Member Info for sadoldgit

Good afternoon HbD. Whist I like the New Scientist a am not in total agreement with what it prints.

CAC is Colon associated cancer!

The present study aimed to investigate the potential function of CHK1 in CAC and colitis in mice. GDC-0575, a inhibitor of CHK1, was used to treat mice with CAC or colitis. Immune cell infiltration and inflammatory cytokine expression in response to treatment of the mouse models with GDC-0575 were measured using flow cytometry, immunofluorescence, and ELISA. The correlation between CHK1 expression and CCL2/CCR2 expression was investigated in CRC tissues. Our results serve as evidence to clarify the function and mechanism of CHK1 in the context of CAC and colitis development and present a potential therapeutic target for CAC.

GDC-0575 Regulates Inflammatory Cytokine Expression in Colon
To determine the potential role of GDC-0575 in inflammatory cytokine expression, colonic tissues were collected for protein extraction and ELISA analysis. As shown in Figure 4A, the inhibition of CHK1 significantly inhibited the expression of TNF-a, IL-6, IL-1ß, and COX-2 and markedly increased the expression of IL-10 in mice with CAC. Our results indicated a significant reduction in TNF-a, IL-6, IL-1ß, and COX-2 levels and a significant increase in IL-10 expression in mice with colitis as well (Figure 4B). The above results confirmed the regulatory role of CHK1 in inflammatory cytokine expression in the colon of mice with CAC and colitis.

This is from April 2021
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058335/#:~:text=Checkpoint%20kinase%201%20%28CHK1%29%20plays%20an%20important%20role,inhibitor%2C%20in%20colitis-associated%20cancer%20%28CAC%29%20and%20colitis.%20Methods

GDC-0575 is a highly selective small-molecule Chk-1 inhibitor invented by Array and licensed to Genentech. Genentech is responsible for all clinical development and commercialization activities.

With Gemcitabine too
Study Type : Interventional (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Phase I, Dose Escalation Study Evaluating the Safety, Tolerability, and Pharmacokinetics of GDC-0575 Administered Alone and in Combination With Gemcitabine in Patients With Refractory Solid Tumors or Lymphoma
Actual Study Start Date : March 23, 2012
Actual Primary Completion Date : January 11, 2018
Actual Study Completion Date : January 11, 2018

There will be no Pd-1 or Wee1 combo patent for this!

Regards

The value of our Tyk2 Jak1 compounds can only be obtained on the results of dose escalation studies. That is it in a nut shell nothing more and nothing less.
CHK1 or to be more precise 737 has already been subject to dose escalation. It has proved very favourable compared to other CHK1 inhibitors.
By the very nature of how a CHK1 inhibitor works it will never cut the mustard a mono therapy. In combo with cancer damaging treatments it will come into its own.
Yes, cancer can develop resistance to Checkpoint kinase inhibitors but investigations and experimentation has identified these potential alternative pathways and indeed also identified inhibitors that address these pathways of resistance.

Regards

Hi BB,
Patent on 737 is to 2033. Combo patents extend to 2037. The value will be in combination therapy. As a mono therapy does not do much especially compared to combo.
Aslo potential here ie Michelle Garrett ( I know I harp on about her) but i would expect 737 to be in combo with AKT and or P-13 inhibitor. These patents will have a life span of 17 years from date of application.

Aber, I have an eye on GSK too. Although it belongs to Sierra Oncology I can see GSK pulling a few strings here to delay. Prefer not to see it happen but have my concerns.

Regards

HI warthog 4, I were replying to JD1066 attempt at pfishing for exit levels.
No offence intended to regular posters.

Regards

Surfing 1961. Where have l predicted 40pounds a share sonny? You need get your facts right.

Regards

Grow up l did not predict 40 pounds a share
You two need get a life and a sense of humour

£45 a share or on license for CCT245737, SDC1801, SDC1803 & Aurora Flt+3 , maybe buyout. Not happening any time soon

Regards

£45 a share or on license for CCT245737, SDC1801, SDC1803 & Aurora Flt+3 , maybe buyout. Not happening any time soon

Regards

It may well open up 90 to 100p. I think they tight for shares. Not many in free float.
1657 sell 90p

After hours trade Basser1.
PH at 16.55 offering 80 sell 100 buy
Small price drop first thing.

Good afternoon BA
Eli Lilly own Gemcitabine but is now a generic drug. Gemcitabine there were attempts to manufacture via the oral route around 10 years ago maybe longer. Oral bioavailability was poor around 10%. As far as I know was never progressed further.
As was mentioned by Scheckler ( I think) there is no reason why a patent could not be applied for a combo 737 Pd-1 and LDG or similar. Not sure how effective this would be in protecting gemcitabine against the generics. it would at least protect the patent owner of subsequent gemcitabine only use in combo.

It is all about combination therapies these days. Not all are compatible and can induce toxic side effects.

Although the CPF will receive all the data on preclinical/clinical testing , I am sure there will be a vast input from Michelle Garrett ( formerly assistant project lead at CRT) and crew if not done already.

Many options available and Tim gave the two main options. Do we ( CPF in reality) go quick on license or carry out more development?

Interested parties so that indicates at least 2. According to the AGM the CPF had been approached themselves. Yes definite interest.

Tims timeframe for assessing the data one day to less than a month.

Regards

Regards

Hello criticalthinker from ADVN aka Steady Danny.

Just been looking at a few ADVN posts. That LPH really is a one, needs psychoanalysing. He certainly has issues. i feel sorry for him. Not sure if SDC1801 or CCT245737 could address those problems.

If you do look in , Wishing you all the best in 2023.

A new year and good start to it for Sareum. I dont think it is far from incoming good news.

Good evening Ahfam, I would not be surprised if there are musings of using SDC1802 in preclinical with CCT245737.
Chk1 SDC1802 in combo and maybe chemo too.

i am not aware of there being any pre clinical work with a CHK1 inhibitor with SDC1802 ( immuno oncology). Not surprising as there are not any as far as I know.

Excerpt below of the new therapies

Next Generation Cell-Based Immunotherapies
Advances in CARs, TILs, and TCRs
21 - 22 JUNE 2023 ALL TIMES BST
Initial good responses to T cell therapies can be followed by rapid relapse owing to tumour-related mutations and evasion mechanisms put out by the tumour. Despite these challenges, these treatments are reaching the clinic and showing benefit to the patient, often when applied in combination or with co-stimulation. What learnings can be gleaned from the first-generation T cell therapies, and how can we apply them to next-generation CARs, TILs and TCRs, targeting NK, gamma-delta, and other macrophage or myeloid cells? The Next-Generation Cell-Based Immunotherapies conference will explore the advances in engineering, in vivo and ex vivo approaches, allosteric and allogeneic platforms, preclinical to clinical updates, and the latest efforts toward solid tumours.

Despite the amazing results from emerging immunotherapies such as immune checkpoint blockade and chimeric antigen receptor T cells (CAR Ts), not all cancer patients have benefitted from these innovative treatments yet because of innate and adaptive resistance. Further investigations into the tumour microenvironment are needed to better understand the mechanisms and develop means to overcome the immunosuppressive TME, thereby improving the safety and efficacy of novel immunotherapies

Wow! these wonderful very recent new ideas are not getting it all their own way.
Liken cancer to Covid 19. As part of development/evolution and to survive they will develop immunity/resistance to treatments.
There will be some successes but 100% in 100% of cancers will not be happening anytime soon.

Am of the belief that value will be achieved on dose escalation studies of SDC1801 which will add value to SDC1802.
Until confirmation is received of potential dosing regimes in treatments derived from dose escalation studies, we cannot fully sell the potential of the inhibitors. Since it is the off target and on target toxicity that places limits on dosing.

I will add ,at 30 times treatment dose no MTD was reached. Tim did say in a Proactive Investor interview we may have to go to 100 times treatment dosages. No idea if this was tried or not.

Dosing was originally given the window of 12.5 mg per day whole body to 10 mg per kilo of body weight up to a maximum of 1000mg per day whole body.

If these values can be proven to be safe with no unacceptable levels of adverse events then it is truly game on.

Biggest killers of drug treatments is toxicity and efficacy. There exists also cancer resistance to a drug which has caused problems in the past, the current day and will also continue into the future. Hence why we have an increasing number of combination therapies.

We also informed in SDC1802 patent that 1802 can be used as a supportive treatment in conjunction with just about every form of current cancer treatment ( this is interpreted from the list of supportive treatments compatible) Additionally, it may lead from a supportive treatment to the dominant treatment.

Some of these current and ageing as well as new cancer drugs, indeed some current treatments cost 150 to 200k dollars for a course of treatment. They are effective up to a point, but no guarantee of success. Poor prognosis still exists in some forms of cancer.

There is a need for more cost effective treatments.
GSK have bought drugs/companies already with commercialised pipelines. Their objective then is to push the drug into any area of treatment they can ie commercialisation. These drugs effectively are pushed into areas where their efficacy and safety become less effective..

Hence why there are so many later stage trial failures.

All treatments will have optimal indications, where they are more effective some more so than others. Many will work better in combination therapy. Not all are compatible with one another. |Level of dosing and the dosing regime just as important as the compounds themselves.

As for ruling out early Jaki's
Momelotinib (MMB) is a JAK1/2 and ACVR1 inhibitor with demonstrated clinical activity in all 3 hallmarks of myelofibrosis (MF): anemia, constitutional symptoms, and splenomegaly.

Approved for use. Speaks volumes for Jaki's

Also bare in mind that Jak1, Jak2 and jak 3 are not specific. They only have selectivity. Hence if you have Jak1 you will also have Jak2 and Jak3 albeit to a lesser extent based on selectivity values.

Regards

From 2019

Sareum TYK2/JAK1 Inhibitor SDC-1802 Demonstrates Anti-tumour Activity in Multiple Cancer Disease Models

Data indicates SDC-1802 works via a novel immunotherapeutic mechanism of action

Preclinical results to be presented at the 2019 AACR-NCI-EORTC International Cancer Conference

Sareum Holdings plc, the specialist small molecule drug development business, is pleased to announce that it will present new preclinical data from its SDC-1802 TYK2/JAK1 inhibitor cancer research programme at the American Association for Cancer Research (AACR) National Cancer Institute (NCI) European Organisation for Research and Treatment of Cancer (EORTC) International Conference, to be held 26-30 October 2019 in Boston, USA.

On Tuesday 29 October 2019, Sareum’s CEO, Dr Tim Mitchell, will present a poster* that describes how SAR-20351, a novel selective TYK2/JAK1 inhibitor discovered by Sareum, significantly reduces tumour growth in disease models of many cancers, including those of the pancreas, colon, skin and kidney, plus B-cell lymphoma. SAR-20351 was formally selected as preclinical development candidate SDC-1802 in September 2018.

These positive results were seen when SAR-20351/SDC-1802 was dosed orally, as a monotherapy, or in combination with chemotherapy. The studies indicate that inhibition of the TYK2/JAK1 pathway is a novel mechanism that promotes an anti-tumour effect by activating the local immune system to attack cancer cells. These findings provide support for TYK2/JAK1 inhibition as a potential new immunotherapy approach and for the further development of SDC-1802 as a novel cancer therapeutic.

Amgen purchased Horizon Therapeutics mid December for around 23 billion dollars.
Not saying we are worth anywhere near that but at the end of the report it does mention acquisitions/mergers to increase in 2023.

Regarding SRA737
From the Journal of Thoracic Oncology

'However, we observed remarkable tumor regressions when we combined SRA737 + LDG with anti–PD-L1. All mice achieved some level of tumor regressions and 8 of 10 (80%) mice had complete tumor regressions which were sustained up to 60 days post treatment'

Full link below
https://www.jto.org/article/S1556-0864(19)30692-6/fulltext

SRA737 was right under the nose of GSK, John V Heymach, one of the authors is an advisor to GSK ( as well as several other pharmas)

I am thinking there is a remote possibility that GSK may have an interest in owning this inhibitor. GSK have stated that they wish to develop treatments for cancer using 'their pipeline' of drugs. CHK1 Pd-1 and LDG outstanding results in combo.
As a second thought on this GSK now in a better position to own themselves with a cheaper option than paying future milestone payments and royalties. Stranger things have happened.

GSK modus operandi at recently has been to purchase compounds that are already in commercialisation and then push the treatments by hook or by crook into other areas, especially those areas of unmet needs.

It would not rule out more than a passing interest in SDC1802 subject to toxicity and safety profile data from development of SDSC1801.

Happy New Year
ps Yes PCS1954 am still in Thurso Scotland. Besdt wishes to you and your family.

I will add it is not the preclinical data in itself which is in question. It is the integrity ie compliance with GLP practices and adherence to.

Regards

The system:
enables sponsors to apply for clinical trial authorisation in up to 30 European countries with a single online application;
allows national regulators to collaboratively process clinical trial applications in more than one country, request further information, authorise or refuse a trial and oversee an authorised trial;
facilitates the expansion of trials to other EEA countries;
enables transparency and access to information for any party interested in clinical trials conducted in the EEA through a searchable public website.
CTIS went live on 31 January 2022 together with the public Clinical Trials website. For more information, see:

Clinical Trials Information System
Development of the Clinical Trials Information System
Clinical Trials website

UK
As of 1 January 2022 the combined review service, (formerly known as Combined Ways of Working (CWoW), is the way that all new Clinical Trials of Investigational Medicinal Products (CTIMPs) applications are prepared, submitted and reviewed. Combined review offers a single application route and co-ordinated review leading to a single UK decision for CTIMPs.

It would seem here that the UK has tried to follow European legislation to be compatible and on par with.

However, although timelines are stipulated in both EU and UK legislation with regards to supplying additional requested information there is no information given when a request for a review by a governing body timescale.

Sareum would have responded to the request for additional information.
There will be timelines here, we can interpret that unless a decision has not been made then approval should been granted.
We know the MHRA have made a request for GLPMA to review.

To place into question a compliant, regulated CRO doubts the integrity of the very institutions that have laid down the governing regulatory framework.

Sareum have made their case through application and response to request for more supportive information with GLP compliance. They can do more.

It is a review of the preclinical data and not an actual inspection of the CRO as I understand.

The question is:- has this data been passed onto the GLPMA for review and if so what are the timescales?

In the event that we have not been informed of non approval or that the application has lapsed due to timescales then the data must have already been presented or provision for access to.

I would surmise that this data has been sent to the relevant authorising/compliance body within the 14 day period.

As much as I can find information on requested inspections of CRO facilities I am unable to find any info on reviewing data by the GLPMA.

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/405710/Guidance_on_the_Content_of_the_Quality_Assurance_Statement.pdf#:~:text=These%20are%20inspections%20that%20cover%20the%20general%20facilities,the%20frequency%20at%20which%20these%20inspections%20a

PCS1954
Worth a quick browse with regards to OECD.

Thus one refer to GLP
https://www.oecd.org/chemicalsafety/testing/glp-frequently-asked-questions.htm

Overview
https://www.oecd.org/about/

It really should pose no problem to Sareum to go the alternative.
Likely to be much more efficient and quicker.

Regards