Member Info for Sangijuelas1

Amgen got FDA accelerated approval for its Lumykras drug in May and it is already on the market.

Lumykras is for treating advanced non small cell lung cancer where the KRAS mutation Biomarker is present and approval came from a Phase 2 trial in 126 patients.

Clinical benefits are that the drug has shown to extend survival in late stage cancer for around a year or so.

It is being hailed as a blockbuster drug.

Sound anything like a drug we are familiar with?

It

I mean so many are crying out for the 0518 data but when MMs start playing games when it is eventually released how many would really be able to tell for themselves how good or bad it is based on the RNS

Once the rampers or derampers start pumping it or describing it as an epic fail. I will have some idea whether it is good or not. Will you?

What I find strange is the way people invest in a small biotech but make zero effort to engage with the validity of the science, the trial process and regulatory requirements etc

Most just look at the price chart and think that looks cheap or listen to some idiot rampers prediction. I mean if someone comes here telling me the price is going to double next week and I listen to them that's on me.

If you really don't know what is going on here half the time are you in the right place? Professional fund managers often avoid small biotechs because they don't understand the science and can't tell a diamond from fools gold. Ones that do get involved like Baillie Gifford or Chardan employ people to advise them on the science.

To be honest with you Michael I would rather explore/discuss thoughts on some of the science stuff I have posted rather than a flippant comment I made about someone's price target.

This article
https://www.frontiersin.org/articles/10.3389/fonc.2021.684098/full

Sorry more science talk but that's where the real value is.

Leaving Glioblastoma aside as it's more a demonstration of future opportunities , let's turn back to lung cancer, which is one of the most advanced 0518 programs.

From the September ESMO presentation the RNS states
"At baseline, patients who achieved complete response, partial response or stable disease for at least six months (collectively 'responders', N=4) from the combination of MRx0518 with Keytruda® (pembrolizumab) had significantly greater densities of CD3+FOXP3+CD8- regulatory T cells (Tregs) and CD3+KI67+ proliferating T cells in tumors at baseline, compared to patients with progressive disease (PD, N=8), p=0.0381 and p=0.0048, respectively."

So the tumour biomarker data showed that 0518 worked best in patients with high levels of Tregs, as 0518 works to overcome Treg resistance to Keytruda (as well as exerting its own anti - tumour effects?).

The problem of Treg resistance to ICIs is discussed in relation to lung cancer in the following paper, which I quote from.

"It is therefore imperative to better understand the barriers to the efficacy of ICIs, particularly additional mechanisms of immunosuppression within the lung cancer microenvironment. Recent evidence suggests that regulatory T-lymphocytes (Tregs) serve as a central mediator of immune function in lung cancer, suppressing sterilizing immunity and contributing to the clinical failure of ICIs"

"Hence, there are still several remaining obstacles limiting the therapeutic efficacy of ICIs in lung cancer that must be overcome in order to further enhance drug responses and improve patient outcomes."

"recent pan-cancer meta-analysis determined that lung cancer patients with higher tumor densities of FoxP3+ Tregs had significantly poorer disease-free survival rates (49). A lung cancer-specific meta-analysis similarly found that, in a combined cohort of 1,303 NSCLC patients across 11 studies, an increase in tumor-infiltrating FoxP3+ Tregs was associated with poor overall survival. "

The article suggests some potential therapies to target Tregs, including chemotherapy drugs and monoclonal antibodies with possible toxicity and efficacy issues.

Maybe the authors would be interested in 0518?

This article highlights how brain cancer is an important area of research for Merck and Keytruda
https://www.healthline.com/health-news/early-immunotherapy-can-help-treat-glioblastoma-cancer

This is a link to an ongoing Keytruda combo trial for Glioblastoma using a polio vaccine

https://immuno-oncologynews.com/2021/02/01/first-glioblastoma-patient-dosed-phase-2-istari-trial-testing-pvsripo-plus-keytruda/#:~:text=Keytruda%20has%20been%20approved%20by,two%20prior%20lines%20of%20therapy.

Here is another example of why 0518 could be so valuable for big pharma like Merck.

Glioblastoma is an extremely aggressive form of brain cancer that is often fatal in a short period of time.

So far no immune checkpoint inhibitors have been successful in P3 trials.

This recent study puts the failure of ICIs in Glioblastoma down to Treg cells resistance.

https://www.nature.com/articles/s41467-021-22885-8

If you turn to slide 12 on the latest investor presentation you will see that it is titled "MRx 0518 Overcomes Treg Mediated Resistance to ICIs"

4D talk about directly effecting the tumour microenvironment. Compare to the quote in this Mayo Clinic article on Glioblastoma "The future is going to involve directly affecting the microenvironment of these cancers"

https://www.mayoclinic.org/medical-professionals/neurology-neurosurgery/news/new-approaches-to-immunotherapy-for-glioblastoma/mac-20488153

Just to add, these are the reasons I am here.

0518 potential and partnerships

Future Merck buyout

The Micro RX platform delivering not just a new drug or two but working to build a new branch of medicine.

I was prompted by a poster on the other board to have a closer look at the uses of Biomarker Data in clinical trials, when going for approval.

"As more biomarkers are identi?ed, they have the potential to enhance the research and development process of new medicines by providing new ways to measure disease activity. Biomarkers can also help measure the impact of medicines being studied and can signi?cantly shorten the time required to show that a new medicine is safe and effective."

The traditional way that drugs get approved is through data on Clinical Outcomes. This data can take a long time to collate and leaves patients having to wait longer for treatments to be approved. An example of Clinical Outcomes would be things like tumour shrinking in cancer and other indicators that make up the Overall Response Rate to a drug.

In recent years the FDA has acknowledged that there need to be accelerated pathways so that patients with high unmet treatment needs are not left waiting for years for treatments that could help to be approved. (Think right now of patients in the UK who have stopped responding to Keytruda that could be taking 0518).

So pending data on Clinical Outcomes drugs can be granted Accelerated Approval on the basis of Surrogate Endpoints. This is where the biomarker data comes into play because it can be used as a surrogate for efficacy or used as a way to grant Accelerated Approval for patients with the right biomarkers.

"For a serious disease or condition where there is a signi?cant unmet need, like cancer, the FDA may allow for the use of a surrogate endpoint to demonstrate the effect of a medicine. A surrogate endpoint is a marker—such as a biomarker or other measure—that is expected to predict, but is not itself a measure of clinical bene?t, and can thus be substituted for a clinical endpoint"

"Between 2010 and 2012, the FDA approved 45 percent of new drugs on the basis of a surrogate endpoint."

So while 4D are continuing with trials to get more data on Clinical Outcomes, 0518 could be approved for patients with specific biomarkers.

This is why I am not bothered about the delay with the interim data readout.

https://www.fda.gov/about-fda/innovation-fda/fda-facts-biomarkers-and-surrogate-endpoints

I get where Michael is coming from but I don't think Porky is being over the top with the price predictions.

If this did get to 170p that would take the company out of the penny stock realm in the US. (Generally stocks under $300m market cap are regarded as high risk penny stocks)

Enabling it to move closer to the Chardan and Landeburg Thalmann price targets and getting a lot more attention.

What I would add is that a lot of people still value the company based primarily on the Blautix potential. Understandable because that's the asset that looks closest to a P3 trial when you look at the pipeline.

Blautix does have good potential but it is nothing compared to 0518, which has already extended the lives of several late stage cancer patients who have exhausted all treatments, has demonstrated a degree of tumour shrinkage and is also being explored in earlier stages of treatment, e. g. as an alternative to chemotherapy before surgery.

There's a reason why 4D has partnerships with the likes of Merck and Pfizer based on 0518. And why they are talking about accelerated approval. They have not put Blautix on the back burner for nothing, it's so that they can focus on bringing 0518 to the market, with Merck on hand to help them with their FDA submissions.

In addition, we are talking about a drug discovery platform that has already generated candidates for IBS, IBD, asthma, multiple cancer types and Parkinsons with more on the way including the second generation cancer ones.

I am starting to see this small UK company based in Leeds as an absolute powerhouse, although I am resigned to the fact that they will probably be taken over by Merck in the next year or two.

Have to wait and see. Would be very interesting Monday if were to hit and hold $10

Getting quite a bit of attention over there. Now nearly 40% up

Sweet

Still way down on the last placing at 110p

Now up 20%

Looks like short squeeze

With some very healthy buys coming in

With 0518 each patient can take it with Keytruda for up to 2 years.
Any delay to the interim readout means more patients dosed for longer periods of time, so more chance of demonstrating significant tumour reductions, partial response and stable disease over time.

Michael, why do you keep ignoring the bleeding obvious?

It is a 2 year trial. They are overdue on an interim update, which they are entitled to give at any time because it is only going to be a snapshot of progress to date.

They have explained that given the ESMO data on biomarkers, that they are now collecting this data for the latest group of patients to present in addition to the data on efficacy.

So they will be able to demonstrate precisely why 0518 works better in some patients than others.

That will enable them to start a further trial for patients with these biomarkers that could lead to early approval.