Immupharma Share Discussion Threads

[nobbygnome] 14/2/2021 07:40

Here is my original post from September 2017 with the references....and I see the dose in the mice was 100ug not 200ug.

[nobbygnome] 14/2/2021 07:32

Hmmm, now I am a little suspicious as you clearly know what you are talking about.

Anyway yes my concerns are two fold with regard to the drug level. The first is the dose used to see an effect in the animal models. They used the same dose as in humans and obviously because of the size difference the blood level would have been way higher in the animals.

However, more important is the concentrations used in the in vitro experiments with human cells. I don't have the figures to hand but if you work it out there is absolutely no way that level will be reached in vivo in humans because of the bioavailability, dilution in boood and very short half-life. From memory the maximum possible concentration was about 100 fold lower than that required to see an effect in the experiments. And of course by the end of the first day virtually all the drug will be gone so it has to carry on working for the remaining 27 days without any drug present.

So this is why the place of action is so important. Most of the literature they produced suggested a systemic effect. However, when I discussed it with Prof Muller she suggested that the injection site is the place of action and clearly that is the only place where the drug concentration could ever be high enough to have the desired effect but it would only be very brief. But it is not credible to me that you can affect the entire immune system by influencing a few cells at the injection site for a few hours. This is why defining the mode and place of action is critical and why so far their thinking has been confused and inconsistent.

In summary the experiments showed the drug does have a chance of working. However, all the published experiments tell you that the dose given to humans is nowhere near sufficient to produce the desired effects. I suspect the FDA are beginning to have the same doubts as me. I did send an email to them a number of years ago highlighting my concern.......

With regard to the sensitivity of the assays, there is no doubt they have considerably improved over the years. Remember this clinical program was started many years ago and because the drug level is so low, there wouldn't have been an assay sensitive enough then to detect it. However, even with the more sensitive assays now available, I doubt they will be able to measure it for longer than the first day. So the question you have to ask is what on earth is the point of doing that. It doesn't really add any extra useful information and that is why it appears there is clearly something the company isn't telling us.

And finally the whole anti-DNA story is a red herring for me. Because of very low numbers I suspect it was a statistical anomaly. After all they saw it in the European cohort but not the American one. That makes absolutely no sense and adds weight to the theory that these findings appeared by chance because of the very low numbers in the groups. After all it was a subset of a subset....

So a long answer....but you did ask!

[bendaddy] 13/2/2021 23:50

Thanks for your expert answers Nobby. On the recent video I was unimpressed with Tim Franklin's waffly attempt at explaining for uninformed investors what a PK assay is and his assertion that we now have more sensitive measuring techniques - so we'll be able to measure active drug / bioavailabilty or anti-drug antibodies in the blood or injection site tissues? Yeah right......ELISA has been around for decades - have spectrometry / microscopy / fluorescence instrumentation really got that much more sensitive in the last 10 years? I've read the original science, mouse studies and P1-P3 results and associated papers and it's clear that P140 has a remarkable effect by interfering with CMA on autoreactive cells (even if at a molecular level the MOA isn't fully understood). What makes you so sure that the dose is too low for SC injection and that the serum half-life / PK / bioavailability of the drug is inadequate to 'work' for anti-dsDNA SLE patients? Have you read any other results or published work that suggests this or is your scepticism based only on email exchanges with Dr Muller?. Is it not just that the first P3 trial design / end-points / recruitment was not right and the next P3 could be successful or do you have good reason to predict that it will fail again?

[nobbygnome] 13/2/2021 09:19

>> eva

I am just thinking about your comment concerning having £177k in IMM. You really are taking an enormous risk. Yes it might go up ahead of phase III results (assuming the FDA approve the trial) but the earliest those results could be out is late 2023 IMHO. You have an awfully long time to wait for things to develop.

I guess there will be a small rise if the trial is approved and that would be an opportune time to sell IMHO. DYOR and NIAI....

[nobbygnome] 13/2/2021 09:06

>> eva

Good to see you are back in to SNG. It could be your biggest winner ever, although of course we need positive trial results. However, that is ever so slightly more likely than Lupuzor chances of a positive phase III result.

[nobbygnome] 13/2/2021 09:05

>> bendaddy

1. Quite likely but pure speculation because as usual the company aren't being honest with investors.
2. The science is exceedingly dodgy and the interpretaion of it inconsistent. As I have said a number of times they have changed the site of action which tells me they don't really have a clue!
3. Not much IMHO. They are little better than IMM in terms of experience. The fact that IMM ended up with Avion as a partner and they paid zero cash upfront tells you an awful lot about the quality of the overall data set! Companies with interest and expertise in this area shunned the drug.

[halfbutt] 12/2/2021 14:46

Ken..your lemmings and mushrooms comment always made me laugh and was certain wed make you eat those words... well I'm not laughing now mate ..... good luck still to others but as the dragons say "I'm out "

[bendaddy] 12/2/2021 13:22

Answers from Nobby please:
1. Could it be that the SPA was rejected and the PK method requested because the FDA have the same concerns re: low dose / half-life and site of action (skin vs mouse model?) - and they want to test this before or as part of the P3 trial proper? The PK methodology and assay results will surely be pivotal as will the trial design / results.
2. How much confidence can we have in the trial designers and the science? Who is designing the next P3 trial? Immupharma's CNRS scientists?
3. How much confidence can we have in a small sales and marketing pharma (Avion) focused mainly on commercial development and acquisition of late stage development assets, who have an unimpressive website, little recent news, are big on women's health and dietary supplements, have no real rheumatology/autoimmune products or scientific experience (except for a new formulation of already proven gout drug (Colchicine)) - do we really expect them to carry on with this or dump the licence deal?

Here's an interesting read about P3 trial design and success rates (in Lupuzor's case the P2 results were also unconvincing) and I hope the trial designers are fully aware of the latest research re: the anti-dsDNA population, and know where best to recruit (eg. we've never had an explanation of the poor P3 result in the US anti-dsDNA cohort and not Mauritius please where participants probably got higher SOC during the last trial).

[wigwammer] 12/2/2021 11:13

Hello Dr Biotech. Yes, I vaguely remember the name. Tell me, were you one of the doubters at 40-something pence who missed the ensuing 300%+ rise to peak, 10 fold if you got in near the lows? Or were you one of the common-or-garden naysayers who always appear AFTER a share multiplies? The latter are a common feature of the biotech world - "it's risky!" they shout - as though the words have value simply because they they are shouting it :)

[nobbygnome] 11/2/2021 19:37

>> dr biotech

Yes I received threats about coming round to 'sort me out'. For a few weeks I was seriously concerned because they found out who I was. Because we are out in the country we usually leave oour doors unlocked but for a few weeks I locked everything up and was extremely wary! It really was absolutely disgraceful....

[antonagis] 11/2/2021 19:34

Anyone else looked at KEN CHEUNGS posts on numerous ADVFN chats? Every single one is a deramp post without exception. Beware of him and THOMAS EARNSHAW. One and the same paid deramper.

[colsmith] 11/2/2021 18:43

SK, thanks for comment, re your:

"So my reading is that yes, Avion and the FDA are working towards a P3 trial design, however that design will be without an SPA"

Nobbie's extract shows the FDA are able to limit the extent of special approval- regulators don't you just love them, precise but vague.

--However, an SPA agreement does not indicate FDA concurrence on every protocol detail, as described further in section III.B.2, Reaching SPA Agreement With FDA.--

So nothings assured even with an SPA, but practically if the clinical trial part is approved by the FDA at the Q2 meeting then, if it is successful clinically, the other stuff can be taken separately - delaying matters of course.

Not anymore to say - but its still the binary bet for the US trial. The US operate in interesting ways - a while ago Skypharma (now VEC) sought approval for Flutiform - it's not even now agreed I believe, but the EU and Japan approved a while back and its on sale. Maybe a multi body approval is best so at least one can accept a practical test - or is it experts disagreeing?

Have a nice day - I'll go of air on this and wait for the next instalment of company output.

[nobbygnome] 11/2/2021 18:30

You have to understand I have tried that approach before. I was having a very informative email conversation with Prof Muller and McCarthy stepped in and stopped the exchange. Conversing with them is pointless if you are asking meaningful questions as RB1206 validates above. Curiously I was proved to be correct in all my assessments...

[nobbygnome] 11/2/2021 18:28

The words IMM management and honest don't go together.....

[wildbunch] 11/2/2021 18:24

Well done Nobby.

Now, what about keeping the management honest by sending them that e mail and dealing with their response. I would be very grateful if you did.

That's all.

[rb1206] 11/2/2021 18:18

Nobby - Oh yes, I remember his posts, good deed for sure.

[rb1206] 11/2/2021 17:47

Nobby - Always appreciate your input. Back in 2018/2019, when everyone was soooo positive about the coming phase3 results and share price shot up to almost £2, it was your rational post saved so many ppl a bundle and others who didn't pay attention left holding the empty hat.
Back in 2018/2019 I went along to one of their investors presentation presented by Tim McCarthy and Dimitri, I asked Tim why hasn't he bought any shares (personal money)if everything is so rosy and are they looking to raise any cash, he ignored both of my questions. Few days later RNS was released, they raised £10m. Than came the results and rest is history. Tim's past record speaks for it self, some ppl even called him kiss of death. I will never invest if I see Tim McCarthy's name on BOD......imho...dyor.

Nobby thank you again and keep up good work.

[nobbygnome] 11/2/2021 17:23

And just to say I think the inexperience of Avion in this indication is really being exposed. I highlighted this as a potential issue when the deal was signed and now it appears the chickens really are coming home to roost!

A bunting of red flags are fluttering in the breeze....

[nobbygnome] 11/2/2021 17:20

The paragraph below is from the FDA guidance (link below) about SPAs, part of which s_k posted earlier. The fact that the SPA has not been granted really is worrying with regard to the acceptance of the study design by the FDA. The company's interpretation of the issue is vastly over optimistic as usual.


An SPA agreement indicates concurrence by FDA with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses) for a study intended to support a future marketing application. These elements are critical to ensuring that the trial conducted under the protocol can be considered an adequate and well-controlled study that can support marketing approval.4 Feedback on these issues provides the greatest benefit to sponsors in planning late-phase development strategy. However, an SPA agreement does not indicate FDA concurrence on every protocol detail, as described further in section III.B.2, Reaching SPA Agreement With FDA.

[sicilian_kan] 11/2/2021 17:04

Hi COLSMITH, it is clear that the SPA hasn't been agreed.

1) An SPA was applied for by Avion, see the RNS on 27 July 2020.

2) Then see the RNS this week stating "As part of the FDA feedback from the meeting on 4 December 2020, it has been clarified that a Special Protocol Assessment ("SPA") will not be applicable". If the SPA issue was going to be considered at the next Q2 meeting then this sentence would have been superfluous.

So my reading is that yes, Avion and the FDA are working towards a P3 trial design, however that design will be without an SPA.

[colsmith] 11/2/2021 15:38

SK re 36837, Yo say the SPA hasn't been agreed but the RNS text says:

"A final guidance meeting between Avion and the FDA is being planned at which Avion will submit the methodology for assessing PK as part of the Phase 3 trial. This meeting, which is expected to take place in Q2, will also confirm previous submissions to FDA on the study design, clinical end points and approval process"

So the SPA point you make seems to be overridden by the statement that P3 design will be sought in Q2 and PK methodology is part of the P3 trial. Clearly its pointless to start a P3 type activity without FDA agreement of the structure. The PK methodology is to be clear and FDA approved before the full P3 clinical trial is given a green light or not. Whether the FDA is deliberately slowing progress for some reason or the fact Lupuzor has some involvement with T cells, which seems to figure in COVID illness activity, is significant in some way and that is why the PK is now in the loop when it wasn't on the previous tests.

Perhaps the only concrete thing is that AVION seem positive on the chances of a successful P3 trail because if they aren't why bother to take matters forward and devote a few million dollars to take Lupuzor forward. clearly for PI's its as previously a binary bet except AVION seem convinced its all worthwhile; I guess from an investor viewpoint that may or may not be relevant.