Member Info for sadoldgit

https://www.icr.ac.uk/news-archive/asco-2019-drug-targeting-dna-damage-response-shows-promise-against-cancers-of-anus-and-genitals

A very long but good read
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918546/

https://pubmed.ncbi.nlm.nih.gov/31639020/

More reading
https://www.cancer-research-network.com/colon-cancer/sar-020106-is-an-atp-competitive-and-selective-chk1-inhibitor/2020-12-17/

Interesting history of CHK1 development.

A bit higgletypigglety.

From circa 2016
CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described.

From 2012
CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs
Conclusion: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies.

From 2016
Materials and methods: We characterized the radiosensitizing activity of CCT244747, the first orally bioavailable Chk1 inhibitor. We used a panel of bladder and head and neck cancer cell lines and monitored the effect of combining CCT244747 with radiation both in in vitro and in vivo models.
https://www.biocrick.com/CCT244747-BCC6423.html

Hold on, surely CCT245737 was the first orally available CHK1 inhibitor. What is the relevence here? What point am I making?

Michelle Garrett and co have been carrying out studies investigating CHK1 inhibitor resistance. Circa 2019 /2020.They have used CCT244747. Not CCT245737.

What is the relationship? Those that have been here years may will remember the early days of CHK1 and may recall that Tim and co had two lead candidates. Subsequently one of them, in Tims own words was 'tweaked to give better efficacy. The later candidate 737 which consequently went forward into trials.

in addition go back to 2010
https://pubmed.ncbi.nlm.nih.gov/20053762/

Forward to late 2019
'Conclusion: The Chk1 inhibitor SAR-020106 is a potent sensitizer for DNA damage-induced cell death in glioblastoma therapy strongly reducing clonogenicity of tumour cells. Selectively enhanced p53-mut cell death may provide stronger responses in tumours defective of non-****logous end joining (NHEJ). Our results suggest that a multimodal therapy involving DNA damage inducers and DNA repair inhibitors might be an effective anti-tumour strategy with a low risk of neurotoxicity.'
Glocastoma is (A cancerous tumour which develops in the brain. The tumour forms in the star shaped cells of the brain called astrocytes, which supports the nervous system.) No known cure.

No mention that this is a sareum compound. However, look at the link below and note the names involved. ( Michelle Garrett and John C Reader) This compound is a soluble compound. Basically i would conclude that this compound to be a precursor of CCT244747. No approval for clinical use of course.

https://pubmed.ncbi.nlm.nih.gov/20053762/

CCT244747 is the earlier untweaked version of CCT245737 ( Now SAR737)

The point I will now make is that Michelle Garrett et al have been using the earlier CCT244747 compound in post 2019 research. Therefore there lies considerable interest in developing 737 for the clinic.

More reading
https://www.cancer-research-network.com/colon-cancer/sar-020106-is-an-atp-competitive-and-

Cenzo0208, it has been postulated on a report that further patent protections with regards to combination therapies could be applied to 737 to increase protection beyond 2037.

Submarine patent or hidden patent applies to Tyk2 Jak 1 SDC compounds and thus not applicable to 737. Basically a patent kept in waiting.
Although with regards to patent on 737alone, time ticks on, it is would be worthy to note that in combo therapy where 737 will prove to be most effective new patents can and may be applied giving a more than adequate protection period for any pharma choosing to progress 737 development.
For example there is no reason 737 could not be patented with alternative pathway inhibitors of which there are several bit would have to identify a specific partner

Most advanced compound is 737. 737 will be the only commercially available ChK1 inhibitor with the added benefit of the oral route of intake. Good efficacy with mild to medium toxicity.

It is pleasing that the long term investor feels a little more relieved about their investment after the AGM meeting today and many thanks to PC1954 who took the trouble to attend, given great, unbiased feedback in contrast to the non constructive, non informative bile that has been posted here over the past few weeks.

Tim and co are not great at comms as we know, but are focused on getting the researched compounds to work to the best of their ability in the indications designed for. They are very good at what they do with regards to the molecular design of a compound. Attention to detail will eventually pay off.

In contrast look at the large pharma that has bought a compound already approved and pushing commercialisation expansion by carrying out stage 3 trials in other indications especially fields with unmet needs. I used to wonder as to why there were so many failures is phase 3 trials and now very much beginning to understand.

GSK now looking to push momo into different areas.

PCS1954 thankyou very much for your valued feedback from AGM

Regards and wishing a merry Christmas and an extremely prosperous 2023.

Missed bits of AGM . However if the patent is returned to CPF then all the better. It will protect 737 in combo up until 2037. Will look through if able a little later and see what can be gleaned from the meeting.
I am certain of considerable interest in 737 development. A French company recently has been using 737 in pre clinical combination studies. I will try to root that one out.
I am inclined to think it will not be in the shop window for long. All down to CPF/CRT. There exists no other CHK1 competition apart from the newly Chinese approved Chinese CHK1

Regards

Not new but an overview of SRA737 in combo in link at bottom.
Note one of the authors who had by the way written an outstanding report on the results of SAR 737 Pd-1 inhibitor and LDG.
This author John V Heymach is also an advisor to the board of GSK.

GSK bought out Tesaro early 2019 for their oncology pipeline. Niraparib had already been used in pre clinical combo with SAR737 and LDG with what was described as outstanding results. Author John V Heymach.

Step forward to 2021 and an offer is made for SO by GSK. Momoletinib their primary reason for buying SO stated by GSK.

SRA 737 the first and only orally available CHK1 inhibitor would be in direct competition with Tesaro pipeline. SRA 737 and LDG produced good results in NSCLC. Far better results achieved when combined with a PD-1 inhibitor.

At the beginning of 2020 the for sale sign came off of 737 for on licence. Combo patent of 737 and LDG granted to SO.

In effect this patent prevented any development work of SRA737 in combo with LDG outside of SO unless express permission granted.

As from early 2020 Michelle Garrett et al were carrying out research work with CHK1 inhibitor and LDG in combo with other treatments.. By around April 2020 prexasertib was used as opposed to SRA737.

Prexasertib is inferior to SRA737. Prexasertib is also a dual inhibitor of CHK1 and CHK2 whereby SRA737 is (from memory here at least 100 fold) more selective of CHK1 over CHK2 with the added bonus of being orally administered. CHK2 has proven to be counterproductive.

Now if we summise that the continuing development of SRA737 in combo with LDG and a Pd-1 inhibitor gave as good a result in clinical as preclinical trial, where would that put GSK with regards to commercialisation for the Jemperli and Niraparib and its BET inhibitor with regards to HGSOC on top of SCLC global commercialisation?

Surely it must be seen as a threat.

Use it or lose it comes to mind and as GSK has paid 5.1 billion dollars for the Tesaro pipeline the last thing they would want is to be hammered by a potentially superior treatment.

It was never in the interest of GSK to allow SO to develop SAR737, but at the same time I believe forces around to prevent or delay development of 737 until at least GSK got their foot in the door.

Of no use to GSK as committed already, but at the same time would not want a rival competitor developing 737.

I am not surprised that much interest has been shown in CCT245737.

https://pubmed.ncbi.nlm.nih.gov/31470128/

That my thinking around the delayed return of 737.

Then there was also the hype around the takeover price of SO by GSK as undervalued. SO them selves stated that SRA 737 may prove to be more commercially viable than momo.
That does not sound to me in anyway shape or form to be a failure of 737.

Regards

I did see his repetitive posts on ADVN. A few days ago.
Getting away from that all looking good and 737 ought to come into play. Sareum may have some involvement with 1802 in combo. Jak 1 and IL-6 regulation of PD-1. Several pros and cons into research into this. if my thinking proves correct should prove outstanding.. SO was looking at trial design with 737 and immunotherapy. Fortunately we are in the best place to proceed with that with our very own 1802.
Interesting to see if SO chose to delay the return as they have certainly delayed things for past 30 months.

Regards

Sounds like love peace and harmony fearg

The HNWI bought at a price that they themselves considered justified. They are long term investors, they entered at a price that they believed was justifiable and can expect a handsome return for their investment. They certainly do not have to justify to anyone on this board as to why they are invested.

If you have been invested years you would have seen your investment grow to 9p a share old money. It was not a donkey then. Nothing has failed, nothing has been rejected and that includes SRA737 at this moment in time.

Regards

Best to have left the other countries out of the RNS. Looks like a GLPMA review required period.
I would not suggest in anyway that the data is corrupt or manipulated in anyway. The CRO would have nothing to gain. They just need check that all the work carried out is GLP compliant. The data results are the data results nothing more and nothing less.
It is not unusual for MHRA to seek these reviews in fact even more so in light of recent events ie pencilled in information.
Close scrutiny will be required as the most important aspects is subjecting healthy volunteers to potential very high dosages of an immune system modifying inhibitor. In a sense the onus is on the MHRA to ensure that all avenues are covered prior to approving a drug for clinical use. The legal implications if they do not would be horrendous.

Somebody has to sign their name for the approval and are accountable. The fear of heavy fines and or criminal negligence if proper procedures are not followed prior to approval is something no individual wants.

Apart from delay i see no other major problem. 95% of applications are approved following requests for further supporting information. Whether this applies to GLPMA review I have no idea.

On the plus side it is not rejected. It all boils down to the integrity of the CRO carrying out research work. If they are GLP compliant then there ought to be no cause for concern but understand the delay will cause anxiety.

Regards

i been accumulating for 10 years. Will continue to do so especially at these levels. We all have that opportunity. But as you say Lazarus 2, it is our decision to buy on what we believe.

Regards

What would be the maximum amount of dose allowed in the study Lazarus? I would think this to be the main concern so in this instance the MHRA would seek guidance from the GLPMA in reviewing the data and how it has been interpreted for justifying No MTD reached. However, it has been known in the past that a maximum dose can be derived at 30 x treatment levels.
Dose range from 12.5 mg per day up to a maximum treatment of 1000 mg.
Effectively maximum treatment at 30 times would give 30,000 mg per day.
Bound to cause a few eyebrows to be raised. That is one hell of dose!

Regards

The MHRA has indicated that it requires an additional review by the UK Good Laboratory Practice (GLP) Monitoring Authority of part of the pre-clinical data included in the application to approve the clinical study. Sareum and its advisers have sought additional clarification from the MHRA and UK GLP on the next steps.

Slight change from previous RNS

It now requires an additional review by GLPMA. Clearly dialogue has taken place. MHRA have now passed the buck over to the GLPMA as is their perogative to request a review. A55 covering exercise.

May well be due to having not reached an MTD. No MTD reached so in effect how do you progress dose escalation study? Be interesting to know exactly what part of the data the MHRA wish the GLPMA to review.

IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion.
1802 compatible with CHK1 inhibitor.
SRA737 in combo with PD1 and LDG 100% reduction and sustained for 35 days in pre clinical studies.
Sierra patented SRA737 in combo with LDG.
Why go to all this effort to protect this combination? One thing it does do is prevent anyone carrying out further research in combo therapy whilst these patents are in place without express permission from the patent holder

Master Patent for what may I ask Ahfam? Happy to oblige.

Bassethd. The only thing we can deduce is the CTA has not been rejected and Sareum have responded to MHRA request for supporting info. Had Sareum not replied we would have been notified of dfinate rejection by now. How long it will take to resolve the matter is anyones guess in the current climate of post covid combined with understaffed and inexperienced MHRA ajudicators.

Regards