Chris Heminway, Exec-Chair at Time To ACT, explains why now is the right time for the Group to IPO. Watch the video here.
Boundless Bio Announces Clinical Trial Collaboration and Supply Agreement with Lilly to Evaluate Verzenio (Abemaciclib) in Combination with BBI-355 in Patients with Cdk4 or Cdk6 Amplified Solid Tumors:
https://www.clinicaltrialsarena.com/news/boundless-bio-lilly-bbi-355/
ATB
1.
Sep. 19, 2023 - Chinese researchers discover new TYK2 inhibitors
Ennovabio (Zhejiang) Pharmaceuticals Co. Ltd. and Shanghai Ennova Biopharmaceutical Co. Ltd. have described 5-membered and 6-membered heterocyclic compounds acting as non-receptor tyrosine-protein kinase TYK2 inhibitors reported to be useful for the treatment of cancer, viral infection, transplant rejection, cardiovascular and inflammatory disorders, and autoimmune, myeloproliferative and metabolic diseases:
https://patents.google.com/patent/WO2023155900A1/en?assignee=Ennovabio&oq=Ennovabio&sort=new
Now, LTH's here will appreciate the info contained within the above patent application - nice that its a relatively easy to understand text; one can glean an awful lot of data from a patent application :) - (although clearly not one for the TLDR crew.)
Background Technique:
"In addition, the JAK-STAT pathway is persistently activated in many cancers, leading to the initiation of multiple trials using JAK inhibitors in hematology and solid tumors, including trials of combinations of multiple kinase inhibitors."
This is the biggie - CANCER - yes we are targeting the catalytic domain, but our boffins deem this superior, time will tell.
All eyes on SDC1801 flying through the current testing and SDC1802 coming to the fore thereafter, will it still be in our hands by then though....
Brucey Bonus - & as alluded to by Thoth2 many moons back:
2. Effect of JAK inhibitors on the three forms of bone damage in autoimmune arthritis: joint erosion, periarticular osteopenia, and systemic bone loss:
https://inflammregen.biomedcentral.com/articles/10.1186/s41232-023-00293-3#Sec18
"Conclusion
JAK inhibitors effectively inhibit inflammation and joint erosion in RA. However, their effects on osteoclastic bone resorption and osteoblastic bone formation in all the types of bone damage in autoimmune arthritis have not been previously evaluated in depth. This study shows that the JAK inhibitor suppressed joint erosion mainly by inhibiting osteoclastogenesis, while it ameliorated periarticular osteopenia and systemic bone loss by both inhibiting steoclastogenesis and promoting osteoblastogenesis. While the currently available JAK inhibitors are capable of inhibiting osteoclastogenesis, the suppressive effects under inflammatory environments may vary depending on the cytokine milieu, JAK selectivity and the specificity of the cytokine signaling pathways. The findings reported here should contribute to the strategic therapeutic use of JAK inhibitors against bone damage in RA."
All the best
...and Supply Agreement with Taiho Oncology to Evaluate LYTGOBI® (futibatinib) in Combination with BBI-355 in Patients with FGFR Amplified Solid Tumors:
https://finance.yahoo.com/news/boundless-bio-announces-clinical-trial-120000783.html
ATB
1.
Several TYK2 snippets to ponder from today's BMS presentation:
direct .pdf :
https://www.bms.com/assets/bms/us/en-us/pdf/r-and-d-day/2023/bmy-r-and-day-presentation.pdf
(BMS-986322)
Pages 19-20 - good to see they are looking at potential CNS penetrant TYK2 inhibitor for Multiple Sclerosis (MS) - currently pre-clinical.
2.
Biologics and oral small-molecule inhibitors for treatment of pediatric atopic dermatitis: Opportunities and challenges:
https://onlinelibrary.wiley.com/doi/full/10.1002/ped4.12400
3. Quick video for the non-reading among us:
How do you explain the difference between the JAK and TYK2 MOAs?
https://www.youtube.com/watch?v=qEwiC9xAGkw
As a side note, there is a HUGE push from BMS (as is to be expected of course and not uncommon with Big pharma) - competitors are lining up accordingly.
Time will tell.
ATB
Tumor suppressor p53 mediates interleukin-6 expression to enable cancer cell evasion of genotoxic stress:
https://www.nature.com/articles/s41420-023-01638-0
"Downregulation of IL-6 renders cancer cells sensitive to genotoxic treatments
IL-6 is a key mediator of multiple cellular processes regulating tumor growth and treatment resistance [7]. We hypothesized that IL-6 expression levels can predict the clinical outcome of cancer patients. Indeed, elevated IL-6 expression was associated with poorly differentiated (high-grade) histology, whereas IL-6 was expressed at relatively low levels in well differentiated (low-grade) lung adenocarcinomas (Fig. 1A). Consistently, lung cancer patients with high IL-6 expression displayed significantly shorter disease-free survival (DFS) (Fig. 1B) and overall survival (OS) (Fig. 1C) than those having lower IL-6 expression. Moreover, we also observed a similar prognostic value of IL-6 in tumors across The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (Fig. 1D), suggesting that the role of IL-6 in promoting cancer progression and hindering patient survival is common among a wide range of cancers."
ATB
Takeda Announces Positive Topline Results from Phase 2b Study Evaluating TAK-279, a Highly Selective Oral TYK2 Inhibitor, for the Treatment of Active Psoriatic Arthritis
https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Announces-Positive-Topline-Results-from-Phase-2b-Study-Evaluating-TAK-279-a-Highly-Selective-Oral-TYK2-Inhibitor-for-the-Treatment-of-Active-Psoriatic-Arthritis/
Dizal Announces Clinical Results of Golidocitinib Published in Annals of Oncology
https://finance.yahoo.com/news/dizal-announces-clinical-results-golidocitinib-090300420.html
"Dizal identified that JAK/STAT pathway may mediate the pathogenesis of PTCL and launched clinical studies of golidocitinib to test the hypothesis. Golidocitinib is the first and currently the only Janus kinase 1 (JAK1) selective inhibitor for treating r/r PTCLs at the stage of pivotal clinical development. Consistent with earlier data, golidocitinib demonstrated potent and durable anti-tumor efficacy in the pivotal study (JACKPOT8 PARTB), with the clinical results selected as oral presentation at 2023 American Society of Clinical Oncology (ASCO) and 2023 International Conference on Malignant Lymphoma (ICML)."
FDA Action Alert: GSK and Alnylam:
https://www.biospace.com/article/fda-action-alert-roche-halozyme-gsk-and-alnylam-s-adcomm/
"GSK Awaits Momelotinib Verdict in Myelofibrosis After Delay
Following a three-month delay to review new information, the FDA is expected to release its decision on GSK’s NDA for momelotinib as a treatment for myelofibrosis patients with anemia by September 16.
Momelotinib is an investigational medication that has a “novel mechanism of action,” inhibiting three signaling pathways: the JAK1 and JAK2 pathways and the activin receptor type I (ACVR1) cascade, according to a GSK press release announcing the delay. The molecule was most recently developed by California biotech Sierra Oncology, which was acquired by GSK for $1.9 billion in April 2022.
By silencing the JAK1 and JAK2 pathways, momelotinib eases symptoms of splenomegaly and elicits improvements in the patients’ constitution. This is complemented by its activity along the ACVR1 cascade, potentially lowering levels of the hepcidin protein, which is elevated in myelofibrosis and contributes to anemia.
The FDA first accepted GSK’s NDA in August 2022 and set an initial target action date of June 16, 2023. On the day of the deadline, the regulator announced it would need three more months to evaluate new data.
GSK supported momelotinib’s regulatory bid with data from the Phase III MOMENTUM trial, which showed that the candidate met its primary efficacy endpoint, reducing Total Symptom Score after 24 weeks of treatment by at least 50%. Momelotinib likewise aced its secondary efficacy metrics, including transfusion independence and splenic response rate."
Japan accepts GSK's regulatory filing for momelotinib for blood cancer :
https://www.marketscreener.com/quote/stock/GSK-PLC-9590199/news/Japan-accepts-GSK-s-regulatory-filing-for-momelotinib-for-blood-cancer-44811510/
ATB
Several very recent links that may be of interest:
1. Potential Mechanism of Fatigue Induction and Its Management by JAK Inhibitors in Inflammatory Rheumatic Diseases:
https://www.dovepress.com/potential-mechanism-of-fatigue-induction-and-its-management-by-jak-inh-peer-reviewed-fulltext-article-JIR
direct .pdf: https://www.dovepress.com/getfile.php?fileID=92627
2. SRA737 mentioned and indeed allegedly bettered by XS-02, a CHK1i from China... time will tell of course.
A new wave of innovations within the DNA damage response:
https://www.nature.com/articles/s41392-023-01548-8#Sec23
direct .pdf: https://www.nature.com/articles/s41392-023-01548-8.pdf
"As cancer remains as one of the top health threats to humanity, new MOAs (mechanism of actions) and drugs are still of great requirements to improve cancer prognosis. Inspired by the precedent success and thriving advancements, we believe the new wave of innovations targeting DDR network will open up new opportunity to expand the toolkit for antitumor treatment."
3. A Chronic Itch: Burrowing Beneath the Skin:
https://www.the-scientist.com/features/a-chronic-itch-burrowing-beneath-the-skin-71305
A fascinating and thought provoking article IMO!
"Itching is more than just sensing external stimuli. For example, our team has found that molecules like JAK1 within neurons act as an internal sensor of inflammation across multiple organs.32 Also, sensory nerves directly incite or tame regulation in various tissues. This means that an itch can help us understand how our bodies process inflammation and a variety of internal stimuli, a start to a new approach in medicine.
The fact that sensory neurons may play a previously unrecognized role in these different settings widens the scope of how and what we sense both outside and inside the body. In the future, could we treat autoimmunity via the vagus nerve?33-34 Is modulation of skin nerves a way to alleviate irritable bowel syndrome? Is pain not simply a symptom, but driving cancer progression via the nerves? These provocative questions could be foundations for new ways to treat many medical disorders in the future.
One thing is clear: we have only scratched the surface of the vast itch biology and neuroimmunology."
4. Diminished antimicrobial drug use in dogs with allergic dermatitis treated with oclacitinib:
https://www.frontiersin.org/articles/10.3389/fvets.2023.1207582/full
Seeing as it's feel-good Friday, who doesn't like a piece involving mans best friend ! (Read-across often applies after all)
ATB
Morning all,
https://www.fiercepharma.com/pharma/patient-cliffs-divestitures-and-biotechs-maturing-its-prime-time-ma-analysts
Nothing new or groundbreaking as such for the well informed among us, but a decent enough snapshot of the current situation IMO.
ATB
Checkpoint kinase 1 inhibitor + low-dose hydroxyurea efficiently kills BRAF inhibitor- and immune checkpoint inhibitor-resistant melanomas:
https://research-repository.griffith.edu.au/handle/10072/425070
direct .pdf: https://research-repository.griffith.edu.au/bitstream/handle/10072/425070/Gabrielli7757124-Published.pdf?sequence=2
Abstract:
"Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low-dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti-tumour immune responses in vivo.
Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi-resistant and BRAFi-sensitive parental tumours produce an identical immune response with treatment."
" This high proportion of sensitive melanomas to CHK1i + LDHU and their remained sensitivity after acquiring resistance to current clinical treatments suggests that CHK1i + LDHU combination could be a useful treatment in patients that have exhausted current therapy options."
SRA737..... ;)
ATB
Pertinent to SDC1802, or even the "backup" molecules Tim & John mentioned :)
https://www.researchgate.net/publication/373658679_Type_I_interferon_and_cancer
direct .pdf: https://www.researchgate.net/journal/Immunological-Reviews-1600-065X/publication/373658679_Type_I_interferon_and_cancer/links/64f6c46848c07f3da3db65df/Type-I-interferon-and-cancer.pdf?_tp=eyJjb250ZXh0Ijp7ImZpcnN0UGFnZSI6Il9kaXJlY3QiLCJwYWdlIjoicHVibGljYXRpb24ifX0
Figure 1 within the paper for a quick snapshot.
"Summary
Type I interferon (IFN) is a class of proinflammatory cytokines with a dual role on malignant transformation, tumor progression, and response to therapy. On the one hand, robust, acute, and resolving type I IFN responses have been shown to mediate prominent anticancer effects, reflecting not only their direct cytostatic/cytotoxic activity on (at least some) malignant cells, but also their pronounced immunostimulatory functions. In line with this notion, type I IFN signaling has been implicated in the antineoplastic effects of various immunogenic therapeutics, including (but not limited to) immunogenic cell death (ICD)-inducing agents and immune checkpoint inhibitors (ICIs). On the other hand, weak, indolent, and non-resolving type I IFN responses have been demonstrated to support tumor progression and resistance to therapy, reflecting the ability of suboptimal type I IFN signaling to mediate cytoprotective activity, promote stemness, favor tolerance to chromosomal instability, and facilitate the establishment of an immunologically exhausted tumor microenvironment. Here, we review fundamental aspects of type I IFN signaling and their context-dependent impact on malignant transformation, tumor progression, and response to therapy."
ATB
06.09.2023
https://www.nature.com/articles/s41586-023-06355-3
"Third, six loci contain candidate causal genes that are linked to the type I interferon pathway (Extended Data Fig. 1c), such as previously reported IFNAR2 (21q22.11), OAS1 (12q24.13) and TYK2 (19p13.2), as well as additionally identified JAK1 (1p31.3), IRF1 (5q31.1) and IFNα-coding genes (9p21.3). Previous studies have reported additional genes in this pathway: TLR7 (refs. 11,12) and DOCK2 (ref. 13). Here we found that the lead variant rs28368148:C>G, a missense variant (p.Trp164Cys) of IFNA10 located within the IFNα gene cluster, increases the risk of critical illness (OR = 1.56, 95% CI = 1.38–1.77, P = 3.7 × 10−12). IFNα is one of the type I interferons that binds specifically to the IFNα receptor consisting of IFNAR1–IFNAR2 chains, in which mutations are also known to increase the risk of hospitalization and critical illness. In the genes that enable signalling downstream of IFNAR, we identified that the lead variant rs11208552:G>T, an intronic variant of JAK1, is protective against critical illness and hospitalization (OR = 0.92 and 0.95, 95% CI = 0.89–0.94 and 0.93–0.96, P = 5.5 × 10−10 and 2.2 × 10−9, respectively). This variant was previously reported to decrease lymphocyte counts14 (β = −0.016, P = 5.5 × 10−15) and increase the JAK1 expression in the thyroid in GTEx15 (P = 6.1 × 10−23). JAK1 and previously reported TYK2 are Janus kinases (JAKs) that are required for type I interferon-induced JAK–STAT signalling. JAK inhibitors are used to treat patients with severe COVID-19 (ref. 16). Furthermore, downstream of JAK–STAT signalling, we found that the lead variant rs10066378:T>C, located 67 kb upstream of IRF1, increases the risk of critical illness and hospitalization (OR = 1.09 and 1.07, 95% CI = 1.06–1.13 and 1.05–1.09, P = 2.7 × 10−9 and 3.74 × 10−10, respectively)."
ATB
Good morning SOG, Ahfam, et al,
Firstly, thank you for your kind words & consistently informative posts.
Regarding getting into spats & such like on here - I was guilty of that way back; wanting to challenge & call out the BS from duplicitous posters – you’d spot them a mile off with their quasi-positive, but always ending-with-a negative posts. However, they'd just start posting under another pseudonym when the current one gets blown. I simply started blocking them the second their posts didn't sit right - and it has been blissful ever since. That's not to say I want to live in an echo chamber, far from it, I actually like the genuinely contrarian views - they force me (as dictated by my personality traits) to scurry off & search for evidence & information to counter the queries & opposing concepts, laying any doubts to bed in the process. Funnily enough this more often than not reinforces the original research & data dig and being a nerd I find the whole process thoroughly enjoyable & quite relaxing. Taking research and nerd behaviour to the nth degree in a given area really can lead one to spot investments & potentially lucrative returns in places where others just gamble.
Anyway, enough bluster & non-science from me, no one comes here for story telling & such yarns – time for a morning stroll across the sparkling dew covered fields of sunny Essex!
Here’s hoping this isn’t a false dawn in Sareum’s history, onwards.
ATVB
Evening HBD, timing was spot on from a personal point of view, and it all feels right. Time will tell of course, but I've never been so confident in our prospects.
Thank you for the excellent posts over the years too, you've kindly shared some superb info !
ATVB
1. Profound seizure suppression and disease modification by targeting JAK1, a key driver of a pro-epileptogenic gene network:
https://pubmed.ncbi.nlm.nih.gov/37662337/
direct .pdf link: https://www.biorxiv.org/content/biorxiv/early/2023/08/08/2023.08.07.552299.full.pdf
"ABSTRACT
Epilepsy is the 4th most prevalent neurological disorder with over 50 million cases worldwide. While a number
of drugs exist to suppress seizures, approximately 1/3 of patients remain drug resistant, and no current
treatments are disease modifying. Using network and systems-based approaches, we find that the histone
methylase EZH2 suppresses epileptogenesis and slows disease progression, via repression of JAK1 and
STAT3 signaling in hippocampal neurons. Pharmacological inhibition of JAK1 with the orally available, FDA -
approved drug CP690550 (Tofacitinib) virtually eliminates behavioral and electrographic seizures after the
onset of epilepsy in a preclinical rodent model of acquired epilepsy. Overall, identification of an endogenous
protective response to status epilepticus in the form of EZH2 induction has highlighted a critical role for the
JAK1 kinase in epilepsy. Targeting JAK1 with CP690550 has a profound therapeutic effect on spontaneous,
recurrent seizures."
2. Phase 1 Dose Escalation and Expansion Study of Golidocitinib, a Highly Selective JAK1 Inhibitor, in Relapsed or Refractory Peripheral T Cell Lymphomas:
https://www.annalsofoncology.org/article/S0923-7534(23)00828-1/fulltext
"ABSTRACT - Background
Relapsed or refractory peripheral T cell lymphomas (r/r PTCLs) are a group of rare and aggressive diseases, which lack effective therapies. Constitutive activation of Janus kinase (JAK)/signal transducer and activation of transcription (STAT) pathway are reported to be associated with PTCLs. Golidocitinib is an oral, potent JAK1 selective inhibitor evaluated in a phase 1/2 multinational study in r/r PTCLs.
Biomarker analysis suggested a potential correlation between JAK/STAT pathway aberrations and clinical activity of golidocitinib.
Conclusions - In this phase 1 study, golidocitinib demonstrated an acceptable safety profile and encouraging antitumor efficacy in heavily pre-treated patients with r/r PTCLs. These results support the initiation of the multinational pivotal study in patients with r/r PTCLs."
3. Choosing Therapies in Ulcerative Colitis :
https://academic.oup.com/jcag/advance-article/doi/10.1093/jcag/gwad025/7259616
The section on JAKinibs is of interest here :)
"The Janus Kinase (JAK) inhibitors are small molecule drugs that block a key pathway in the mediation of effect of numerous pro-inflammatory cytokines. There are several JAK inhibitors that have been studied in UC and shown to be effective for both induction and maintenance therapy. A highly efficacious oral agent that can be used for both induction and maintenance therapy would be a major breakthrough for UC patients
ATB
Afternoon all,
As eluded to here previously, Sotyktu isn't exactly setting the world on fire by grabbing a huge market share off Amgen's Otezla:
https://www.fiercepharma.com/marketing/amgen-tipped-keep-otezla-market-share-fight-bms-sotyktu-leaving-opportunity-jj
Sareum shareholders and our BOD might suggest this isn't just an opportunity for J&J either ;)
Spherix polled U.S. dermatologists to understand how things have played out since Sotyktu became the second oral plaque psoriasis drug on the market. The analysis found Amgen is yet to lose “any material share” to Sotyktu and generated evidence that the Big Biotech can continue to retain its riches.
“Sotyktu currently has and is projected to continue to make incremental gains in market share over the next six months; however, prescriber projections reveal that Sotyktu success will more likely come at the expense of the approved injectable biologics, as opposed to Otezla,” the analysts wrote in a statement."
TYK2/JAK1 !
ATB
Very well said people!
It would be great to see some forward movement with this potentially lifesaving combo treatment!
The Chinese via Taiwan are certainly having a dabble themselves with "PEP07" an oral CHK1 inhibitor: (and who can blame them !)
https://classic.clinicaltrials.gov/ct2/results?cond=pep07&term=&cntry=&state=&city=&dist=&Search=Search
http://pharmaengine.com/en/newsView_590
ATB
On the covid tip, interesting to note Pubmed putting up the following link in the last 5 days:
Identification of six genes associated with COVID-19-related circadian rhythm dysfunction by integrated bioinformatic analysis:
https://pubmed.ncbi.nlm.nih.gov/37624450/
"Patients with coronavirus disease 2019 (COVID-19) might cause long-term burden of insomnia, while the common pathogenic mechanisms are not elucidated. The gene expression profiles of COVID-19 patients and healthy controls were retrieved from the GEO database, while gene set related with circadian rhythm was obtained from GeneCards database. Seventy-six shared genes were screened and mainly enriched in cell cycle, cell division, and cell proliferation, and 6 hub genes were found out including CCNA2, CCNB1, CDK1, CHEK1, MKI67, and TOP2A, with positive correlation to plasma cells. In the TF-gene regulatory network, NFYA, NFIC, MEF2A, and FOXC1 showed high connectivity with hub genes. This study identified six hub genes and might provide new insights into pathogenic mechanisms and novel clinical management strategies."
direct .pdf link to the original document from back in May'23 for fellow data diggers:
https://assets.researchsquare.com/files/rs-2934767/v1/b314e0c6-a82c-43ee-a993-4bbca0d602a0.pdf?c=1689635672
"5. Conclusion
Through bioinformatic means, CCNA2, CCNB1, CDK1, CHEK1, MKI67 and TOP2A were identied as hub
genes. They were mainly involved in cell cycle, cell division and cell proliferation, and significantly
associated with plasma cells, indicating that they might be potential biomarkers for COVID-19-related
insomnia. Overall, our research might provide new ideas for further mechanistic studies."
ATB