
RSV A 1.9
RSV B 1.5
Now refer to truck post 10339
Geometric mean fold rise Microneutralization titers as given from the table for PH III elderly
RSV A 1.69
RSV B 1.88
So, we can see that PH III efficacy for strain A was about 89% (1.69/1.9) as effective as PH II. PH III efficacy for strain B was about 125% (1.88/1.5) as effective as PH II.
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Would like to see the 56 day time point and ideally the 182 day time point (duration of protection). The footnote at the bottom states" Analyses based on sera from ALL per protocol for immunogenicity subjects". The PCA data and Anti F IgG states from 447 subjects. They seem to be prioritizing the MN data.
The limited MN data seems to be tracking with the Phase II.
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Por último, una conversación kilométrica acerca de por qué tendría mucho sentido para una BP adquirir ahora NVAX:
GSK has their own RSV program, although it seems not so successful. Were suppose to have a Phase II readout last November, from what I can see the trial results have never been made public. Other vaccine companies, Pfizer, Merck, and Sanofi IMHO are in the mix. At this discounted price other players may surface now that the price is discounted.
When you look at companies R&D budgets.
The spend is huge and NOT very productive. Assuming the science is intact with multiple shots on goal of potential Billion dollar vaccines (Elderly, Maternal, NP flu) you need just one to hit to justify a 3-5B acquisition. Hell BP blows that in little over a quarter internally on their apathetic R&D pipelines. The risk can further be mitigated by adding a CVR structure to the deal. Partnership would be what NVAX desires, not sure they will have that option. Just takes one BP to make a run and go public. Didn't Sanofi recently do that with Mediation? Sure did!!! Sanofi has the most to loose if NVAX gets in another BPs hands.
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I totally agree with you in that NVAX does not want to give up the ball. I believe their primary objective is to create a partnership. My fear, as posted by Bill C. (Message # 9627), is that NVAX will attempt to create the Holy Grail...they want to combine RSV with Quad Flu with their super-duper M-1 adjuvant which can only be found in the soap-bark tree grown in Chile in a specific latitude range.
If you read the 10/7 press release carefully, it is the only fair assessment one could come to. The problem is, even if they start now, and everything goes as planned, we won't see Phase III results until the end of 2018.
The Company's perspective will be: Look, even I have to give up 40% of the Company to get the funding to run these trials, that vaccine alone could be worth $12B+ given a $10B+ market. So, 60% of that number would give shareholders ~ $20/share. Of course, in the interim, the stock will have a hard time getting past $4/share. The shorts will be in total control of the Company for a 2-year period. That would be hard to stomach, given where we have been. But, we should not be shocked if that is NVAX's message on November 9th.
Let's see if one of the B/Ps who is not in line to get the partnership is willing to make the run that you speak of...Certainly NVAX has shown all of them what's under the hood of this coveted vaccine candidate.
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Equity I understand the potential for that type of strategy, however, I believe with it comes additional risk that may or may not payoff. If it doesn't payoff it could bring the company to its knees.
A Phase I/II would have to be run as previously described. Four arms studying NP flu and RSV alone and in combo with and without Matrix M (1H 2017) and then 3Q 2017 a Phase III which reads out in 3Q 2018, with a 2019 approval.
It would be a co-formulated product that adds another variable.
IF I am BP and I were to cast a path forward I would want multiple shots on goal with a high level of confidence that one will hit. Run a two year adaptive design Phase III RSV Elderly with a futility analysis at year one with 3 arms, one shot, two shot (0 and 30 days) and placebo that is large enough to offset LAR say 20,000 plus potential of another 20000 the second year PLUS a booster RSV Elderly (6000 patients from Resolve) as a separate study. That gives you 3 shots on goal, one shot, two shot, booster for success. I would also fund the Phase I/II combo as planned (smaller not as expensive). I would put the pedal to the floor on all programs.
Good chance Elderly hits and the combo is right behind it. Only behind a year. Its all about time to revenue.
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Truck - As someone that has defended failed trials to the FDA, your insights carry a lot of weight. Your scenario would give NVAX 3 shots on goal with Resolve and we still have another big shot on goal with Ph3 RSV MI Prepare and other shots as well (NP flu, the Flu/RSVcombo, MERS, Ebola, pandemic flu, SAB transgenic cows, and widespread use of Matrix-M)
To those that are worried that "the vaccine does not work." Do they mean that the NVAX RSV won't work at all or just as a single dose in the elderly??? Are they worried too, that the RSV won't work protecting newborns via MI? Do the mean "the vaccine" has NOT worked with MERS & Ebola in producing protective antibodies? It pretty vague to say "the vaccine doesn't work." (reminds me of a Thomas Dolby song.)
They (doubters & bashers) will at least agree that a LAR rate makes it more difficult to prove efficacy. They also can't deny that last winter was the warmest on record in 48/50 US States. They also can't deny the attack rate in the placebo group (1.8% & .4%) was extremely low. They can't deny that only .2% of trial participants came from nursing homes or LTC where rates rates can be double that compared to communal living. They also can't say that the Ph2 RSV elderly booster data was not positive.
There will always be doubters & bashers concerning the efficacy of Resolve until NVAX/BP produces positive data and the 3 shots on goal you have suggested make a lot of sense:
"IF I am BP and I were to cast a path forward I would want multiple shots on goal with a high level of confidence that one will hit. Run a two year adaptive design Phase III RSV Elderly with a futility analysis at year one with 3 arms, one shot, two shot (0 and 30 days) and placebo that is large enough to offset LAR say 20,000 plus potential of another 20000 the second year PLUS a booster RSV Elderly (6000 patients from Resolve) as a separate study. That gives you 3 shots on goal, one shot, two shot, booster for success. I would also fund the Phase I/II combo as planned (smaller not as expensive). I would put the pedal to the floor on all programs.
Good chance Elderly hits and the combo is right behind it. Only behind a year. It's all about time to revenue." Truck
I'll bet BP is thinking along the lines that you are Truck and that negotiations are underway.
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Truck,
I couldn't agree more with your analysis. You've essentially laid out the blueprint for any serious prospective bidder to follow. This will optimize the chances of success while immediately establishing the path for attaining the big prize (Combo with M-1).
Even if ALL these trials (and associated overheads) were to cost $1B, if I'm Big Pharma, why wouldn't I acquire NVAX for $4B, and then be poised to dominate the entire RSV/Influenza landscape, for $5B? Five years from now, the revenues from these markets could be $8B - $10B, and yield an additional $32B - $40B in market cap (~4X revenues) to the acquirer.
Again, if I'm B/P, I would think my M&A team would be high-fiving themselves if they could put this entire plan in motion for a cost of < $5B.
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Equity you echo my sentiments as it relates to potential ROI. Am I would guess there are added aspects of the design and path forward that BP has thought of that I have not. The deal structure can mitigate risk by including CVRs.
The climate is also ripe for this type of deal. BP continues to struggle to show top line growth. Loss of patent protection on key drugs coupled with apathetic production from internal R&D spend has to give them great sense of urgency to do deals and take on more risk than they typically would and not just do conservative acretitive deals. The political rhetoric is growing increasingly louder as it relates to price controls. As a result the sector continues to falter and can get no real sustained momentum as indicated by the performance of the IBB.
The potential revenue that NVAX represents and the fact that it is a vaccine company obviously must draw the attention of BP. 4B to purchase with a 1B spend to fuel the engine doesn't seem so outrageous to me given the multiple shots on goal and the potential for one to hit. If just ONE hits (Elderly, Maternal, NP flu, Zika) well worth the investment. If they all hit, it is the steal of the century. Unprecedented opportunity IMHO, thus, as you say, have to think BP is salivating!!
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Truck....thanks for your thought on this subject. I'm just curious about one statement that seems to be a double edge sword; you write: "If just ONE hits (Elderly, Maternal, NP flu, Zika) well worth the investment."
If an acquirer would be happy with only ONE success out of the available possibilities, then why wouldn't NVAX be just as happy by continuing to own the franchise? I believe they are confident the maternal trial is, and will continue to move along successfully. As it is an ongoing trial that will be terminated for only one of two reasons, NVAX could cut staff and overall costs and just let that trial play out. BTW, the two possible outcomes would be: If the statisticians determine there is enough evidence to prove the vaccine is both safe and effective, the trial is terminated and a BLA is filed. That could happen in month 18 or month 36 or anything in between. If the statisticians determine there is NO evidence the vaccine confers protection, the trial is terminated for cause.
I'm not advocating that direction....it's just a reality and lends credence to the position of those who prefer NVAX remain independent. As for myself, I'm hoping a deal is struck with a partner whereby the partner funds a more robust PIII...hopefully, combo....with an option to buy.
