Member Info for sadoldgit

Chk1 is also considered one of the targets for tumor treatment studies have shown that BEBT-260 enhances the activity of chemotherapy drugs in a variety of tumor cells BEBT-260 exhibits significant anti-tumor activity when administered alone or in combination with chemotherapy drugs
Therefore, Bibert Pharmaceuticals intends to use the product alone or in combination with chemotherapy drugs for the treatment of various solid tumors(especially with TP53 mutations), no ChK1 inhibitors have been approved for sale worldwide;
There are also fewer ChK1 inhibitors being developed clinically, and companies such as Lilly, Roche and Sierra Oncology are known to be developing such products congratulates Bebert Pharmaceuticals BEBT-260 on its approval for clinical development and looks forward to the smooth progress of the follow-up research on the product, which will bring innovative therapies to patients as soon as possible

They should be finding out about CHK1 inhibition resistance in some cancers and also resistance to chemo about now.
I cannot see much chance of this being approved in the US or Europe.

CCT244747 the precursor to the tweaked CCT245737 is available to purchase for non clinical research. I would not put it past the Chinese to have attempted to copy this as they copy everything else.

6 week course you end up looking like Quasimodo.

in all seriousness now. There is plenty of scope for CHK1 inhibitors, originally to enhance chemo. Early inhibitors poor safety profile. Yes there are cancers that develop resistance but that is what cancers do to any form of prolonged treatment. Our innate immune system is the cause of that.

Good to see a competitor C79. Indicates that CHK 1 inhibitors has good potential. It is however around 4 years behind Sar737.
The Chinese have there own CHK1 in clinical testing for large tumours. Similar claims as is made by all pharms's.
Not think I would trust myself if their christmas tree lights are anything to go by.
https://topic.echemi.com/a/chk1-inhibitors-bibert-pharmaceutical-class-1-new-drug-approved-clinically_85250.html#:~:text=According%20to%20the%20information%20published%20by%20the%20Drug,innovative%20therapies%20to%20patients%20as%20soon%20as%20possible

Good morning Blastoid7,
The molecule is as is, ie there can be no tweaking as in effect you are changing the compound. There will be no delays in this aspect. Only delay is CTA approval.
Tim and co have done as much as they can. They have clearly submitted all required information. All accredited CRO organisations.
I could understand a review being taken if it were in house. The caboodle for a CRO is to develop accurate data whilst following a strict protocol.
That being said we have 2 compounds both TYK2 and Jak1.

With regards to psoriasis I will take a look through video footage.
Tim an co have stated that they believe 1801 to be more effective in psoriasis than current allosteric Tyk2.
To a certain extent this has been validated by Pfizer with there Tyk2 jak1 inhibitor.
All jak inhibitors are not the same and Sareum have always developed compounds with good safety profile.
Personally i see no reason why our compound should not prove favourable over allosteric Tyk2.

There will be areas where allosteric tyk2 have the edge and areas where TYK2 Jak1 will have the edge.
This is where clinical trial results will be of the upmost importance.
We should be streets ahead of Tyk 2 alone with TYk2 Jak1 in IBD.
Pure Tyk 2 here in my opinion is too selective for this target.

regards

Apart from the HNWI's how many true investors are there?
So many now post who claim to have been here years yet seem to know SFA.

None have a valid argument.

I am a true investor, I have old some but at the same time increased my share holding.and not to be confused with the in and out brigade who change their tune accordingly.

Yes I have kept when could of sold and by some half wits assumption makes me a mug?

Happy to add when price is low when others smirk'

Smirk as much as you want as am adding and will continue to do so.

Goodnight all true investors.

Many shares are down especially AIM.
The war in the UKraine. Higher cost of living.
Investment has become decimated.
If Sareum were the only share to have dropped 80% you would have a point.
You are being played by the NWO. Lets keep the war going.

AIM as a whole dropped circa two thirds. close to 80 billion as of 12 months ago.

Whilst the war rages and being ultimately financed by the tax payer there will be little change. Invest in arms and weapons manufactures and their suppliers, have done obscenely well in past 18 months

Effects of covid and people working from home. Bloody nightmare these people never available. No communication.

Regards

Worth a read.
https://www.biopharmadive.com/news/gsk-jemperli-immunotherapy-fda-approval/598962/#:~:text=GSK%20set%20Jemperli%27s%20list%20price%20at%20about%20%2410%2C400,at%20a%20larger%20dose%20for%20longer%20intervals%20thereafter.

GSK 46% ORR ( overall response rate of complete tumour regression or significant tumour reduction. Now this applies to a chemo and dorstalimab. Not triple combination.
Sareum 737 LDG and PD-1 8 out of 10 mice ( although preclinical which will be in humanised mice) achieved 100% tumour regressions. All mice experienced tumour regression.

Although much better result with SAR in triple combo we need take into consideration GSK just chemo and dorstalimab (Jemperli)a monoclonal PD-1 inhibitor.

Unless GSK have an additional agent to control P53 pathway then it appears that they are way behind in terms of efficacy
in terms of ORR in comparison to SRA737 triple combo.

GSK
Hesham Abdullah, Senior Vice President, Global Head of Oncology Development, GSK said: “The head-to-head data from the PERLA trial showed that dostarlimab combined with chemotherapy provided robust anti-tumour activity in patients with previously untreated metastatic non-squamous non-small cell lung cancer. The positive results from this trial inform our future development plans and highlight the potential for dostarlimab to be our foundational immuno-oncology therapy as a single-agent and in combination with standards of care and novel therapies within our pipeline.”

The primary endpoint was overall ORR by Response Evaluation Criteria in Solid Tumours (RECIST) as determined by blinded independent central review (BICR) and was 46% (n=56/121) in the dostarlimab treatment arm versus 37% (n=45/122) in the pembrolizumab treatment arm (difference in ORR: 9.32%; 80% CI: 1.46% to 17.18%).

The key secondary endpoint, mPFS, was 8.8 months (95% CI: 6.7 to 10.4) in the dostarlimab treatment arm versus 6.7 months (95% CI: 4.9 to 7.1) in the pembrolizumab treatment arm (HR 0.70 [95% CI: 0.50 to 0.98])

Sar737 PD-1 and LDG
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.

Also note the phase
' in combination with standards of care and novel therapies within our pipeline.”

Bare in mind also
Clinical results and preclinical results will be different as clinical are in humans.

Very much on favour with 737. GSk not wanted it as had recently purchased triple combo therapy from Tesaro in 2019. Gsk were committed. Gsk not want 737 at the same time they wanted no one else to. All delayed with patents and bs.

Back to where we are now

If you have time take a look at the Journal of Thoracic Oncology. Combo therapy 737. LDG and PD-1.

Bare in mind this will be lung cancer only!

We further demonstrated that the combination of SRA737 with LDG shows striking activity in combination with ICB in SCLC and warrants further mechanistic investigation. In the present study, we examined for the first time the effects of LDG either as single agent or in combination with ICB and SRA737 on T-cell infiltration and APC subsets. We observed that the combination of LDG+SRA737+anti-PD-L1 leads to enhanced T-cell infiltration with coincident decrease of T-cell exhaustion. We also demonstrated a significant effect of this triple combination on APC subsets in SCLC. We found that LDG+SRA737+anti-PD-L1 modulated macrophage polarization leading to an increase of the M1 subtype and a decrease in the M2 subtype. Macrophages have previously been shown to play a crucial role in ICB resistance and the balance of the M1 and M2 macrophages is believed to effect the long term efficacy of anti-PD1 blockade in multiple cancer types. Here we show that the SRA737+LDG regimen in combination with anti-PD-L1 enhances dendritic cells in the tumor and leads to a decrease in pro-tumorigenic MDSC populations. Most notably, the establishment of the strong anti-tumor immune microenvironment observed when SRA737 is combined with low dose gemcitabine opens an opportunity for a highly efficacious and tolerable treatment regimen with a potentially distinct mechanism from that of standard chemotherapy or DDR inhibitors alone. Further studies are warranted to determine if this approach would be beneficial with other chemotherapies, such as low dose platinum-based doublets, in combination with ICB and DDR inhibitors. While the RPP SCLC model used in the immune-competent animal experiments represents only part of the heterogeneity of SCLC12, 23, our previous work with olaparib and prexasertib in combination with anti-PD-L18 suggests that our observations are more broadly applicable to SCLC. As with many other cancer types, pre-clinical studies are limited to only a few immune-competent models of SCLC, consequently further validation of the combinations described here, will likely need to take place in a clinical setting.

Given that anti-PD-(L)1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737+LDG regimen is well tolerated in clinical trials in SCLC (NCT02797977), our preclinical data provide a strong rationale for combining this regimen with inhibitors of PD-(L)1 pathway in the clinic.

Feel free to draw your own conclusions here!

Discuusion/conclusion

The present study explores the combination of SRA737, an oral CHK1 inhibitor with or without anti-PD-(L)1 in multiple cancer models where DDR inhibitors are currently under clinical investigation. We show that the combined treatment of SRA737 and anti-PD-(L)1 leads to anti-tumor response in multiple cancer models, including SCLC. We further show that combining low dose non-cytotoxic gemcitabine, a known RS-inducing agent, with SRA737+anti-PD-L1 can significantly increase anti-tumorigenic CD8+ cytotoxic T-cell, dendritic cell and M1 macrophage populations. Also, the regimen led to significant decrease in immunosuppressive M2 macrophage and MDSC populations in an SCLC model. The triple combination also increased the expression of the Type 1 interferon gene, IFNß and chemokines CCL5 and CXCL10.

Despite having a very high mutational burden, SCLC is relatively immunosuppressed 16. We and others have shown that targeting the DDR pathway is an effective therapeutic strategy for SCLC 4, 5, 12, 17–22. Furthermore, we have recently shown that DDR pathway targeting potentiates the anti-tumor immune response of PD-L1 blockade through activation of the STING/TBK1/IRF3 pathway-induced activation of cytotoxic T lymphocytes 8. In this study, we demonstrated immuno-modulatory effects of SRA737 treatment through activation of STING and interferon signaling and induction of expression of PD-L1 and inflammatory chemokines, CCL5 and CXCL10 in vitro and in vivo. We further demonstrated that SRA737 potentiates the anti-tumor activity of ICB in multiple cancer models which, we believe, suggests that this combination may have potential for translational impact in several cancer types. Comparison of different SRA737 treatment schedules in combination with anti-PD-(L)1 highlights the need for careful optimization of treatment dosing in order to maximize the intrinsic anti-tumor and immune-modulating activities of SRA737.

Nearly there!

Adding gemcitabine chemotherapy to SRA737 enhances the effect of PD-L1 blockade by modulating the immune microenvironment in SCLC

Gemcitabine-based chemotherapy has been used for relapsed SCLC patients, but its activity is limited to a minority of patients when used as a monotherapy at standard doses1, highlighting the limitations of this treatment paradigm. In contrast to standard cytotoxic doses, low doses of gemcitabine induce RS and increase reliance on CHK1 without overt DNA damage and cytotoxicity. This mechanism synergizes with CHK1 inhibition to induce potent tumor cell death while also avoiding the potential for overlapping toxicities.

To explore this combination further, we tested the SRA737+LDG in the HT-29 in vivo model of colon cancer. In order to mimic the treatment schedule used in the current SRA737+LDG clinical trial (NCT02797977), mice were treated with RS-inducing LDG (40mg/kg) on the first day, followed by inhibition of CHK1 by SRA737 (50mg/kg) for two consecutive days and a dose holiday for the last 4 days of the week. This combination led to a strong inhibition of tumor growth after 3 weeks of treatment (TGI = 83%) highlighting the intrinsic anti-tumor activity of this combination in HT-29 immunodeficient model (Fig. S3A).

Finally,

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

Undoubtedly will be interest in this area.
Progression by SO I feel most likely to have led to cloinical trial and resultant patent protection in this area.

Basic intended form of 737 and LDG patented.
Plenty of scope in some cancers for SRA plus ICB
'Remarkable' results in LDG 737 and ICB in this case PD-1 inhibitor.

we have so far

SRA737 augments ICB-induced anti-tumor response in multiple cancers
Next, we tested several syngeneic models representing the other cancer types from Fig 1A, namely colon, bladder and pancreatic cancers. Tumor cells were implanted into the flank of immunocompetent C57BL/6 or C3H mice and once tumor volumes reached 150–200 mm3, mice were randomized to treatment with either monotherapy SRA737 (100mg/kg; 5/7), anti-PD-1 (10 mg/kg; 2/7 days) or the combination. Similarly to anti-PD-L1 treatment in the SCLC model, monotherapy treatment with anti-PD1 showed very limited activity in the colon (MC38 tumor growth inhibition (TGI) = 23%), bladder (MBT-2 TGI = 18%) and pancreatic (Pan02 TGI = 25%) models, while SRA737 monotherapy (100mg/kg, 5/7) induced moderate tumor growth inhibition in all models (MC38 TGI = 48%; MBT-2 TGI = 53%; Pan02 TGI = 59%). However, combination treatment of SRA737 and anti-PD1 resulted in a substantial additive improvement in efficacy in all three models (MC38 TGI = 76%; MBT-2 TGI = 69%; Pan02 TGI = 70%)

To assess recruitment of infiltrating immune cells, MC38 tumors were harvested 15 days after treatment initiation with SRA737 (100mg/kg) with a modified treatment schedule of 7on/7off either alone or in combination with anti-PD-1 (Day 3, 7 and 11). The infiltration of CD4+ and CD8+ cells was determined by immunohistochemistry staining of tumor sections harvested at Day 15. SRA737 treatment either alone or in combination with anti-PD1 led to a marked increase in CD4+ and CD8+ cells infiltrating into the tumors (Fig 3F). These results further demonstrated the ability of SRA737 to modulate the anti-tumor immune response and warranted further exploration of the strategies that maximize the intrinsic and immune-mediated anti-tumor activity of SRA737 in combination with immune checkpoint blockade.

Anti-PD-L1 (300µg)8 was administered on the third day of every treatment week either alone or in combination with SRA737 (n = 10 per group; Fig 2A). Mice treated with anti-PD-L1 alone showed no anti-tumor response in this model (Fig 2A). Animals treated with single agent SRA737 showed significant reduction in tumor growth as compared to either vehicle or anti-PD-L1 treatment alone, with SRA737 schedule of 5/7 (Treatment/Vehicle (T/C)=0.27; p<0.001) being moderately more effective than SRA737 schedule of 3/7 (T/C=0.32; p<0.001). In contrast to the single agent activities, combination of SRA737 (5/7) and anti-PD-L1 resulted in a complete inhibition of tumor growth within one week of treatment (T/C=0.064; p<0.001) (Fig 2A).

Anti-PD-L1 (300µg)8 was administered on the third day of every treatment week either alone or in combination with SRA737 (n = 10 per group; Fig 2A). Mice treated with anti-PD-L1 alone showed no anti-tumor response in this model (Fig 2A). Animals treated with single agent SRA737 showed significant reduction in tumor growth as compared to either vehicle or anti-PD-L1 treatment alone, with SRA737 schedule of 5/7 (Treatment/Vehicle (T/C)=0.27; p<0.001) being moderately more effective than SRA737 schedule of 3/7 (T/C=0.32; p<0.001). In contrast to the single agent activities, combination of SRA737 (5/7) and anti-PD-L1 resulted in a complete inhibition of tumor growth within one week of treatment (T/C=0.064; p<0.001) (Fig 2A).

All of this carried out by SO.
They would of had plans ( finalising of trial design) ie 737 and ICB that once stood on pipeline progress on their website.

However, in addition to this we have SRA737 plus PD-1 and LDG in combo.

TBC

Just a few pointer here with regards to where 737 is at.

Dec 2019
Despite the enthusiasm surrounding cancer immunotherapy, most small cell lung cancer (SCLC) patients show very modest response to immune checkpoint inhibitor monotherapy treatment. There is therefore growing interest in combining immune checkpoint blockade (ICB) with chemotherapy and other treatments to enhance ICB efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the Food and Drug Administration (FDA) for the frontline treatment for SCLC. Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-PD-(L)1 leads to an anti-tumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737+anti-PD-(L)1 significantly increased anti-tumorigenic CD8+ cytotoxic T-cells, dendritic cells and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and MDSC populations, as well as an increase in the expression of the Type I interferon gene, IFNß, and chemokines, CCL5 and CXCL10. Given that anti-PD-(L)1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that SRA737+low dose gemcitabine (LDG) regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of PD-(L)1 pathway.

tbc

There was much discussion on the subject of patents at the time the agreement was made. Around 6 years ago.
The resulting conclusion at the time was that patents that were within the designs and indications of a treatment were part of intellectual property and would be passed on to CPF in the event of termination of the agreement.. However if a patent covered an invention out side of the scope of the license treatment it could be retained by Pronai Therapeutics.

For example if SRA were patented for toothache then the patent would remain the property of Pronai Therapeutics.

Good input as usual from you PCS1954

The Patents that were granted covers CHK1 as a mono and combo with gemcitabine in treatment of cancer and there fore would be returned to CPF.
CPF could request that all research data to be destroyed and patent protections withdrawn,
That is not going to happen.

A RNS will not drop before the AGM as I have told you and no not tomorrow either, point 2 no clear concise answers on the CTA will be released tomorrow it will be vague and will leave all investors with more questions. This will get sorted but NOT YET wait for the new year, where I suspect further data testing is required that bit is speculation, on a more positive note all noises are good it will proceed and the CTA will be granted.

Now use this information as you see fit, you can't fight the market tail winds, its happening deal with it, name calling and copying and pasting positive data changes nothing. The current fundamentals have to play out. I'll leave it there and won't reply to any daft comments as it's too time consuming.

The market knows this hence the drop, be under no illusion it will drop sub 50p,

The information that was relayed was wrong
There was an RNS
The SP did not drop sub 50p
Your speculation on further data testing also proved incorrect.

All in all a very negative post and indeed there has been a series of such, for those that choose to read this board.

Then it is posted
Fully loaded up and ready for the gradual rise again, entry price achieved and from the AGM its all systems go. Bring on the rerate, that's for you Affy.

I would suggest that those pharma who have successfully developed compatible combination treatments with a CHK1 inhibitor will be extremely keen to keep an eye on SRA737 and the results achieved so far. There exists no competitive CHK1 inhibitor as far as I know and happy to be proven wrong on this even by the doom and gloomers.
Yes, there is a recently Chinese approved CHK1, Chinese made and approved for the clinic. Most likely a knockoff of 737.

Regards

Not previously posted HbD. Excellent find. Very relevant in the current SRA737 and CHK1 situation. A lot of research and work been done with 737 since put on the back burner by SO.
There is much more recent news on development in combo coming from more than 1 front.
It improves treatment in combo with LDG and far more effective when used with LDG and Pd-1.

Postulated by those in the know of combo with AKT, Pl-13 and USP inhibitors to just a few. These inhibitors are of course available and some already have NDA approval.

Regards

When a takeover or interest in a takeover would be considered all aspects and stages of compounds must be understood. Valuation with regards to certainty/ uncertainty.
I would however not rule out a takeover although not of the opinion would be imminent.
On return to CPF/CRT of licence and data it would enable a company to pursue an option of takeover in its entirety of 737, 1801 and 1802 should they see positive results/progress in compound and clinical data.

As yet we have not received the data back from SO. This data package would not only include the studies being currently undertaken but also the rationale for future in combo therapy. This data will be present, otherwise there would have been no design of future combination stage by SO.

Bear in mind here that an early valuation was made prior to the release of any results carried out by research undertaken by Sierra Oncology of circa 120 million dollars based on a 15% chance of successful outcome of trials with a 15% share of a predicted market.
Results have since progressed well and take into account that this was merely for the success of 737 as a mono and in combo with LDG, plus a vague possibility of being effective in combo with other therapies.

Original license package with milestones circa 320 million and 27.5% of an estimated 10% royalty fee based on turnover, equating to around 2.75 royalty payment for Sareum.

SDC 1801 value will be determined by the phase1 dose escalating studies of which we are waiting CTA approval. This will also indicate validity of SDC1802 as a potential for oncology.

Were pleased to hear that pure Tyk 2 signals via allosteric and that Sareum is using the Jaki route. Proves my point of what I have been saying for well over a year that Tyk2 signals via the allosteric route only, but we have that advantage of also signalling via the non allosteric route ie JH domain 1 by Jaki's

Before a takeover would ever be considered all data would need to be received from SO and the interpretation of plus the results of dose escalation studies.

CHK 1 has great potential and our CHK1 developed inhibitor is a later generation derived inhibitor which is vastly superior to earlier discontinued poor off target inhibitors with associated poor safety profile.

Due to development and early clinical trial success of 737 an on licence valuation would be vastly in excess of the circa 320 million made in 2016. Double at least and more likely much closer to threefold of original license agreement, of which Sareum entitled to 27.7%. Interest has been shown already as confirmed by AGM.

Very roughly 160 million dollars on achieving all milestones and with the amount of shares which Sareum have would be worth around 240 to 250p per share on its own.
50 million knocked off of the price of shares within a few days since the announcement of return by SO.

Value of SDC compounds would be additional to this.

Not far away from Potnaks valuation

Groverlad, is that the same boil bb where you posted the following statement?
You posted
Oct 20th 22 SP at 0.3p
'The unexpected bonus is getting out for a while and picking up some baron oil (boil) recoup losses. Big announcement on or before 26th'

Regards and keep your fingers crossed.