Member Info for sadoldgit

Good evening Damion.

I had a look through end of year presentatition again. Interesting that there was no Jak2 activity detected in Phase 1a trials.

My opinion here for what it is worth is in this statement they are saying no Jak2 home dimerisation which of course is the unwanted adverse side effect.

My belief is that due to the selectivity and molecule formulation that the Jak2 which we are selective over pairs with Jak1 and via STAT hetero dimerises being very effective of IL-10 and a member of this family 1L 22 which is associated not only with psoriasis but also IBD.

In addition Jak2 can pair with Tyk2 further inhibiting 1L 23 which is a major concern in Psoriasis.

Early on in preclinical there were no adverse toxicology issues at 30 times max therapeutic dose. Tim mentioned we may have to go to 100 x but never know if they attempted this and Tim did say we may have difficulty in doing this due to amount of compound that could be produced.

But interesting to note here no adverse events at 30 times max therapeutic dosage so not surprising the very good results obtained in phase1a.

At the end of the day you can make as many in vitro and in vivo claims that you like but the proof of the pudding is in clinical trial.

As for efficacy should be no problem in several Indications. Problems arise when dose limiting toxicology inhibits efficacy and long term use giving rise to an unsatisfactory release in MACE.

Once long term toxicology results completed l don't see Sareum being sareum anymore hence the now pushed activity in 1802.

Regards

TLL-018 predominently Jak 1 at 4 nM with Tyk2 @ 5nM.

effectively no Jak2 or Jak3 which due to the nature of Jak selectivity does appear a little hard to believe.

There are in vitro means and in vivo means of determining selectivity and efficacy and the 2 at times are miles apart.

In vitro in petri dishes and in vivo in living organisms. Results can be a way of a distance apart.

interestingly a survey fairly recently of close to 250 different molecules put the median selectivity of 50nM with the larger less selective molecules put at close to 1000nM.

But of course we need a ball park base to start from.

TLL-018 Jak1 selectivity higher than the Tyk2.

Does not bode well as there are associated problems with Jak1.

I will put a post together over the weekend as to why and in depth.

I dont envisage us having serious adverse event problems.

Basically we are over 95% selective of Tyk2 over Jak1 and other Jakis.

Tyk2 is proving its worth but lacks efficacy in some areas hence we have what TM referred to as an optimum amount of Jak1.

Regards

Isation value. you will have restrictions due to this new yellow box jak labelling as you are not 100% selective for tyk2.

True we are not and with the figures provide by Damion on SDC1801 we are predominently Tyk2 around 95% plus selective of TYk2 over Jaks 1, 2 and 3,

It is all about having the additional benefit of an optimum amount of Jak in addition to the TYk2 as such increasing efficacy but not compromising safety. Note rthe difference between 1801 and 1802.

1802 immuno oncology and hence not restricted as such by the likes of restrictions put in place for immuno therapy.

Once you get your heads around this you will see the benefits and understand what the doubts are.

The fault I find with Sareum is I wish they would develop some sort of sence of urgency as opposed to just drift along.

Regards

selectivity potency.

sdc1801 tyk2 0.6 nm, jak1, 23nm, jak2 26nm, jak3 41nm.

sdc1802 tyk2 3nm, jak1 29nm, jak2 91nm, jak3 243nm.

sdc1801 40 fold selectivity of tyk2 over jak1

sdc1802 10 fold selectivity of tyk2 over jak1,

clearly agrees with tim at agm in much reduced jak1 content with 1801 as autoimmune.

of course we exhibit jak 2 albeit small amounts and to a lesser extent jak3.

of course this is only part of the equation.

we know jakis work in pairs :-

jak1 with jak2, jak3,and tyk2

jak2 with jak1 and tyk2 and of course jak2. ie jak2 hom0 dimerises with jak2 to give the most unwanted of off target effects leading to dvt, epo and other blood disorders.

jak3 can only pair with jak1.

a dilemna here is how do we avoid jak 2 jak 2 ****dimerisation?

surely if either the tyk2 molecule or jak1 molecule has higher affinity to bind creating hetro dimerisation then this is of benefit. jak1 jak2 inhibits il-10. il-10 is made up of 4 sub units 2 of which made up by jak1 and 2 of which made up jak2. a precurser and upline signalling of il-6.

so we not only have selectivity but he ability to bind. how long does the docking site remain phosphilised for?

now for what ever reason deuterium whilst being identical to h1 with the exception of an addition of a neutron is able to maintain bonding for a longer period of time. one of the reasons why only once a day dosing is required in 1801.

so all very complex.

glad to see in your later post nm and not nm which in science means 2 different things.

nm refers to nano mol,

as from memory 6.022 x 10 to the power of 23 ( avagadros number)

a nano mol being 1,000,000,000 th of a mol.

it is indeed complex and there will never be 1 treatment that fits all. safety does not have to significantly compromise efficacy when being applied to a specific indication.

pharmaceutical company greed is the problem wanting dominance and to ge a drug into commercialisation first with a broad base selectivity resulting in poor efficacy to to dose limiting toxicities.

regards

Thankyou for the selectivity figures Damion.

Yes Deucravacitinib has lower number ie 0.2 nM. It will threfore not exhibit any off target effects associated with Jaks 1, 2 and 3.

However it is important not to confuse potency with efficacy.

Deucravacitinib gave reasonable results in Psoriasis but failed dismally to meet its end points in Ulcerative Colitus.

This problem was raised many years ago with the idea that inhibitors could become overly selective.

Broad based Jak inhibitors gave problems due to insufficient selectivity, at the other extreme you can experience over selectivity.

Regards

Deucravacitinib

Selectivity.

Difficulty in finding anything with regards to selectivity on SDC1801.

However for those that have a slight interest, selectivity of Brepocitinib below.

Jak1 17nM

Tyk2 23nM

Jak2 77nM

Jak1 only has around a 4 and a half fold selectivity over Jak2

Jak1 selective of around 1 and a third over Tyk2

Tyk2 selective around 3 fold over Jak2

it will inhibit Jak3 to a certain extent but no figure for this.

Now SDC1802 and this from memory

Tyk2 4 fold selective over Jak 1 of which Jak1 is 4 to 5 fold selective over Jak2 and Jak3.

1801 has considerably less Jak1 content.

if we take a pessimistic 50% reduction in Jakis 1, 2 and 3 and in my opinion we are more reduced than this.

As a rough guide Brepocitinib 52% selectivity jak1, 38% Tyk2, and 10% jak2

SDC1801 90% Tyk2, 7% Jak1, 2% Jak2, and 2% jak3.

In addition and again from memory here the moleculesof Breprocitinib look far more complex than the SDC compounds.

This should shed a tad more light on why we ought to establish why we are best in class.

As Tim stated 'we have added what we believe to be an optimum amount' clearly in this instance circumventing the problems associated with Jak3 and especially Jak2.

All about selectivity.

As for AI?

it will have its uses.

An idiot can learn and so can a genius but all comes down to the information it takes in to learn from.

AI also makes mistakes. who checks for these mistakes?

is AI capable of creating an invention?

AI could be fed with 1 plus 1 is 2

another 1 plus 1 is 10

Enki

'If the molecules are that good they would have been snapped up by now or SAR wallowing in funds to progress. The BoD are an embarrassment.'

Telll me Enki how do you determine how good a molecule is.

Clearly you do not have a clue like most little boys of your immaturity.

Enki. Imuno therapy you mention.

SDC1801 is immuno threrapy

Indeed SDC1802 is immuno oncology.

AI although helpful is not the be all and end all.

For example tell me how AI contributes to computational quamtum chemistry. the more complex a molecule the harder it comes to predict.

It does not predict whether it will work or not just the probability of interaction and binding.

since how it interacts or how it binds cannot be determined with any certainty there will be odd target events.

AI cannot be used as a tool for determining the acceptable safety of a compound.

Our compounds are patented as are the molecules.

The proof now will be in the advancement of toxicology studies in 1801 to support establishment of its safety profile.

!802 safety profile requirements will not be as limiting as is immuno oncology and not immuno therapy.

Regards

In addittion Damion , get your facts right!

|SDC1801 was never rejected approval by the MHRA. They stated they were unable. It is not the same thing.

Initially was all planned for phase 1 a and a phase 1b.

Since when did it become a requirement to have longer term toxicology studies prior to phase 2 clinical trial?

How long were the original toxicology studies carried out over in preclinical trilas for 1801.

Unfortunately the goal posts have been moved since late 2022.

Tell me why it is a rquirement to have laboratory studies carried out on Jak inhibitors and uet Allosteric Tyk2 inhibitors are not required.

We are predominently TYk 2.

As I see it in 2022 there was no requirement for long term toxicology studies in compounds similar to ours.

They are scientists Damion not clairvoyants.

DWILSON

Just exactly what do you expect Sareum to do?

They are entering into toxicology studies to increase the value. What part of this do you not understand?

Does anybody that posts here know of the importance and relevance of these toxicology studies?

You will not get a much better promotion than best in class long term toxicology results. The proof of the pudding is in the eating. We can all talk bs to promote something or indeed degrade it.

At the end of the day it is all down to the science ie how the 1801 compound behaves.

Of course a value cannot be applied as of yet we do not know what exactly the outcome will be confimed to be.

I am certain of it being good.

As for February i have no importance placed on this particular month.

Regards

I asked Potnak a simple question. So hw stick your nose in?

He cant answer it and you certainly cannot.

Both beyond your very limited level of comprehension.

Ponak, where is this demand for a reply sonny?

I asked you a simple question with regards to probabilities.

Was was Deucravacitinibs probability of entering commercialisation after phase 1 trials success

What was the probability of failing a phase 2 test in UC for deucravacitinib after already being granted aouthorisation for use in another indication?

AS for the results of a tox study preliminary results will be known long before final toxicology results. No mention of you of any news about 1802, is this one of thecompounds you are blaming.

Potnak,

I did not demand an explanation sonny,

You come out with trupe as you don't know with rhus world view of this archaic 90% risk of failure.

Failure is down to compound design being ineffective or dated. Are all inhibitors similar.?

If we have 10 identical onhibitors are you that mentally challenged to believe they all have a 90% chance of failure?

IBreprocitinib withdrawn in 7 Indications in Phase 2

If the drug has failed why are they trialling it in an other indication?

One minute you are valuating Sareum at 2 billion the next 90% risk of failure.

As for me knowing the risk you condescending clown , l do very much understand the risk unfortunately to understand you need an order of magnitude of understanding to be able comprehend what exactly these toxicology studies all about..

What long term effects are we looking at?

Do you know? I doubt it.

To find out if most things will work we need understand things right down to the absolute basics.

That goes right down to the structure of the molecule. How do the molecules attach. How are the atoms arranged.

Sareum use Deutererium which is an isotope of Hydrogen in some components of its molecules.

For what purpose is this and anticipated advantages?

1801 predominantly Tyk2!

Where do you think BmS derived the word Deucravacitinib from?

Do you think that their big claim of using this novel Deuterium atom had anything to fo with it?

Fo you know what it achieves?

I doubt it.

Molecule and compound protection there are reasons that Sareum have gone to great lengths to protect.

If somebody decides to sell up l have no problem.

They have chosen to go into crypto currency.

I don't know anywhere enough where to begin as never had any interest in.

Somebody sells up does not cause a failure of the compounds .

Selling up can cause SP to drop and create further decline and negative market sentiment.

They may chose to buy back in later which is their perogative. But at least they have taken action based on their beliefs.

Do you understand what tge object of these toxicology studies are?

What is the k ock on effect to 1892?

Simple questions,

Regards

'My opinion (world view) is that, basing on the pharma industry norms, the probability of failure at this stage is still higher than success. I'm OK with that.'

You are looking at probabilities here Potnak, to be more precise statistics.

At what stage is the highest failure?

Phase 2 clinical study.

Deucravacitinib failed in Phase 2 in Ulcerative colitus.

it is very unlikely to be entered into Crohns disease. Is this statistical or of a predetemined derivation.

Statistics are important. they give us some information but not everything.

Explain your reasonings Potnak how you derive the highest failure point being this point in toxicology study?

Based on exactly what?

Pure statistical analysis?

Has this taken into account or included with early 1st generation failures

What about compounds that have passed 3 phase 2 studies, how does that affect the figures? Compound is only commercialised once.

Do you fully understand failures at phase 2 clinical trial?

How are these figures made up?

How many previous toxicology studies have taken place at this point, taking into account the yellow box labelling restrictions limiting clinical usage by the approval agencies especially NIH.

Are you aware that we can accept an already approved drug for clinical use from the USA with no requirement in the UK in the slightest to access its safety?

In addittion can you define what you understand by failure?

What are the objectives of this toxicology study?

Tim M gone to a lot of trouble to create a compound such as 1801 with lower jak content.

Have you taken this into account with your worlwide view?

Sometimes i think I would be better off not posting.

It is not to my benefit at all.

Warthog you must be a supporter of that Funnyguy chappie.

What is your objective of repetitive posting of the negative events regarding business finance and dilution?

What do you hope to achieve?

Funnyguy,

How long have you been an investor here ?

How long have you been on the LSE chatboard?

You are communicating to others that I work for either a broker or Sareum or a bio magazine.

What is your intention here?

What are you trying to achieve.

I work for none of the above so on all 3 counts you are wrong but guiltyof posting misleading /false information.

The question here is what is your objective.

You imply that all the posts i have written however detailed do not read correct.

You submit vain attempts to try and undermine and stick the proverbial knife in whenever you can.

Absoluste disgusting behaviour but of course that is the nature of a prawn.

You have a growing number of likes. What on earth will they do when you sell up?

Sareum has an objective to onlicence its SDC compounds. With recent funds and tax rebate from Australia the cash pot is healthy. We are entering into toxicology studies, correct me if I am wrong but that is a fact.

The exact starting date of tox study is yet to be determined.

Early part of year can be interpreted from January to June?

My guestimate which is not to be taken as fact is February.

We are still in January and you chose to find fault that I put February.

I am happy for SP to remain where it is and in effect if it drops a tad gives me no concern as i will add 20k to ISA in new tax year 6th of April which will be visible on trades shown on LSE. That is me putting my money where my mouth is.

May I suggest that I believe that you should put your money where your mouth is and sell up if you are so concerned as to your claimed position here.

It will do 2 things, it will prove without doubt your belief in your negative agenda and also prove you have the backbone to support your convictions.

I see no benefit in you remaining here to anyone and that includes yourself!

Regards

Funnyguy, l have been here now approaching 13 years.

Who l work for has nothing to do with you. Why should that interest you.

The science compound side is one thing and with regards to 1801 a lot of what l have said has been proven right, yet you fail to acknowledge this.

The company can experience delays in many ways as can CRO organisations.

All you ever do is try and find fault.

I do not run the company and can only put my views on likelihood of receiving news in a certain time.

Does the the CRO carrying out the company need to import non human primates?

I don't know but if they do then that can certainly create delays.

You tend to choose every obstacle you find.

Not once have criticised anyone on the company failing.

It beats me why you claim to be invested here.

Regards

Preliminary data phase 1a very good to say the least.

Longer term studies you are looking at myocardial events of which some can be serious.

I don't envisage we will experience any of these major events.

It does not help being put in the class of the other jaki inhibitors.

BMS l would suggest has pushed this agenda as pay funds to a body that regulates the use and authorisation of drugs.

Deicravacitinib as an allosteric Tyk2 inhibitor are exempt from all lab testing which is carried out on other Jaki inhibitors. We are not first generation.

We are primarily Tyk2 with what Tim regarded as an optimum amount of addition of Jak1.

I would guesstimate around probably 5 to 7 % maybe less.

I suppose l could see if l can track down selectivity in the compound and take it from there.

Reminds of the film Kez whereby the young boy who was asked to deliver a message to the headmaster stood waiting outside the headmasters office with two other boys who had committed truancy or smoking.

He was taken in with the other two and was subsequently caned.

Over 45 years ago l saw that film. Offences and numbers may be slightly out for which l apologise. At least you should get the gist.

Regards