Member Info for sadoldgit

Phase 2 does have a tendency to have a higher failure rate.

The main reasons for this is drug being trialled for different indications. An initial indication may be a fairly simplistic indication such as Psoriasis ( where at the moment exists an unmet need for new treatments), If we were then to select another indication such as Crohns or Ulcerative Colitus it may well fail the phase 2 trial. This can be proven by factual reporting

'Bristol Myers Squibb’s deucravacitinib has hit its first bump in the road. After blowing Amgen’s Otezla away in psoriasis, deucravacitinib went into a phase 2 readout in ulcerative colitis flying high—only to fail to meet the primary or secondary endpoints.'

At present we have Tofacitinib (2016) for IBD
IL-2, -4, -6, -7, -9, -12, -15, -21, -23, and -27
Essentially, tofacitinib inhibits these signal transduction pathways, resulting in downregulation of a variety of inflammatory mediators. Several JAK inhibitors have been developed for the treatment of rheumatoid arthritis, IBD, and psoriasis. Each of these agents has variable selectivity for the different JAK isotypes (JAK 1, 2, 3, and TYK2). In this respect, tofacitinib broadly inhibits JAK 1, 2, and 3. In ulcerative colitis, the dominant benefit is likely via JAK 1 inhibition with downregulation of IL-6 and interferon-gamma.

From April 2022
Inflammatory bowel diseases, comprising ulcerative colitis (UC) and Crohn's disease, are chronic, immune-mediated and progressive inflammatory disorders affecting the gastrointestinal tract. Tofacitinib is the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved by the National Institute for Health and Care Excellence (NICE) for use in moderately-to-severely active UC after intolerance, inadequate response, or loss of response to conventional treatment or biologic therapy. The pivotal OCTAVE studies demonstrated the efficacy and safety of tofacitinib for the induction and maintenance of remission in UC. A growing body of evidence from real-world data supports the positive clinical and endoscopic benefits observed with tofacitinib treatment in the OCTAVE trials. This narrative review summarizes the current literature regarding the mechanism of action of tofacitinib, data from registrational trials, emerging real-world evidence, and an overview of the most recent safety evidence.

We could conclude in the absence of contradictory data from above, that it is unlikely for a pure TYK2 inhibitor on its own for IBD as does not inhibit all the pathways shown above.

it is virtually impossible to have specificity of JAK 1, 2 or 3. Selectivity yes.

An indication in a patent description is not to be taken as a guarantee that the compound will work effectively enough to reach clinical approval. Likewise there will be an indication or indications that a compound will be highly likely to reach clinical approval. These indications will come to light after phase1 trials.

Star786. Since the dreadful tranformational deal expectation delivered by Tim at the end of 2012 for which he was severely lambasted for, it is unlikely they will inform us with even the slightest degree of detail.
There really is very little PR from SAR.
The best we get is the rare and becoming rarer) Proactive Investor video with the smooth talking Aussie, Andrew Scott interviewing Tim Mitchell.

A good technical report in the Thoracic/head and medical Oncology journal. Aug2019

Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.

Methods and results: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti-PD-L1/anti-PD-1 significantly increased antitumorigenic 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 myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNß, and chemokines, CCL5 and CXCL10.

Conclusions: Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine 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 the PD-L1/PD-1 pathway.

Early 2020 patent protection and for sale sign taken down for 737, therefore not available to license or at the very least develop further.

Dr. John V. Heymach is the Chairman of Thoracic/Head and Neck Medical Oncology, the Chief of Thoracic Medical Oncology, and an Associate Professor in the Departments of Thoracic Head and Neck Medical Oncology and Cancer Biology at The University of Texas MD Anderson Cancer Center.

He has also much researched info on NSCLC.

John V Heymach is also an advisor to a few large pharma, GSK being one of them. GSK therefore would have known of the potential for commercialisation of SAR737.
GSK in December 2018 completed buyout of TESARO for 5.1 billion dollars

Would GSK want 737 to enter the clinic first or not at all, as would be direct competition and would threaten GSK being first to get foot in door with a treatment. No alternative treatment available, so just need to clear the bar to provide for unmet need.

GSK projected turnover of Jemperli alone is 4 billion per annum.

GSK made 34 billion in profits in 2021.
Emma Walmsley 17% pay rise putting her on 8.2 million a year

'This is the highest risk time for a drug development company, entering the clinic for the first time'

No, it most certainly is not. Highest risk is at phase 2 clinical trial. it used to be around 22%. Recent data from 2021 at 29% success. P1 trials success between 65 and 75% success depending on statistical source.

In immuno oncology success rate can be significantly improved via the use of, and I will put correctly used biomarkers and this applies to all stages of both preclinical and clinical development.

Phase 1 clinical trial is to a establish a safe/ maximum safe therapeutic dose.

Once a maximum therapeutic dose has been established, these doses can be applied in a stage 2 trials for a selected indication or indications.

As for everything has been in Sareums control. Sareum cannot control the results of preclinical testing. Please provide factual information to prove otherwise.

In the extremely unlikely event that Sareum received catastrophic results for phase 1, it would not be a case of not having money for a second shot. It would be complete and utter downfall of sareum.

However, there are very few believe in failure as can be seen on this board. We only have to look at those that post they have sold and are waiting to jump back in at a lower price. I have nothing against that.

The science is not reflected in the SP only the market sentiment.

Regards

You will have many traders. On a negative RNS there will be a big rush to sell for fear of heavy loss. it will cause a cascade of selling. then there is a tendancy for the SP to gain some of its losses.
Market sentiment. The only people that definitely make money are the MM's. Plus a few bargain hunters near the end of trading day ( sometimes later).

As I have posted before since May the AIM market cap across the board has fallen from around 140 billion to 90 billion.

If we look at a positive approach to recent intent to return SRA737 by SO to CPF there exists a potential to on licence again. As much development being completed with regard to combination therapy excellent data on results so far achieved. Research work has recently been completed with regards to CHK1i resistance.

Based on what I know that puts me in a far better position to make a decision whether to buy or sell than those that state **** or bust.
I may be wrong in my views and certainly were when led to believe that SO after the takeover would be continuing development of 737. In hindsight it should have been returned at least 12 months ago.

What is required is info regarding funding for phase 1b trials. That is my concern at the moment. I dare say it is hand nut Sareum are as tight as a gnats chuff unless it is preclinical compound data updates.

Enough from me this weekend and will to the delight of some give this board a rest for a while.

Regards

Joey on what basis do you view that this really is a **** or bust share.
if none of us know how it will play out and by definition that includes yourself, on what basis do you view that this really is a **** or bust share.
Yes there are of course risks, that the majority here are aware of. It may well prove to be a multi bagger from here in a few months and if it proves to be the case then much more at later times.

Regards

Intent will suffice Hbd
Unless of course legal action is taken and in this case the word 'shall' would be used. SO would want to go anywhere near a legal case.
No reason for them not to return all relevant materials in a timely manner. Expect around 30 days. They no longer hold the license so cannot sell on and even if they did then I believe the milestone payments would become 100% payable to CPF, Not 100% sure on this, as would need to refer to original License agreement for clarification.

If they were interested why not on licence 6 month ago or 3 month ago or 1 month ago? The new owners of SO would not approve.

There is plenty of info here for anyone interested in previous GSK antics. Court documents. Some of it is laughable.
GSK had 1,900 salesman visiting doctors to promote Paxil

'Breakthroughs in the Treatment of Child and Adolescent Depression and Anxiety'
We have a Dr Karen Wagner a leading child psychiatrist. (promoting Paxil) I have taken info from evidence sheets. These are sales pamphlets.

Depression is a lethal disorder and requires treatment.
We have child depression with threats of suicide. (2.5)
Paxil is one of the few pharma treatments that has safety and efficacy data to support its use in the patient population, and more is on its way.

Be vigilant of these signs.

irritable mood, complaining about everything
naps after school.
feelings of guilt, nobody likes me, I am stupid.
diminished interest in activities.
sleep disorder, exhausted when time to get up.

Now we have the large paroxetine study ( this will impress you)

Paroxetine 66% of group improvement
Imipramine 52% group improvement.
placebo 48% group improvement.

Look at these statistically significant results. paroxetine was significant, Imipramine no better than placebo.

As a result of this study, Dr Wagner s said we can say that paroxetine has both efficacy and safety for treating adolescants with depression.

Side effects

Paroxetine only 7% cardio vascular side effects,
No other mention of side effects in this promotion,

Later down Dr Wagner pointed out that one of the big challenges treating children with depression and adolescents, is getting them to stay on their medication. As soon as a parent sees side effects in their children they stop them fron taking drugs,

Dr Wagber then says, 'there are two things to keep in mind, first of all, start patients on low doses 5 to 10 mg, then work up to 20 mg over a 12 week period. Sometimes 40 grammes is better. A gradual build up reduces noticeable side effects'.

No mention of these side effects.

To cut a long story short. they GSK) employed 20 clinical investigators ( 2 GSK employee investigators) and a contractor to provide editorial assistance.

There were 11 SAE's from Paroxetine group.
worsening depression
emotional lability
hostility
headaches

Final draft. only one SAE related to Paroxetine ( headache)

Paroxetine was approved for use in adults 1992. There was never FDA approval in under 18 year olds.

Such statements of Paxil a ' demonstrates REMARKABLE efficacy and safety'
' GSK bringing forward 'cutting edge scientific data'

There is much more.

But just to make a point this is what large pharma can do to influence buyers.

Sales in Paxil 2001 and 2002 1.8 billion dollars per year.

Regards

www.justice.gov/opa/gsk-docs.html .

GlaxoSmithKline Scandal
A Chinese court ordered GlaxoSmithKline to pay $492 million in 2014. The fine resolved charges of bribing doctors in China to use GSK products. It was the biggest penalty ever imposed by a Chinese court.

The court sentenced Briton Mark Reilly to four years in prison. He was the company’s British executive for China. Four other Chinese employees received the same punishment.

But the employees may never serve prison time. The court postponed the sentences. Reilly was deported.

In February 2018, GSK was still answering to fraud investigators in its home country.

Step forward to 2020
In March 2020, the Department of Justice (DOJ) sent GSK a notice of a civil investigation it had opened into allegations of False Claims Act violations by the company because of Zantac. DOJ requested documents on June 18, 2020. On the same day, the New Mexico Attorney General filed a lawsuit against GSK for violations of false advertising statutes and state consumer protection, among other claims.

2011
GSK set aside $6.4 billion for future lawsuits and settlements.

Much earlier 1993 to 2003.

Wellbutrin: The United States also alleges that, from January 1999 to December 2003, GSK promoted Wellbutrin, approved at that time only for Major Depressive Disorder, for weight loss, the treatment of sexual dysfunction, substance addictions and Attention Deficit Hyperactivity Disorder, among other off-label uses. The United States contends that GSK paid millions of dollars to doctors to speak at and attend meetings, sometimes at lavish resorts, at which the off-label uses of Wellbutrin were routinely promoted and also used sales representatives, sham advisory boards, and supposedly independent Continuing Medical Education (CME) programs to promote Wllbutrin for these unapproved uses. GSK has agreed to plead guilty to misbranding Wellbutrin in that its labeling did not bear adequate directions for these off-label uses. For the Paxil and Wellbutrin misbranding offenses, GSK has agreed to pay a criminal fine and forfeiture of $757,387,200.

A couple of points to note

(Alliance News) - Sareum Holdings PLC on Wednesday after Sierra Oncology Inc, a subsidiary of GSK PLC, said it intends to return the rights for SRA737 to the CRT Pioneer Fund LP. Shares in the Cambridge, England-based drug developer for cancer and autoimmune diseases were down 19% to 159.00 pence each in London on Wednesday morning.

A subsidiary company is a separate legal entity from its parent for the purpose of tax, regulation and liability. Subsidiaries can be larger than their parent company, as the relationship is controlled by ownership shares and voting power rather than the number of employees at either company.

Effectively SRA737 remained with SO after takeover. They are the licensees and hence hold the licence until effectively
revoked by breach of contract.

Of no significance. It does however prove that as company is bought out, becomes a subsidary company and still responsible for its own legal and tax affairs. It would not be in the interests of GSK the parent company for SO to pursue development of 737. There is no Sierra website as such now as you can only access info from this wonderful politically correct, utopian GSK website.

GSK previous

In 2012, GlaxoSmithKline pleaded guilty to federal criminal offenses. The company’s crimes included misbranding of its antidepressants Paxil and Wellbutrin. GSK also failed to report safety data to the FDA about its diabetes drug Avandia.

GSK admitted to illegally promoting Paxil for treatment of depression in children.

The company reached a civil settlement with the U.S. federal government in which it agreed to pay a fine of $3 billion.

GSK also failed to report safety data to the FDA about its diabetes drug Avandia.

The plea represented the largest health care fraud settlement in U.S. history. It resolved allegations of pricing fraud.

To be continued

HbD most of EU legislation is still in place. To all extent and purposes for the time being it will remain the same.

Regards and thanks for your posts along with C79, fearg C007, notalot & gunner.

I am extremely disappointed with SO that whilst they carried out sterling work on 737 then sat on it for over 2 years preventing further development,

FFS they even put patents in combo being aware that the likes of Michell Garrett et al carry out no further work.

Nick Glover left under a cloud.
Who was screwing who over here? Nick Glover, or those that took over. Clearly he did not fit in the mould. Corruption is rife. Mr Glover you are here by summoned, you can take retirement with a years notice of 900k and a compensatory payment of over 3 million, on the condition you dont rock the boat.

All sound very fair to you and corrupt free?

The result being 737 back in the hands to those that have a deep vested interest for the benefit it can do.

I will post no more as under the influeunce of several beers and a bootle of wine whilst cooking my dinner. I will add

The new journey for CCT245737 begins.

Regards to all and keep the faith

if it were sufficient to carry us through phase 1b fearg that would be the best option/outcome.
Tim and co would have decent idea of 1b costs. 100 people around 50k per person a ball park figure I would throw in.
However, SDC1802 requires funds as will nearing preclinical. You cannot run a company on an empty bank balance.
Question remains is how much funding required and for what?

Regards

Thanks for that HbD, good informative and factual post.
It does reinforce the debate that acess to funds are required.
My understanding prior to your post would be you have to demonstrate how you will fund the total trial.

CRT funded CTA for CHK1 in 2017, money by Sareum around 790k was paid in December 2016. Application was not made until Feb 2016. CTA was granted within 60 days.

Am sure Sareum will be aware. I would also hasten to add that any form of licensing partnership from initial stages take around 3 months. That not me. that I was was told a few moons ago by specialist solicitor in company law who due to cancer is no longer with us. That was his estimation on timelines so do not take it as exact.

My take on it is that after 30 days from receipt of CTA which takes us to end of August, then around 10 to 12 weeks before we receive notification of funding. That absolute latest. May well be earlier.

No big problem envisaged, dependant on terms of course. The return of 737 should make absolutely no difference to an interested potential partner in this case.

Regards

I will add if PH had insider knowledge god forbid why they not drop the days earlier?
The price dropped on what is called on' market sentiment'.
Can you explain market sentiment to me? The nearest I can understand it is, that whatever way you think the market will go, market sentiment chooses the other path.

Very rarely are timelines adhered to.

If we were not successful in trial application we would have been notified by now. The only thing PH would be aware of is if they have been approached regarding funding. It would be an extremely lucrative market before them.
They well may have been approached and agreed financing additional shares ( dilution) it is then in their best interest to keep the current SP as low as possible.

Of course they cannot divulge that information.

If you honestly believe Gunner 68 that we may not go into trial next year, then why not short the stock?

AIM market caps across the board have been reduced from around 140 billion in May to just over 90 billion as of now.

Answer me a question if you have time please, have all these companies BOD's taken their eye off the ball?

Difficult times with world events and not predicted to improve in 2023.

We have had nothing from SO/GSK CHK1 in 5 years. Please enlighten me as to why and the justification that a compound that has been securely protected by compound patents, that has been returned to the CPF should warrant a 40 million market cap price drop for a company in this instance?

Regards

.

Celtic007
Good afternoon. I am not worried, but at the same time have a degree of concern as to a delay in receiving info with regard an update at least.
60 days on receipt of CTA decision given
After 30 days initial assessment a yes with provisions or a mind numbing NO. You have 14 days in which to respond ( which may take much longer)

The only concern I have in this respect is are we as in Sareum required to have sufficient funds to finance stage 1a and 1b clinical trial, to satisify approval of CTA?

Why do I think this way, as I may be wrong?

We have sufficient funds for stage 1a. So in this respect you would expect the corresponding yes from the granters of the application.
Now if we take an example of the CTA with regards to CHK1 it was notified via RNS within the 60 days of receipt of application.
As far as I am aware it is a requirement for the applicant to prove he has the funding or at least the ability to the means to these funds.
A bugbear may arise, that should Sareum believe that they will on success of a phase1a trial, be able to raise adequate funds on this result alone, to be acceptable to meet the criteria to raise funds for stage 1b. Would that satisfy the governing body and consequent CTA approval? I dont know, really I do not as always so many hidden terms in contracts and applications.

However, if were the cause for delay, There are two options

We become financed by raising money via dilution of shares. Or we can become funded with either partnership or license agreement.
There is really no other viable option. HNWI's I do not think will come aboard last 3 have been hammered so far, and I certainly do not see them taking their options up as is way higher than the current SP.

Maybe Sareum were waiting for the peanuts half a million intimated by SO at beginning of year. Strung along nicely!

If I am correct in assuming that all funding is required as a prerequiste, then we can expect an RNS detailing what the arrangements are for funding .

Sareum stating will be in 1a by end of year. What do they know?

No news is not good for our SP and what have we got? 10 weeks to 2023.

They are in the drivers seat and we sit in the back with a bag over our heads.

I certainly do not envisage any other problem with application, but cannot be ruled out.

We have 1801 and the return of CCT245737 to create a new era.

I dont believe we have a problem raising funds through either option, but raised they must be or all ceases.

We will be notified in due course. It will not be ceasing.

As Former President and Chief Executive Officer at SIERRA ONCOLOGY, Nick Glover made $4,446,258 in total compensation. Of this total $905,148 was received as a salary, $0 was received as a bonus, $3,524,091 was received in stock options, $0 was awarded as stock and $17,019 came from other types of compensation. This information is according to proxy statements filed for the 2020 fiscal year.

How the hell can you resign and get compensation? Corruption afoot.

You are welcome fearg.
I reckon you will be pleasantly surprised as to what it contains. A vast majority, believe me requires skipping through, as after all it is a full research report.
Regards

Slight correction to your post fearg.

Triple therapy has not prevented CHK1 inhibition as such. Triple therapy great in some indications. However there still exists CHK1 inhibitor resistance in difficult to treat cancers HGSOC, pancreatic and breast.
It is a big hurdle to cross, but not impossible.

Please take a look at the research article Michelle Garrett ( heavily involved in our CCT245737 development) which I posted earlier and is the long report on C79's post. Need download the pdf. You can read and skip bits, there are some very, very pertinent points. Especially with regards to alternative pathway blocking.
Effectively they have discovered why CHK1 inhibition becomes or is ineffective and concludes with recommendations to overcome this.

The other point that has recently occurred to me, is that SO had a patent grant in combo for 737. Am of the opinion, and please express your views, that as Michelle Garrett et al were carrying out research work with SRA737, Gemcitabine and either PD-1 or PARPi. They had been using SRA 737. Around the same time of patent protection MG and co then began using an alternative CHK1 inhibitor Prexertib( prexertib discontinued but still available for research purposes),effectively SO has thwarted development of 737 in combo. Was this intentional?

The handing back is by no means a bad thing and as you imagine and I am of the likewise opinion that we will get a better deal.

I dont think we will here of any developments with SRA737 soon with regards to on licensing as takes time to reach agreements with potential interested parties.
Would expect soon news from Tim and Co for future plans now the old gal is back.

Regards

Notalot. Yes there exists an extremely lucrative market. But it takes many years of research and huge finance just to get a candidate compound like 737 just to clinical trial.
It is known what the limitations of CHK1 are. Alternative pathways developed by some cancers to bypass CHK1i.
Much work undertaken by Michelle Garrett in overcoming this.

'To me the prices you state say that anyone who can produce an alternative, perhaps better, stands to make a handsome profit.'

At the same time anyone that does so will create an equal and opposite loss to those that have developed a drug in clinical use for the same indications.

What measures would you take to ensure you get to clinic with your compound first, set the bar and then to maintain it?

'GSK had apparently been forecasting for peak sales of $1 - $2bn for Jemperli, but if the drug could establish supremacy to Keytruda in its flagship indication of NSCLC, then peak sales could potentially enter the double-digit billions.'