Member Info for sadoldgit

GSK bought the Tesaro pipeline for 5.1 billion. Why spend additional money in milestones and Royalties on a compound in area that thus pipeline of compounds treat?

Question is why did SO remove 737 from the shop window in 2020?

In link.below reference to AZD5305

2nd generation inhibitor PARP1 over 500 gold selectivity over PARP2. Current results look good and are in trials. Work well with platinum based chemo.

Not 737 related as such.

The toxiicities of Parpi have been know for a while but this later generation looks to have tackled this somewhat.

Regards

Good morning 007.

That excellent news for prostrate cancer patients.

737 has had preclinical work with both Niraparib and Olaparib as shown in excerpt below.

If being trialled over here it may be very likely that 737 has or may soon become an addition to a trial.

CRT would be in involved in this should this be the case.

Maybe AZ have already shown interest in availability now of 737 as returned to the CPF.

'Inhibitors of PARP1 are approved therapeutic agents in ovarian carcinomas. We determined whether the novel clinically relevant CHK1 inhibitor SRA737 interacted with PARP1 inhibitors to kill carcinoma cells. In multiple mammary and ovarian cancer lines SRA737 synergized with the PARP1 inhibitors olaparib and niraparib to cause cell death. The [SRA737 + niraparib] drug combination activated an ATM-AMPK-ULK1-mTOR pathway which resulted in the formation of autophagosomes, temporally followed by autolysosome formation.

Phosphorylation of ULK1 S317 was essential for kinase activation against ATG13. The drug combination elevated eIF2α phosphorylation which was causal at increasing Beclin1 and ATG5 expression, reducing MCL-1 and BCL-XL levels, and causing CD95 activation. Knock down of CD95, eIF2α, ATM, AMPKα, ULK1, Beclin1 or ATG5 reduced drug combination lethality. Blockade of either caspase 9 function or that of AIF each partially prevented cell death.

Expression of activated mTOR or of c-FLIP-s or of BCL-XL reduced cell killing. In vivo, SRA737 and niraparib interacted in an additive fashion to suppress the growth of mammary tumors. Multiplex analyses revealed that drug combination treated tumors had reduced their plasma levels of sERBB1, sERBB2, sVEGFR1, sVEGFR2, sIL-6R, HGF, PDGFAB/BB and CXCL16 and enhanced the levels of CCL26, IL-8 and MIF. Surviving tumors had activated ERK1/2 and AKT.

This finding argues that IL-8/ERK/AKT signaling may be an evolutionary survival response to [SRA737 + niraparib.

Still a little way to go on cancer resistance to drugs via signalling via an alternative pathway but then again we have known of this for some time.

737 has much benefit in the areas of combo therapy.

Regards.

'Our mechanistic and in vivo findings provide a strong foundation to perform phase I clinical trials in these malignancies combining SRA737 with the PARP1 inhibitor niraparib. Recently, within the past two months, Sierra Oncology has signed a clinical supply agreement with Janssen Research & Development, LLC. for access to TESARO’s ZEJULA® (niraparib). Sierra intends to evaluate its CHK1 inhibitor, SRA737, in combination with niraparib in the United Kingdom in patients with metastatic castration-resistant prostate cancer (mCRPC).

This was in 2018. Tesaro and Zejula

The same company GSK bought the pipeline from just over a year later.

Interesting read especially at the end

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154848/#:~:text=SRA737%20is%20a%20CHK1%20inhibitor,signals%20to%20activate%20the%20AMPK.

It is well known that ICB's (yes that includes ICB's) are known for a higher percentage of adverse events.

'Since 2015, anti-CTLA-4 and anti-PD-1 antibodies have shown tremendous efficacy when used in combination, with increased response rates in patients with advanced-stage melanoma8, renal cell carcinoma (RCC)9, microsatellite instability (MSI)-high cancers10, small-cell lung cancer (SCLC)11 and non-small-cell lung cancer (NSCLC)12,13 compared with either agent as monotherapy, albeit at the cost of increased toxicities. These toxicities are mainly considered immune-related adverse events (irAEs), meaning that they are off-target effects of an excessively activated immune system.'

In this instance it is not possible to rule out SDC1802 or maybe 1801 to be of benefit.

From the patent description SDC 1802 may be used as a supportive therapy to other treatments ( yes includes PD-1) to enable greater effectiveness.

.

Regards and food for thought

A big if. True HBD

Timescales from handing back 737 with all trial data at end of March.

3 months to evaluate data is about right.

Triparna Sen from 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141083/

There is much ongoing work with DNA damage repair

I for one would certainly not rule out an agreement with Merck of some sorts.

One thing for sure in Metcks favour is it would significantly increase patent protection timeframes for Pembrolizumab.

If we take into account the link by TS then the big if may not be as big as we think it is.

A main advantage with 737 is that it can be taken orally.

It would make sense to carry out any modelling prior to any licence agreement in any form and with whoever before such an agreement is made.

Regards

A very lengthy report on DDR in endometrial cancer. This is from April 23.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10144486/

The development of Chk1 inhibitors in income therapy is very much alive.

Pembrolizumab was investigated by SO in combo with 737. Ironically just after this in early 2020 SO removed the for sale sign so as to speak as 737 removed from their website.

I don't remember the name of the poster who noticed this at the time but ot does strike very odd that good results in preclinical, 2 patents applied granted then the for sale sign taken down later. Final design for a clinical trial is as far as they went.

Is it just coincidental that the area of treatment coincides with the GSK pipeline from Tesaro?

GSK had just spent over 5 billion on this pipeline.

Merck surely would have been aware of these developments of incombo preclinicsl work. The future was looking very rosy for 737. No Indications that 737 would offer less than satisfactory performance. The pharmaceutical world sure is a strange place.

1801 will take as long as it takes to progress through dose escalation studies. You can't stop it happening ot is just that it has to run the course.

Current events in the world make it extremely difficult for small companies especially with regards to finance.

Regards to all invested.

People see a sea of red and think they are all sells. Hence at 72.50p per share being the mid price shown what is traded above or below can be misleading.

Myself l purchased at 72.35 which is shown in red as a sell when it in fact a buy.

That is my explanation as there have been many disagreements on here as buys to sells.

It is only a shown trade price and nothing else.

One thing that I don't understand is why people bother to post drivel that is neither factually informative, neother informative as an opinion or point of view or has no relevance to the company its compounds or anything at all.

A good debate is what a chat board should be about so we gain a better understanding.

Joey5000 and Sutfie1961 apart from knocking the BoD what would you like to see posted here?

Ty Schecks.

It will come good l feel.and still a little room left in ISA for this year.

Regards

One possible and ever increasingly probable interested partner would be Merck.

Patent life running out fairly soon for their PD-1 inhibitor, Combo therapy with a Chk1 1 inhibitor with patent protection will extend protection period

The competitor to us in this area will be Acrivon who are making significant gains with Prexasertib.

Regards and enough from.me for a few days.

Most pertinent extract

'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 (Fig 4A).'

Regards

Whoops

Triparna Sen. Bl00die predictive text!

Apologies to the young lady.

Regards

Good afternoon HBD

Been posted several.times before! Worth a reminder.

Tripena Senn

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141083/

Keytruda as most of us know is a PD-1 inhibitor.

Chk1 Inhibitor, LDG and PD-1 potential outstanding combo as very compatible.. Secondly if it were patented in combo therapy would increase protection from generic drugs for a good few years.

Https://www.reuters.com/business/healthcare-pharmaceuticals/mercks-keytruda-gets-us-fdas-nod-expanded-use-lung-cancer-2023-10-16/

Good afternoon Fuunyguy.

Background

Mechanical engineering as a youngster.

I worked in research and development. Became a field engineer at 23 installing and repairing cardboard packaging machinery including 100 tonne corrugators, die platter cutters and development of new crank driven machine opposed to cam operated.

I worked also in the making of silicon wafering machines that at that time General Signal did have. They owned everything else to make the silicon chip apart from the wafering machine.

I started work in the Nuclear Industry mid 1986 and have stayed within the Industry ever since mostly in the field of Rzdiological Protection.

Did my OU degree early 90's

Overall l have found basically you need separate fact from c..p.

Nigh everything in life is a compromise. Over 11 years here and whilst l have made some money in sells here l could have made far more if sold at peak.

Over past several.years looking at the science ie different STAT pathways through which cell signalling is manged. There is much crosstalk and up and down signalling which is complex to say the least. There is much l don't understand. Like most things the further you go in the more complex it becomes. Much is not fully understood by the large pharma themselves.

One thing l do know is that small specialist companies are far better at reaching a success than big companies.

I have found out over years in a big company that a few do not give a flying f if something works or not. When you ask why their answer is well l still get paid and therefore not my worry.

It also pays when you produce anything to look at what competition there is around and if their product is failing is it a trend in that type of product or a result of work being undertaken with lack of attention to detail.

Big companies by comparison to small specialist companies have a far greater turnover of directors. The objective of the new director may not be the same as the old.

You can look at Sierra Oncology as an example of this.

Not all is what it seems. Hence l pay very little attention to the media as they are controlled by those that have their own agenda.

Regards

I will add that niraparib is A PARP inhibitor and not PD-1 which l gave the impression of in last post.

Regards

As such that many of us here would like to see a buyout it would be very difficult with the unknown entity of 737.

What is the value of 737?

What would be nice is an RNS release of on licence of 737 for around 20 million with considerable milestone payments exceeding the original pronai CPF agreement.

Difficult here is finding someone to take on 737 whilst at the same time access to a suitable PD-1 or Wee inhibitor. If they do not own that themselves then an agreement would need to be made with a pharma that owns one.

GSK niraparib has already been tested in preclinical along with LDG with very good results

Regards

Good afternoon Schecks.

Larger sell just after me of 27k.

20495 added to ISA over past 2 weeks. Have just under 4k left.