Member Info for sadoldgit

Kat strangler, you bought in at the drop in March at 105p and sold in April. Well done you must have made a few pennies.
What made you decide to 'buy in' in the first place? A chance to make a quick buck as opposed to long term term investment. The only thing I can deduce is that you are looking to buy back in at a lower price. It is therefore in your interests to see this go southwards. Yes shares do go up and down. AIM is volatile.

'but it's also valid to ask if there are any blatant reasons beyond 'it's the market' to see why progress, at least in the sp, isn't forthcoming'

That is your statement. You claim to be an investor, so I think best you sort that one out for yourself, as is your decision alone.
Clearly you have doubts as I can understand. I take it you have an understanding the SKI market and while some make it and others fail.
If we understand at the basic level, the objectives of a specialist company to put their compound into clinic and the amount of time, effort as well as finance then we ought then to be in a position to decide for ourselves whether we choose to invest.

Regards

From 2013. How they were singing the praises.

'Expert opinion: JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development. Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling. The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic. These advances are expected to lead to further significant progress improving patient outcomes and quality of life.'

They looked at the plus points, but the minus points ie severe side effects, they were either ignorant or financially swayed not to. Those at the top want their performance related bonuses. As long as they get a drug into the clinic is all they are interested in.

Regards

It looks like the side effects associated here ofJakies 1, 2 and predominantly 3 are the problem here. Jak 3 is well known to increase risk of infection due to reduction in white cell production..
The days left for current inhibitors of mainly Jak1, Jak2 and Jak3 look seriously numbered certainly with regards to covid. Of course this will apply to viruses that have similar effects.

Regards and good update there Citizen.

To answer your question. Yes 737 would qualify. NHS desperate for new effective treatments. SDC 1802 especially and that is able to work in combo as a mior or major supportive role.

CART therapy
Although CAR-T cell therapy has been a revolutionary cancer treatment tool, high rates of toxicities with some fatalities have prevented CAR-T cell therapy from becoming first-line treatment.

SRA 737 firstly was out of our hands as was licensed to sierra so NHS out of the question

Secondly at this time the NHS were wanting cancer treatments at a knockdown discount price. This put many companies off. ( very much reduced profits)

Now owned by GSK maybe they will push development of a 737 combo into a much needed treatment.
Overall looks good for any promising inhibitors SDC1802 included. Only time will tell.

Regards

Interesting to note they discontinued the oral route I would think due to Jak2.

That is one less competitor we not have to worry about!

Brepocitinib (PF-06700841)
Brepocitinib is a dual TYK2/JAK1 inhibitor with partial selectivity over JAK2, which binds to the active sites in the catalytic domains of TYK2, JAK1, and JAK2.64 In a phase 1 trial, brepocitinib was well tolerated in healthy subjects and psoriasis patients; however, platelet and reticulocyte counts were reduced due to JAK2 inhibition.67 In a phase 2a trial, patients treated with brepocitinib experienced significantly greater changes from baseline in PASI at week 12 (primary endpoint) compared with placebo recipients (P < .05). Brepocitinib was well tolerated and there were no herpes zoster infections.68
Biomarker analyses indicated that brepocitinib treatment reduced the expression of various inflammatory genes and cellular pathways involved in psoriasis pathogenesis.69 Brepocitinib induced IL-17A/F inhibition more rapidly than did tofacitinib in psoriasis skin biopsies (2 weeks vs 4 weeks).69,70 Improvements in molecular and clinical measures of psoriasis were also more rapid and complete with brepocitinib than with tofacitinib.69,70 Although development of oral brepocitinib for psoriasis has been discontinued, Phase 2b trials will evaluate topical brepocitinib in mild-to-moderate psoriasis and oral brepocitinib in active PsA, moderate-to-severe ulcerative colitis and Crohn's disease, and SLE (Table I).
PF-06826647
PF-06826647 is an oral, dual TYK2/JAK2 inhibitor that binds to the active site in each kinase's catalytic domain.66 In 2 phase 1, randomized, double-blind, placebo-controlled trials in healthy volunteers and patients with moderate-to-severe plaque psoriasis, PF-06826647 was well tolerated with an acceptable safety profile.71,72

Regards

From Jan21

Regulatory authorities recently issued boxed warnings that tofacitinib 10 mg twice daily was associated with increased risk of pulmonary embolism and higher mortality in RA patients.16 Tofacitinib failed to gain regulatory approval in the United States for psoriasis. Clinical development of JAK1-3 inhibitors for psoriasis has largely been abandoned because of the low therapeutic index stemming from their relative nonselectivity.

Taken from link shown below.

from early 2022

Abstract
Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.

A further longish but interesting read here in the following link.
https://www.jaad.org/article/S0190-9622(21)02017-X/fulltext

Regards

I would think Ahfam that GSK are well aware of both our tyk2 programmes. If 1802 were a little further down the road ie passed stage 1 then they would be looking at combo with a range of compounds. My opinion here being if this were the case and should it prove ok ( no reason as to why not only being subject to safety profile) then they will want to own it and not be a licensee. That would mean taking on both compounds, our 27% share of 737. SKIL platform amd FLT +3.

I am certain that success in phase 1 trials for 1801 will be pivotal and indeed transformational.

If GSK have not had a perusal of our pipeline then they ought not to be out looking to corner the immuno therapy and immuno oncology market.

Regards and beer time coming up.

I will post this again It relates to 737 from
Relating here to SCLC only, an exerpt. From 2019.

Next, we expanded our study to an immunocompetent SCLC model to explore both the intrinsic and immune-mediated anti-tumor effects of SRA737+LDG regimen in combination with anti-PD-L1. We first determined that SCLC cell lines H209, H524 and RPP were resistant to monotherapy gemcitabine in vitro (Fig. S3B), with the RPP tumor model described above selected for further in vivo testing. RPP tumor bearing B6129F1 immunocompetent mice were treated with LDG (40mg/kg, 1/7, first day of week), SRA737 (100mg/kg, 2/7 first and second days of week) and anti-PD-L1 (300µg, 1/7, third day of week) as single agents or in combination. SRA737+LDG regimen mimicked the schedule currently being used in the clinical trial described above with or without anti-PD-L1 on the third day of a weekly cycle. We did not observe a significant anti-tumor effect with any single agent treatments (anti-PD-L1, SRA737 or LDG), and only a moderately delayed tumor growth with combined SRA737 and PD-L1 treatment (Fig 4A). However, we observed remarkable tumor regressions when we combined SRA737+LDG with anti-PD-L1. All mice achieved some level of tumor regressions and 80% of mice (8/10) had complete tumor regressions which were sustained up to 60 days post treatment

Given that anti-PD-(L)1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737+LDG regimen is well tolerated in clinical trials in SCLC (NCT02797977), our preclinical data provide a strong rationale for combining this regimen with inhibitors of PD-(L)1 pathway in the clinic.

Regards

My thinking is along the lines of:-
Cancer we can kill by chemo or radiotherapy, we cannot kill all of the cancer at once. Repeat treatments are required,
During this time and as part of our own immune system the cancer tries to repair itself or replicate to overcome the damage that has been done. Our own immune system via the make up of cells whether non cancerous or cancerous will do its best for the survival of both. After all both cells are produced by our bodies and are part of us.

We can destroy parts of a cancer by chemo or radiotherapy and to a certain extent limit cancer growth, by various treatments for example PARP, Chk1, Wee1 Endocrine ( ie hormone therapy treatment for OC). However some cancers will learn to overcome and divide by mitosis into new DNA altered cells. As we can control the signalling to prevent new cells being produced, guess what? The cancer overcomes these inhibitive treatments to learn new ways to survive.
The body however, can discriminate between a normal and a cancerous cell. It can consume them ( macrophages) basically envelope and digest. It cannot however and does not have the ability to consume tumours.

Since as stated previously that our bodies can destroy individual cancerous cells ( not tumours as these are a multitude of cells with no apoptosis ie programmed cell death) then an additional treatment that increases the population of natural killer cells ( innate immune system) would be required to prevent new cancer growth developing.

We have as previously stated a means reducing and in many cases effective tumour reduction). When new cells are likely to be most prolific ie after tumour/cell damage then surely the best form of treatment would be an inhibitor that can increase the innate natural killer cells that can eradicate these new population of cancer cells.

We have helper cells and killer cells which both need regulating during the treatment of cancer. Complete eradication of the cancer I am not supposing, but more of a control of the disease. Well within the remit I would suggest of a well designed immuno oncology inhibitor such as TYk2 or Tyk 2 with an optimal amount of Jak 1 haha

Just as important as the efficacy of a compound it is also important as to when and a dosing regime of inhibitors.

What I am learning is that there are gaping holes for new and more effective treatments. One size does nor fit all. There is a massive market out there approaching over 275 billion dollars a year, I am sure we have at least two potential wholly owned compounds that would not only take a fraction of a slice of this but also bring much needed relief to those that need it most.
Regards and the beer is getting to me.

All is well thanks Gunner.
I have spent the evening researching ovarian cancer. Both 1L-8 and IL-10 are well elevated as the disease progresses.
Cross referencing but nothing really to do with 8 and 10

From 2015
Summary:
Tyrosine kinase 2 (Tyk2) is an enzyme involved in intracellular signalling and has an important role in activating the immune system. But enzymatically active Tyk2 can also promote excessive immune reactions and growth of certain cancer types.
Since several years, scientists are developing substances to specifically inhibit the kinase activity of Tyk2 for the treatment of inflammatory diseases and for potential use in cancer therapy. However, complications may occur: Tyk2 crucially contributes to the maturation and activation of natural killer (NK) cells. NK cells form part of the innate immune system and are the first defence against virus infections and cancer. They recognise cancer cells and produce a series of proteins capable of destroying them. Inhibition of Tyk2 could therefore also weaken NK cells and block an important front of the body's own defence against cancer.

It then goes on to state

Tyk2-deficient mice were not able to control cancer growth. NK cells of these animals exhibited incomplete maturation and were unable to destroy cancer cells. Surprisingly, in mice whose Tyk2 was present but enzymatically inactivated, cancer growth was strongly suppressed and NK cells retained their ability to kill the cancer cells.

Project leader Birgit Strobl explains: "Until now, it was unknown that Tyk2 has effects within the whole organism that do not depend on its enzymatic activities. Without its kinase activity, it still drives NK cell maturation and boosts their activity. Here lies the key for cancer medicine. Drugs that inhibit the kinase activity of Tyk2 -- and there are currently several of them in the testing phase -- do not hamper the immune system in its work. These drugs are therefore even more promising for cancer therapy than previously thought.

Since the immune system now can recognise and destroy cancer cells I am pretty certain as to why Sierra were looking at 737 with PARP or WEE1 + an Immuno Oncology inhibitor!

Or maybe I am as mad as a hatter.

Gunner, good evening. I am of the opinion that the CTA acceptance is not priced in. There is always the element of doubt. I think a cause may well be the mention of raising funds further down the line. The options are:-
Raise funds via dilution whether via Peel Hunt or by a placing.
License or partnership via a pharma.
Sooner or later funds will be required for later stages of Tyk2 Jak1 development.

That is the crux of the matter.
Just how far Sareum can go before they need further funding I would hazard a guess around beginning of phase 2 trials.
However it is normally prudent to raise funds in advance before you actually need to use them.
That is just about the downside in a nutshell.

However, we may or may not as the case may be be due a milestone payment soon should GSK push SRA737.
Yes their primary aim was to buy momo.
Why did they not just buy momo outright?
They must of had a secondary aim too.
Development in the pharmaceutical world can be painstakingly slow at times. GSK have their own compounds too.
We also have to take into consideration as to why Sierra oncology took down the for sale sign early 2020 around the same time as they had 737 patented for combination with two other therapies.
Any news from across the other side of the water with regards to continuing development of 737 should give the SP here a nudge up as with regards to further milestone payments. Half a million will not take us far, it is the development of 737 that will encourage investors. ( circa 70 million is possible milestone payments)
Sareum need an income whether via milestone payments and or royalties.

Unfortunately we do not know how Sareum intend to play their hand. We know what is in their hand but we dont know who the other players are and what they have in their hand.
Do they on license 1801 on its own and use funding for development of 1802.
Or do they hang on and license both together?
They may well be in late stage informal discussions. At the same time Sareum will need to demonstrate that they themselves can raise their own funds and therefore not be at the dictatorship from a large pharma. if we cannot demonstrate that we can raise funds then that would put us at the mercy of any potential licensee/buyer. If we have funds we dont need to license or sell. If an outside company want it they have no alternative but to pay the price ( whatever that may be)
Yes we may have a trip south, but for what we have a hundred million market cap is peanuts. Inflation predicted at circa 13% we should be going up not coming down.
In any form of investment, persons want to make as much money as possible from their investment by whatever means and that includes negotiations with and by pharma's as well as our selves.

I wont sell but if we drop a little more I will be adding.

Regards.

Ustekinumab, sold under the brand name Stelara is a monoclonal antibody medication developed by Janssen Pharmaceuticals, for the treatment of Crohn's disease, ulcerative colitis, plaque psoriasis and psoriatic arthritis, targeting both IL-12 and IL-23.

Ustekinumab is designed to interfere with the triggering of the body's inflammatory response through the suppression of certain cytokines. Specifically, it blocks interleukin IL-12 and IL-23 which help activate certain T-cells. It binds to the p-40 subunit of both IL-12 and IL-23 so that they subsequently cannot bind to their receptors.[14]

According to information provided by Centocor, maker of one medication based on ustekinumab, their version of ustekinumab is associated with several types of serious adverse effects. These include an increased risk of infection, such as by tuberculosis and an increased risk of certain types of cancer. As with some other immunosuppressant drugs like ciclosporin, the brain swelling of posterior reversible encephalopathy syndrome is a risk. The pharmaceutical company also reports serious allergic reaction as a possible side effect. More common side effects are upper respiratory infection, headache, and tiredness.[12]

Clinical trials have shown that subcutaneous ustekinumab was generally well tolerated. Most treatment-emergent adverse events were of mild severity.

Star. It was not that the Aurora FLT+3 does not work. It was that the chinese could not formulate the compound to be taken orally. Similar problems were experienced with Tyk 2 compounds for the manufacture of large quantities sufficient for clinical trials which has since been overcome. Crystallisation of a compound ( for which a patent now exists) clearly helped resolving this formulation issue.
Furthermore it was an undisclosed chinese pharma that took this issue on, around the same time that there was the Covid 19 outbreak whereby other kinase inhibitors were being experimented for the control of the disease. Much controversy yes. There is absolutely no reason why a similar solution cannot be applied to Aurora (funds permitting).
Sareum have concentrated all their resources into our Tyk2 compounds which is very similar to what Sierra did with momo.

Regards

Whoops missed at bit, this from Jan 10th 2022

The study, published today in Nature Cell Biology, was carried out by Cancer Research UK and supported by Breast Cancer Now.

PARP inhibitors, which include olaparib and rucaparib, are used to treat some patients with ovarian, breast, prostate and pancreatic cancers – usually patients who have inherited a faulty BRCA1 or BRCA2 gene.

So far, more than 30,000 patients have been treated with olaparib worldwide.

PARP inhibitors target PARP1, one of the DNA repair tools – rendering it inactive and locking it in place, trapped on the DNA. Not only does this stop DNA repair, but the trapping of PARP1 onto DNA will eventually cause cancer cells to die. But PARP inhibitors don’t work for everyone, and it’s estimated that over 40% of patients with a faulty BRCA1 or BRCA2 gene don’t respond to them.

AZ released an RNS this morning, an extract from follows

This approval by the European Commission was based on results from the OlympiA Phase III trial published in The New England Journal of Medicine in June 2021 and follows the recommendation for approval in the EU by the Committee for Medicinal Products for Human Use of Lynparza in this setting.1 In the trial, Lynparza demonstrated a statistically significant and clinically meaningful improvement in invasive disease-free survival (iDFS), reducing the risk of invasive breast cancer recurrences, new cancers, or death by 42% versus placebo (based on a hazard ratio [HR] of 0.58; 99.5% confidence interval [CI] 0.41-0.82; p



Lynparza also demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), reducing the risk of death by 32% versus placebo (based on a HR of 0.68; 98.5% CI 0.47-0.97; p=0.009). The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials.
BRCA

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells.9 When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional alterations that can lead to cancer. Cancers with BRCA mutations are more likely to be sensitive to PARP inhibitors including Lynparza.13-16.

'Cancers with BRCA mutations are more likely to be sensitive to PARP inhibitors including Lynparza.13-16.'

Sounds very good and is true. But if we look at the excerpt from below it states that estimation of over 40% dont repond to them.


PARP inhibitors target PARP1, one of the DNA repair tools – rendering it inactive and locking it in place, trapped on the DNA. Not only does this stop DNA repair, but the trapping of PARP1 onto DNA will eventually cause cancer cells to die. But PARP inhibitors don’t work for everyone, and it’s estimated that over 40% of patients with a faulty BRCA1 or BRCA2 gene don’t respond to them.
Full report in link below.
https://ecancer.org/en/news/21461-study-reveals-cancer-s-mechanism-of-resistance-to-parp-inhibitors#:~:text=Scientists%20have%20revealed%20how%20cancer%20can%20resist%20PARP,PARP%20proteins%20that%20get%20trapped%20onto%20their%20DNA.

Regards

Tyk2 not cut the mustard on its own and neither will Jak1.

Antibody-based treatments
Antibody specific to select immune components can be added to immunosuppressive therapy. The monoclonal anti-T cell antibody OKT3, once used to prevent rejection, and still occasionally used to treat severe acute rejection, has fallen into disfavor, as it commonly brings severe cytokine release syndrome and late post-transplant lymphoproliferative disorder. (OKT3 is available in the United Kingdom for named-patient use only.)

The dear old cytokine release syndrome or in this case severe cytokine release syndrome.
From Wiki
In addition to adoptive T-cell therapies, severe CRS or cytokine reactions can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS).
Graft-vs-host disease
Graft-versus-host disease (GvHD) targets JAK 1 and 2, the human tyrosine kinase protein required for signaling in multiple cytokines. When these kinases are activated, signal proteins of the signal transducer and activator of transcription (STAT) protein family - which include transcription factors for target genes that serve proinflammatory roles - are phosphorylated.[9] The severity of GvHD is highly variable and is influenced by the amount of native cells present in the environment along with other regulatory T cells, TH1, TH2, or TH17 phenotypes.[10] Both CD4+ and CD8 IL-17 producing T cells have been shown to cause aTH1, causing tissue inflammation and resulting in severe GVHD.[11]

Treatment for less severe CRS is supportive, addressing the symptoms like fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and antihypotensive agents to raise blood pressure. For moderate to severe CRS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgment must be used to avoid negating the effect of drugs intended to activate the immune system.[5]

Tocilizumab, an anti-IL-6 monoclonal antibody, was FDA approved for steroid-refractory CRS based on retrospective case study data.[5][6]

Lenzilumab, an anti-GM-CSF monoclonal antibody, is also clinically proven to be effective at managing cytokine release by reducing activation of myeloid cells and decreasing the production of IL-1, IL-6, MCP-1, MIP-1, and IP-10. [23][24] Additionally, as a soluble cytokine blockade, it will not increase serum levels of GM-CSF (a phenomenon seen with tocilizumab and IL-6).[25]

Although frequently used to treat severe CRS in people with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.[1

We have already proven to good effect SDC1801 in Covid 19. Cytokine release syndrome was controlled (

Of interest regarding the patent is of course in the description.
https://worldwide.espacenet.com/patent/search/family/047754367/publication/EP2634185A1?q=pn%3DEP2634185
Good reminder Ahfam

Good evening Deesamax,

Interesting to note is the little bit of JAK1. Kinase inhibitors work best in pairs. Clearly this is the case for psoriasis. Dont pay too much attention to the Jak2 and 3 as they are just not selective enough in my view. Selectivity is vital. interferon gamma inhibition required and cannot on its own be achieved with Tyk2. Jak1 to the rescue albeit in optimum quantities. IL-6 I believe also required for Tyk 2 inhibition of Il-12 and 23.

Looking good but unfortunately not reflected in the SP at the moment.

Regards