Member Info for sadoldgit

in my opinion after looking at some of what GSK have in their pipeline i notice gaping holes with regards to dose related side effects. In oncology they hold very little.
SRA737 and SDC1802 would plug them nicely. We are still at early days with our Tyk2 jak1 inhibitor in human clinical trials.

Will add more info later when have time

Regards to all
I am certain they have their eye on a SRA737.

Good post Zylo. I will add:-

From GSK announcement 29th April 20. :-
FDA approves Zejula (niraparib) as the only once-daily PARP inhibitor in first-line monotherapy maintenance treatment for women with platinum-responsive advanced ovarian cancer regardless of biomarker status

About Ovarian Cancer
In the US, ovarian cancer impacts nearly 222,000 women annually,[2] and it is the fifth most frequent cause of cancer death among women.[3] Despite high response rates to platinum-based chemotherapy in the front-line setting, approximately 85% of patients will experience disease recurrence.[4] Once the disease recurs, it is rarely curable, with decreasing time intervals to each subsequent recurrence.

About Zejula (niraparib)
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in multiple pivotal trials. GSK is building a robust niraparib clinical development programme by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes several combination studies, including a phase III study as a first-line triplet maintenance treatment in ovarian cancer (FIRST).

GSK in Oncology
GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics 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.

Taken from an oldish circa 2013 report
Collectively our data demonstrate that PARP1 and CHK1 inhibitors interact to kill mammary carcinoma cells and that increased DNA damage is a surrogate marker for the response of cells to this drug combination.

This means that a CHK1 inhibitor increases the cancer killing ability of a PARP inhibitor.

Our SDC 1801 may well also be very effective in this area too. From memory one of the targets is ovarian. So much overlap here but our SDC1802 is very versatile and compatible with other treatments ( that is what is claimed from our most recent patent news)

Watch this space as they say.

All very odd to me Aber, we get three days of heavy gains An RNS about unexpected GSK buyout of Sierra followed by today's dip.
More of a rise on the patent grant than good toxicity results.

Would like to know what will be happening with 737. GSK to all intensive purposes own Sierra,s license agreement. Should be no lack of funds now!
Regards

Effectively half price from last year's high. Covid front gone quiet but not over. Sufficient funds to take 1801 through Stage 1 clinical and 1802 to end of preclinical. Tox results with no known problems, so comparatively cheap still
Regards and new highs will.be hit further down the line.

A few months time and you will be sitting 40% up I feel.

I would add that Deucravacitinib is forecast to hit 4 billion dollars annual turnover 2029 and they have failed stage 3 in IBD. No use in covid 19 either as far as I can see or would already have been alongside Baricitinib which on tox issues alone far superior to.
We have 1801 and 1802. Plus at some time revenue from SRA737 which should happen when Sierra get their finger out.
Regards

Hi HBD. With respect to bringing PH on board for consolidation and possible raising of funds, it does give Sareum an option. If we have no other options then we are at the mercy of the buyer.

Should the need arise we can, irrespective of however financially costly this may be, raise funds and hence not be reliant or dictated to by a potential partner or licensee. This gives us far greater bargaining power. Effectively making it a sellers market.

Expect the best but be prepared for the worst so as to speak.

Regards

Parallel is :- Sareum worked the ICR on a checkpoint inhibitor. The problems were encountered in the treatment of cancer developing resistance to treatment. DNA damage repair being of them. Sareum dealt with the chemical composition of a compound to inhibit the P53 checkpoint as well as have a good safety profile.

Our Tyk 2 Jak1 compounds will have a similar pedigree. There will be vast amounts of data within the kinase inhibitor library. The result being certain identification of not only the kinase inhibitor targets to hit, but also the importance of the selectivity required to ensure minimisation of toxicity. We can control our immune system chemically.

Sareum will be sufficiently researched to identify the pros and cons of 1st generation inhibitors. As with the attention to limiting the toxicity effects in the designing of the chemical composition with respect to a checkpoint CHK 1 inhibitor this will have also been applied to Tyk2 Jak1. Such is the level of selectivity we have 1801 for immuno and 1802 for cancer. this clearly demonstrates that Tyk 2's are not all the same, only similarity is the pathways they signal via. The same is with CHK1, others have failed whereby SRA737 developed between the ICR and Sareum continues, albeit on a financially restricted basis to prove extremely effective when used in combination with other therapies.

Sareum are fully aware of what is needed and at the same time what is not to improve upon any treatment currently available.

Regards

Regards

Good question Celtic007. Am of the inclination there are people taking the advantage of the new tax year.
I believe we are still undervalued as the absolute minimum should be around 200p. 1st quarter now over and a period of time passed since consolidation. A few traders would have exited during this time. All the brakes are now off. into 2nd quarter, and by the end of this quarter will know if CTA successful. No reason as to why it should not. Our compounds are good ie we are out of the same stable as our original CHK1 which has very good results especially in combo. As far as i know CHK1 is predominantly a JAK1 inhibitor. We have experienced no serious problems here ( or to be precise Sierra Oncology)

1801 of which the intention by Sareum is to licence at end of preclinical/ stage 1. I would hazard a guess that they are looking to raise enough funds from the on license of 1801 to take 1802 possibly into stage 3.

Sierra still dragging their heels with regards to CHK1 development. They want Momo on licensed. Until then I do not see them doing much. Just how long does it take to design new combination therapies? Over 3 months, we have heard no more. I dont think much will happen or a milestone payment by end Q3 this year. Next year yes. far bigger market and bigger potential with CHK1 especially in combo.

Interesting point here is that SDC1802 can be used in conjunction with gemcitibine when effectiveness reduced due to the cancer developing resistance against chemo.

News could arrive at any time as there is just no telling with Sar. I would not rule out a partnership of some sort. There will be a long informal discussion period beforehand. Tim and co will be far more in the know than us, but Sar are water tight with regards to letting info slip.
With regards to SP a gradual rise up to the old 5p prior to news. On good phase1 results which I cannot envisage problems with nothing else involved circa 12 to 15p a share old money. MCap around 400 to 450 million. with no delays 10-12 month away max.

if we get a bad virus outbreak which cannot be ruled out then a double of SP ie 24 to 30p per share old money.
Strange this very rough guide not far away from Thoth 2 28p per share old money long term prediction.
My opinion here nothing else.
One thing I will say is the further we go down the line the more our compound is worth. Funds although a long way from being required, will be required at some stage. We have as you know at least two options.

Regards

Jamesp21. Interestingly a vast amount of info in the link to the patent grant was absent in other patent descriptions.
Source of info I have used here is below. A long difficult read but much info to be gleaned.
You can also look at other patent associated applications which are given

WO2018073438A1

Regards

Taken from the patent application but note the following:-

One particular subset of cancers against which the compounds of formulae (1 ) and (2) and their pharmaceutically acceptable salts should prove particularly active are cancers which are characterised by upregulation of BCL2 and/or elevated levels of
phosphorylated STAT1 , phosphorylated STAT3 and phosphorylated STAT5 and/or BCL2. Methods of detecting phosphorylated STAT1 , STAT3 and STAT5 are well-known to those in the art and include western blotting and flow cytometry (see for example the methods used in Pratt et al., "IL-6 driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis", Ann Rheum Dis 2014;0:1 -8). Examples of assays for the detection of STAT1 , STAT3 and STAT5 are described below in the experimental section of this application. Methods of detecting BCL2 are well-known to those in the art and include flow cytometry and western blotting (see for example the methods used in Coustan-Smith et al., "Clinical Relevance of BCL-2 Overexpression in Childhood Acute Lymphoblastic Leukemia", (1996), Blood., 87(3), pp 1 140-1 146.)
In particular, it has been shown that the compounds of formulae (1 ) and (2) and their pharmaceutically acceptable salts may be useful in the treatment of a hematopoietic cancer. The hematopoietic cancer may be a leukaemia, such as an Acute Lymphoblastic Leukaemia (for example, T-cell Acute Lymphoblastic Leukemia).

Note the IL-6 and also note BCL-2 (Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.
Maybe why it is initially more likely that 1802 will be used as a combo therapy. Think about that for a minute. We are not in this instance an immediate threat to present, less effective competition but can compliment as a co therapy.

All in all I would conclude we have one of the best if not the best inhibitors in the world. Correction, 2 of the best.

Regards a great weekend to all, but not like this new chat set up.

Now very importantly and very briefly.

Our SDC 1802. Much info can be gleaned by those who read in depth the patent description. Link posted by James21 originally ( thankyou)

Our SDC 1802 can be used in combination not only with other kinase inhibitors but also other forms of therapy. Eventually these other therapies will become less effective as the cancer develops resistance. Our SDC 1802 is intended to be used to supplement these treatments. In this case 1802 is not the major treatment, but would enable the effectiveness of these non kinase inhibitor treatments. At a later stage it is prudent to note that 1802 may well become the dominant treatment.
In addition our 1802 can be used in combination with other kinase inhibitors.

Taken from the patent

G. Cells that have shown intrinsic or acquired resistance to proteasome inhibitors such as:
Bortezomib
in cancers such as multiple myeloma; and
H. Cells that have shown intrinsic or acquired resistance to other small-molecule or monoclonal antibody cancer therapies such as:
Vorinostat, Abiraterone, Venetodax, Trastuzumab, Bevacizumab, Rituximab, Ipilimumab, Pembrolizumab, nivolumab.
in cancers such as:
T-cell lymphoma, prostate cancer, chronic lymphocytic leukaemia, melanoma and Hodkin's lymphoma.

Other competitors.
Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are disabling conditions characterised by chronic, relapsing inflammation of the gastrointestinal tract.

Current treatments are not universally effective or, in the case of therapeutic antibodies, are hampered by immune responses. Janus kinase inhibitors are orally delivered small molecules that target cytokine signalling by preventing phosphorylation of Janus kinases associated with the cytokine receptor. Subsequently, phosphorylation of signal transducers and activators of transcription that relay Janus kinase signalling and transcription of cytokines in the nucleus will be diminished. Key cytokines in the pathogenesis of inflammatory bowel diseases are targeted by Janus kinase inhibitors.

Several Janus kinase inhibitors are in development for the treatment of inflammatory bowel diseases. Tofacitinib, inhibiting signalling via all Janus kinase family members, was effective in phase 2 and 3 trials in moderate-severe ulcerative colitis. GSK2586184, a Janus kinase 1 selective inhibitor, induced clinical and endoscopic response in ulcerative colitis; however, the study was discontinued at an early stage due to liver toxicity observed in systemic lupus patients receiving the drug. ( oh dear !)

Filgotinib, a Janus kinase 1 selective inhibitor investigated in treatment of Crohn's disease, was superior to placebo. As adverse events associated with the broad immunological effect of these agents have been reported, the future application of these drugs is potentially limited. We will discuss the treatment efficacy of Janus kinase inhibition in inflammatory bowel diseases, how current Janus kinase inhibitors available target immune responses relevant in inflammatory bowel disease, and whether more specific kinase inhibition could be effective.

There exists vast potential with our Tyk2 Jak1 inhibitor.
Deucravacitinib is an oral small molecule TYK2 inhibitor. In contrast to JAK1–3 inhibitors, which target the ATP binding sites, deucravacitinib, via binding to the regulatory domain, selectively blocks IL-23, IL-12 and type I-IFN-mediated signaling, but does not block cytokine reactions mediated by other kinases (such as IL-6, hematopoietic growth factors and the ?c-receptor family). Therefore, deucravacitinib can be considered highly selective, which probably contributes to an improved safety profile. The results of the first-in-human phase I study with 108 participants supported this assumption, since no serious adverse events occurred. The study therefore resulted in the further testing of deucravacitinib in diseases such as psoriasis [27].

Now interestingly Deucravacitinib flunked in IBD. Pure Tyk2 we have here. IL-10 inhibition will be restricted as IL-10 consists of four sub units, 2 of which are Tyk2 and 2 which are of Jak1.

Combination Therapy

It is envisaged that the compounds of Embodiments 1.1 to 1 .93 will be useful either as sole chemotherapeutic agents or, more usually, in combination therapy with

chemotherapeutic agents or radiation therapy in the prophylaxis or treatment of a range of proliferative disease states or conditions. Examples of such disease states and conditions are set out above.

Particular examples of chemotherapeutic agents that may be co-administered with the compounds of Embodiments 1.1 to 1 .93 include:

• Topoisomerase I inhibitors

• Antimetabolites: (e.g. Cytarabine)

• Tubulin targeting agents

• DNA binder and topoisomerase II inhibitors

• EGFR inhibitors (e.g. Gefitinib - see Biochemical Pharmacology 78 2009 460- 468)

• mTOR inhibitors (e.g. Everolimus)

• PI3K pathway inhibitors (e.g. PI3K, PDK1 )

• Akt inhibitors

• Alkylating Agents (e.g. temozolomide)

• Monoclonal Antibodies.

• Anti-Hormones

• Signal Transduction inhibitors

• Proteasome Inhibitors

• DNA methyl transferase inhibitors

• Cytokines and retinoids

• Hypoxia triggered DNA damaging agents (e.g. Tirapazamine)

• Aromatase inhibitors

• Anti Her2 antibodies, (see for example

http://www.wi po.int/pctdb/en/wo.jsp?wo=20070561 18)

• Anti cd20 antibodies

• Inhibitors of angiogenesis

• HDAC inhibitors • MEK inhibitors

• B-Raf inhibitors

• ERK inhibitors

• HER2 small molecule inhibitors e.g. lapatinib

· Bcr-Abl tyrosine-kinase inhibitors e.g. imatinib

• CDK4/6 inhibitor e.g. Ibrance

• Mps1/TTK inhibitors

• Aurora B inhibitors

• FLT3 kinase inhibitors

· IDH1 or IDH2 inhibitors

• BRD4 inhibitors

• Inhibitors of immune checkpoint blockade signalling components including PD1 , PDL-1 and CTLA4; and

• steroidal compounds

Moreover TYK2 is necessary for the induction of key anti-apoptotic proteins such as BCL-2 and myeloid cell leukemia sequence (MCL) 1 to promote cell survival following FGF-2 signalling. Thus, it is envisaged that TYK2 inhibitors could enhance the effectiveness of other cancer therapies modulated by FGF-2 driven cell survival. It is envisaged that the compounds of the present invention will be useful in treating cancers where resistance towards initial drug treatment has arisen. Thus, the compounds can be used to target a different biochemical pathway (for example TYK2-STAT1 -BCL2) than the biochemical pathway targeted by the drug against which resistance has developed. Accordingly, in a further embodiment (Embodiment 2.52), there is provided a compound of formula (1 ) or formula (2), or a pharmaceutically acceptable salt thereof, as defined in any one of Embodiments 1 .1 to 1 .93 for use in the treatment of a subject suffering from a cancer wherein the subject has been receiving drug therapy for the cancer and wherein a reduction in effectiveness indicative of drug resistance has been observed. In another embodiment (Embodiment 2.53), there is provided a compound of formula (1 ) or formula (2), or a pharmaceutically acceptable salt thereof, as defined in any one of Embodiments 1 .1 to 1 .93 for use in the treatment of a subject suffering from a cancer wherein the subject has been receiving drug therapy for the cancer and wherein tests carried out on the subject and/or the cancer have established that the cancer is less sensitive to the drug than it was when treatment with the drug was first initiated.

Clarification, Aurora +FLT or AML.

Jak/TYK2 for T-ALL

Compatible in combination therapy too, with many other know treatments.

T-ALL is a niche market. Approx 200 people diagnosed in UK alone each year. No.competetitors and around 12 months life expectancy. Some may look upon as too smaller a market. Same can be said with pancreatic cancer with a slightly better prognosis. There are competitors probably the biggest threat being our developed SRA737 in combo. Our SDC 1802 compatible with CHK 1 inhibitors.

All looking good and folk taking advantage of the new tax year.

Regatds

Note. Particular examples of agents that can be co administered. Just about everything including checkpoint kinase inhibitors and Pd1 PDL-1 CTLA-4.

Never seen this amount if info before.

JUZT HD a very quick look as dates not tie in with Aorora FLT.
There is a number associated Pharmaceutical compounds US patent US2019350905A1.

I can look through patent guru. Very interesting
Treatment of T-ALL.

Scroll down to 0001. ' which depend on the Janus Kinase TYK2 for cancer cell survival. It does go on a bit but a brilliant although sometimes difficult read.

It also mentions resistance to DNA binding agents. Will give good perusal later when have time.
Apologies being a bit muddled as busy.

Regards

Apologies. Should read ALL and not AML. Bloody predictive text.
Regards
PS Aurora + FLT3 was once our jewel in the crown.