Member Info for sadoldgit

Clearly there has been a move away from the Jakies due to associated off target effects. Whilst efficacy was good, a move was made for a means of avoiding these side effects.

Off target effects increase with dose. However, it does look as if as opposed to using Jak1 2 and 3 and replacing them withTyk2 that it may well be far more beneficial for the Jakis in combo to be more supportive in terms of efficacy.

You can understand the reasonings behind it as Tyk2 will have very little off target effects and hence safety guaranteed allowing FDA approval for commercialisation but at the same time you have compromised efficacy in some autoimmune indications.

Deucravacitinib proved favourable in Psoriasis but failed abysmally in IBD ( UC),

BMS solution to this is are plans to increase dosage.

'IL-6 is an important driver of inflammation in IBD in addition to IL-12 and IL-23 [17, 18]. These cytokines all mediate their effects via the JAK-STAT pathway: IL-6 via JAK1, JAK2 and TYK2, which activate STAT3; and IL-12 and IL-23 via JAK2 and TYK2, which activate STAT3 and STAT4, respectively [19, 20]. Pre-clinical murine models have shown the importance of these cytokines in the pathogenesis of colitis and support the use of JAK in the treatment of gastrointestinal inflammation'

Full link below

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098109/#keaa896-B21

In addition Interferon alpha

'Signaling through the receptor for type I interferons (IFN-α and -β) requires two members of the JAK family, Tyk2 and JAK1 (3, 4). Both enzymes are associated with the receptor, which is composed of IFN-α receptor (IFNAR) 1 (5) and IFNAR2–2, the longer splice variant of the IFNAR2 gene (6, 7). Tyk2 was shown to interact with the membrane-proximal region of IFNAR1 (8, 9), and JAK1 with IFNAR2–2

This will be of particular reference to SLE.

'SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms'

A link below to CHK1 inhibitors. (Prexasertib doing well)

https://www.sciencedirect.com/science/article/pii/S0304383520304857

I dont think you will find presentations on 737 as SO had no funds after diverting all resources to momo. Tripirna Senn made a presentation at ASCO early 2019 and was reported in the journal later that year.

Plenty of research work done since I might add albeit not by SO. M Garrett in from day 1 ,long before anyone else.

C79. Tyk 2 or to be precise Deucravacitib does not block Jak1 and 3 it regulates. Not the same thing.

There were many other projects in the making with Sar B raf,

An early report from proactive investor with our Aurora = FLT3

The share price rocketed over 1,600 percent in just three days, rising from 0.275 to 4.79 pence.

Okay, the company’s results look very positive. An in-vivo study of Sareum's Aurora+FLT3 Kinase programme, targeting the most common form of adult leukaemia, showed that the leukaemia had regressed to such an extent that no detectable cancer could be found in any of the cases treated - ten in total.

By comparison, leukaemia increased five to fifteen fold in the study examples treated without Sareum's compound. '

SDC compounds out of the same stable.

There are other compounds of which SAR intended to develop. getting a little late to progress these I feel.

SKIL what is it?

Worth a read especially if you been here less than 5 years

https://www.proactiveinvestors.co.uk/companies/news/21457/sareum-holdings-an-early-stage-drug-group-with-a-very-interesting-future--25583.html

Regards

I very much doubt we will get an update. it will either be regarding an on license or carry out further development. i dont envisage it will be the latter option.

With regard to 737 these discussions will unfortunately take time.

A very good analytical post by SCHeckler earlier and cannot add anything of value to this.

Regards

C007,

I dont which is the bigger market per se. Many companies will go for Psoriasis. IBD treatments most effective with the Jak1 2 and 3, primarily Jak1 and 3, Jak 2 has inherent safety concerns and in addition is a part of the package with Jakis.

Own personal view prefer if we were good in IBD and there is not much decent competition. Add also that IBD in many cases leads to cancer. i would expect better results in Psoriasis and definately substantially better results in IBD.

Smaller areas of unmet need

There is also transplant rejection, Graft verses host disease in which out TYk 2 compounds may prove invaluable. It is autoimmune

Tim an co will have far more knowledge than we have and I dont think they will let the cat out of the bag just yet. They will have have a very good idea as to what indications 1801 is suitable for.

There are many indications that are not the mutts nuts with regards to a massive market size but there does exist smaller markets in areas where there still exists unmet needs.

Good evening HbD,

There was an end date to trial enrollment around mid May i think was the 9th.

Indicative of being on target for anticipated commencement of dosing June 4th,

With regards to dosing I foresee no problem whatsover on a 5 mg daily dose.

We have Jak1 2 and 3. Pessimistically looking at our compound it will be this that limits safe dosage. But we are mainly Tyk 2.

Tyk 2 will not cut the mustard in all indications.

Pure Jak1 2 and 3 have given better efficacy in Psoriasis and BMS flunked IBD with deucravacitinib in UC.

We ought to at least have a slight improvement of efficacy in Psoriasis.

IBD I believe we will excel at.

We cant be best at everything but we potentially will be better in some.

As for developing a reaction on first dosing as someone postulated I see that as pure codswallop. I have never seen any adverse reaction from any Jak inhibitor and that includes JAk 1 2 and 3.

Safety like most drugs will be dose dependant related.

In healthy volunteers that have a healthy immune system we are in fact interfering with that hence I believe the reason for such a low escalation dose starting regime. I feel certain in the absence of reaching an MTD this may well of caused concern for the MHRA. However, unlike the Ozzies that will find a way forward and address the situation positively our MHRA in effect in what can only be described as an ar5e covering exercise will push the decision on to another department or governing body.

What I strongly believe is that we have predominently a JAK 1, 2 and 3 bias that will prove extremely beneficial in some indications. Our Jak2 part showed very little contribution in whole cell assays. Of vital importance and welcome any comments to the contrary.

Sareum have extensive experience in Oncology, and as a few will know the early summise that CHK1 importance in AML.

By comparison to other producers,taking CCT245737 as a one and only example in clinical trial. efficacy was good but more importantly our safety profile indicated superiority over the rest.

The only true problem we encoutered was solubilty issues with Aurora + FLT3. Sinilar but not exactly the came issues arose with our 1801. Difficulty encountered producing high enough amounts for even preclinical study.

We are not there 100% as if we were SP would be multitudes higher than as we sit now.

The proof of the pudding is in the eating and in this respect this relates in its entirety to dose escalation studies. There will be an inevitable knock on effect to 1802.

Regards HBD and appreciate the extremely informative posts and links related that you have contributed.

Wow Potnak of course you will make the same percentage as the long term holder, but your 50k ish shares holding 80% less than mine you will make 80% less.

'Will we get there? History says its unlikely.'

On what factual basis do you make such an absurd statement? It cant be that unlikely as you claim to be invested.

What is the success rate on reaching stage 2 trials in oncology, immunotherapy and what advances have been made in the past 3 years in the treatment for oncology?

What are the major causes of failure?

What is the biggest cause of failure?

Why are newer immunotherapy and ICI drugs being developed and later 2nd generation inhibitors?

What are the significant advances made in ICI and immuno therapy ?

How is the success rate predicted to rise in later more modern developed drugs

Why is combination therapy seen as a way forward even using earlier drugs that have not reached phase 3?

How is the suitability of a drug determined for a patient?

Is suitability criteria for a patient likely to change?

Are drugs that have not reached phase 3 due to safety concerns likely to be used in patients with advanced cancer?

Why is it difficult to recruit patients in human trials?

What is the average cost to a pharma for an early stage trial?

How much does it cost to replace a patient that has dropped out of a treatment?

What is the current statistical mortality rate in clinical use related to the treatment drug?

Are there any inhibitors that have been discontinued due to toxicity and safety concerns awaiting mid stage clinical trial approval?

If there are then what is the reason for this?

Regards

People will come on this board and post what they like Potnak. They will not be concerned as to those that cannot or are unable to see why.

Investors can chat at a weekend as is no law against it just as there is no law against those that post on a weekday trade and adjust their view to satisfy their own agenda.

Doom and gloom of the company, not releasing news as would be disastrous one minute and the next a 1 to 2 billion pound company.

Unstable or attempt to manipulate me thinks.

Regards

Interesting proactive investor I will post link again.

Overview of 737 why Aurora FLT=3 were stopped and difficulties reaching MTD in 1801

https://www.youtube.com/watch?v=G_b59aQ14q8

This time next month healthy volunteers will be taking dose escalation studies with our SDC1801. A first for them ans a first or Sareum.

Very confident we will experience no untoward events.

Regards

I ill add that it may well be the later developed compound from 2021 patent description that shows a better biochemical assay figure ( and most likely an improved whole cell assay result) than shown in earlier 2014 journal.

Referral is made to compound 1 and compound B in 2021 patent description.

Yes a great help HBD,

We have biochemical and cellular assays.

Effectively we take here Ic50 values as selectivity ( Ic50 is a measure of how much of a drug is required to inhibit a biological process by half)

Tyk2 0.6

Jak1 23

Jak2 26

Jak3 41

So we have Tyk2 selectivity of 41 over Jak1

46 over Jak 2

73 over Jak3

These are the figures provided. Yes I can see that 41 x 0.6 is 24.6 ( yes figures most likely rounded up)

Tim expressed concern of Jak2 side effects.

At first if we look at selectivity over Jak1 and Jak 2 very little difference, it can be understood that this may cause toxicity concerns. The dreaded Jak2.

However, all is not as it seems.

' In addition, SAR-20347 inhibited JAK1-mediated IL-6 pSTAT3 signaling at an IC50 of 345

nM in TF-1 and 407 nM in CD4+ cells. These data indicate that SAR-20347 is 2.7- to 3.9-fold more selective for TYK2 relative to JAK1 (Table I). Importantly, SAR-20347 poorly inhibited JAK2- mediated STAT5 phosphorylation from IL-3 (in cell lines) and GM-CSF (CD14+ cells) with an IC50 of 1.06 and 2.22 mM, respectively, and JAK3 with an IC50 of 1.608 mM (Table I). These

data indicate a preferred selectivity for SAR-20347 (8.4- to 20.8- fold) for TYK2 over JAK2 and JAK3. Although in these cell based studies the IC50 is higher compared with the biochemical assays, these findings are not surprising as compound potency in whole-cell assays is usually lower than in biochemical assays (15,18). Overall, the relative inhibition in these cell-based assays confirmed the previous biochemical data and indicated a selectivity of SAR-20347 for TYK2 . JAK1 . JAK2 ∼ JAK3.

'compound potency in whole cell assays.

Tyk2 2.7 to 3.9 fold more selective over Jak1

Importantly SAR 2037 poorly inhibited Jak2. ( marvellous)

Tyk2 8.4 to 20.8 fold more selective over Jak2 and Jak3.

It is these figures that will be more indicative of efficacy than the bio chemical assays.

There are later developments as in crystalline structure of a compound patent, Basically the form of the structure can be selected but have very little idea as to the relevance of this.

Biochemical selectivity can look impressive but is the whole cell assay that is of vital importance me thinks.

Thanks for the link HBD..

Yes a great help HBD,

We have biochemical and cellular assays.

Effectively we take here Ic50 values as selectivity ( Ic50 is a measure of how much of a drug is required to inhibit a biological process by half)

Tyk2 0.6

Jak1 23

Jak2 26

Jak3 41

So we have Tyk2 selectivity of 41 over Jak1

46 over Jak 2

73 over Jak3

These are the figures provided. Yes I can see that 41 x 0.6 is 24.6 ( yes figures most likely rounded up)

Tim expressed concern of Jak2 side effects.

At first if we look at selectivity over Jak1 and Jak 2 very little difference, it can be understood that this may cause toxicity concerns. The dreaded Jak2.

However, all is not as it seems.

' In addition, SAR-20347 inhibited JAK1-mediated IL-6 pSTAT3 signaling at an IC50 of 345

nM in TF-1 and 407 nM in CD4+ cells. These data indicate that SAR-20347 is 2.7- to 3.9-fold more selective for TYK2 relative to JAK1 (Table I). Importantly, SAR-20347 poorly inhibited JAK2- mediated STAT5 phosphorylation from IL-3 (in cell lines) and GM-CSF (CD14+ cells) with an IC50 of 1.06 and 2.22 mM, respectively, and JAK3 with an IC50 of 1.608 mM (Table I). These

data indicate a preferred selectivity for SAR-20347 (8.4- to 20.8- fold) for TYK2 over JAK2 and JAK3. Although in these cell based studies the IC50 is higher compared with the biochemical assays, these findings are not surprising as compound potency in whole-cell assays is usually lower than in biochemical assays (15,18). Overall, the relative inhibition in these cell-based assays confirmed the previous biochemical data and indicated a selectivity of SAR-20347 for TYK2 . JAK1 . JAK2 ∼ JAK3.

'compound potency in whole cell assays.

Tyk2 2.7 to 3.9 fold more selective over Jak1

Importantly SAR 2037 poorly inhibited Jak2. ( marvellous)

Tyk2 8.4 to 20.8 fold more selective over Jak2 and Jak3.

It is these figures that will be more indicative of efficacy than the bio chemical assays.

There are later developments as in crystalline structure of a compound patent, Basically the form of the structure can be selected but have very little idea as to the relevance of this.

Biochemical selectivity can look impressive but is the whole cell assay that is of vital importance me thinks.

Thanks for the link HBD..

From patent description Oct 2021

For example, in biochemical assays, the compound of formula (1) has approximately 25- fold selectivity for TYK2 compared to JAK2 and 110-fold selectivity for TYK2 compared to JAK3. The suitability of the crystalline forms of the compound of formula (1) as defined in any one of Embodiments 1.0 to 5.2 for use in treating psoriasis can be determined by testing their effect on imiquimod-induced psoriasis-like skin inflammation in mice:

Comparative Data - Conclusions The data obtained from assays (i) to (vi) above indicate that the compound of the formula (1) has significant advantages over the structurally most similar compound (Compound B) in WO2015/032423. Thus, compound (1) is more active than Compound B in the TYK2 kinase inhibition assay and has greater selectivity for TYK2 versus JAK1, JAK2 and JAK3 kinases than Compound B.

WO2010/055304 and EP2634185 (both in the name of Sareum) disclose a family of substituted oxazole carboxamides for use in the prophylaxis or treatment of autoimmune diseases and in particular multiple sclerosis. The compounds disclosed in WO2010/055304 are described as being FLT3 kinase inhibitors. The kinase inhibiting effect of oxazole carboxamides is also disclosed in International patent application W02008/139161 (Sareum).

WO2015/032423 (Sareum) discloses the use of a subset of oxazole carboxamide compounds as TYK2 kinase inhibitors. The compounds are described as being useful in the treatment of inflammatory and immunological disorders such as autoimmune diseases.

Still cannot ascertain the selectivity of TYK2 over Jak1 in 1801.

Not sure if already posted but a couple of informative links below.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9959504/

https://www.targetmol.com/compound/SAR20347

Good hit HBD

pre clinical studies to establish dosaging is done in vivo. typically murine are involved in preclinical study work but it is normal to use 2 different animals.

https://pacificbiolabs.com/maximum-tolerated-dose-mtd-an-effective-preclinical-dose-determination-strategy

https://www.avac.org/preclinical-research#:~:text=mice%2c%20rabbits%2c%20guinea%20pigs%20and,the%20specific%20strategy%20being%20tested.

https://www.proactiveinvestors.co.uk/companies/news/926488/sareum-holdings-focused-on-striking-a-deal-for-its-immunotherapies-926488.html

https://*********************/media/sareum-holdings-edison-open-house-interview-04-05-2021

As far as I know 30x therapeutic dose is ok in the absence of reaching an MTD.

Ultimately toxicity issues will be identified in phase 1 studies.

Considerable pre clinical toxicity studies were carried out on TYK2 Jak 1 by Sareum CRO.

Dosages of 30 x therapeutic dose with no observed effects. Tim stated we may be looking at going 100 times but no idea if this route were taken.

No MTD was established and hence a likely hood that this may have been cause for concern,

It is both unusual and uncommon to have this 'problem'

Toxicity issues would have been carried out on mice to identify any organs likely to be susceptible.

Starting dose is very low on trial ie no greater than 5mg per day.

I believe the doses in the dose escalation studies are based on similar Jak inhibitors albeit non Tyk2.

Regards

Regards

Regards

Lazarus . One severe factor removed is the approval, and now we have authorisation to start clinical trials. There were those intimating something must be wrong as non approval by MHRA.

Tim and co been pushing like crazy to get 1801 into clinical trial. They have now succeeded despite the delays by the MHRA. We stand to make a shilling or two but there exist patients in urgent medical need of new effective treatments.

What the doom and gloomers have to say about this?