Lo he puesto en el otro hilo pero supongo que ahora está mejor aquí...
Ya me he leído la CC, pero volveré a hacerlo porque hay mucha información que digerir. 2017 H1 inician fase 1 Zika si preclinical ok a finales de enero. Inicio fase 3 H2 si se alinean los astros. Resultados fase 2 RSV Q3. Datos si le parece bien a la FDA de Prepare 2H 2017 (pero creo que dieron dos respuestas diferentes...). Siguen los estudios de serología.
Mensajes interesantes de IV (y respuestas). Nuevo método para testear la afinidad de los PCA, parece mentira que la compañía no estuviera más al día:
I’m not going to bother going through the whole presentation (eventually I'll look at the Zika data), I caught the audio of from mid Glenn on, and it seems it largely was a verification of the suspicions that some of us had. LAR was a factor, but the PCA assay was inadequate to the task, or at least that is what it sounded like when they started talking about affinity.
Not to sound like a snob, but the industry folks often leave those more in the academic circles scratching their heads. I love that they make cures and stuff, but some of the details get obscured by stock options, that supposedly the obsessions of academics are not adequately product related.
Since the dawn of mAbs, the use of mAbs to define markers, the development of the whole “cluster of differentiation” naming system (e.g. CD4, CD8 etc), the use of mAbs to characterize cell types, to elicit responses in signal transduction, to elicit lymphokine production, to trigger the complement cascade, to enable immunoprecipitation, purification, demonstrate protein/protein interactions, for immunodetection (western blots, ELISA, FISH) and finally, to provide viral protection,…. Long long ago, way back then, it was known that just because one antibody can compete away the binding of another does not mean they will produce the same result downstream (in this case protection). Such competitive binding is a strong indication that one will get the same downstream result … but it is far from certain, PARTICULARLY as it pertains to, say, protection from viral infection. I’m going to say this was sorted out in the 1980s, but perhaps my memory is a bit off on this.
Glenn and colleagues were surprised that PCA did not 1:1 dictate protection. One thought is they could Go Back to School. I had wondered about and tried to explore on this, but the fact is I can’t look at their lab books, I only get to see what they choose to show. Had they been defending a thesis based on this surety, they’d have gotten a whoopin’, at least where I come from. Seeing that they’ve been kicking the PCA assay around for a few years, it would seem one would have had ample opportunity to do some homework on it. Oooo, yes that is what they say too, they do have ample opportunity, freezers full of archived serum, and it seems they are finally going to do what I have previously argued one would imagine they must have already done … and do some PCA verification versus protection. Crap, they have put hundreds of millions into this, and these trials go on for months and years, one would think that over the course of these years they would have some freeking analysis of these freezers full of serum, and for a couple hundred million maybe even have SPR on every bloody one of the P2 vax arm samples.
Or just be surprised, and then get excited that they have rediscovered the 1980s.
That being said, the maternal franchise appears solid, the biological basis for the differential response of Resolve versus Prepare is very easy to imagine, and perhaps a bigger stick (e.g. adjuvant) will prod along the whole somatic hypermutation/affinity maturation bag of tricks. And of course keeping in mind that in a normal AR year the data likely would have looked much better.
So going forward it seems they believe they are developing/have developed a refinement to the PCA assay that allows them to not only ask whether the serum has antibodies that obscure palivizumab binding, but whether those antibodies have binding characteristics that are predictive of immunity (and I wouldn’t be surprised if it is SPR). If they nail said assay well, it is a stronger surrogate argument, and would enable the development and presentation of more convincing data at every stage. The vision thing would be that one would see PCA+ affinity curves, MN curves, and protection curves (in cases where one has a decent sample size) and get concordant results.
Conclusión: fue un error no usar adyudante.
They came up this year with a new method called SPR to test the affinity of the PCAs.
* Affinity is the ability to neutralize RSV-F Site II, thereby neutralizing RSV.
* PCAs are Palivizumab Competing Antibodies that were generated by the immune system in response to NVAX RSV vaccine.
They used the SPR method to measure the affinity of the blood samples taken from vaccinated animals and people of preclinical, phases I, II, and III studies.
They found out that those who got a good affinity score also fought RSV infections very well. Those who got low score fought RSV poorly. This means the affinity test is a good predictor of vaccine efficacy. That is, now they can predict if the vaccine is efficacious simply by measuring affinity in the lab. You no longer need to wait for vaccinated subjects to catch RSV to find out if the vaccine is protective (efficacious). You can predict efficacy even if nobody caught RSV (zero attack rate). However, keep in mind that although this affinity test and its correlation with efficacy is powerful and reliable, it is nevertheless just an indication of the potential for success. The FDA will still expect NVAX to prove efficacy in phase III, where vaccinated people catch RSV and get only a bit sick or not sick at all.
Using the affinity test, NVAX found out that the vaccinated people in RSV elderly phase III did just OK, but not great. Based on affinity results the efficacy should have been about 30% (unsure of exact value, and don't really care -- it's not good). Then, why did we get ZERO efficacy result instead of about 30%? Answer: Because of LAR (Low Attack Rate). You need a good number of subjects to actually catch the real RSV before you can know for sure about efficacy. Thus, the LAR ruined the test, but the results would still have been poor even with a good AR.
I repeat: The LAR ruined the test, but the results would still have been poor even with a good AR.
Fortunately, there was a huge flag in the affinity results from the blood samples of all the past/present studies that pointed to this: Adding an adjuvant or giving a booster shot increased affinity to high levels.
Conclusion: It was a mistake to vaccinate the elderly with an unadjuvanted vaccine. Add adjuvant to NVAX RSV vaccine, and the vaccine would definitely be efficacious. You still need the AR to be not too low. To circumvent the effect of a LAR you could double the sample size from 12,000 to 24,000, or you could run the test in areas/groups that consistently have high AR. I think the latter is a better solution.
Hopefully, after you read this message, you'll realise why it's futile to lay blame on Stan, Greg or anyone else. Everyone was equally guilty. By "everyone", I mean NVAX, analysts, BioInvest and the experts of this board. At least we now have a bright light at the end of the tunnel. The stock will recover late next year when maternal results are out. Successful RSV maternal mean successful RSV for all age groups. The market will not wait for FDA approval or billions of dollars in sales. They'll rally the stock hard long before that. And, there is no need for dilution before end of next year. I'm pretty sure Stan will wait for maternal results before diluting, partnering or selling the company.
Affinity for all intents and purposes in this context is the "on rate" divided by the "off rate" which gives an "association constant". Think of magnets, a strong magnet will fly onto a a piece of iron faster than a weak magnet, that is the on rate. Once the magnet is actually stuck, and lets say the piece of iron was vibrating massively and irregularly, there will be a rate at which the magnet flies off, or the off rate. It is generally the off rate that drives the values in Ab interactions.
One can take a snap shot, a freeze frame in time, and look at how many site II's are occupied with antibodies. Higher affinity antibodies will achieve higher occupancy at lower concentrations, when they stick they are much less likely to fall off.
So one has a concentration of antibodies, the above mentioned association constant, and whalla, one has an occupancy level (% of sites bound) at a particular concentration. The effect on efficacy is not a black and white thing per se, but given that affinity maturation can reduce Kd (off rate) by an order of magnitude, the effects on titer requirements for protection can be dramatic.
In short, higher affinity (among other things) lowers titer requirements. Lower affinity antibodies would like drive protection too, if the concentration was uber high. The PCA assay, even without SPR, could reveal this ... it would be at the level of the wash steps, more stringent or longer washes would kick off more lower affinity Abs revealing site-II for the pavilizumab binding. This appears to have been under-explored. Sandwich EILSA, while used quantitatively, has an arbitrary sensitivity component determined in part by wash steps. Their assay appears to be biased towards high sensitivity (detecting lower affinity competing antibodies). There is an art component, and one plays with things and settles on a standardized assay. SPR on the other hand, is a real time direct measure, there is no hocus pocus.
Did a little digging in the mudd and found an adjuvanted prime boost in flu driving affinity maturation as measured by SPR.
or a more technical workflow for serum analysis
If you are correct in your assessment why wouldn't Erck, Glen, and others on the BOD come charging in to buy more shares at this point??? Wouldn't it be a slam dunk if in fact they truly believed that it was only a matter of time until the stock went considerably higher? Wouldn't you agree that Human Greed and their level of "skin in the game" is the best indicator to verify the validity of their convictions? As a result, due to their lack of personal involvement, wouldn't that make you somewhat suspect of their motivations and potentially question their scientific explanations? I certainly hope I am wrong...but something has a bad smell here. I trusted this company initially based on Dr. James Young's involvement and he clearly has skin in the game.. and a bonifide track record. However, upon my investigation of Erck & Glen's past history, candidly I am dismayed and now question if Young's business and people acumen are at fault. Most scientists skills are in the lab and I wonder if Young is one that has elevated himself due to his past scientific success beyond his capabilities.
I was appalled how the CC was carefully orchestrated only allowing pre-screened analysts to ask benign questions that were uncompromising. They never made any reference to Partners or additional funding and clearly avoided anything relative to their inefficiencies of trial design. I clearly am not a scientist but their solution as you indicate is apparently to beef up the successive trials with booster shots and adjuvents which at first blush seems like only one side of the equation. Why was their no analysis on how the next trial would be strategically designed to make every effort to not be subjected to low attack rate? In addition, we have no clue as to certain financials such as their fixed lease obligations. Another question looming is...if in fact the science was so terrific and was subjected to an unlucky LAR trial, why wouldn't Large Pharma be knocking on their doors big time especially at these bargain prices???? Candidly that should have happened already....Again, I am just trying to be objective.....and this exercise just doesn't pass the smell test anymore. I hope I am wrong.
Now that the quarterly results and trial analysis are behind us, a stock trading period window is probably again open for employees for a short time. I am watching for form 4 filings all the time now. Open purchase buys would be great and sells would be very bad.
In some ways the timing of the low attack year was painful but probably fortunate for the long term viability of the company. What if we saw a raging RSV attack year 2015-2016 and Resolve barely passed, then got approved and was followed by a weak attack year where Resolve did not work at all. It would destroy the entire RSV program including Prepare. Expense levels of the company at that point would make it even more challenging to stay afloat.
Yes, we suffered a major set-back, but there may be a path forward now for a viable and probable valuable company.
Lo que hubiera estado bien que dijera la directiva en la CC:
What I would have done simply, is say emphatically.
The trial failed because of LAR.
We as executives should have done a better job reducing our risk exposure to LAR
We are bringing in outside experts to ensure the next trial has a better outcome..
We are scientifically confident that Resolve will work
We apologize for the impact on our shareholders ....... and then announce some Executive level restructuring.......along with the reduction in force