Member Info for sadoldgit

Interesting point you make LeMajor.

If it were not important it would not be patented. Sareum very quiet on this one.

Consider the crystallisation of a compound and the importance thereof. Why Crystallise the compound? Sareum have experienced difficulty in the past with ( FLT+3) formulation issues. In addition new options had to be looked at ( Tim Mitchel statement when interviewed on Proactive investor, early last year). for the purposes of manufacturing sufficient quantities of the TyK2 Jak1 compounds. ( all are similar compounds under the group protected by patents going back to 2013) All originate from compounds of group 0, 1 or 2. Nothing wrong with FLT3 + Aurora, just could not formulate the compound to be orally available.

I am firmly of the opinion the a solute is formed from these compounds and at some stage a recrystallisation will take place including the solute ( this may well be what the patent is for).

What is the advantage of this? It is indicative that the manufacture, storage, longevity and quality of the compounds are reliant on this process of crystallisation. Indeed for success may be of paramount importance. With me so far?

Now the big hit! How long are our compounds protected for? Since the manufacturing (including crystallisation of a compound) will now be protected by patent,it will mean no bugger can manufacture them. Effectively all of our compounds if using this method will be protected from April 2020. This will include Aurora FLT which from memory protected by patents circa 2013.

I may be barking up the wrong tree or barking mad. I cannot see the importance placed on the patent for any other reason.

Regards.

I will add here as a sidetrack with regards to IL-6.
Am of the opinion that successful Il-6 inhibition can only be undertaken with the addition of JAk1 as enables gp130 which is a sub unit of IL-6. ( glycoprotein130 sometimes referred to as IL-6ST or IL-6beta it is a transmembrane and vital for down signalling) Vital written all over it.

Extract here
gp130 has no intrinsic tyrosine kinase activity. Instead, it is phosphorylated on tyrosine residues after complexing with other proteins. The phosphorylation leads to association with JAK/Tyk tyrosine kinases and STAT protein transcription factors.[10] In particular, STAT-3 is activated which leads to the activation of many downstream genes. Other pathways activated include RAS and MAPK signalling.

Regards and have a good weekend.

Good spot HBD

Good post citizen79 interesting read.
Regards
SOG

Hi T2. apologies late getting back as been on nightshift this week. As far as I am aware kinase inhibitors work best in pairs. As I understand it the type of kinase inhibitor is around how it works and inhibits which signals. Having a Tyk2 inhibitor does not mean it can inhibit IL-6 and I will use the word effectively. I will wake fully have a cuppa and look into some more. I would find it odd that we are the only TYk2 inhibitor (albeit with Jak1) that affords effective inhibition of IL-6. It maybe that one or more of our patented molecules have nailed it, but cannot support that with any evidence, The deeper you look into it the more complex it becomes. I have attached below some early research. Paragraph 3 interesting.

The Janus kinase (JAK)1family of non-receptor tyrosine kinases consists of four mammalian proteins (Tyk2, JAK1, JAK2, and JAK3) that play a critical role in initiating signalling cascades of a large number of cytokine receptors .

All JAK proteins possess a carboxyl-terminal tyrosine kinase (TK) catalytic domain, a central kinase-like (KL) domain, and a large amino-terminal (N) region, which has been subdivided into five JAK homology regions (JH7 to JH3) based on sequence conservation (3). The specific and noncovalent association of these kinases to the intracellular region of cytokine receptors governs their activation upon ligand binding .


' We are interested in understanding the mode of action and specific roles of Tyk2, which is activated, together with another JAK family member, by the type I interferons (IFN) (several a and one ß subtypes), by interleukin (IL) 6, IL-10, and IL-12 .'

The IFN-a/ß receptor is present at low numbers on the surface of all cell types and consists of two transmembrane proteins called IFNAR1 and IFNAR2 . The IFNAR2 gene generates several alternatively spliced forms, but only the product harbouring a long intracytoplasmic domain (IFNAR2c) is part of a functional IFN-a/ß receptor (12). Whereas the stoichiometry and spatial organization of these components within the receptor complex are unknown, the epitopes on the IFN molecule contacting IFNAR1 and IFNAR2 are being identified . High affinity binding of IFN-a/ß to the receptor results in tyrosine phosphorylation and enzymatic activation of the associated JAK1 and Tyk2 in a defined temporal order, which is thought to result from the topology of each kinase within the complex . Studies of kinase-deficient mutant cell lines showed that in the absence of either kinase, high affinity IFN-a binding is impaired, demonstrating a structural role of these enzymes in the formation of functional receptors. Our recent in vivo studies of deleted forms of Tyk2 expressed in Tyk2-deficient 11,1 cells have highlighted distinct functions of the protein toward the expression and the binding activity of the receptor complex. Each function appears to be contributed by a different domain adding more complexity to the receptor-kinase complex.

Good morning Ahfam. Our Tyk2 Jak1 inhibitors look to have so much scope it is difficult to predict at which targets they will aim at first.

The Tyk 2 Deucravacitinib ( Tyk 2 only and an allosteric inhibitor)) has a good safety profile which is extremely encouraging as Tyk2 on its own, This does contradict with Tyk 2 having known side effects and reinforces its safety profile as a viable form of treatment.

Note a salient point from the Deucravacitinib report. ' TYK2 is an intracellular signaling kinase that mediates signaling of IL-23, IL-12 and Type I IFN, which are naturally occurring cytokines involved in inflammatory and immune responses.

Our Tyk2 ( SDC 1801) is 'contrary to reports in TYK2-/- mice, signalling by a wide variety of cytokines was found to be impaired thus highlighting non-redundant roles for human TYK2 in the function of Type I IFNs, IL-6, IL-10, IL-12 and IL- 23.'

Note we have IL-6 and IL-10 in addition to type 1 interferons, IL-12 IL-23 and IL-12. In addition we are non allosteric.

I am not going to say here that one of these inhibitors is far superior to the others. what I will say however as these new generation of Tyk2 inhibitors come through, they are showing a much improved efficiency at treating targeted diseases
and without doubt showing a far greater safety profile. First generation JAK inhibitors need replacing badly.

Well done BMS for this additional and safer treatment, in this instant for treating patients with moderate to severe plaque psoriasis. However, I will add and interesting to note that no information with regards as suitable, or to be more precise, investigation the use of against Covid 19. Nothing to indicate IL-6 and IL-10. I would doubt Deucravacitinib would prove effective in treatment of Covid 19 as would have already been investigated ( as after all recommended by WHO to use Tyk2 inhibitors). This would also indicate a shortfall in treating other serious lung infections too such as pneumonia.

All in all looking very very favourable for our SDC1801 Tyk2 (with an optimal amount of Jak1 according to TM).

Regards

From April 2020.

https://cancerres.aacrjournals.org/content/80/8/1735#:~:text=Checkpoint%20kinase%201%20%28CHK1%29%20is%20a%20key%20mediator,in%20cancer

As far as I know treatment was continued to individuals who continued to show benefit from the CHK1. We never got to hear any more unfortunetely.
As a Checkpoint kinase inhibitor very little is gained as a solo therapy. Cancer cells are apoptosis ie they have no programmed cell death. CHK1 does little to nothing here as there is very little cell replication. Where CHK1 will be of extreme value is when used in conjunction with another form of therapy eg chemo. Chemo will kill the cancerous cells in a tumour, unfortunately after a while the cancer will return and start to grow very rapidly ( replication stress) . It is at this stage CHK1 is vital as, after mitosis (Cell division) it prevents the divided cell ( now 2 cell) from growing.

Interesting read and better than I can explain is an extract below.

Abstract
Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell-cycle progression, DNA damage repair, and DNA replication. Small-molecule CHK1 inhibitors sensitize cancer cells to genotoxic agents and have shown single-agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased large-scale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified subunits of the B-family of DNA polymerases (POLA1, POLE, and POLE2) whose silencing sensitized the human A549 non–small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage, and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacologic blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE, and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single-agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy.

Significance: These findings demonstrate how the therapeutic benefit of CHK1 inhibitors may potentially be enhanced and could have implications for patient selection and future development of new combination therapies.

Regards

WIP. you are welcome.
Just a bit to add here below, yes, another extract. This regards crystallisation and would appear to be a desired character as opposed to already admittedly achieved. This i believe and have done so for some time, is where our all important ' crystallisation of a compound' will come into its own. ' I do like the recrystallisation with a solvent' . It would indicate guaranteed compound purity as well as excellent ADM in the ADMET. This would also be vital for production on a larger scale where quality control is of paramount importance and of course can be relatively easily monitored with TGE and X ray crystallography ( there is just no room for rogue molecules).

'Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.

Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.103 and 1.104, the invention provides:

1.103 A method or compound according to any one of Embodiments 1.0 to 1.102 wherein the compound of formula (0), (1) or (2) is in the form of a solvate.
1.104 A method or compound according to Embodiment 1.103 wherein the solvate is a hydrate.
For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3 .

Alternatively, rather than existing as a hydrate, the compound of the invention may be anhydrous. Therefore, in another embodiment (Embodiment 1.105), the compound of formula (1) as defined in any one of Embodiments 1.0 to 1.102 is in an anhydrous form.

Regards

A few extracts that may interest you WIP. My opinion for what it is worth is the new patent will be for the crystallisation of a compound. As I see it our compound or to be more precise series of molecules that we can use under the guise of TYK2 are already protected by patent.

Summary of the Invention ( EP2634185A1)
It has now been found that a subgroup of compounds of the type disclosed in WO2008/139161 and WO2010/055304 are particularly effective inhibitors of TYK2 kinase and, furthermore, demonstrate selectivity against TYK2 compared to the other three JAK kinases JAK1, JAK2 and JAK3. Such compounds therefore provide a means of treating inflammatory conditions and diseases whilst exhibiting reduced or substantially no side effects associated with JAK1, JAK2 or JAK3 inhibition.

Accordingly, in a first embodiment (Embodiment 1.0), the invention provides a method of inhibiting a TYK2 kinase, which method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a compound having the formula (0):

or a salt or stereoisomer thereof; wherein:
n is 0, 1 or 2;

Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.

Compositions for parenteral administration may be formulated for administration as discrete dosage units or may be formulated for administration by infusion.

Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

(( this certainly looks very favourable at the versatility of our compounds)

Good afternoon Citizen79 and apologies late getting back WIP. The following is an extract from our patent EP2634185A1. This is not the patent we are awaiting at the moment for full protection. More on that later. Note here is mentioned sarcoidosis. This post more aimed at Citizen 79. i have put my comments in double brackets (( ))

The non-receptor tyrosine kinase TYK2 plays essential roles in both innate and adaptive immunity. A lack of TYK2 expression manifests in the attenuated signalling of multiple proinflammatory cytokines and a profound imbalance in T helper cell differentiation. Furthermore, evidence from genetic association studies supports that TYK2 is a shared autoimmune disease susceptibility gene. Taken together, these reasons suggest TYK2 as a target for the treatment of inflammatory and auto-immune diseases.

Overexpression of TYK2 kinase has been implicated in the development of some disease states. For example, elevated levels of TYK2 were found in patients suffering from progressive pulmonary sarcoidosis ( Schischmanoff et al., Sarcoidosis Vasc. Diffuse., 2006, 23(2), 101-7 ).

Several JAK family inhibitors have been reported in the literature which may be useful in the medical field ( Ghoreschi et al, 2009. Immunol Rev, 228:273-287 ). It is expected that a selective TYK2 inhibitor that inhibits TYK2 with greater potency than JAK2 may have advantageous therapeutic properties, because inhibition of JAK2 can cause anemia ( Ghoreschi et al, 2009. Nature Immunol. 4, 356-360 ).
(( Interesting to note here, that Tofacitinib is a Jak1 and Jak 3 inhibitor. I would suggest the IL-6 is inhibited by the Jak1 kinase via STAT3 pathway. In theory our TYk2 jak1 should prove far superior even if only on toxicity and side effects.))

Even though TYK2 inhibitors are known in the art there is a need for providing additional TYK2 inhibitors having at least partially more effective pharmaceutically relevant properties, like activity, selectivity especially over JAK2 kinase, and ADMET properties. Thus, an object of the present invention is to provide a new class of compounds as TYK2 inhibitors which preferably show selectivity over JAK2 and may be effective in the treatment or prophylaxis of disorders associated with TYK2. (( We have already demonstrated excellent ADMET properties))

Good morning WIP.
An extract from our compound patent :-

Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.'

Regards

A HNWI comes aboard. There are criteria for being a HNWI. Just having 1 or 2 million pounds will not suffice.

As for the identity of the Individual or individuals that is protected by data protection. They are not a company. It does not mean however that they do not own a company.

Judging by the 12,121,212 shares they bought for 1 million ( too exact to be coincidental) , my opinion is you will never get to know who it is, but at the same time 'they' will not be selling any time soon. Why would they?

The HNWI individual or Individuals would have had the risks and rewards laid out before them . Most likely had explained to them Sareums options, and likely hood of market cap and share price forecast subject to certain milestones being met.

They will know more than us and will not be impatient either.

Regards

Formulation SDC 1801,
Getting close to being tested and done,
For years we have waited,
Argued and debated,
A compound that is second to none.

Regards

A limerick is 5 lines, first line, second line and fifth line rhyme as do 2nd and 3rd lines

Had anybody taken notice of the HNWI purchase of 12,121,212 shares.
Just take a look at the symbolic meaning of the numbers.

Regards all

My opinion, and also that I have noticed recently is the volume when shown being higher than combined buys and sells the price falls a few percent even though buys outweigh sells ( in reality it is the trade prices above and below the mid price of the spread) When the volume is around the same wnd with only several hundred thousand more buys shown than sells the price goes up.

i do not think there are many available shares to buy, as limits set a fair way above current levels hence on only a few buys up the price goes. Perhaps the covid has sent me mad.

A change of subject here. I am of the opinion that Agile will not be happening. Not because it is not available. But I reckon we are in talks and getting close to an agreement for licensing of SDC1801. Tim did mention last year of looking to on license at the end Q4 21.

'Subject to successful completion of the ongoing preclinical toxicology studies, requisite approvals and financing, the Company aims to commence Phase 1 clinical trials for SDC-1801 in early 2022. The timing and design of the clinical trials for Covid-19 applications will be determined following consultations with experts in the field.

Dr John Reader, CSO of Sareum, commented:

“The results from our Covid-19 research project are very encouraging and provide clear evidence of the potential of SDC-1801 to reduce the excessive inflammatory response seen in severe Covid-19. We are keen to progress this project to the next stage and will now explore our options to find the best way to fund these next steps. This could include the UK government’s AGILE clinical development platform, which was established to fund Phase 1 trials and fast-track the development of potentially ground-breaking Covid-19 treatments. These activities are expected to run in parallel with the broader SDC-1801 development plan targeting autoimmune diseases. We look forward to providing updates on our progress as we reach key milestones in the development of SDC-1801.”

Worth looking at following two sentences.
'The timing and design of the clinical trials for Covid-19 applications will be determined following consultations with experts in the field.'
Note the use of the word 'will'.

This could include the UK government’s AGILE clinical development platform, which was established to fund Phase 1 trials and fast-track the development of potentially ground-breaking Covid-19 treatments.

Now note use of the word 'could'.

I can only conclude from the use of these words that SDC1801 will be used in trials for Covid either with but I think most likely without AGILE funding.

If a pharma wants SDC1801 it would not be wrong to think he will want complete control of.

Regards

With a 40 to 1 consolidation, with a sell or license of Momoletonib, followed by SRA737 successful on license l would not put 140 dollars a share out of the question. All their resources going into Momoletonib.

Cannot see much happening with SRA 737 until they have got shot of Momoletonib.

Regards

I will also add the importance of the actual dosing rates and the importance of selectivity here. Selectivilty of Tyk2 being up to a hundred fold greater selectivity than Jak2.

Exerpt below to reinforce

'In cell-based assays, deucravacitinib has a greater than 100-fold selectivity for TYK2 over JAK1/JAK3 and a greater than 2000-fold selectivity for TYK2 over JAK2 (half-maximal inhibitory concentration [IC 50] data; Table 2). 24, 45 Deucravacitinib selectivity for TYK2 reduces the potential for toxicities such as those associated with JAK1-3 inhibitors.

further reading here
https://academic.oup.com/ibdjournal/advance-article/doi/10.1093/ibd/izab135/6293782

Note here also the comment on TYK 2 Allosteric inhibitors. As we know they do not target the actual site but a site near too. in this instant they state a control in the form of a reduction and clearly this is not complete elimination. I am not knocking allosteric just indicating a perceived shortfall in its performance when compared with a site targeted Tyk2 Inhibitor.

Regards and curry and beer time for me.

Good morning all. Yes Sareums MTD with regards to 1801 as far as I know was never reached. Stoney40 yes was tried at 30x therapeutic dose. This still had no observed ill effect. At this point Tim stated we would go very much higher. Still nothing although we do not what the highest doseage was. I seem to recall Tim saying 100 x higher but then again no actual dose at the time as a reference point.

However SDC1801 can be administered from 12.5 mg per individual to 10 mg per kilo of bodyweight up to a maximum of 1000 mg per day per individual.

If we take Baricitinib the maximum dose is given at 4mg per day with 2mg per day per person recommended. Black box warnings have a dire effect here. The advice from below is of course Covid 19 orientated.

https://www.covid19.lilly.com/baricitinib/hcp/dosing-administration

Clearly one compound it would seem, is head and shoulders above the other, certainly with regard to toxicity and safety concerns. Yes. it can only be truly confirmed in human trials. But then again none of Sareums previous compounds have had any issues with toxicity. There is a pedigree here,

Regards