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Will make this simple.
UK Specials revenue only went up to some time in March before the Damn Panic intervened. So it is not a full 3 months anyway.
And we don't know how they book revenue.
What we do know is that they have very limited production capacity at CCGTT. So that is a limiting factor in itself and is the most pressing reason for getting Sawston up and running.
And we don't know if there is more demand than they can service or less. We do know that they were operating a waiting list.
So it's difficult to accurately calculate average patients treated per month. And it's difficult to know how much patient numbers will increase when Sawston is up and running.
As for patients treated this year, I suspect you have erred on the low side..
Agreed. Those comments made at or near the time strongly suggest the hold was not the result of a 'fail' at an IA.
But they also suggest the hold wasn't for a super positive reason either.
That's how I read the remarks anyway.
FWIW, here's a good analysis of the possibility of a period of stagflation coming our way.
It's primarily analysing the UK, but probably also could be applied to the US.
https://www.ii.co.uk/analysis-commentary/why-stagflation-likely-and-how-protect-your-portfolio-it-ii512406
'Twas never described by NWBO or by the FDA as a mandatory hold.
Though I suspect it was de facto mandatory..
As in; 'we advise you that you need to do this straight away..'
Unilaterally imposed mandatory holds or halts tend to get an FDA news release as well as a company release. Don't they?
Doesn't the FDA maintain a register of trials for which there has been an order imposed?
Did they fall or were they pushed?
Call it semantics if you like, but if NWBO had been slapped with a mandatory order, they would surely have been required to announce the fact with a timely PR.
Which they didn't do.
My supposition is that they initially thought that a written response to whatever the issue was, would suffice, and lead to an early resolution. Thereby enabling them to restart screening with minimal impact on the trial.
But whatever their response was to the regulator (certainly the FDA, but not named as such at the time), it didn't lead to regulatory satisfaction, because the 'advice' to hold new screening wasn't rescinded until at least 18 months later.
From 21 Aug 2015:-
The only change in status of the trial is that new screening of patient candidates for the trial has been temporarily suspended while the Company submits certain information from the trial for regulatory review.
Such screening involves the initial evaluation of patient candidates to determine whether they meet eligibility criteria for the trial (e.g., whether they are within the eligible age range, do not have certain viral diseases, etc.)
Some blogs and social media comments have noted that the EudraCT trials database in Europe states that there is a “Temporary Halt” of the trial in Germany. In actuality, the trial status in Germany is that the trial is ongoing as noted above, and the Company has only undertaken a temporary suspension of new screening.
The Company has sought to have the EudraCT listing corrected, but the database includes only certain pre-specified categories and there is no category that corresponds to a temporary suspension of new screening only, while a trial is ongoing.
The Company is in the process of preparing the trial information for regulatory review and anticipates submission within the next couple of weeks.
A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy involving the investigational drug unless specifically permitted by FDA in the interest of patient safety.
My only fear around here is that Longfellow will come and bludgeon me to death with a dictionary for abuse of the English language.
The question is does Linda still get her salary when/if nwbo goes bankrupt?
As you say, there are various sets of stopping rules, with varying degrees of conservatism. And each time you do an efficacy IA, you spend a tiny amount of alpha. Multiple efficacy IA's cost you more alpha.
Apparently if you have no real intention of stopping early, then you should opt for Haybittle Peto, because it costs virtually nothing in alpha, but also means you will be very unlikely to pass the necessary statistical hurdle at interim stage.
I am not sure what NWBO specified in protocol at the outset, though I have a vague memory of a reference to O'Brien-Fleming, which is the middling one of the three most often used.
Apparently, if you really are aiming for an early efficacy halt then you should opt for Pocock, but that costs more in alpha.
Discussed here:-
https://online.stat.psu.edu/stat509/node/80/
And this blog (second entry dated Nov 21 2016) discusses the issue mainly with respect to Haybittle:-
https://onbiostatistics.blogspot.com/2016/11/
Certainly, I reckon that in our trial, they have only had a maximum of one IA, probably some time in 2015. It's possible they never had one, but unlikely, imo. If they never had one at all, then they would have known by not having one, that they were passing up any chance of an early efficacy halt, and committing to go full-term.
The place of PFS in the final SAP is one of the big imponderables.
Though that doesn't stop me pondering on it..
They have to hang the alpha hat on something at the end of the day.
And they have the choice of using PFS as the primary, with all of the alpha spent there. But that would mean that you can only go on to the OS secondary (other than for exploratory analysis) if the primary achieves stat sig...
And given that my personal hypothesis is that PFS delta at 2015 interim was not as good as they had hoped for (but not a trial fail either), that would involve a big leap of faith on the part of the company, to effectively 100% invest in PFS passing muster. And presumably they would only do that if; (i) they knew that PFS adjudication was acceptable to the regulators and; (ii) they believed that adjudication would overcome any adverse impact on the data arising from possible L pseudo-progression.
So I just can't buy that. They either have an alpha split between PFS and OS. Or they have gone all in on OS.
But that's as far as I can go. You come up against the information black hole, which surrounds the putative IA in Summer '15, and the subsequent partial hold.
Between that point in time, up until JTM in May 2018, there were, I think, one or two somewhat veiled PFS references in PR's or filings.
But it was only in JTM itself that they made a concrete statement regarding PFS, with the reference to it being the primary endpoint (present tense), and that it would be (future tense) the subject of a multi-factorial assessment by an expert panel.
And that was their last public reference to PFS.
The only reference that I am aware of that, that indicates the plan for alpha spend and alpha split, was the 'trial enhancements' PR from back in Aug '14, which talked about the plan to spend 0.02 on PFS.
Which would leave 0.03 for OS.
All of which leads me to conclude that I really have no firm idea at all, as to what they ended up with in the final SAP!
He’s biased.
Wonder if AF will be asking Buzdar for a comment.
Or is it OK now for a company to tout interim P1 results?
Lol.
LA JOLLA, Calif., July 13, 2020 (GLOBE NEWSWIRE) — INmune Bio, Inc. (NASDAQ: INMB) (the “Company”), a clinical-stage immunology company focused on developing treatments that harness a patient’s innate immune system to fight disease, today reported clinical data demonstrating that its lead drug candidate, XPro1595, decreases neuroinflammation in patients with Alzheimer’s disease. Interim results from a Phase Ib clinical trial show that treatment with XPro1595 decreases white matter free water, a biomarker of neuroinflammation measured by MRI. XPro1595 is a next-generation inhibitor of tumor necrosis factor (TNF) that selectively neutralizes soluble TNF, an inflammatory cytokine implicated in Alzheimer’s pathology, without affecting transmembrane TNF or the TNF receptors.
Specifically, INmune compared biomarker data obtained from six patients treated with XPro1595 for 12 weeks with data from 25 Alzheimer’s patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that are part of a natural history database in patients with Alzheimer’s. Over a 12-week period, whole brain inflammation increased by 5.1% in the ADNI patients compared to an increase of 1.7% and a decrease of 2.3% in patients treated weekly with 0.3mg/kg or 1.0mg/kg of XPro1595, respectively. A more detailed analysis revealed a 40.6% reduction in neuroinflammation in the Arcuate Fasciculus in patients treated with XPro1595. The Arcuate Fasciculus is a major white matter anterior/posterior tract (white matter bundle) containing long and short fibers that connects the frontal, parietal and temporal lobes and is important for language and short-term memory. By contrast, the ADNI cohort had a 4.6% increase in Arcuate Fasciculus neuroinflammation.
“We are extremely encouraged by these findings at such an early stage in our clinical trial,” said CJ Barnum, Ph.D., Director of Neuroscience at INmune. “Not only do we see a clear reduction in neuroinflammation, but we also know where in the brain this is occurring, which may inform us on the domains of cognition that might be affected.”
Don't forget that a lot of Yanks like to employ a middle initial.
So that is a minimum of three stages to the signing-off process.
You can't rush these things.
Excellent sentiments, with which I fully concur.
But does such a potential partner exist?
Is there an investor out there that would want to support and financially nurture DCVax over the medium to long term?
Not many of those around. Though the Cognate buyout shows there are possibilities.
But not in the US, I think.
Though that is what I would like to see; major 'Angel' investment (in the best sense) from a partner outside of the existing Pharma cabal.
Woodford actually almost represented that, but for multiple reasons it ultimately didn't work out.
In my opinion, Covid has not shown established Pharma in a good light at all.
Nor the Regulators, nor the Public Health agencies.
Not a hope in hell of Merck getting involved, imo.
Their ICI is going to be the biggest selling drug in the world in another year or so. Why would they partner with a firm that has a potentially superior immunotherapy, with wide application over many cancers, and thereby jeopardise the market for their own drug?
Ain't going to happen...
JMO.
...but I would think this is a buy at 25%.
Tiddles would have got away, if he wasn't already tiddled.
Yes, a very slow day.
Must be a joke to be had there somewhere..
Does anyone know what day it is?
Look, as long as he doesn't know the price of steak...
That's the important thing.
https://herdsy.com/the-top-5-most-expensive-steaks-in-the-world/
SOMETHING STINKS HERE!!
Broadly agree.
And for FDA read EMA.
But (and there is usually a but...)
....there is really no such term as MMA (except in ring sports).
Approval in the US equates to Marketing Authorisation ('s' not 'z') in the EU. And this is shortened to MA.
MAA (not MMA) is a Marketing Authorisation Application.
Equivalent to an NDA / BLA.
CHMP is the Committee for Medicinal Products for Human Use.
So yes, basically equivalent to CDER / CBER.
CHMP is the committee that does the evidence review on any given MAA.
But, for advanced therapies (ATMP's) there is a separate committee called the CAT; the Committee For Advanced Therapies.
This committee does the review of the MAA in the case of advanced therapies, and comes up with a draft opinion, before the CHMP adopts a final opinion.
So maybe you could say that the CAT is somewhat akin to CBER, but not exactly equivalent.
DCVax-L would come into the ATMP category, so the CAT would do the appraisal of the MAA.
I believe bribery arrangements are broadly similar between jurisdictions, though I couldn't find any official guidance documents.
Doesn't the parliamentary vote on a no deal Brexit still stand?
Well; it's akin to sleepwalking to disaster.
The UK has decided not to extend the transition year, and the end of June deadline for doing that has now passed.
That's not to say it definitely won't happen.
Because if both sides decide they want a transition extension come the autumn, then it will probably happen.
Crashing out at the end of the year without a deal on border controls, will lead to a customs nightmare for any sort of international freight forwarding.
Trade tariffs will likely be introduced, and Dover and the surrounding road network will likely become the world's biggest lorry park.
All sorts of supply lines will likely be disrupted, including of course, medicines.
Seeing as my views on possible wider consequences may be a little on the alarmist side, I'll keep them to myself for now...
Regarding MHRA drug approvals going in to 2021, one can only speculate. Covid vaccines will be warp-speeded.
And BP oncology drugs will get some form of mirror approval.
Not sure where that will leave us...
https://ukandeu.ac.uk/can-the-brexit-transition-period-still-be-extended/
JMO.
Good for you. Research suggests any cheap antiviral (such as IVM) that acts as a zinc ionophore, allowing zinc bio-availability, does the trick.
IVM appears to be a very versatile, safe and cheap intervention. It also has potential in the oncology field, as this article demonstrates:-
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835698/
Now that's a treatment I'd like to see combo'd with DCVax..
Could you summarise how the chart has changed since the last time you posted it.
And does it mean anything?
Much obliged.
Can't understand when Board opinion gets polarised with:-
(i) 'Datalock is imminent', 'it'll be here tomorrow'. 'Probably already happened' type stuff..
Or:-
(ii) 'Don't ever expect it'. 'It'll never happen'. 'You're all being played' kind of stuff...
Covid delays are real. Or bad actors use it to delay NWBO.
NWBO will never be granted a smooth passage or an expedited passage in this whole endeavour, as I've come to realise...
Unfortunately, that comes with the territory for a small bio with a potentially disruptive platform.
Right now, I would just repeat my request to the company that they provide a fortnightly detailed update, regarding the datalock scenario.
We had the 10-Q update the week before last.
So I'd quite like another update this week, please.
Can't disagree..
SNO’s abstract deadlines have already passed
If the company give any projection about data lock (such as 'end of next week'), it is pretty meaningless, unless they make it explicit whether they are talking about soft lock or hard lock.
Soft lock, after all, is just an interim stage before hard lock.
And the gap between soft lock and eventual hard lock could be as little as a week or as long as maybe six months.
I imagine the Stats could do a preliminary run of the data after a soft lock. But what benefit does that give?
Those Stat guys would then have to be ring-fenced until hard lock, and not pass any unblinded data information to the company for reasons of data integrity. Otherwise, the company could face accusations down the line, of tweaking a trial parameter in the gap between soft and hard lock.
I rather wish they had never publically introduced the concept of a preliminary soft lock, because it has set expectations going, but also added confusion.
The only rider I would add is that if the soft lock has everything included, other than non-essential and non-substantive additional data, such as the IDH breakdown, they could conceivably use a data analysis derived from a soft lock and use that analysis to go all the way to a topline announcement. And then release the full trial findings after a hard lock, at a suitable time and place such as a Conference like SNO.
But I'm not at all sure such a strategy would be a wise one.
As we are now only 6 or 8 weeks away from having availability of full 5yr data for every subject in the trial, it does indeed invite the question of 'why not wait?'.
But equally that would mean that you couldn't sign off any site that still has a currently living subject, as the relevant patient file would be incomplete until that 5yr mark had been passed.
Personally, I've returned to an 'it'll come when it comes' stance, rather than be on tenterhooks about things.
Though I still want timely updates, as the company has promised.
Just opinion.
TBH Senti, despite what they may have said, I have my doubts as to whether they are being entirely transparent on this issue...
Not sure who did the further pressing in detailed private conversations, unless you are referring to ones you may have had yourself?
If they are being open on the skew, then they should be acutely aware of how the skew is possibly not good news for the trial. And considering appropriate action in response, rather than appearing to shrug it off.
But the whole wider issue of the the putative IA in Summer 2015, its outcome, the subsequent partial hold and its causation, plus the randomization skew, are all shrouded in mystery.
So it's a wider chain of events that, for whatever reason, they can't or don't feel able, to be open and transparent about.
It will great if all is revealed in due course (one day?)
The point regarding efficacy against particular subtypes being considered for approval is supported by the comment Dr LL made right after she stated everyone is living longer.
Paraphrasing, she said that there should be an approval path (which I took to mean at least for the subgroup(s) that appear to be benefiting like never before.
Is that provisional soft data lock or final soft data lock?
Hmmm. The million dollar combo.
We should note that LG and DI have insisted rather profusely that this is all coincidence and that everyone was randomized as the trial had planned.
It's not the DMC that does the statistical analysis post data lock.
It's statisticians contracted to do so by the company.
It would have been the DMC who may have made a recommendation at an interim analysis based on an interim data.
Par for the course.
Yes. But the question that remains is whether a subject is considered off-trial purely because they elected not to crossover at deemed progression, as you have asserted.
We know that crossover is offered, but is it actually a protocol requirement to crossover?
And even if it is, such a patient could be followed as an ITT subject, if not as a per protocol subject.
I think it is wrong to suggest that a patient who elects not to cross over is automatically 'off trial'
Unless you know of a specific reference to that effect in a version of the protocol.
I knew this was likely to happen, and that is why I have repeatedly advocated for the company to give timely updates, regarding anything that might further hold up datalock. And the need for them to be clear if projections (like 'end of next week') refer to soft lock or hard lock.
So up until such time that they are able to confirm a hard lock has taken place, I think we need at least fortnightly status updates.
If they do this, they will be doing both us and themselves a favour.
Patient tries Avistin.
To suggest that it is only NWBO that has difficulty in data-gathering in the time of Covid is ridiculous. It's across the board with many clinical trials being completely halted or postponed.
The hope is, that in the case of the DCVax trial, it was only the acquisition and signing off of the very last bits of data that has been affected.