Member Info for sadoldgit

Yes combos can and have been protected by patent. It was done with SRA737 with in combo by sierra and posted a few weeks ago. Share chat was categorised under subject.
Much earlier on sierra website it was reported of the outstanding results obtained in combo. ironically as stand alone not significantly effective. but in combo extremely impressive. Not long afterwards all info removed.

We should hear pretty soon of any developments and an update from GSK in next few weeks.
Finalising trial design. Yes and at the same time patent protection in combo.
Discussions been going on for months.
Waited for momo good data news, Set up a share target price for sierra, and bingo up pops GSK with offer of target price and all done.
Early 2020 the for Sra737 sale sign was taken down. Discussions between interested parties. Informal chats. All engineered. There will be those in the know of course.
Yet you will get people post on here, if SRA737 is that good why has it not been sold?
It bl00dy well has been now.
Would you rule out such a scenario with Sareum?

Pave the way for Wee1 in combo.
Because Wee1 is a known important negative regulator of G2/M transition and cell cycle checkpoint [[31]], we further investigated whether Wee1 might play a key role in the cell cycle progression of the resistant cells. The messenger (m)RNA and protein levels of Wee1 were significantly up-regulated in H792LYR and GLC4LYR cells compared with the parental cells, irrespective of prexasertib exposure (Fig. 2A,B). Wee1 is a critical negative regulatory kinase, which phosphorylates and inactivates CDK1 to block G2/M transition.

To determine whether Wee1 plays a causal role in the resistance to Chk1 inhibitors, we examined the cytotoxic effect of prexasertib in combination with the Wee1 inhibitor MK1775 in acquired-resistant cell lines (H792LYR and GLC4LYR) and four additional parental SCLC cells (H82, H128, H209 and DMS114).

The combination of prexasertib and MK1775 resulted in a synergistic effect in these cells (Fig. 2C,F and Fig. S3A–C); the addition of MK1775 drastically improved the sensitivity of the H792LYR and GLC4LYR cells to prexasertib (approximately 70-fold from 8415 to 119 nm for H792LYR and 100-fold from 4700 to 33 nm for GLC4LYR). H128 cells expressing more Wee1 showed better survival under prexasertib treatment but there was no significant correlation between RB expression and drug sensitivity. MK1775 alone and in combination with prexasertib caused reduction of phospho-CDK1(Y15) levels in both prexasertib-resistant cells. Accordingly, the mitotic marker phospho-histone H3 (pHH3) increased when cells were exposed to the Wee1 inhibitor, and combination of MK1775 and prexasertib induced ?H2AX and PARP cleavage (Fig. 2G). To confirm the specificity of Wee1 inhibition, we used a different siRNA to knockdown the Wee1 expression in resistant cells. The results were similar to those obtained with the Wee1 inhibitor MK1775. The IC50 for prexasertib decreased over 1000-fold in the resistant cells when Wee1 was knocked down (Fig. 2H). WB results also demonstrated abrogation of G2 arrest (increased pHH3) and more DNA damage upon knockdown of Wee1 (Fig. S3D).
These data suggest that Wee1 plays an important role in acquired resistance to Chk1 inhibition.
i will put again

These data suggest that Wee1 plays an important role in acquired resistance to Chk1 inhibition.

If we look from another angle what is the potential of Wee1 without a CHK1 inhibitor?

So we have p53 regulation where resistance to CHK1 will lower its efficacy, however by the addition of Wee 1 inhibition we remove the resistance of cancer to CHK1.

A bit long winded of me so my apologies. Night shift over and on my 5th bottle of beer'

CHK1 and the prevention of DDR replication via the P53 checkpoint is essential in preventing cancerous cell growth.
It works by stopping mitosis ie as one cell divides into 2 (requiring the P53 checkpoint ) 2 new cells are created with the damaged DNA. This will repeat ad infinitum. The cell divides, Think of it as a mother cell. It divides and produces 2 new daughter cells. These in turn become mother cell and again will produce 2 new daughter cells. PS we also have meiosis which divides into 4 daughter cells.

in normal cell replacement this goes on in our bodies all the time with healthy undamaged cells replicating

In some cells there will be DNA damage. With regards to CHK1:-

From 2005 (Note Michelle Garrett a strong supporter of our CHK1 who we worked in partnership with at CRUK Therapeutics unit.)
'.. Checkpoints are induced by cell stress, such as that caused by DNA damage, hypoxia, pH changes, heat shock, and oncogene activation (Collins and Garrett, 2005). Retinoblastoma (Rb) proteins are important mediators of checkpoint control, as is the p53 tumour suppressor, which can lead the cell into one of the above described cell fates, depending on the strength of the stimulus (Stewart and Pietenpol, 2001, Itahana et al., 2002

The cyclin-dependent kinase (CDK) family of serine/threonine kinases regulate progression through each stage of the cell division cycle and as such are major targets for deregulation in cancer. This has led to the development of several small-molecule inhibitors of CDKs as potential therapeutic agents for the treatment of this disease. Progression through the cell cycle is also monitored at several positions known as cell cycle checkpoints, two of which occur during G1 and G2 in response to DNA damage. These are often defective in cancer, leading to the suggestion that inhibition of one or both of the cell cycle checkpoint kinases CHK1 and CHK2 may drive a cancer cell that already has defects in its cell cycle checkpoints towards death.

My belief here is that for CHK1 to work as it should :-
An agent whether chemo radiotherapy will kill some cells but not all. The cells that have been damaged by therapy can go on to replicate and at the same time develop a resistance to this type of exposure.

'Gain of Function. The p53 gene is mutated in around 50 percent of cancer cells, but in addition to its role in tumor suppression, cancer cells themselves can find ways to inactivate and alter the gene leading to new functions that help sustain the growth of a cancer. These are referred to as "gain-of-functions.".

We now have a problem with resistance to CHK1.

Far from game over I might add.
will continue

Plenty of pace Basser. They have been finalising the design stage of 737 for the past 7 months. Must be almost nearly there by now.
An update and 6 monthly report should be due soon.

Regards

Agree Ahfam no real.news for 4 months now. Unfortunately we are not privileged to k ow exactly what is going on and more importantly with whom.
Am of the opinion however that all will pivot around clinical trial results. We are not pure Tyk2. Optimum amount of Jak1 according to Tim and he did say in all modesty. What we are very good at is chemistry.

Am feeling very confident at the moment.

TM had an interview with the smooth talking aussie Andrew Scott. Around early 2020. Basically Tim's intention was to on licence our 1801 which would be the main focus. Then that money would be used for development/ early trials for 1802.
The only mention of Aurora +FLT was that was shelved due to focus on Tyk2 Jak1 compounds.

Our Aurora +FLT 3 showed great promise preclinical but as you correctly state there was an issue with solubility resulting in a lack if bioavailibity via the uptake via the oral route
Similar issues were encountered with our Tyk2 Jak1 compounds. As far as l can gather it was the production of sufficient quantities for trials use.
The Tyk2 Jak1 inhibitors have now had this issue well and truly resolved as per our capsule formulation. Extremely high purity via crystallisation of a compound. Manufactured to meet demands and recognition of Good manufacturing procedures.
I see no reason as to why the formulation issue cannot be resolved with Our Aurora+FLT 3.
Once regarded as our Jewel in the Crown.

Not sure what you mean by optimising delivery at the site of the cancer. Our Co.pounds are delivered orally and absorbed into the body via the stomach. All that is required in regards to this is good LADMET properties which in preclinical modelling we have easily surpassed( exception being Aurora FLT 3 of course). As we all know Aurora + FLT aimed at A M L and blood cancers.

There are l believe issues with developing resistance to FLT3 inhibitors Apart from that and as to why l know sweet fa.

Regards

Certainly correct on that one bailiff. A lot to ponder indeed.
We dont need PH to on license.
We have not needed PH to raise funds in the past.
Significant funding will be required at some stage if not licensed or sold. (only bug bear I can perceive) Unless of course informal discussions/agreements have been made with a proviso.
Sufficient funding for phase 1 trial we have as well as completing pre clinical on SDC 1802. Not sure if we have sufficient funds for Phase 1 in 1802. We get a milestone payment from GSK in next few months or maybe not. It is not guaranteed as to a timeline.

The pharma industry is certainly not the fastest in these matters. All of a sudden there is an announcement out of the blue that an offer has been made by such and such a company to buy or license from such and such a company.

Regards

One further tin hat/mad opinion.

Peel Hunt may well have been put in place to facilitate a takeover. I, like many am not keen on what they have done to the SP since appointment. However, this does make sense and Tim and co don't do things without a reason. It all takes time.

Stars are beginning to align I believe.

The only difficulty I see is how do you price a company with a potential 1 to 2 billion potential, with a current market cap of 130 million?
We have no target price, and again difficult to calculate. if any of what I am saying makes sense then we ought to see a massive increase in MC on completion of phase 1 trials. In deed should be a sizeable increase on granting of CTA I would hazard a guess at 30 to 50%, but dont take this as gospel or financial advice, as after all it is my thoughts and opinion on this matter.

Regards to all.

From 2021 (NIH)

Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer.
Link is here for further info.

https://pubmed.ncbi.nlm.nih.gov/28847989/

Note AURKA (aurora kinase A [ Homo sapiens (human) ])
Abstract
Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine.

There is much going on. Mostly behind the scenes.

If we take into account citizen 79's posts regarding 737 and continued behind the scenes development we can conclude that there will be a significant interest in Sareum not for one but all compounds.

A while ago I would have said a buyout is not on the agenda.
We have Aurora FLT3. Good results in preclinical, but unable to manufacture oral compound due to lack of bio availability.
Sra737 Chk 1 we have a 27.7% interest ( now owned by GSK)
Tyk2 1801 and especially 1802 of importance, ) SDC 1802 (from recent patent grant) compatible with many other treatments. CHK1, PARPi and WEE. Will improve treatment with LDG when the cancer has developed resistance to it.

Call me mad or whatever, but I am beginning to believe that a take over of Sareum is now likely.
We have Peel Hunt on board.
It has now been 4 months ( ignoring the presentation attendance April) since we have heard anything remotely regarding any developments our compounds. *
Although at much earlier stage it was not until Sierra announced their success with Momo only for a company to buy out a couple of months later. Informal communication must have been going on for months on end. Once the milestone has been reached then serious formal offers a

GSK in oncology

'GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, tumor cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody-drug conjugates and cell therapy, either alone or in combination.'

Abstract.
Review Cancer Discovery. 2021 Jul;11(7):1626-1635. doi: 10.1158/2159-8290.CD-20-1503. Epub 2021 Apr 1.

Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically "druggable," including loss-of-function mutations in tumor suppressor genes required for carcinogenesis. Recent technological advances have led to an inflection point in our understanding of genetic interaction networks and ability to identify a wide array of novel SL drug targets. Here, we review concepts and lessons emerging from first-generation trials aimed at testing SL drugs, discuss how the nature of the targeted lesion can influence therapeutic outcomes, and highlight the need to develop clinical biomarkers distinct from those based on the paradigms developed to target activated oncogenes. SIGNIFICANCE: SL offers an approach for the targeting of loss of function of tumor suppressor and DNA repair genes, as well as of amplification and/or overexpression of genes that cannot be targeted directly. A next generation of tumor-specific alterations targetable through SL has emerged from high-throughput CRISPR technology, heralding not only new opportunities for drug development, but also important challenges in the development of optimal predictive biomarkers.

'CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic lethality.'

Note the wording 'to achieve a sustainable flow of new treatments'
GSK now own a CHK1 inhibitor.

Regards

Has been posted before but does no harm as an overview of what we do and have, plus the competition.

https://www.edisongroup.com/publication/treading-the-tyk2-trail/29435/#:~:text=Sareum%20is%20a%20development%20stage%20company%20specialising%20in,the%20potential%20to%20expand%20to%20other%20therapeutic%20areas.

Sareum are not biologists their field of expertise is in chemistry . In auto immune they worked in collaboration with SRI which have phenomenal resources in research and development. Sareum worked in partnership with CRT.
In essence they use the kinase inhibitors which they can develop (including trial) to inhibit kinases identified by research. Auto immune or oncology will make no difference as the molecular formulations ( chemistry) are invented/developed using Sareums kinase inhibitor library that enable development with the minimum amount of toxicity.
Sareum
About SRI International

Innovations from SRI International have created new industries, billions of dollars of marketplace value, and lasting benefits to society—touching our lives every day. SRI, a nonprofit research and development institute based in Silicon Valley, brings its innovations to the marketplace through technology licensing, new products, and spin-off ventures. Government and business clients come to SRI for pioneering R&D and solutions in computing and communications, chemistry and materials, education, energy, health and pharmaceuticals, national defense, robotics, sensing, and more.

www.sri.com

http://www.sareum.com/news/press-releases-and-news/2013/sareum-and-sri-international-announce-co-development-agreement/
https://www.jimmunol.org/content/193/7/3278.abstract
http://www.sareum.com/news/press-releases-and-news/2018/selection-tyk2jak1-autoimmune-diseases/
http://www.sareum.com/news/press-releases-and-news/2020/research-update/

Thankyou bailiff, so am I oddly enough.

Regards

Good afternoon bailiff. I will not be around as a large share holder. Will keep circa 25k shares.
in body and mind I intend to be around a good few years yet. Am 61 so plenty of time left yet god willing.

Agree Potnak. Market cap is low for us at circa 140 million at the moment.
We await CTA application news, but my feelings is this news are it will be released when application has been granted.
Around a couple of months after CTA we should know of whether it has been granted.
We had RNS in March with regards to toxicity report. Very little to no detail on this. All been eerily quiet since.
Now looking at approaching 4 months since any news regarding SDC1801and 1802.
From the March RNS tablet capsule manufacturing on schedule.
GMP has to be established, batch consistency specified with regard to forming part of the CTA application. Prospect of likely delay and the data being available for CTA was well adressed by WIP's post a short while ago. WIP works in the pharma sector and in much more knowledgeable than myself on this ( great post from WIP regarding procedures on this)

If we allow 2 to 3 months to complete application and 2 months for trouble free granting of the CTA we will in effect be looking at mid to end of July until mid to end of August at the latest. In essence any time from now until mid to end of August for a red dot regarding this matter.
With regards to intended treatment of phase 1 clinical trial. Sareum expect to commence in H2. Since 1st of July we have been eating into H2. Fairly sure here but, not 100% certain that enrolment for trials cannot happen until granting of CTA. Around 6 to 8 weeks is my estimate ( it may well be that they already have candidates in place prior to an enrolment) for suitable healthy candidates to be selected for ascending dosage trial.

Then of course we need look at Covid 19 too. Mutation 2.75 a variant of concern should give cause for the development. or to be precise, fast track as an authorised treatment ( superior to Baricitinib and better profile than Demaxathone) . Much potential here I feel.

All looking good but akin to watching paint dry at times.

1 to 2 billion in next 12 months is certainly achievable as a market Cap. It is not guaranteed however, so carries a degree of risk. HNWI will be a little more in the know than us peasants.

Longer term ( 5 years from now)and with 1802 plus SRA737 coming on song and 5 billion will look extremely cheap for our pipeline. I will like many will be long gone from here by then.

Regards

This relates not to one of our compounds, but a competitor. It is pure TYk 2 and in this sense may well be inferior to SDC1801/SdC 1802 This is just an indication of expectations of turnover on meeting a makers objectives. Further down the line of course, but as is a large pharma would you mock the expected turnover.
Auto immune and oncology predicted be around 200 billion dollars a year by 2026.

A long time wait yes to reach these heady heights. But value of company will increase on each milestone achieved.

.'The drug is seen as a potential top-seller, leading a new class of oral drugs that could challenge the injectable biologics used by millions of patients with different autoimmune diseases.
Deucravacitinib could also soften the blow of losing Otezla, an anti-inflammatory medicine Bristol Myers was forced to sell as part of its acquisition of Celgene in 2019. Additionally, the drug is a key component of Bristol Myers' plan to replace the revenue that will disappear when Eliquis, the company's blockbuster blood thinner, loses patent protection in a few years. Bristol Myers expects deucravacitinib to generate more than $4 billion in annual sales — a little less than half of Eliquis' 2020 total — by the end of the decade.

From March RNS.
SDC-1801 is being developed as a potential new treatment for a range of autoimmune diseases and for the acute respiratory symptoms of Covid-19.

The report confirms that the studies met their objectives of identifying any organs or tissues that might be susceptible to high-dose toxicity and determining an appropriate dose range to test in first-in-human studies.

I am sure Sareum will be aware of organs most likely to be affected by high dose toxicity. Issues with heart is not well known but has been documented as far back as 2012 and before. This especially with Tyk2 as well as other kinases.

From memory there are 31 patented molecules which go to formulate our SDC compounds. Fine tuning of a compound can be adjusted by the addition of a higher or lesser quantity of each of these molecules. Selectivity is of the utmost importance. I myself do not see it as a 'big if' but should sail through Phase 1. Phase 2 efficacy in the targets that Sareum select should not prove troublesome.

No reason not to get the same valuations as other phama's. Of prime importance is selectivity. There is no one size fits all here. Sareum will have a good idea already of what they will target. Nothing of course will be stated regarding their intentions. It is a very competitive business and the less our competitors know about this the better

SDC1801 on its own should be worth a minimum of around 250 to 300 million on its own end of phase 1. Phase 2 good results and depending on what indications we can treat this figure can increase 2 to 3 fold. Good results in stage 3 a three fold increase on stage 2.

But agree there are still hurdles to overcome. Efficacy in stage 2 I feel will be a bit of a toughie. This is more down to the dosing schedule. You can have a great compound but even that can fail if dosing/ treatment schedule is less than bang on. This of course will be beyond Sareums capabilities but top notch experts in this field should meet their objectives.

SDC 1802 to follow.

New Variant of concern is 2.75.

Good morning BD.
If the MF thinks we are in the discovery phase they are around 7 years behind the times .Entering clinical trials is by no means at discovery level. They state in their opinion they have concerns. They cannot even get their facts right.
We have no license agreement with Sierra.
What are these license agreements we have with other companies?

SP spike on April 1st he thinks caused by GSK bid for Sierra.
GSK news of this not released until around 13th April.
Actual ownership of Sierra by GSK not confirmed until 4th of July.
( The reasoning and statements made by the Fool relating to the above dont make any sense at all)

Yes agree it is a a tad frustrating at the moment but on no news as with most AIM companies we experience an SP journey Southwards.
3 months since any significant news released by Sareum . Not good but that does not mean nothing happening.

Regards all

Anyone not think it a little odd that shown sells outweigh buys yet the price still rises.
Market sentiment.