Member Info for sadoldgit

Very pertinent posts you have there Krone.
Firstly it is removing elements of doubt regarding safety and efficacy of TYk2 compounds. This include competitors and to a lesser extent Sarem. It demonstrates also that all TYK2 compounds are not the same.
However we are not Total Tyk2 but also have as Tim stated as what they believe is an optimal amount of Jak1.

' In contrast to this single-kinase inhibitor, PF-06700841 is a potent dual inhibitor of both TYK2 and Jak1. PF-06700841 is expected to inhibit Jak-dependent signaling at multiple points in the pathogenic cycle, including keratinocyte signaling, maintenance of inflammatory T-cell infiltrate, and direct inhibition of TYK2-dependent IL-23 signaling (Fensome et al., 2018). In this in-human, phase 1 study, PF-06700841 100 mg and 30 mg daily dose levels improved disease activity over 4 weeks, as measured by PASI in patients with moderate-to-severe plaque psoriasis (Banfield et al., 2018).'

Note there is relevance in the 'keratinocyte signaling' Jak 1

Note that selectivity is not about the potency and dose limiting of a compound as such. 1000 times more selective does not mean you can administer 1000 times more as a dose regime. Selectivity here relates to the degree of selectivity over other areas of kinase inhibition ie Jak 1 Jak2 and Jak3. Effectively you are hitting an intended target as opposed to off target which in respect to off target may lead to undesirable if not adverse effects. At the same time selectivity is important and regarded as essential when TYk2 is used. Tyk 2 postulated to be much more effective with regards to safety profile when the aims of a high selectivity are met. There are reports on this. I am sure also remember the difficulties we experienced in reaching an MTD. All looking damn fine.

BMS flunked phase 3 in IBD. Remember this is a TYK2 compound. it was effective in psoriasis. Ventyx is Tyk 2 compound. However, I would not put any place any degree of certainty on Ventyx being successful on IBD as non Tyk1. That my thoughts on this.

Of most importance it shows that the big pharma does not have the potential best in class compounds at the moment. It is a very competitive market. The older compounds are edging towards becoming obsolete. It shows that smaller more specialist companies are producing later and more effective compounds and the composition thereof.

Are we inferior to Ventyx? I believe not. Looking at attention to detail, formulation of capsule as an oral, route plus the inclusion of an optimal amount of Jak1 ought to keep our nose in front.

It does reinforce our arguments for being successful in phase 1. All good for Ventyx, all good for Sareum but oh not so good for big pharma. Very few TYk2 compounds have FDA approval.

Slightly off topic but of the opinion that surely it would be prudent to patent crystallisation of a compound for TYK2 SDC1801. It would protect the manufacture of generic compounds much further down t

Correct Scheckler no link as I can see.

Regards

Hi HbD

I am just curious as why it has appeared all of a sudden. It is after all fairly old data. From around end of 2021 I would guess.
From Sar Bulletin circa end 2020
In addition, Sierra Oncology and their collaborators have published encouraging preclinical data demonstrating the synergy of SRA737 or SRA737+LDG in combinations with immune checkpoint, PARP and DNA polymerase inhibitors.

Curiosity nothing else. May be a rogue page left.
The only qeustion I have is. Do SO continue on as have access to funds or do GSK take the reigns?
It may well be that SO will progress under the watchful eye of GSK.

Regards

Rather odd as had not seen much regarding SRA737 for many months, with exception of small occupancy in pipeline . it was always Momo.
https://www.sierraoncology.com/chk1/

Looks like recent addition. Nothing exceptional.

https://www.sierraoncology.com/chk1/

Spot on there HbD,

Targeting JAK
Janus kinase (JAK) inhibitors are small molecules approximately 400 Da that could be administrated as oral medicines. In addition, they are easy to reach the inside of cells and directly inhibit intracellular signaling molecules (Jegatheeswaran et al., 2019). Different JAK inhibitors have different targets: Tofacitinib targets JAK1-JAK3, Baricitinib targets JAK1 and JAK2, Upadacitinib and Filgotinib target JAK1, Peficitinib targets JAK3 and JAK1, and Decernotinib targets JAK3 (Jegatheeswaran et al., 2019). Results of phase IIb and phase III clinical trials demonstrated significant clinical efficacy and safety of Tofacitinib (5 and 10 mg bid) in patients with RA

Clinical experience with tofacitinib (Xeljanz), the first approved JAK inhibitor, illustrates the potential versatility of the drug class, as it is approved for use in rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

The newer agent apremilast (Otezla) has FDA approval for both psoriasis and psoriatic arthritis. Janus kinase (JAK) inhibitors are an emerging option for multiple dermatologic conditions, and investigational inhibitors of tyrosine kinase 2 (TYK2) signaling have shown promise in early clinical trials. This one is Tyk2 Jak2.

Otezla cost
Most people who take Otezla have private insurance and pay $0* a month through the $0 Co-Pay* Program. The list price for a 30-day supply of Otezla is $4,344.18 †. This price is based on the wholesale acquisition cost of Otezla. List price is also referred to as wholesale acquisition cost, or WAC.

The most common side effects of Otezla include diarrhea, nausea, upper respiratory tract infection, tension headache, and headache. These are not all the possible side effects with Otezla. Ask your doctor about other potential side effects. Tell your doctor about any side effect that bothers you or does not go away.

diarrhea
need be careful here as can cause IBD but may hidden under the term of diarrhea.

Nigh 4 grand a month for the pleasing symptoms of the 5h1ts. Quality of life? Keep at no further than 20 metres from an Egdar Allan or wear incontinence pants. That look good on a beach while you sat soaking up a few rays.

More serious now
Otezla was first approved for the treatment of psoriatic arthritis on March 21st, 2014 by the FDA and was on the market soon after (by the end of March 2014).

Apremilast was approved for use in the European Union in January 2015.
In 2019, Amgen acquired Otezla from Celgene for US$13.4 billion.

Tyk2 Jak1 has the pathways sewn up for psoriasis yet we have an old early stage Jak inhibitor in the driving seat at the mo.
Is it any wonder why we are entering Psoriasis as an indication.

Regards

Good afternoon HbD. Make note of when the results submissions were made/ Late 2021 onwards. Around 18 months after end of trial. Trial designs completed I would hazard a guess.
Deliberate I would say and an indicator that GSK are about to put their foot on the gas pedal.

Results of clinical trials can be accessed by almost anyone and that includes competitive pharma's.

Regards

It may well be that it is not that effective in all tumour regressions. There may well be in others.
However, it is that effective in SCLC an therefore should be fast tracked into clinic.

The other aspect of PARP is they are indication early stage almost to the point of being preventative. Good in theory but a tad harder in reality. Many cancers not recognised at early stage. Dependant on the stage PARP will only be effective at early stage in mono therapy. However to maximise efficacy 'remarkable tumour regression' would it not be better to administer in combo ie CHK1 Gemcitibine and PARP inhibitor as early as possible before resistance to PARP develops?

Sierra have a patent for combo trials as you well aware.

We may not hear of intentions by GSK but I reckon we will hear of continuation for trial applications in various forms of cancer. Phase 2 and fast track a very valid and likely possibility .

Regards

Funding for the research

Financial Support:

This work was supported by: Research funding from Sierra Oncology (LAB); NIH/NCI award U01-CA213273 (JVH, LAB); NIH/NCI award 1-R01-CA207295 (LAB); NIH/NCI CCSG P30-CA016672 (shRNA and ORFeome Core, Boinformatics Shared Resource); The University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE (5 P50 CA070907) (JVH, LAB); NIH/NCI T32 CA009666 (CMG); the Lung Cancer Research Foundation (TS); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (JVH, JW, LAB); MD Anderson Cancer Center Physician Scientist Award (LAB); and The Rexanna Foundation for Fighting Lung Cancer (JVH, LAB).
Regards

Aug 2019
SRA737 was provided by Sierra Oncology. Gemcitabine was acquired from The MD Anderson Cancer Center pharmacy. Anti-PD-L1 antibodies (clone 10F.9G2) and anti-PD-1 antibodies (clone RMP1–14) were purchased from BioXcell.

Next, we treated B6129F1-immunocompetent flank RPP tumor-bearing mice15 with SRA737 (100mg/kg) at two frequency schedules of either 3 days on-treatment followed by 4 days off-treatment (3/7) or 5 days on-treatment followed by 2 days off-treatment (5/7). Anti-PD-L1 (300µg)8 was administered on the third day of every treatment week either alone or in combination with SRA737 (n = 10 per group; Fig 2A). Mice treated with anti-PD-L1 alone showed no anti-tumor response in this model (Fig 2A). Animals treated with single agent SRA737 showed significant reduction in tumor growth as compared to either vehicle or anti-PD-L1 treatment alone, with SRA737 schedule of 5/7 (Treatment/Vehicle (T/C)=0.27; p<0.001) being moderately more effective than SRA737 schedule of 3/7 (T/C=0.32; p<0.001). In contrast to the single agent activities, combination of SRA737 (5/7) and anti-PD-L1 resulted in a complete inhibition of tumor growth within one week of treatment (T/C=0.064; p<0.001) (Fig 2A).

We did not observe a significant anti-tumor effect with any single agent treatments (anti-PD-L1, SRA737 or LDG), and only a moderately delayed tumor growth with combined SRA737 and PD-L1 treatment (Fig 4A). However, we observed remarkable tumor regressions when we combined SRA737+LDG with anti-PD-L1. All mice achieved some level of tumor regressions and 80% of mice (8/10) had complete tumor regressions which were sustained up to 60 days post treatment

Question here is which company bought for research ? This from late 2019. Then in 2020 Sierra take the for sale sign dowm. No further development by SO as concentrate resources on Momo. Early 2020 you have patent for 737 Gem and a PD1 inhibitor. Clearly SO sat on it but at same time were not prepared to on license or sell.

Sierra clearly aware of potential. GSK likewise by now the main difference is they DO have the finances to pursue.

Regards

Triparna Sen ( from 2019 but still very relevant)

Introduction: Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC. Methods and results: Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti-programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti-PD-L1/anti-PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNß, and chemokines, CCL5 and CXCL10. Conclusions: Given that anti-PD-L1/anti-PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.'

PARP is a way forward. But unfortunately resistance develops. PARP inhibitors need in combo therapy to assist.

'Abstract
BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks. Here, we review the mechanism of PARP inhibitor resistance.'

Good morning, well tis afternoon now citizen.
Indeed it does look good for both CHk1 and Sdc1801. Evidence is quite compelling as to increased efficacy with Jak1 in addition to TYk2. High purity capsule formulation that ought to give us the edge on anything else currently available in clinic and late stage trials.
Avoid looking up Sar 20347. This is a Selleck compound of Jak1 Tyk 2 Jak 2 and Jak3.

Regards

https://pubmed.ncbi.nlm.nih.gov/35608188/

https://pubmed.ncbi.nlm.nih.gov/34471993/

https://pubmed.ncbi.nlm.nih.gov/33929045/

Even longer read here

https://reader.elsevier.com/reader/sd/pii/S0022202X20300270?token=369CF891EA0EA7E62F009A4AD61A5AD94C3328BFCE23D7CCFAFC034B90DA0B0D534D0D5FD24EFFF11116011E0902AD97&originRegion=eu-west-1&originCreation=20220813214301

https://www.sciencedirect.com/science/article/pii/S0022202X20300270#:~:text=TYK2%20and%20Jak1%20are%20critical%20for%20signal%20transduction,through%20Jak1%20in%20keratinocytes%20%28Sohn%20et%20al.%2C%202013%29.

Good evening citizen79
Regarding Deucravacitinib, it is Tyk2 only. Not I believe as effective as a TYK2 Jak1 ingibitor.

Excerpt below

Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.

There is I believe a criteria to be met. Fairly sure it was 75% reduction of PASI score over a 12 week period. This would then make it eligible to be used as a treatment subject to satisfactory adverse effects and safety profile.

Full link below and apologies if posted before.

Regards