The latest Investing Matters Podcast episode featuring Jeremy Skillington, CEO of Poolbeg Pharma has just been released. Listen here.
Https://www.nature.com/articles/s41590-024-01804-1
direct .pdf: https://www.nature.com/articles/s41590-024-01804-1.pdf
ATB all genuine posters :)
Couple of links for the non-readers:
1. Lupus Forum: https:k
09:52 Minutes in, TYK2 discussion: https://www.youtube.com/watch?v=pXBT7HQUfnk
2. Looking Ahead for the Management of Plaque Psoriasis
https://www.dermatologytimes.com/view/looking-ahead-for-the-management-of-plaque-psoriasis
3. From Pathophysiology to Therapeutic Progress: TYK2's Significance in Plaque Psoriasis
https://www.youtube.com/watch?v=S8M7ZLSwLoA
ATB
And Clinical Pharmacodynamic Data on its Lead Extrachromosomal DNA (ecDNA)-Directed Therapy, BBI-355, at the American Association for Cancer Research Annual Meeting 2024
https://finance.yahoo.com/news/boundless-bio-presents-preclinical-clinical-120000512.html
Here's hoping the folk who took CCT245737 on haven't got a vested interest in seeing it shelved.... As many have alluded to already, Pharma is an extremely shady business at times.
ATB
Bit more detail and meat to the bones of the same story:
https://scrip.citeline.com/SC150039/Roivant-May-Take-On-AbbVie-In-Uveitis-With-Strong-Phase-II-Efficacy
Anything that takes some market share off Humira will be worth a few quid...
Looking forward to SDC1801 results!
ATB
Great find Krone, you'll no doubt have spotted one of the authors is Udai Banerji - Top man at ICR:
"The authors would like acknowledge grant funding from Cancer Research UK (CRUK 23819) and infrastructural funding to the convergence science centre. The authors would also acknowledge infrastructural funding for the Experimental Cancer Medicine Centre and the NIHR biomedical research centre. UB has received NIHR funding (RP 2016-07-028).
Competing interests
SRA737 was discovered in collaboration with HEI (higher education institution). The Institute of Cancer Research. AS, JS, LP, ADHB, FR and UB are employees of The Institute of Cancer Research. UB has spoken at Sierra Oncology advisory board (non-remunerated) and his institution has received funding to run clinical trials of SRA737. GN and SS are employees of LXRepair."
Of note and also on the CHK1i trail:
30.03.2024:
The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
https://pubmed.ncbi.nlm.nih.gov/38555285/
direct .pdf: https://www.nature.com/articles/s41467-024-47215-6.pdf
29.03.2024: - Boundless Bio (Christian Hassig)
Rampant transcription replication conflict creates therapeutic vulnerability in extrachromosomal DNA containing cancers:
https://www.biorxiv.org/content/10.1101/2024.03.29.586681v1.full.pdf
ATVB
decent enough piece for those who want to delve a little deeper into chk1i:
https://www.sciencedirect.com/science/article/pii/s2590098624000101?via%3dihub#s0080
"cct245737 (21, sra737) is a clinical candidate for chk1i, originally derived from the purine template hit 18. the initial optimization aimed to improve the kinase affinity and selectivity by targeting the interior pocket of chk1, generating compound 19. the pyrimidoazaindole tricyclic scaffold was designed with a pyridine moiety located into the specificity region and an additional nitrogen atom contacting a water molecule. however, compound 19 exhibited issues with conformational deviation and molecular rigidity [70]. through further optimization, the five-member ring-disconnected compound 20 (cct244747) was obtained, which maintained the high intrinsic potency, selectivity and cellular activity. besides, cct244747 has been identified as an orally effective single agent in a mycn-overexpressed neuroblastoma model [71]. however, cct244747 had low metabolic stability in human hepatocytes, and with oral bioavailability of only 61 %), high doses were required. subsequent work focused on the 4-position of the pyridine substituents situated in the ribose binding pocket of chk1, which was confirmed to maximize affinity. a diverse set of 4-amino-substituted pyridine derivatives were synthesized, unexpectedly, resulting in the clinical compound cct245737, which exhibited the excellent chk1 enzymatic activity (ic50 = 1.3 nm), increasing metabolic stability, and improved pk properties with reduced in vivo clearance and good oral bioavailability of 100 % [72]. fan et al. confirmed a strong synergistic anti-cancer effect of cct245737 and vp-16 in chronic myeloid leukemia (cml) cell line k562. furthermore, cct245737 prevented vp-16-induced g2/m arrest, inhibited both brca1 and rad51 (the most significant component of the ****logous repair pathway) and induced cml cells apoptosis [73]. the result of the phase i/ii clinical trial (nct02797964) showed that cct245737 was well tolerated and had good pharmacokinetic profiles (t1/2 = 6.23–10.4 h, cl/f = 18.4–119 l/h, vd/f = 215–1590 l). however, the single-agent potency of cct245737 was not considered to be significant enough for development as a monotherapy for cancer. therefore, subsequent clinical trials will be conducted in combination with other drugs [74]."
atb
Https://www.fiercebiotech.com/biotech/roivants-inflammatory-med-gets-back-track-phase-2-eye-disease-data
Roivant buying back shares too....
ATB
IRONS
1. Potentially bodes well for SDC-1802 when/if we get it moving into trials (decent data on SDC1801 is of course critical, not just for 1802 but the whole ball-game!):
Targeting TYK2 alleviates Rab27A-induced malignant progression of non-small cell lung cancer via disrupting IFNα-TYK2-STAT-HSPA5 axis:
https://www.nature.com/articles/s41698-024-00574-1
2. Of mice & men.... discussed here many times with some excellent data shared previously; if TYK2 inhibition is helpful in T1D treatment, the potential rewards are huge:
Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice:
https://www.biorxiv.org/content/10.1101/2024.03.20.585925v1
ATB all Genuine posters, fingers crossed we can look back on this period from a far better place in the months to come.
..who appreciate them, those who don't, simply skip on by, there's no need to make sarky comments.
1. As SOG has remarked, TYK2i alone failed in UC....
Histological Outcomes And Jak-Stat Signalling In Ulcerative Colitis Patients Treated With Tofacitinib :
https://academic.oup.com/ecco-jcc/advance-article/doi/10.1093/ecco-jcc/jjae031/7632257?searchresult=1
2. Good to see JAK/TYK2i works equally well for both sexes, unlike some treatments...:
New Study Investigates Impact of Patient Sex on Response to Treatments for Psoriatic Arthritis:
https://www.womenscollegehospital.ca/new-study-investigates-impact-of-patient-sex-on-response-to-treatments-for-psoriatic-arthritis/
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(23)00264-3/abstract
3. P165 Kinetics of mucocutaneous and musculoskeletal responses to deucravacitinib in patients with systemic lupus erythematosus (SLE) in the phase 2 PAISLEY trial:
https://www.researchgate.net/publication/379007893_P165_Kinetics_of_mucocutaneous_and_musculoskeletal_responses_to_deucravacitinib_in_patients_with_systemic_lupus_erythematosus_SLE_in_the_phase_2_PAISLEY_trial
ATB
Good morning HBD, hope you are well.
Yes, I agree now regards Numedii almost certainly a blind alley!
An additional private company to potentially keep an eye on though is Hibercell, dabbling in overlapping combination areas to CHK1i (and VEGFR - an area Sareum previously held an interest too:
3 Products:
https://hibercell.com/pipeline/
Filed for a Patent that includes potential combinations(as ever there are bundles of other compounds noted) with a CHK1i and they name SAR020106:
GCN2 MODULATING COMPOUNDS AND USES THEREOF
Document ID
US 20240083897 A1
Date Published
2024-03-14
Clutching at straws, (still tentatively buying) during this awful downturn - nothing to add that hasn't already been said on that front!
All the very best Andy, PCS, et al enjoy the catch-up & any beers, looking forward to your feedback/conclusions.
Would be good to have a jolly once the dust has settled one way or another in the future!
Though a busy life with young kids oft provides little opportunity!
ATB to all genuine posters & holders.
Morning all, apologies if any links have been shared previously:
1. TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes:
https://www.nature.com/articles/s41467-024-45573-9
2. New Data Reinforce JAK Inhibitor Efficacy for the Most Challenging Types of Alopecia:
https://www.medscape.com/viewarticle/new-data-reinforce-jak-inhibitor-efficacy-most-challenging-2024a10004tv?form=fpf
3. Psoriasis biomarkers modulated with TAK-279 treatment:
https://www.healio.com/news/dermatology/20240315/psoriasis-biomarkers-modulated-with-tak279-treatment
4. Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors:
https://www.sciencedirect.com/science/article/abs/pii/S0014299924001729?dgcid=rss_sd_all
5. Practical Use of Upadacitinib in Patients with Severe Atopic Dermatitis in a Real-World Setting: A Systematic Review:
https://www.tandfonline.com/doi/full/10.2147/CCID.S329442?src=exp-la
6. Interesting piece on the development and timescales of Momelotinib's journey to the clinic:
Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval:
https://www.nature.com/articles/s41408-024-01029-3
7. JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis and Their Clinical Significance:
https://link.springer.com/article/10.1007/s11926-024-01144-x#Sec14
ATB
Just to mix up the board a little: I am not a finance guy and there are those here far more qualified to give their reasoning's and thoughts on the latest management debacle/funding turmoil.
CCT245737 may provide the quickest income stream to keep the wolves from the door and the lights on, so certainly deserves our attention.
A little digging has thrown up Prolynx LLC as a potential suitor for a CHK1i –
Private Company, in the field of Combos with DDR, CHK1i… https://prolynxinc.com/PLX038.html
Patent updated yesterday on USPTO website - SYNERGISTIC CANCER TREATMENT
https://patents.justia.com/patent/20240082436
Couple of articles for reference of SN38:
The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eμ-MYC driven B-cell lymphoma:
https://core.ac.uk/download/pdf/326653346.pdf
Abstract B181: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including low-dose gemcitabine, in preclinical models of cancer:
https://aacrjournals.org/mct/article/17/1_Supplement/B181/239190/Abstract-B181-The-Chk1-inhibitor-SRA737
https://pitchbook.com/profiles/company/307046-53#overview
Still have an inkling for Numedii too…. Time will tell.
Just to add, I would be happily onboard with a potential offering of additional shares, subject to certain terms and conditions of course, as highlighted by several of our esteemed LTH.
ATVB all genuine posters, and thank you for sharing your ongoing thoughts & insights.
Nothing is ever simple with Sareum!
From X (Twitter); the author of the below article on TYK2 has made a complimentary copy of the full paper available for a bit. For those who want to read :
https://twitter.com/EricFMorand/status/1767281666740146374?t=H-CGU_1flgG3WdkB_-UQyg&s=19
Also, note the comments from Mike Putman of EBRheum who reckons TYK2i will be the next big thing.... here's hoping a splash of JAK1i enhances things too!
ATB
1.
TYK2: an emerging therapeutic target in rheumatic disease:
https://www.nature.com/articles/s41584-024-01093-w
2.
Latest data of InnoCare’s ICP-332 for the Treatment of Atopic Dermatitis Presented at LBA Session of 2024 AAD:
https://www.eqs-news.com/news/corporate/latest-data-of-innocares-icp-332-for-the-treatment-of-atopic-dermatitis-presented-at-lba-session-of-2024-aad/2011397
https://www.innocarepharma.com/en/development/TYK2Inhibitor
Below is a science-heavy piece for fellow nerds:
3. A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape
https://academic.oup.com/bib/article/25/2/bbae079/7620507#442991429
ATB
Https://www.degruyter.com/document/doi/10.1515/hsz-2023-0111/html
"The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL."
ATB
- Beer-Garden Time, (Coat on of course)
Morning gents, you are right, it is only a tiny little doubt - that's the conspiracy theorist in me!
I trust CCT245737 will break cover in the near future and all will be revealed; as you say onwards and upwards.
ATVB
Boundless Bio bumps IPO market back to life after sleepy few weeks:
https://www.fiercebiotech.com/biotech/boundless-bio-bumps-ipo-market-back-life-after-sleepy-few-weeks
FORM S-1 - REGISTRATION STATEMENT with SEC
https://www.sec.gov/Archives/edgar/data/1782303/000119312524060708/d493037ds1.htm
Boundless Bio Announces Multiple Upcoming Presentations at the American Association for Cancer Research Annual Meeting 2024:
https://finance.yahoo.com/news/boundless-bio-announces-multiple-upcoming-213000930.html
And don't forget Cambridge, UK based Sentinel Oncology with their CHK1i:
2020 - Sentinel collaboration with PharmaEngine for Pep-07 / Sol-578 (brain penetrant), they're also developing CASC-578 an oral CHK1i.
A Study of PEP07 (Checkpoint Kinase 1 Inhibitor) in Patients With Advanced or Metastatic Solid Tumors:
https://clinicaltrials.gov/study/NCT05983523
Will continue to dig into who may have taken CCT245737 on, but can't shake this tiny nagging fear that some bu@@er has licensed it to shelve it for their own ends.... Pharma is a duplicitous, deceitful business at times.
ATB all genuine holders & posters.
Good morning Krone, I hope you are well and thank you for the concern.
I am very much still here, and continuing to buy (I certainly didn't envisage such a drastic share price decline when the science was striving on through trials). I must admit I grew tired of the inane nonsense posted by several multi-ID's which was often timed to clog up the board & push decent info/science based posts down the order. The regularity with which it happened was as comical as it was sinister to be fair.
I am of course regularly digging (cannot change the habit of a lifetime!) but have eased up posting the science heavy pieces here as the board in general is more about tit-for-tat share price this, Parker that, Tim should do this, RF that.
But, it is a discussion board after all and good luck to those who wish to repeat various points with their 20/20 hindsight vision and to snipe at others.
That being said & just for the craic:
1. 03.03.2024 - Employing zero-inflated beta distribution in an exposure-response analysis of TYK2/JAK1 inhibitor brepocitinib in patients with plaque psoriasis:
https://link.springer.com/article/10.1007/s10928-024-09901-2#Sec10
Good luck to all genuine holders, researchers and posters, I feel good news is imminent, I can feel it in my bones!
ATVB
Interesting to see Nature posting up a paper that came out back in November '23 - was posted here on Nov 13th :)
ATB