Member Info for sadoldgit

Good evening SD. It does appear that Sierra would be using the AZD5153 in conjunction with Momoletinib. There route I believe would be to heavily complete development of. This is not to say however, that this cannot be used in combination with SRA737.

Cuvio good post and good to see results submitted.

Last but not least, many happy returns of the day to you Ahfam.

Regards all

Ndr50, never assume anything. Sareum have a 27% financial interest. That is all. Sierra have pumped millions into development and have carried out some outstanding work. They will not want to lose that. Financial lawsuits would result on the demise of Sierra or the CPF. Neither party wants to risk that.

For what my opinion is worth Sierra will not be doing much until Momelotinib has been either licensed or sold. Sierra will need to pay around 180 million dollars for all milestone payments as only put 6 million up front. Effectively you have to take this as a 180 million dollar debt albeit by definition, it is not a true debt in the sense of the word.

Yes we are all a little peeved here as to the suspension of development which l cannot stress enough, that this is not through any short comings of SRA 737.

Regards

Ndr50. The deal with regards to SRA737, has absolutely nothing to do with Sareum. The deal was made between the Cancer pioneering fund and Sierra Oncology ( previously Pronai Therapeutics). On what factual information are you relying on to make such an absurd inferral
that the deal is between Sareum and Sierra ?

Regards

A very astute comment Mayhem 55.

Also bare in mind Tim Mitchells ' transformational deal' circa 2012. He will not go through that again.
When confirmed ( no longer subject to), up and coming anticipated positive news is released then, that will then involve formal offers to which we will have to be notified.

Regards

Interesting you state for Covid 19. I m looking at Covid 19 or not, the discussions would be for the later prerequisites informal discussions in place for formal offers to be made. Outside of Covid 19 our immuno potential treatment is nigh unlimited.
Sareums objective is to on license 1801 at end of preclinical stage. Delays have happened, it is inevitable due to Covid. we have 1802 also.
For a large company to be involved in an on license, that company it deals with must have a sound financial holding. We have been circa 200 million for a few months. We have raised closed to 5 million so in effect have no financial problems in immediate future.
Discussions would be ongoing. Sooner or later an offer will be made for subject to certain milestones being reached,

With regards 737 and a recent increase in SP, movement of Momoletonib may well be coming up up license. They will owe Gilead millions in royalties but should at least then allow forward development of 737 then allowing I would guess a circa 3 to 5p increase in Sareum SP.

The Science will speak for itself, Sareum will be on the radar of that we can be sure. Not expecting much news on Gilead for a couple of moths but may be wrong

Regards

Citizen good afternoon. IL-6 is also linked to increased depression and suicide.

In addition in auto immune Tim stated many many moons ago about the potential to treat diseases like sepsis. I will dig a couple out later.

Regards

Great post Bobbler, I think the GDM's are way behind us on this one.

I will digest over a few cans of Tennents

Regards and again good post lad

Interesting to say the least Bobbler. I an wondering if CHK1 could play a part also in the treatment or may it just be that Tyk 2 that we have is sufficient on its own. 10 years ago it was predicted there would a vast market for kinase inhibitors for use in cancer alone.
Mind boggling potential. There is very little out there but what is will make current early inhibitors obsolete.

First thing needs is to establish safety profile and we look to have under control. I get the feeling that we are only now just coming under the big boys microscope.

Regards

I will add in this instance that the treatment is normally administered through a nebuliser.

Regards

Hi SD
Post copied below from May 21

A point I will make here is Synairgen and their inhaler (Interferon beta) is primarily for the treatment for asthma. I see no other associated Covid 19 targets.

In this instance an inhaler when administered for asthma acts as a relaxant. it opens the bronchial airways. if the lining of the lung villi, is flooded with mucus then an inhaler in this sense will do nothing. Yes it may be able to administer a steroid but at this stage would appear pretty pointless as steroids take time to work.

In addition from the Lancet:-

'In all viral infections, especially those caused by novel strains where there is little to no established adaptive immunity to the pathogen, the infected host is dependent on innate immune responses to limit the severity of illness once infection occurs. Essential to this innate response is the action of interferons, key orchestrators of the antiviral immune response with both potent antiviral and immunomodulatory functions.5 The type I interferon (interferon-ß) is one of the first cytokines induced by viral infection of a cell and is a primary driver of innate immune responses in the human lung.6 SARS-CoV-2 directly suppresses the release of interferon-ß in vitro,7 and a recent clinical study of patients with COVID-19 showed significantly decreased interferon activity in patients who developed more severe disease.8 At-risk groups, such as those with comorbidities, older people, and recipients of immunosuppressive medication, produce less interferon-ß, which contributes to the risk of more severe lung disease.9, '

Regards

Good evening SD, apologies for late getting back, Looking through loads of old posts. Regarding blood clotting a post from June
First time I have seen the Sareum presentation.
Some interesting points. Control of interferon alpha and gamma controlled by Jak1 ( covid affected)
Secondly is Jak2 effects (EPO) Erythropoiesis Tyk2 and Jak 1 does not.
Why do I think this is important?
Erythropoiesis controls production of red blood cells. Our bodies can over produce red blood cells which is not good. What does it lead to? Thickening of blood and hence blood clots. Our bodies in most cases can regulate this. The cytokine storm which can cause lung problems reducing our amount of oxygen will produce more red blood cells. Jak2 may seem to counteract this. However, if we treat the cytokine storm which will reduce the inflammation of our lungs then blocking of ERO is not necessary. In this case reducing ERO will prove to be counterproductive to effects of treating covid as will limit production of red blood cells and at best would be dose dependant ie serious side effects.
jak 3 is too broad a spectrum ( ie it will again hit some of the keys we do not want to hit)
Tyk 2 along with Jak1 will control inteferon alpha and Interferon gamma. In addition Tyk 2 will hit one Interleukin 6 Jak stat pathway whilst Tyk2 will further control Interleukin 6 from another STAT pathway.

Interesting in the slides it does neither give the full spectrum for Covid 19 with regards to inhibiting all the Interleukins required for control of Covid ie no mention of IL-10. IL-7 and IL-23 for example and neither the full spectrum of what our Tyk2 and jak 1 will control.

I will research further as beginning to understand and enjoy. What I will add is that our TYk 2 Jak ! as far as I can see hits all the right targets for control and treatment of cytokine storm, whilst certainly having no serious side effects and looks also looks effective as a recovery treatment. There are a couple of Interleukins it also hits but I cant see if likely to be detrimental in any way.
With regard to Covid 19 Jak 2 and Jak 3 are about as much use as Jak 5hit.

I have been very certain of our Tyk2 Jak1 with regards as an effective autoimmune treatment in other indications but as I see it at the moment I am aware of nothing that comes even close with regard a treatment for Covid 19. Is it any wonder Tim and Co are so excited.

I repeat it again, nothing else come close. Jak2 and Jak 3 over selective. Pure Tyk2 misses vital Interferon control but the addition (optimum amount as Tim put it) adds to what pure Tyk 2 misses. No need I feel for another compound. It is to all intensive purposes all there all ready.

Regards and thanks to whoever posted the presentation.

We are unique in our compound with much of the research being done with SRI. Clearly they had found that pure TYk2 could be improved upon. Although Tyk2 can inhibit the IL-6 group it would appear that a precursor is required for this, in this instance the Jak 1 interacting with glycoprotein 130 to enable IL-6 to be inhibited by signal transduction. Furthermore Jak 1 is the only Jak that gp130 interacts with.
So from this information which I cannot substantiate conclusively it does appear that unless Jak1 is used alongside TYk2 then its kinase inhibition of certain interleukins are somewhat restricted.

As much as we can speculate about who is looking for what, and how much we think we can pay at the end of the day it is the science that does the talking. From the valency of atomic elements, the formation of molecules to the inhibition of the activity of enzymes. Enzymes are mostly protein, as they do contain other constituent parts ie metal ions and cofactors (in the form of vitamins) required for catalytic activity. Proteins are made up of amino acids. Enzymes speed up chemical processes in our body. We have a complex immune system that relies on these for correct metabolism,
Enzymes can change the constituent parts of a molecule and reform a molecule made up of the constituent elements. ( think of a 3 dimensional jigsaw.)

Without science we would not be able to deduce why our TYk2 is effective in inhibition of IL-6 and others are not. I will admit I am far from being an expert, ( The likes of Tim and Co along with researchers like SRI, the ICR are the experts) the complexity of bio chemistry whilst intriguing is extremely complex to say the least and I have not even scratched the surface.

Regards

Good morning SD, may be of use and give you a general idea of which what and how came first.

Been surfing through all old news. Regarding Tyk 2

Initially as auto immune Feb 12 Tyk 2
Agreement with SRI Apr 2013 auto immune and inflammatory.
First mention of Tyk2 Jak1 immune Feb 2014
Proof of concept Tyk2 Jak1 auto immune June 2014
First patent ( European) grant Tyk2 programme Nov 2014
Evaluation of Tyk2 in IBD, MS and Lupus Feb2016
Successful outcome of Cancer feasibility study of Tyk2 ( T-ALL) October 2016
Patent Grants in Japan and China for Sareum’s TYK2 Inhibitors Dec 2017.

Sareum reaches preclinical milestone in TYK2/JAK1 inhibitor programme - Potent, selective small molecule inhibitor of TYK2/JAK1 selected for further development as a potential treatment for autoimmune diseases ( note this is first mention of SDC 1801), closely related molecules Sar 20347 also evaluated ( Tyk 2, Jak1,2 &3) 10 Sept 18.

Potent, selective small molecule inhibitor of TYK2/JAK1 selected for further development as potential treatment for certain types of leukaemia, lymphoma and solid tumour ( first mention of SDC 1802) 26 sept 2018.
Sareum TYK2/JAK1 Inhibitor SDC-1802 Demonstrates Anti-tumour Activity in Multiple Cancer Disease Models Sept 2019.

Encouraging Preclinical Results Generated with Sareum’s TYK2/JAK1 Inhibitors in a Disease Model of Lupus. This was with Sar-20351 now known as SDC-1802 July 2020.

US Patent Allowance for Sareum’s SDC-1802 TYK2/JAK1 Inhibitor Oct 2020. I do recall some difficulties in obtaining a patent for SDC 1802 as was considered to close to the original compounds. This from memory ran on for some time.

TYK2 Identified as a Key Genetic Mechanism of Critical Illness in Covid-19 and as an Important Potential Target for Therapy Dec 2020.

US Patent Formally Granted for Sareum’s SDC-1802 TYK2/JAK1 Inhibitor Jan 2021. patent number no. 16/351,620

US Patent Notice of Allowance for Sareum’s SDC-1802 30 July 2021 patent number (US Patent Application no. 16/343,639)

That brief background of our Tyk2 Jak1 kinase inhibitors.

Will piece together your ideas on who how and what may be going on from your previous posts.

Regards

From 2018 RNS note the following

The preclinical development candidate SDC-1801 was nominated from a novel series of compounds designed and identified by Sareum following a rigorous selection process. The company is also completing its assessment of further dual TYK2/JAK1 inhibitors for the potential treatment of certain cancers and/or as a back-up to SDC-1801 and expects to nominate this candidate in the near future.

note the last sentence of 'completing its assessment of further dual Tyk2 Jak1 inhibitors for potential treatment of certain cancers or as a back up to SDC1801'

AFAIK candidate selection has already been established for 1801 and 1802. However, the above sentence would intimate that there would be a very high probability of at least one more candidate. I am fairly certain that the rule of thumb would be patent protection before selected candidate at end of pre clinical.

Those that have postulated another molecule or candidate may be proved correct after all.

Indeed Sareum have got us on a guessing game. There is so much going on that we are not privvy to.

This gets really interesting SD. looking through old RNS.
It will take a while to dig into. There have been many patent applications which of course different application numbers.

I will digress a bit. Do we have or have we ever had a TYK2 jak 1, Jak2 and Jak3 inhibitor?

The candidate molecule, SDC-1801, demonstrated high selectivity for TYK2 and JAK1 kinases (particularly over related JAK2 and JAK3), compelling activity in disease models of psoriasis and rheumatoid arthritis, the potential for once-daily oral dosing and a good early safety profile. Closely related molecules, including SAR-20347, have also shown good activity in models of inflammatory bowel disease and systemic lupus erythematosus (lupus). These attributes strongly support the progression of SDC-1801 into preclinical development and, pending satisfactory progress, advancement into human clinical trials, which could begin in 2020.

The preclinical development candidate SDC-1801 was nominated from a novel series of compounds designed and identified by Sareum following a rigorous selection process. The company is also completing its assessment of further dual TYK2/JAK1 inhibitors for the potential treatment of certain cancers and/or as a back-up to SDC-1801 and expects to nominate this candidate in the near future

Sar 20347

A JAK family kinase inhibitor (IC50s = 0.6, 23, 26, and 41 nM, for TYK2 and JAK1-3, respectively, in cell-free assays); inhibits IL-12-induced TYK2-dependent phosphorylation of STAT4 in NK-92 cells (IC50 = 126 nM) and IL-6-induced JAK1-dependent phosphorylated STAT3 signaling in TF-1 cells (IC50 = 345 nM); inhibits IL-12-induced INF-? production and reporter gene activity in PBMCs at 5 µM; inhibits the production of serum IFN-? in mice at 60 mg/kg; reduces keratinocyte activation and skin levels of IL-12, IL-23, IL-6, IL-22 and IFN-? in a mouse model of imiquimod-induced psoriasis

Good evening SD.
Monoclonal antibodies are not new. Similar to an anti viral.
These may well prove 'satisfactory' short term until virus develops resistance. It provides breathing space for a period of time.
I am surprised they give to HIV infected persons as they are a breeding ground for new strains of Covid 19. In addition this new treatment has been agreed/ appraised/ evaluated before we had variants of concern, weeks ago.
It certainly does not rule out SDC1801.
The virus shows no signs of retracting. The virus is now classed as endemic and not pandemic. That means treatments will be needed for the foreseeable future.
We still are at risk from a more contagious and damaging strain.
Government can only work with and put into clinical use treatments that have a known positive effect. Has our SDC1801 been fully evaluated?
Of concern is this winter when the virus will be at its most dangerous in cold damp conditions and people mostly restricted to indoors.
Next year new strains and new treatments required.

One important difference here is this mono clonal antibody is a treatment for acute and mild Covid 19. SDC1801 when described as 'indeed does down regulate the cytokine storm' is clearly for a different kettle of fish. One may be classed as a preventative and the other a cure with regards to cytokine storm.

I have a feeling here that although this mono clonal antibody will be used from next week further treatments will become necessary. We need be one step ahead and not one step behind.

Side effects
Several monoclonal antibodies, such as bevacizumab and cetuximab, can cause different kinds of side effects. These side effects can be categorized into common and serious side effects.

Some common side effects include:

Dizziness
Headaches
Allergies
Diarrhea
Cough
Fever
Itching
Back pain
General weakness
Loss of appetite
Insomnia
Constipation[58]
Among the possible serious side effects are:

Anaphylaxis
Bleeding
Arterial and venous blood clots
Autoimmune thyroiditis
Hypothyroidism
Hepatitis
Heart failure
Cancer
Anemia
Decrease in white blood cells
Stomatitis
Enterocolitis
Gastrointestinal perforation
Mucositis[58]

New treatment for patients who may become ill with Covid. Maybe some one caught wind and decided to sell 4 million shares. It is a treatment and government have ordered significant amount. I wonder how much of a bung was taken by the deciding panel.

https://www.msn.com/en-gb/news/uknews/life-saving-antibody-treatment-for-covid-19-to-be-rolled-out-across-uk-from-next-week/ar-AAOyG7q?ocid=msedgntp

Agreed HBD, Patent pending is not the same as patent granted. What is pending is the decision.

All in all looking very good here. Most likely as Sareum in control and not reliant on others as with the SRA 737. Clearly Sareum have raised money which is around the circa 5 million that we would have received had those Jodrell bankers paid up nigh 12 months ago.
They are still delaying under the guise of finding suitability in other pharmaceutical combinations.

Regards and beer oclock

Good hit Bobbler!