Member Info for sadoldgit

Michelle Garrett had carried out much research work on CHK1 inhibitors. The discontinued Prexasertib has now been resurrected and undergoing phase 2 trials with planned development of combination therapies. Prexasertib has little to no patent life. Can only be administered intravenously and has inferior toxicity issues compared to 737.

As part of the licence ELi Lilly has first refusal on buy back. Milestone payments and dates are in the agreement but actual information at to how much and when has been omitted.

The only thing we know for sure is that 5 million dollars was paid up front.
Acrivon were over subscribed in raising 100 million dollars.

Michelle Garrett had carried out much research work on CHK1 inhibitors. The discontinued Prexasertib has now been resurrected and undergoing phase 2 trials with planned development of combination therapies. Prexasertib has little to no patent life. Can only be administered intravenously and has inferior toxicity issues compared to 737.

As part of the licence ELi Lilly has first refusal on buy back. Milestone payments and dates are in the agreement but actual information at to how much and when has been omitted.

The only thing we know for sure is that 5 million dollars was paid up front.
Acrivon were over subscribed in raising 100 million dollars.

I too look forward to 'an expansion regarding SRA737 chemical structure and what concerns regarding evolving regulatory climate.'

Phase 1 and 2 dose escalation and toxicity reports have been completed and maximum therapeutic doses established.

Dear Michelle Garrett carried out work in advisory capacity and carried out further investigational work on CHK1 inhibitors and resistance too.

These investigations and recommendations are invaluable in establishing the curent worth of 737 as it sits now.

Michelle Garrett does have a vested interest in CHK1 inhibitors.

Regards

It will depend on who and what the licensee is prepared to pay and what the licenser is prepared to accept. We know we have at least two interested parties.
Initial payment from memory was 2 million dollars paid up front.

The 7 million for first god damn mother treated in the US was renegotiated to 2 million
dollars.

A very modest 10million upfront of which Sareum would receive 2.75 million would propel the SP considerably more than 2,75 million. By the very nature to be on licensed would double the current SP I feel. Must not be greedy or unrealistic here.

My opinion is an up front of circa 25 to 30 million with milestones of 750 million plus.

As a complete buyout absolute minimum range of 400 to 600 million and that is based on Edisons valuation risk at 15 and 25% chance of success from 2018/19. Triple combo therapy likely to increase this considerably. Patent protection on combo therapy I have my doubts as to the real benefit to 737.

I wonder how the orderly queue is forming.

There is also the fact that had SO continued development of 737 they would have been liable for 2 milestone payments totalling 14 million dollars at a time when all funding was funnelled in to momo.
How many here were aware of that? Not many i would estimate.

Now there's a thought for the 'there must be something wrong with it brigade'

Michelle Garrett did not continue to use SRA737 after patent protection by SO. I find this very odd as the dear Michelle was an advisor to them.
Yes M Garrett does have a vested interest in CHK1 inhibitors especially CCT245737.

If we go for a mediocre on licence it will be worth considerably more than the upfront payment 6 and a half years ago.

On the dosing of the first patient in the US a milestone payment of 7 million dollars to be paid. The next milestone would have been another milestone payment of 12 million dollars.

SO clearly thought that one through. Had all the trialling down outside the USA!

Regards to all

This is post Sierra Oncology development. Michelle Garrett and co responsible for this, i believe

Combined pharmacologic blockade of CHK1 and B-family DNA polymerases synergistically inhibits cancer cell proliferation
To confirm that the synthetic lethal interaction we observed was due to loss of both B-family polymerase and CHK1 catalytic activity, we adopted an orthogonal validation approach by performing combination studies using small-molecule inhibitors of both CHK1 and B-family DNA polymerases. We tested SRA737 in combination with aphidicolin in a panel of human cancer cell lines. We found that SRA737 and aphidicolin cotreatment was synergistic in eight of nine cancer cell lines tested (Fig. 4A; Supplementary Table S3), including A549 lung and SW620 colorectal cancer cells

This is post Sierra Oncology development. Michelle Garrett and co responsible for this, i believe
full link below

https://aacrjournals.org/cancerres/article/80/8/1735/647725/CHK1-Inhibition-Is-Synthetically-Lethal-with-Loss

'Aphidicolin I believe from earlier report ( Michelle Garrett) is toxic to humans and an alternative treatment needs to be investigated prior to use in clinic.

A very heavy read on TP53 mutations below. Fairly recent publication.

https://www.nature.com/articles/s41419-022-05408-1

From Aug 2021

Cancer deaths are predominantly due to metastases rather than the primary tumors, and thus there is an urgent need for the discovery of more effective drug therapies for metastatic cancer. Recent genomics, transcriptomics, and proteomics studies have identified tyrosine kinase 2 (TYK2) as an oncogene that is frequently mutated or overexpressed in many types of cancer and metastases. A member of the Janus kinase (JAK) family, TYK2 mediates the signals of numerous cytokines involved in immune and inflammatory signaling. In cancer cells, activation of TYK2 can lead to decreased cell death as well as increased cell growth and invasion. Multiple drugs that specifically block TYK2 or JAKs are currently FDA-approved or in clinical trials. In this review, we provide an overview of the screening, molecular, and animal studies that have characterized the role of TYK2 in cancer and metastases, and the potential of TYK2 inhibitors as effective cancer therapies.

Apologies for late getting back HbD but breakfast and chores out of the way now.

You may find what I have posted below of correlation between SDC1802 and CCT245737 of interest. Did the partnership between CRT and Sareum on CHK1 inhibition lead to the design and development of SDC 1802?

SDC1802

The patent (US Patent Application no. 16/343,639) will protect the SDC-1802 molecule and pharmaceutical preparations thereof as a therapeutic to treat cancer selected from pancreatic, colorectal and kidney cancers, melanoma, and B-cell lymphoma by inhibiting TYK2 kinase. This programme is in preclinical development.

T.ALL
TP53 mutations are detected in 15.7% of patients with ALL and are correlated to a low hypodiploid karyotype and to MYC -translocations. Disruption of both TP53 alleles is associated with adverse prognosis in ALL. Abstract TP53 is the most extensively studied gene in cancer.

Pancreatic
Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53

Colorectal
Emerging evidence from laboratories and clinical trials shows that some small molecule inhibitors exert anti-cancer effect via reactivation and restoration of p53 function.

Kidney
In conclusion, for many years, the role of the p53 pathway in renal cancer has been the subject of seemingly conflicting results. However, recent studies appear to be generating a consensus, which suggests a clear link between p53 expression and disease progression, particularly in CCRCC. ( clear cell renal cell carcinoma).

Indications for SDC1802 above.
All have one thing in common and that is inactivated P53 and or P53 mutation.
How does SDC1802 counter these problems with P53 checkpoint?
Is it pure coincidence that SDC1802 is designed to cope with indications with P53 mutation or lack of P53? Take into consideration here the very nature of CHK1 which was developed in collaboration with the ICR and CRT.

Would it be feasible to assume that maybe Sareum independently of CRT and ICR had garnered a compound that is in fact in some areas, to be superior in efficacy and toxicity to 737. ( SKIL ) Notwithstanding, but can also be used in combination with to enhance not only 737 but also counteract cancer resistance to Gemcitabine ( as per 1802 patent description)

Food for thought at least.

A long way off.
Just contemplating how 737 in combo with SDC1802 would work.
SDC 1802 is compatible with CHK1 and many other inhibitors and as stated in the patent description can be used as a supportive treatment and may become the dominant treatment.

Liked to have asked that at the AGM. Have or do Sareum have the intention of trialling this combination inclusive of LDG too.

A waiting game for all concerned at the moment.

Cancer Research Technology and Sareum need get their heads together I feel.

Glad you posted C79. The pure Tyk 2 brigade will not be able to cure UC if it had 2 holes up its backside. Excuse the vrry basic scientific terms.

UC responds best to Jak 1 and jak 3. Although Tyk 2 is reported to ' control' jak 2 and 3 via signalling from Jh2 domain it controls or to be precise regulates.

My understanding of Tyk2 is it controls via JH2 domain the JH1 domain. JH1 domain you can take as the active site.

Tyk 2 seems fantastic. Wow it will only hit the kinase targets we want and not affect those we don't want.

However by the use of defined regulation imposed by process of pseudo kinase inhibition or control of processes in active site by specific Tyk 2 regulation it would not be unreasonable to conclude that the treatment of UC and Krones disease ( they see very similar) will have no success
Irrespective of however much they administer a dose.

In the attempt to make a perfect kinase inhibitor and to avoid the so called black box warnings a pure Tyk2 inhibitor will have limitations imposed on it as the Indications it can treat.

Do you the more you understand about the science. Science is not just limited to the compounds. But after a while you can understand the rationale behind big pharma ideas.

Pure Tyk 2 will be restrictive in what it can effectively treat.

As TM stated. Our Tyk2 Jak1 inhibitor may prove favourable over Deucravacitinib and vice versa.

Regards

Thanks CD. Although Tim was referring to our Tyk2 Jak 1 compounds he did mention the market and basically what is the 'in thing' The latest drug craze for want of a better phase. Stating we cannot deviate too far away from what the market sees.

CHK1 has been well documented and in a sense, as a monotherapy achieved very little.

It is understandable in the way it works.
It works by preventing successful cell division and replication if the cell is DNA damaged.

In this sense the P53 does not effectively diminish tumour size. Prevent growth? Yes, up to a point. Then we encounter CHK1 resistance by the cancer. ( mutant P53)

However if we introduce a DNA damaging agent such as chemo or radiotherapy tumour cells can be killed. Unfortunately, now what happens is the cancerous tumour will prolifically try to repair the damage done. Our bodies unfortunately don't recognise oncogenic or cancerous cells.
737 works by the addition of the cell p53 checkpoint which if the cell is fine it is allowed to replicate but if the DNA is damaged the cell goes through apoptosis basically programmed cell death.

Chemo and 737 combined has a higher rate of success.

However we can combine a programmed death 1 or a programmed death ligand receptor. These effectively kill the oncogenic cell. As far as I know they only attack the oncogenic cell.

Now we can combine LDG, PD-1 and a checkpoint kinase inhibitor.

In this combination the increase in efficacy is significantly increased and according to Tripirna Sen is caused by the micro environment created by this combination.

In mouse models ( SCLC) the success was 8 out of 10 mice had 100% tumour regression which lasted over 60 days. I know this is not the same, as in human trials as we are not mice.

However the results do suggest in SCLC outstanding results compared to any other treatment out there at the moment. The other two mice encountered partial response. Overall response rate would be 100%

The use of bio markers and patient selectivity should see similar results in human trials.

There are no CHK1 inhibitors approved for use with the exception of Bibert a chinese CHK1 inhibitor. The wording is nigh exactly the same as the Sareum and SO description of 737. They are even putting Bibert into combo with LDG and proposed further combo with PARPi and PD-1 inhibitors.
Bibert er si wu qi san qi. 2 4 5 7 3 7
Bibert does not state the above numbers in mandarin, just my attempt to be humourous.

Acrivon has licence for Prexasertib a chk 1 inhibitor with no patent life left, now in stage 2 clinical trials. 100 million was raised ( oversubscribed) around or just after the licence was granted.

You can make your own decisions as you see it yourself.
There exists plenty of scope for CHK1 in my opinion in a variety of cancers.

Regards

I am certainly not of the opinion that GSK would want a competitive compound in the market that may likely lose revenue on the commercialisation of the Tesaro pipeline which they paid 5,1 billion for in 2019. However, good or not so good it would just not be good business acumen.

Why pay circa 300 milion in milestones on top of running later stage trials plus Royalty payments to put a compound into the same arena as the now GSK owned Tesaro pipeline?

Clinical trials to assess the use of Zejula in “all-comers” patient populations, as a monotherapy and in combinations, for the significantly larger opportunity of first line maintenance treatment of ovarian cancer are also underway. These ongoing trials are evaluating the potential benefit of Zejula in patients who carry gBRCA mutations as well as the larger population of patients without gBRCA mutations whose tumours are HRD-positive and HRD-negative. Results from the first of these studies, PRIMA, are expected to be available in the second half of 2019.
GSK also believes PARP inhibitors offer significant opportunities for use in the treatment of multiple cancer types. In addition to ovarian cancer, Zejula is currently being investigated for use as a possible treatment in lung, breast and prostate cancer, both as a monotherapy and in combination with other medicines, including with TESARO’s own anti-PD-1 antibody (dostarlimab, formerly known as TSR-042).

In addition to Zejula and dostarlimab, TESARO has several oncology assets in its pipeline including antibodies directed against TIM-3 and LAG-3 targets.

They have also comparatively recently added

EOS-448 is currently in an open-label phase I study in patients with advanced solid tumours. GSK and iTeos plan to start combination studies of EOS-448 with dostarlimab in 2022. GSK’608 (anti-CD96 being developed in collaboration with 23andMe) is in phase I as monotherapy and in combination with dostarlimab. GSK expects to submit an Investigational New Drug application for GSK’562 (anti-PVRIG in-licensed as SRF-813 from Surface Oncology) by mid-2022.

Monoclonal antibodies are very expensive to produce and also have produced more side effects than originally predicted, difficulties in producing specific antibodies.

These are later developed treatments for cancer. They sound good given the GSK hype but no mention of DDR pathways especially P53 which exits at up to 98% in late stage HGSOC.

GSK have their pipeline. Very costly treatments too.

Jemperli has not been without its setbacks either.

I would hazard an educated guess Leggster that 737 will be taken on via some form or another in the US.
Sierra took the for 'sale sign' down in early to mis 2020. there are no shortage of companies of similar size to Acrivon looking for promising compounds to develop.
A concern would be the up front payment with these smaller companies ie circa 200 to 500 million Market Cap.

Regards

Nubex how much patent life we have left? 10 years on the compound itself.

No, they did not omit the word all on purpose There was no need to use the word all. Far better to use the word 'completed' which they did.

Potnak. They cannot evaluate until all the relevant data is received. Some will be in original paper format. Much of this data and documentation will be required to enable later clinical trial.
Do you understand the importance with respect to future commercialisation based on patient selectivity and profiling?
.
You post.
'Someone has sat on this news for a month and it isn't Sareum.' What factual basis do you have to substantiate this statement? One should not try and read into something that is not there.

Much of the data will be known about from reports. However, to fully understand and evaluate ,there will be a need to see the original data and where necessary in its original format. Very little difference between this and the MHRA evaluating SDC1801. CTA application.

The CPF Cancer Pioneering Fund are the financial arm of the CRT. Persons along the lines of CRT and ICR scientists need to evaluate this data.

What are you going to base future clinical trials on?

Potnak, do you know when and what the last piece of documentation or data relating to the clinical trial contained?

Regards

Cambridge, UK, 6 March 2023 - Sareum Holdings plc (AIM: SAR), a biotechnology company developing next generation kinase inhibitors for autoimmune disease and cancer, today announces that Sierra Oncology, Inc. ("Sierra") (a subsidiary of GSK plc) has completed the return of the Clinical Study Reports and other associated documents and data related to SRA737 to Sareum's co-development partner, the CRT Pioneer Fund LP ("CPF").

All i can read into this is the recent completed return of the clinical study reports and associated documents. Nothing here that explicitly states that all the data had been received in January.

CPF would have notified Sareum on completion of return. Sareum have now released an RNS stating that all document transfer is complete. To think that someone has sat on this all through February is reading into statement something which has not been stated.

Had it all been returned in January why wait until now to release an RNS?

Regards

Agree 100% Mafuta. Clinical trial data 737 with and without LDG plus the added bonus of LDG 737 and a PD-1 inhibitor in preclinical.
Clinical trial in triple combo should prove very interesting.

Options given were on licence quickly or carry out further work then on license.

What we do know is that SO were in no hurry to return the supply of all the relevant data in its entirety.

Regards