Member Info for sadoldgit

Clinical trial application below for anyone wanting a gander.

https://www.gov.uk/guidance/clinical-trials-for-medicines-apply-for-authorisation-in-the-uk

Points to look at is initial review after 30 days. I interpret as if no problem all is ak then 30 days it is. If they CTA is refused you need to respond within 14 days and the outcome will be given at end of 60 days.
An abstract below

We may refer other applications for expert advice if we identify issues during the assessment process. Examples of trials where expert advice may be needed include first-in-human (FIH) trials with novel compounds where the:
( Note here it states may be needed and shall be required)

mode of action involves a target that is connected to multiple signalling pathways (target with pleiotropic effects), e.g. leading to various physiological effects or targets that are ubiquitously expressed
compound acts (directly or indirectly) via a cascade system where there may be an amplification effect which might not be sufficiently controlled by a physiological feedback mechanism
compound acts (directly or indirectly) via the immune system with a target or mechanism of action which is novel or currently not well characterised
is novelty in the structure of the active substance e.g. a new type of engineered structural format such as those with enhanced receptor interaction as compared with the parent compound
level of expression and biological function of the target receptor may differ between healthy individuals and patients with the relevant disease

If you are a sponsor of a FIH or early stage clinical trial you should read the ' Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. 'You should use the document to help you identify risk factors and create mitigation strategies.

Sponsors should use the criteria above to decide if their trial needs expert advice. You can get pre-submission advice from us if you are unsure if your compound falls into the ‘higher-risk’ category.

Complex but Sareum i envisage should have no problems with this.

All quiet in the meantime and very little news expected until confirmation of acceptance and commencement of trials starting I would guess. Still early for news over the other side of the pond.

Regards to all.

Regards

Good post stoney and my belief is !801 will pi55 all over Humira. Tim was wanting to get into a less competitive market and if you look at what we have an the indication of psoriasis all should bode well. 10% of the market would give us circa 3 billion a year.
A Tyk 2 with optimum amount of Jak1. Tyk2 no way will cut the mustard on its own in many indications. 1l-10 consists of 4 sub units 2 in Jak1 and 2 in Tyk2. Il-6 is inhibited by Jak 1. Where others are failing we should gain.

The biggy of course will be 1802 in oncology and look out for combination therapies too. We dont need to dominate just move into the market.

Sareum have picked a good auto immune in psoriasis. 2% of the worlds population suffer from it and some badly. Most are embarrassed as dont want to roll their sleeves up and suffer much discomfort too. There is no cure for it.

On the negative side long term use of kinase inhibitors can cause side effects. All drugs do to an extent. All we need be is better than what else is out there at the moment. All eyes will be upon our Tyk2 Jak1 in FIH trials. Similar but not identical compounds should send a shudder through the pharmaceutical world as opens the door for 1802.

Been a long time coming. A billion pound market cap is not out of the question at end of stage 1 and into stage 2 for 1801. That is 1801 only.

Regards

Results: NSCLC CD133+ CSC-like cells were enriched upon radiation. Survival of NSCLC CD133+ cells after radiation was higher than that of CD133- cells. Survival of IL-6 expressing NSC LC CD133+ cells (sc) was higher than that of IL-6 knocked-down cells (IL-6si) after radiation. IL-6 played a role in protecting NSCLC CD133+ cells from radiation-induced DNA damage and apoptosis.

Conclusions: IL-6 signaling promotes DNA repair while protecting CD133+ CSC-like cells from apoptotic death after radiation for lung cancer. A combined therapy of radiation and agents that inhibit IL-6 signaling (or its downstream signaling) is suggested to reduce CSC-mediated radioresistance in lung cancer.

Full read in link below

https://pubmed.ncbi.nlm.nih.gov/26572130/

Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the ?-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).

Overcoming resistance to Kinase inhibitors.

Long, very long read. Interesting further down regarding Allosteric inhibitors of which Tyk2 is one. from Jan 2022.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800859/

Cancers are not an easy target. Cancers mutate and can adjust to treatments.

Last but nor least. I wish you a speedy recovery Thoth and thankyou for your previous imputs with keeping the good ship Sareum afloat in times of difficulty and doubt, to which most here are indebted to you.

Regards

Good hits Bobbler and HBdS. i reckon spot on. Recruitment will be 3 to 4 months prior to requirement at least. i reckon a lot going on in the background lads!
All coming together rather nicely. Around 120 patients will take one hell of a lot data recording. Would estimate a cost of around 10 to 15k per head per individual on trial. Up to 6 month trial period at most. But an educated guess at anything from 12 weeks upward t0. This not being inclusive of drug cost of course.
Looks like phase 1a preparing to me.
Regards and will get my beers down my Gregory.

Good evening 007.
A great RNS which signals the direction we are heading. All looking rather good I must add.
A gaping hole paves the way for a top notch inhibitor, irrespective of recent IL-23 and iL-17 mono clonal antibodies.
There is no cure for psoriasis. So treatments will be ongoing to sustain control of the disease. Current latest treatments cost around 10k per year, but this dependant on dose.

Good call by SCHeckler on her prediction of indication!

TYK2 and Jak1 are critical for signal transduction of many key cytokines driving psoriasis. TYK2 is mainly associated with IL-23 and IL-12 signaling (Tokumasa et al., 2007) in T cells (Ishizaki et al., 2011), whereas many other cytokines signal through Jak1 in keratinocytes (Sohn et al., 2013). Hence, dual blockade of TYK2 and Jak1 has the potential to rapidly attenuate both the immune and epithelial components that create the psoriasis phenotype.

In depth info link below

https://www.sciencedirect.com/science/article/pii/S0022202X20300270

I will post one of the links here regarding Tyk2 and Jak1.
https://www.jidonline.org/article/S0022-202X(20)30027-0/pdf#:~:text=TYK2%20and%20Jak1%20are%20critical%20for%20signal%20transduction,key%20cytokines%20driving%20psoriasis.%20TYK2%20is%20mainly%20associated

long link and even longer read.

Regards

Abstract, We report results from a phase IIa study of efficacy and safety of PF-06700841, an oral TYK2/Jak1 inhibitor, in patients with moderate-to-severe plaque psoriasis (NCT02969018).

Methods: Patients were randomized to PF-06700841 30 mg once daily (QD), 60 mg QD, or placebo (4-week induction), followed by 10 mg QD, 30 mg QD, 100 mg once weekly, or placebo (8-week maintenance). The primary endpoint was week 12 change from baseline in PASI score. Secondary endpoints were the proportion of patients achieving 75% and 90% reduction from baseline PASI at week 12.

Results: In total, 212 patients in 35 sites were treated; mean (SD) baseline PASI score was 20.8 (7.68). Decreases in PASI at week 12 were statistically significant compared with placebo in five treatment groups. The greatest change from baseline (least squares mean change -17.3 [95% confidence interval, -20.0 to -14.6]) was observed in the 30-mg QD continuous treatment group. Overall, 136 patients experienced treatment-emergent adverse events, including six serious adverse events in five patients and 13 discontinuations in treatment groups because of adverse events. No herpes zoster cases or major adverse cardiac events including thromboembolic events occurred.

Conclusions: PF-06700841 was generally effective and well tolerated in patients with moderate-to-severe plaque psoriasis.

Also note the following:-

Inhibition of the Jak family of kinases, resulting in a broad inhibition of inflammation, holds promise for treating a variety of inflammatory diseases. Some Jak inhibitors are associated with side effects at higher doses, including anaemia and
thrombocytopenia, because of the inhibition of Jak2-mediated signalling of cytokines such as erythropoietin and
thrombopoietin. The adverse effects of targeting Jak2 could therefore be overcome with Jak inhibitors, such as
PF-06700841 that primarily targets TYK2 and Jak1. Our results suggest that targeting of TYK2 and Jak1 kinases
with PF-06700841 induces a rapid attenuation of the IL-23/

( Now note in the above 'primarily targets Tyk 2 and Jak1' Now PF-06700841 also to a lesser extent also exhibits inhibition of Jak2 and Jak3. These Jak2 and Jak3 kinases are associated with severe side effects especially the latter.

I am sticking my neck out here. But as far as I can reasonably postulate Tim and co will be very well aware of this PF-06700841 adverse effects. Now my theory is that as such, our 1801 compound has a much greater selectivity for Tyk2 and Jak1 than Jak 2 and 3. Henceforth we have very little to no competition in this area. Only now have they released this initial indication in psoriasis. No other indications mentioned.

Not all Tyk2 compounds are the same. Some are more selective than others. Our SDC compounds are formulated by patented protected molecules. It is these patent derived molecules that Sareum can effectively choose selectivity.

There exists, for the time being a big gap in the treatm

The newest drugs for the treatment of plaque psoriasis are the interleukin-23 antagonists, which are FDA approved under the brand names Skyrizi, Ilumya and Tremfya.

Interleukin-23 antagonists work by blocking interleukin-23 (IL-23), a pro-inflammatory cytokine thought to play a major role in chronic immune-mediated diseases, including plaque psoriasis.

Interleukin-23 antagonists are part of a wider group of drugs called biologics. Biologics are administered via subcutaneous injection or intravenous infusion and are reserved for moderate to severe cases of psoriasis. Other biologic drugs include tumor necrosis factor-alpha (TNF-alpha) blockers, interleukin 12 and 23 (IL-12/23) antagonists, and interleukin 17 (IL-17) antagonists.

Systemic therapies, including biologic treatments, are only used for psoriasis that has not responded to other treatments (topical treatments and phototherapy).

Full link below with regards to treatments.
https://www.drugs.com/medical-answers/new-drugs-treatment-plaque-psoriasis-3511670/

One of our competition below.
Stelara contains the drug ustekinumab. It’s a monoclonal antibody, which is a type of drug that’s made in a lab from immune system cells.
Note :- Some monoclonal antibodies are associated with a higher risk of inflammatory lung disease. Skin problems. Sores and rashes on your skin can lead to serious infections in some cases)

Results they give
After 12 weeks of treatment:

Up to 73% of adults taking Stelara had very few plaques to no plaques on their skin. Of those taking a placebo (treatment with no active drug), 4% had the same results.

Tyk2 Jak1 in psoriasis to follow

With regards to prostrate cancer 737 should work fine in combo with LDG.
HGSOC is somewhat more difficult as develops resistance to CHK1 via mutation of P53 checkpoint. The resistance to this or to be more precise the cause of the resistance can be overcome by Wee 1 inhibitor.
Chk1 is not the be all and end all. However if we remove Chk1 from.the equation that we have no effective treatment for over 50% of tumour cancers.
Yes some will be difficult but that is the advantage of Chk1 in combo with a multitude of different treatments and ideally an immuno oncology inhibitor.
Interesting that Sar have pre iously indicated pancreatic and HGSOC as a target for 1802.

Of upmost importance is the dosing schedule, the actual dosage and other treatments is in combo with
Ideally and not in anyway being biased would be Chk1 plus LDG and an IO inhibitor.
Chk1 plus LDG and Wee1 and possibly addition of IO as further support.

That is my understanding.
Not a case of if but more a case of when.

We are now heading towards nearly 5 months of no significant development news.

Longest l have known for Sar not to even give an update.

U less of course an update may well.let the proverbial.cat out of the bag.

Interesting to know when 1802 is coming to an end of pre clinical and how they intend to use ie on its own or in combo.

Would it be out of the question to use 1802 in como with CHK1?

A good wait to hear on this one l feel.

Regards

in between low and profile i omitted the word kept

An astute comment SCHeckler.
The only poor outcome would be is to announce that SRA737 is not going to be continued.
That is not going to happen. It is low profile. For GSK to negotiate any form of acquisition for SRA737 then it will not be in their interests to 'big up' 737.
Sierra have carried out some outstanding work in combo. GSK will want to know what Sierra's intentions are with regards to final design of combo treatments. Until this is established I feel we will here very little more.
But bare in mind I can see no other control of the P53 checkpoint ( over 50% of cancer tumours) than a Serine/threonine inhibitor. Some cancers can develop resistance to CHK1 inhibition ( proven). This resistance can be stopped with other combination therapies ( proven). No ifs and no buts, look forward to anyone that can post to the contrary.

It will take time before we here news, the news i am certain when we do hear will be in our favour.

Regards

Regarding on licence of SRA 737.

Since GSK want to increase their cornering of the oncology market, Why would they choose to on license it?
Far more financially beneficial to keep in house than to sell on. Works very well in combo yet we have not heard of the full potential especially with immuno inhibitors. Patented in combo as well.

Financially worth worth more than momo with a relatively small investment on development.

If GSK choose not to list it makes no difference.

GSK is forecast to hit 1,900 a share up from around 1,750p.
Momo will be in their pipeline so there is no reason for SRA737 not to be shown in their pipeline .Although still at early stage of ownership 'Finalising design' ought to be a little further forward. After all, subject to finding an alternative form of funding to continue development of SRA 737 is no longer a hurdle for GSK owned Sierra. Peanuts to a company like GSK.

Sierra stated it was an intention to continue development mid year/ early H2 ( from memory).
Very little work to do with Momo, so that just leaves a vast amount of resources available for progression of 515 and 737.
Patent protection (early 2020) for CHK1 in combo therapy so no need not to go into a little more detail.

There is an urgent need to get a new treatment for HGSOC and pancreatic cancer. The latter does have a very poor prognosis. Chk1 does slot into the GSK pipeline very nicely. No reason they cannot corner this part of the market as they have done with Momo in treating myleofibrosis.
Resistance to CHK1 ( not in all cancers) can be overcome in combo therapy. I would like to think that GSK will be pushing hard, to get these therapies completed and approved ( may be by fast track) so can enter into the clinic.

One more point. Part of the combination in design is with SRA737, Immuno Oncology and LDG.
Great results obtained in combo with 737. Jumping ahead of myself now but would there not be a reason to use our SDC1802 in combo here?
It is coming to end of preclinical,
Compatible as a supportive treatment for CHK1.
Compensates for the resistance of cancers to Gemcitabine.

Have a great weekend all, Notalot and Ashpot especially.

Regards

The deal would not be closed until it has been voted through by the shareholders.

Yes fairly quick at 5 months?

Good news indeed that your cancer is in remission notalot. I sincerely hope it stays that way.
Not so good about your femur that will take a time to heal.
SP will edge up I feel but what we need is an RNS with some decent news.
Not many shares in free float me thinks.
Regards and wishing you a speedy recovery lad

Good morning Krone. Yes it was reported initiated and agreed in around two months. But these would be done under formal proceedings as opposed to informal.
We are according to Tim an co in discussions with interested parties. However. it is evident that we have yet not entered a formal stage.
If there were formal discussions relating to licensing, or even an offer of a take over, we would as share holders be legally obliged to notification of such. There is no requirement to report any informal discussions as this leads to speculation.

Do you remember the heading to a transformational deal' that TM stated in an RNS circa end of 2012 ? Share price dropped like a stone some 60% when no transformational deal took place. Tim was heavily slated for it.. He will not make that mistake again.
Regards

Thankyou 007.
It all looks extremely promising.
Pharmaceutical companies take a long time to reach deals.

I remember a few years ago when Aurora was all.the talk here and rumours of a buyout and takeover were rife

An old solicitor friend l used to have a beer or 4 with were chatting. I asked how long do company and pharma deals take. Around 2 to 3 months?

He looked at me and squinted his eyes a bit, similar to Clint Eastwood in his Dirty Harry films.

No by dear boy it does not. I asked how long then
Typically a 6 months to a year. More than likely a year to 18 months and not uncommon for 18 months to 2 years.

I ask why so long. He goes into detail about informal discussions. They cannot divulge the details to who the company is as creates too much speculation. What does the buyer want and what is the seller prepared to accept. What is the financial status of the Company. How big is the risk of failure.

A company will be in discussions with another company for months and months on end. Due diligence is carried out. An eye is kept closely on developments. Is the company reaching its targets? Integrity of the company and its Directors. What failures and successes they have. They keep an eye on company events and typically come back to us when you have reached a certain milestone. They will also be in discussions with competitors to see if their product is better. It don't go down well when you state you will do something and 12 months later they ask you have you achieved such and such and you tell them no. You have just ruined your credibility.

Big companies like things in place. Big companies tend not to get Involved with smaller companies. Small unheard offs. Very little status. Minnows.

He worked for over 30 years in his field of company law. He refused to go into criminal law as went against his morals.

He had represented many large companies. Marconi, ICI, Thorn, Laing, BP the MoD and many others
He is dead now. He died of cancer almost 2 years ago. Throat cancer which became very aggressive.
Cancer not only robs our lives, l have lost my mother, father and sister to the big C along with many friends young and old.

The sooner we can get more effective cures into the clinic the better.

Money is not the be all and end all.

Would like to retire soon and do the things that l would like to do in life as would many here. My choice of investing was to put money into something which l think worthwhile. I have easily spent well over 5000 hrs just on research of inhibitors alone and how they work. How they are likely to fail. I just have a need to understand. If l dont l won't.

I remember many moons ago you commented on cancer needing to be tackled from all sides and changing treatments so as not to give the chance of recovering. Stay one step in front you said.

Not sure if you realise just how right you were, as in fact that is exactly what is happening at the moment.

No such thing as

I think you will find the chemical engineers are Tim and Co. They formulated the compound. No GSK when they started. What GSK do have his financial clout. Money talks.
Now if we look at a potential here with Chk1. A wee one inhibitor and LDG which should at least pi55 over anything else out there if not outstanding.
Bare also in mind that resistance to Gemcitibine will happen and this can be compensated for by the addition of our 1802. ( it states that in the description of the recently granted European patent.

I would put my bets on CHK1 being used in pancreatic and ovarian cancer. Pancreatic prognosis is poor at best. Circa 12 months expectancy with treatment. HGSOC also poor but not as poor as pancreatic.

If you delve a little deeper you will find both ovarian and pancreatic are Indications for SDC 1802
Now you have GSK wanting to corner the oncology market. GSK seriously interested in developing immunotherapy oncology.

Combination of IO, 737 and LDG was mooted very early on with greater expectations then for previous combination investigations.

Prexertirb (Chk1 inhibitor) is nigh ancient coming to end of patent life. Not as good as 737 l will also add.

Now exists a 17 year plus patent protection for 737. 737 can be used with PARP or a Wee 1 inhibitor along with LDG

If you look at the desire to add a IO kinase inhibitor then you need a decent patent life on your inhibitor. You also need a decent inhibitor.

Can anyone suggest a promising IO inhibitor with around a 17 year patent life that is compatible with CHK 1 , PARP, Wee 1 and LDG?
CHK1 PARP Wee1 and LDG are half the equation
A decent selective IO inhibitor is the other half.
Nothing to stop GSK carrying out preclinical work with our SDC 1802 in combo.

Just my thoughts whilst sat idly at work. Not going to happen overnight, however the Sareum pot bubbles away.