Member Info for Fadec92

Thanks Krone!

I guess when your talking about offers, then which one are we talking about as too me there seams a different plan for the Tyk2 , with SDC1801 no poster data and a human lupus trial with no recognition only what Thoth found on the internet with US army and SDC1802 with a poster presentation for different cancer indications of mouse models at the EORTC with a novel way of treating tumors but using the same group of molecules tailored for different type of diseases, first one more readily accepted by the industry as the mechanism is in clinical trials but the later not accepted by industry as there is nothing like it around, so to me there is a different business model being applied, but if there was any sort of discussions going on with SDC-1802 then I would have thought it is early days as the poster has only just been published for it, with SDC-1801 I cannot tell there might be an nda, I don’t share the thoughts that they can’t do a deal but if people know the other directors and know their past experiences in business then I’ll go with what’s being said, but it’s like most here need reassurance that they made the correct decision, i know their PR is non existence as I’ve emailed twice with no answer but except that they are not the type of company that is going to spend time keeping their share holders happy as this is a company that thinks doesn't need it and proving things by what they do is what they are doing and for me so far they are doing that!

Gilead want to get into the Autoimmune market they thought they could do that through Galapagos unfortunately not going so well with toxicity in Filgotinib which is a risk when targeting JAK1, Gilead are taking a reduced sales royalties and dropping their $5m milestone payment what do they get in return other than the move ensures that the company can continue and provide a return for Gilead but for me why the reduction in royalties?

When Mome is commercial that’s when it’s making money and can provide the royalties if anything the loss of the $5m should increase the royalty payments not decrease and take a share issue interest in the company’s assets!

“The deal will give Gilead an option over Gapalagos’ GLPG3121, a JAK1/TYK2 inhibitor aimed at inflammation which recently engtered Phase I. The TYK2 space has seen growing interest from investors, not least because of the potential in a number of autoimmune conditions and the fact they have become an area of interest for antitrust regulators in the pending Bristol-Myers Squibb-Celgene deal. The UK’s Sareum (SAR) has a preclinical TYK2/JAK1 inhibitor, SDC-1801, which is one of the few unpartnered assets in this particular class.”

https://quoteddata.com/2019/07/trust-favourite-gilead-expands-deal-galapagos/

Thoth I think that was discontinued!

“We recently stopped a Phase 1 study with GLPG3121, a JAK1/TYK2 inhibitor targeting inflammation, due to an
undesirable PK profile”

https://www.glpg.com/docs/view/5d39f7f0c03eb-en

From the Article:-

“If synthetic lethality is a kind of one-two punch, the trick in fighting cancer is landing the right second punch. The only precedent is a type of drug called PARP inhibitors, such as Clovis Pharma’s rucapirib (Rubraca). PARP inhibitors knock out an enzyme, poly (ADP-ribose) polymerase, that cancer cells use to bounce back from treatment. In cells that are also missing the tumor suppressor genes BRCA1 and BRCA2, the PARP knockout takes down the entire cell. But not all the time, warns Tango CEO Weber: “It’s all context dependent,” she says, noting that PARP inhibitors have worked better to date in BRCA1 or BRCA2-mutated ovarian cancer than in breast cancer.

PARP inhibitors can stop working, too. Writing in Science in 2017, Christopher Lord of the Institute of Cancer Research in London and Alan Ashworth of the University of California, San Francisco, noted, “As with other targeted therapies, resistance to PARP [inhibition] arises in advanced disease.” In the 1990s, Ashworth helped make the connection between BRCA mutations and PARP inhibition, sparking the use of synthetic lethality to fight cancer. He is a Tango cofounder.”

So PARP resistance is the problem:-

“Furthermore, in cells with restored fork protection, cells depend on RAD51 recruitment to the fork for proper protection. Importantly, both PALB2–BRCA2 recruitment to DNA breaks, and RAD51 recruitment to stalled forks, are ATR-dependent in these PARPi-resistant cells [99]. Combining PARPi with ATR inhibitors therefore holds great promise to overcome PARPi resistance in tumors with restored HR or restored fork protection. Inhibitors of ATM (ATMi) seem to hold the same promise because cells with combined disruption of BRCA1 and TP53BP1 or REV7 are resensitized to PARPi by ATMi

99 = In tumor cells derived from patients, ATR is also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.

So research ATR pathways and what’s inline downstream = CHK1

https://imgur.com/a/HZzU9Ua

But there’s a limited about of ATR/ATM/CHK1 inhibitors, AstraZeneca has the lead on ATR inhibitors and I think only 1 in the running but it dosnt synergies with chemo very good but SRA737 does!

Add in a bit of PD-L1 immunotherapy:-

From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation

https://www.nature.com/articles/s41416-018-0017-x

Re-negotiated contract no 5m upfront so they will be a share holder instead!

We may also use a portion of the net proceeds to acquire or license new product candidates or technology that could result in other product candidates. However, we have no current commitments or obligations to do so.

As of the date of this prospectus supplement, we cannot specify with certainty any or all of the particular uses for the net proceeds to us from this offering. We also cannot estimate precisely the allocation of the net proceeds from this offering among these uses. The occurrence of unforeseen events or changed business conditions could result in the application of the net proceeds from this offering in a manner other than as described in this prospectus supplement. As a result, our management will retain broad discretion over the allocation of the net proceeds from this offering.

$103m

Might be worth something to the community where they they could buy the leases as a conglomerate to stop any future drilling activity as the Rocky Flats has 2 areas an inner zone and the outer zone which the later was opened to the public a short while ago but the most of the drilling pads were from a property an industrial section on the western edge where there is also an open clay pit mine if I can remember rightly, and has full rights to land signed by the owner to access and setup drill pads!

Keytruda is the better and the sales are bigger and definitely in Q3!

https://imgur.com/a/GWQnlzS

Checkpoint Inhibitors

Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced, MSI-high colorectal cancer

Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced, MSI-high colorectal cancer

Many immunotherapies that show promise in addressing other types of cancer are in clinical testing for colorectal cancer.

https://www.cancerresearch.org/immunotherapy/cancer-types/colorectal-cancer

Biggest sellers of Cancer Drugs!

https://i.imgur.com/YjBcMo1.png

Keytruda (Merck) vs Opdivo (BMS) Sales!

https://imgur.com/a/GWQnlzS

That one is a combo of chemotherapy and a penetrating enhancer!

cisplatin/vinblastine/cell penetration enhancer

“A formulation composed of three agents in a fixed ratio: two chemotherapeutic agents, the platinum compound cisplatin and the vinca alkaloid vinblastine, and a proprietary amphiphilic excipient that acts as a penetration enhancer, with potential antineoplastic activity. Upon intra-tumoral (IT) injection of INT230-6, the dispersion/cell penetration enhancer excipient of INT230-6 facilitates dispersion of the two drugs throughout the tumor tissue and enables increased cellular uptake of these agents into tumor cells. Once inside the cell, cisplatin forms highly reactive, charged, platinum complexes which bind to nucleophilic groups such as GC-rich sites in DNA, which results in apoptosis and cell growth inhibition. Vinblastine kills the tumor cells through binding to tubulin and thereby inhibits microtubule formation, resulting in disruption of the mitotic spindle assembly and cell cycle arrest of tumor. In addition, the tumor cell killing leads to recruitment of dendritic cells (DCs) and induces a tumor-specific T-cell-mediated immune response that attacks both the injected tumor and distant tumor lesions. Local administration of both cisplatin and vinblastine, without the diffusion/penetration enhancer, results in to poor diffusion and a lack of cellular uptake of the agents; INT230-6 increases the intracellular concentration of cisplatin and vinblastine, thereby improving efficacy. Check for active clinical trials using this agent.”

https://eventpilotadmin.com/web/page.php?page=Home&project=AACR19MT&nav=true

Glad they added the #target19 tag and this and is on the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics App underneath Paul Workman from The Institute of Cancer Research London talk session!

Ahfam isn’t that for SDC-1801 for Autoimmune so not too do with current poster presentation of late, so why is there no presentation for that, obviously 2 different business strategies for both molecules!

I think that most of the hard work is done with SDC-1802, they have a molecule that their happy with and with professional practice evidence and presenting it at the American Association of Cancer Research AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, there can’t be a bigger event for showcasing the work, the hard work is getting this far the next step is finding the right partner too take forward with a production molecule as being synthesized to provide for testing to whoever is interested which there should be a firm interest, I think sometimes we focus on they can’t get a deal but the thing is we have only just provided the evidence to the market, in the RNS’s they have done what they said and now we await whether a deal can be done, I’ve got no evidence to say they can’t only can’t if the product is not good enough to sell which evidence is pointing is not the case!

So this is the Abstract of the new poster presentation!

“We have previously reported on SAR-20347, a 1,3-oxazole-4 carboxamide, which is an orally bioavailable potent and selective inhibitor of TYK2, which causes tumor regression in in vivo models of T-ALL, and which has shown striking reductions in STAT phosphorylation downstream of IFNa signalling, and IFN? production in response to IL-12 both in vitro and in vivo. Here we report the effects of SAR-20351, an orally bioavailable optimised analog of SAR-20347, on tumor cell viability and components of the tumor microenvironment in immunocompetent mouse models.”

Old Abstract of SAR20347, hard to get anything with this as is lock and need permission!

https://imgur.com/a/SXDM1aV

In the poster presentation the references at the bottom of page relate to John and Tim’s work in T Cell with the older SAR20347 which reported that targeting Tyk2 could be a therapeutic strategy for T ALL patience, since then they have discovered a better molecule to reduce tumors in Pancreatic, Colorectal, kidney cancers, melanoma and B-cell lymphoma with the new SAR20351 molecule!

5. Characterisation of TYK2 Inhibitors as Potential T Cell Acute Lymphoblastic Leukemia Therapeutics. Reader, J. 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics,

Theres no way a GSK Rip1k inhibitor for pancreatic cancer has been dropped for a totally different drug target for last nights poster presentation of mouse model of different cancer indications models of Panc02, CT26, MC38, B16F10, Renca and A20 models, not taking away anything for how exciting the pre-clinical preparations and posters are though!

I think some have turned him grey! Lol...

https://twitter.com/hybridanllp/status/1189446572519710720?s=21

Utah there’s not much research out there for Tyk2 in Cancer, so too my mind there’s nothing wrong with looking and learning at the different aspects of how things fit together with the inhibiting the signaling but I do understand also that it’s not going to create to much excitement but maybe one or too people will find it helpful!

Establishing the role of tyrosine kinase 2 in cancer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583936/pdf/onci-2-e22840.pdf