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Yeah I looked at that stuff a while back. Had consciously forgotten but was there at the back of my mind if you know what I mean.

In terms of the biomarker data. Did you take a look at the Korean company Genome and Co that I posted about yesterday?

Very similar to 4D and just started a Keytruda trial with their single strain candidate.

Phase 3 or 4 doesn't really matter but the link you posted had one very interesting point.

If 0518 was approved in the late stage patients the confirmatory trial would not have to be conducted in other late stage patients.

It could be confirmed from data from the earlier stage Bavencio trial, the pancreatic cancer trial and the monotherapy trial.

Also reminded me that early approval could be secured from what's called Surrogate Endpoint which is where the Treg resistance biomarker data would come in. Independently of clinical bene?t if you can meet surrogate endpoint e. g. Reducing Tregs that could work for early approval

I am not sure exactly how it works but Merck got Keytruda approvals following P2 but still had to do P3 in bigger patient cohorts. And it was pulled in a couple of cancer types when P3 trial results inconclusive.

Maybe people dosed with the combo once on the market can opt in to the P3 trial and maybe the usual P4 is rolled up with P3.

P4 can often apply several years after approval to demonstrate no long term side effects.

Just to clarify - I don't mean Merck is currently running dendritic cell cancer vaccine trials with 0518.

I mean 0518 is one of the candidates for future use in trials as adjuvant to nasal dendritic cell vaccine

A lot hinges on the 0518 results. If they are good I don't think 4D will ever take anything to market themselves.
Merck will buy 4D.

If that belief is wrong, (good results but circumstances not right for immediate buyout) there is still scope for 4D to finish Part B of the Keytruda trial and with Mercks background support secure an early approval of 0518/Keytruda combo.
This is because the drug combo is trying to address an urgent, unmet need. A P3 would still be needed but product could be on the market in the meantime.

Commercialisation of Blautix would require a P3 trial, which would take at least 18 months to set up and run.

But 4D could outlicense and get upfront payment. They are playing cards close to their chest with regard to whether in house or out licensed. I think they are waiting on FDA feedback on trial design options as that would affect the cost.

The vaccine adjuvant collaboration with Merck is a strange one in that milestone payments and future royalties were outlined but the collaboration was specified as 3 years. Even taking into account possible Covid delays I don't think any vaccine could have been brought to market in this time frame. We know that some progress has been made. Presumably it could be extended and maybe a milestone payment could be triggered when that happens. 4D are prevented from using the Micro RX platform for vaccines with any other party while the collaboration is ongoing.

We know that it is for nasal vaccine adjuvants. I suspect they are adjuvants to dendritic cell cancer vaccines as Merck is running a couple of trials for these and I also suspect 0518 is involved. If for cancer vaccine same urgency possibly applies as with the Keytruda study.

An important factor is whether the Seres licence application for SER 109 gets approved. That is expected in the next couple of months. That would represent the 1st approval of a live biotherapeutic product and would stimulate much more interest in the microbiome companies.

At some point Oliveira will stop selling as he has no more left to sell.

A pessimistic view would be that he still has £2m worth to dump but it could be significantly less but probably not lower than £1m.

These are getting to be amounts that can be more easily absorbed by buys. Buys on Monday must have been about £600k.

Angle plc price suffered massively when Jupiter were selling. Look at the chart for them and it was down to 40p. Once Jupiter stopped selling the price rose to well over 100p.

So we have a seller closing out, shorts will need to buy back and critical news due any day now.

I have been buying quite a few at these levels.

I am very overweight 4D

https://www.investopedia.com/terms/s/shelfoffering.asp

Yeah it's a step you put in place to file documents with the SEC so that you can tap into it quicker because you have already provided certain information to the SEC.

So you can act quickly if the SP is good so as to raise capital

In this very good article from January, interview with DP and Charlie Badham, a South Korean company called Genome and Co is mentioned.

https://www.genengnews.com/topics/omics/microbiome-drugs-multiplying-recent-gains/

They are like a Korean version of 4D in that they focus on single strain Live Biotherapeutics rather than trying to use a complicated consortia approach.

http://genomecom.co.kr/

Similarly to 4D they are going beyond using the microbiome to treat gastrointestinal disease and are focusing on oncology and neurological disease.

They already have 1 collaboration with German Merck/ Pfizer for Bavencio.

Just so happens they have just last week announced a Keytruda combo trial for bile duct cancer with Merck.

http://www.koreabiomed.com/news/articleView.html?idxno=13233

So I think this a good demonstration of continued focus from Merck with microbiome derived live biotherapeutics and also their belief in the single strain approach employed by 4D and Genome and Co.

If I have converted correctly from Korean Won Genome is valued at about $350m down from double that a few months ago.

This is not about 1 or 2 drug candidates. It's about a new branch of bioscience and medicine.

In 8 years treatments progressing for

Gastro intestinal disease
Oncology
Asthma
Parkinsons and other neurological diseases
Auto immune disease

Been revisiting some of the science behind the 0518 and Keytruda combo by skimming thru some scientific papers.

What 4D is doing is science at the cutting edge and is potentially of significant value to Merck.

The Keytruda combo trial is in patients that stopped responding to immune checkpoint inhibitors but the initial data from Part 1 showed that some patients began responding again with 0518.

One reason that Keytruda and other ICIs can stop working is due to Treg resistance to the therapy, which suppresses the anti tumour activity of the immune system. (Possible even that ICIs cause this to occur through t-cell exhaustion when fighting larger tumours).

Keytruda is very effective in some cancer patients (about 30%) and in this group of responders it stops working in about half.

One therapy that has been identified as a way of suppressing Tregs is a monoclonal antibody type called agonist anti - GITR. Merck did a trial a couple of years ago with this in combination with Keytruda and presented results at ESMO.

https://www.esmo.org/oncology-news/GITR-Is-an-Attractive-Target-for-Immunotherapy#:~:text=Glucocorticoid-induced%20tumour%20necrosis%20factor,hamper%20regulatory%20T%20cell%20suppression.

This worked fine in patients that had not previously been treated with an immune checkpoint inhibitor but had no responders in the ones that had previously received ICI treatment.

4D had previously confirmed a reduction in Tregs from the topline data from Part 1. The biomarker data they provided is from the tumour microenvironment, which is a still emerging field, and was further confirmation of the likely reason for 0518s mechanism of action as it worked in the 4 in 12 patients who had much higher levels of Tregs in their tumour.

The reason for the delay in the topline data from the 0518 trial was that they are going to present it with the biomarker data, which involves a tissue biopsy and I suspect would be conducted by a 3rd party specialist.

2 further points
Merck can see the trial outcomes. They haven't got time to waste with their Keytruda collaborations as they are dealing with many different combo trials. This has now been running for nearly 4 years and Part B well over a year. If the data was bad I think they would have pulled it by now.

Also why would 4D be spending time and resources setting up the next 0518 trial with Bavencio if the Keytruda data is bad?

So over £1m worth traded today. Given the rise say £550-600k buys.

What do we reckon - small retail on a gloomy day for the market or someone with deeper pockets?

Come on guys, be nice to Oaf-idian or he'll run away and not tell you about any more rumours

Spread is ridiculously tight
27.80 to sell and 27.89 to buy

You guys nearly had me at 49p.

4D are in the process of getting the 0518 with Bavencio trial up and running.

A lead investigator is in place and the trial location is set. Expected to start in the next few weeks.

Who thinks 4D would be using up their scarce capital resources if they have already seen bad data coming out of the 0518 /Keytruda trial?

I think what is meant is that we could be presented with data that shows efficacy in say 7 out of 30 patients.

This would be pounced on by derampers saying what a terrible result, when in fact it would be a decent result. Where before you would have had 30 patients with no treatment options facing death you would have 7 that can survive longer because 0518 is getting Keytruda to work.

This obviously needs to be supplemented with a full data package around the mechanism of action and we now know that additional biomarker data is to be expected.

But it would be a very significant step along the way to commercial development.

If the P2 data is good enough it could lead to a conditional early approval as happened with Keytruda.

The drug would be on the market but a P3 trial would need to be run at the same time and if later results were not good enough it could be pulled.

I think by that time it would be a problem for Merck, not 4D as we would have been bought out long before.

Exactly, just keep in mind the response rate is not likely to be high.
The initial Merck standard of basic success was to have 1 in 10 rate of clinical bene?t.

And that's still the level set to release the second tranch of Oxford money.

Get 2,3 out of 10 or better and it's a winner

Although shorts could start closing and bump it up even if retail didn't get it