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As ever, keeping an eye on the competition:
1.
https://finance.yahoo.com/news/galapagos-announces-start-phase-2-200100002.html
2.
Galapagos: Good To Have An Approval, Bad To Have No Major Catalysts:
https://seekingalpha.com/article/4631081-galapagos-stock-good-to-have-approval-bad-to-have-no-major-catalysts
3.
InnoCare Releases 2023 Interim Results and Business Highlights:
https://www.bloomberg.com/press-releases/2023-08-29/innocare-releases-2023-interim-results-and-business-highlights
"ICP-332
* Phase I data demonstrated a dose proportional and favorable PK profile, no observation of significant food effect, and well tolerated and good safety profile. InnoCare initiated a Phase II study of ICP-332 in atopic dermatitis (AD) with a data readout expected by the end of 2023.
* ICP-332 is a potent and selective TYK2 JH1 inhibitor that is being developed for the treatment of various autoimmune disorders, with 400 folds of selectivity against JAK2.
* According to the source of Pharma Intelligence, AD has become a major autoimmune disease with a global market potential of US$10 billion by 2030^5."
ATB
Https://www.mdpi.com/2072-6694/15/16/4141
"One important new finding from our study is the identification of a Sotorasib-regulated interaction between KRAS and JAK1 that has not been highlighted before. Reassuringly, it must be noted that a recent proteomics screen performed by the Kiel group using a similar protocol also pulled down JAK1 and STAT3 as specific interacting proteins of KRAS WT, KRASG12C, KRASG12V, and KRASG12D [47]. In our AP-MS proteomics experiment, we see that Sotorasib increases JAK1-KRAS interaction and at the molecular level we demonstrate that Sotorasib causes an inhibition of STAT3 phosphorylation in HEK293 cells but not in MEF cells that express only one of the KRAS proteins. This finding is particularly intriguing as it indicates that JAK1 might be specifically interacting with KRAS bound to GDP and this interaction prevents JAK1-dependent activation of STAT signalling. This new connection between KRAS and JAK-STAT signalling might be of clinical relevance as JAK1 inhibition has been shown to reduce murine KRAS mutant adenocarcinoma progression [63]. We show that the clinically approved JAK1/2 inhibitor Ruxolitinib increases caspase three cleavage in MEF-KRASG12C cells but not in MEF-KRAS WT. Remarkably, this experiment led to the unexpected observation that JAK1 inhibition alone causes a significant increase in expression of both KRAS WT and KRASG12C. Taking into account evidence from clinical trials that show an effect of JAK1 inhibitors in EGFR and possible KRAS mutant tumours (NCT02155465, NCT02145637, NCT02917993, and NCT03450330) [63], this serendipitous finding might be of relevance to explain a possible mechanism of action of JAK inhibitors in cancer. One possibility is that JAK1 inhibitors, among other mechanisms, might induce high levels of mutant KRAS expression that leads to the activation of the apoptotic pathways mediated by this RAS isoform [2,73]. It must be noted that this is an acute increase in KRAS expression, which might have very different effects than KRAS overexpression caused by gene amplification that has been associated with resistance to EGFR and KRAS targeted therapies in colorectal cancer cell lines"
ATB
The section on JAKinibs makes interesting reading.
https://www.dovepress.com/emerging-therapies-for-ulcerative-colitis-updates-from-recent-clinical-peer-reviewed-fulltext-article-CEG
If SDC1801/02 can avoid/lesson some of the side effects noted with current drugs such as Tofa, Brepocitinib etc. we are on to a winner, pure and simple IMO.
Thanks SOG for your thoughts, much appreciated as ever.
Keep well.
ATVB
Cheers Chaps, and thank you SOG for the informative post.
Your considered thoughts on the below earnings call would be most appreciated should you have the time to peruse; it's starting to look likely (to me anyway) that Brepocitinib could be the main rival/challenger to our SDC1801 going forward.
Looking at Roivants 10k form below, they have certainly committed a good few dollars to Brepocitinib development !
Direct .pdf
https://investor.roivant.com/static-files/a7b36392-1f44-4251-87cf-8dd572f3034e
It is almost astonishing to think how far Sareum have come with such a small team and budget in the TYK2/JAK1 arena!
It also seems Sotyktu is suffering underwhelming up-take with many Dermatologists across the US, with big fears over its safety versus efficacy compared against existing treatments. Time will tell of course and a new drug needs time to bed-in and grab market share, but since launch, sales have certainly not set any records.
I would like to think there is plenty of room for alternatives!
ATVB
An alternative link to the transcript incase folk get membership/walled out of the previous link.
https://www.insidermonkey.com/blog/roivant-sciences-ltd-nasdaqroiv-q1-2023-earnings-call-transcript-1183495/
"And we’ll go through the rest of the material on this slide in greater detail later, but we think that we really have the potential to become the leading oral therapy and loop given the dual inhibition of TYK2 and JAK1 should provide greater efficacy than inhibition of either one alone. That is a large global study that is designed to serve as 1 of 2 registrational studies."
ATB
In addition to yesterday's post, some here may find this of interest - - or maybe even tantalising.....
Bare in mind again this is an auto-generated transcript and some erroneous words appear - due mainly to talkers' accents to be fair: I've quickly cut & paste a few pertinent parts below, apologies in any mistakes, but would recommend a few minutes of your time to have a proper read via the link. Its pretty easy to guess the word corrections needed throughout the written piece. - Alternatively, if you have the time you could listen to the call :)
Some interesting additional info noted regards markets, treatment areas and Sotyktu plus much much more insight.
Sareum are bang in an industry sweet spot, we just need to get SDC1801/02 into patients now and prove they work!#
Remember, we only need to be better than the competition in 1 or 2 indications and, a as a relative minnow, our value will soar many multiples of our current levels.
Roivant Sciences Ltd. (NASDAQ:ROIV) Q1 2023 Earnings Call Transcript August 14, 2023
https://seekingalpha.com/article/4628397-roivant-sciences-ltd-roiv-q1-2023-earnings-call-transcript
"And then actually, what we’re going to spend the bulk of time on today is we’ve been getting more questions about brepocitinib and we’ve actually got some new data there in Crohn’s disease. So we’re going to share that and talk through again a reminder of sort of how we’re thinking about that program as we approach the lupus data in the back half of the year and more beyond."
"so yes, please turn to Slide 13. So as Matt said, I want to take the opportunity to talk a little bit about one of, I think, what I consider one of the sleeping giants within our portfolio. To the extent that brepocitinib is going to get some notice for investors, I think it’s mostly through the lens of being a pivotal study catalyst for Roivant by the end of this year. And while that is true, we do have the lupus data later this year. I think the lupus story is just a small part of what we’re trying to build with brepocitinib. And so I want to go through that story of fresh here today, the punch line, from my perspective, is don’t sweat on brepocitinib. So put simply, brepocitinib is a unique, highly, highly active dual inhibitor of both TYK2 and JAK1 that has already shown spectacular efficacy in a broad range of auto immune diseases."
ATB Genuine posters.
Brepocitinib validation for TYK2/JAK1 inhibition:
https://investor.roivant.com/news-releases/news-release-details/roivant-reports-financial-results-first-quarter-ended-june-30
"Priovant: In August 2023, Priovant announced the sixth positive Phase 2 study of oral brepocitinib, out of six conducted, with statistically significant, positive results from the 12-week induction period of Pfizer’s Phase 2 study of brepocitinib in adult patients with moderate to severe Crohn’s disease. The primary and key secondary endpoints were met with safety and tolerability generally consistent with prior brepocitinib studies, further validating TYK2/JAK1 inhibition activity in highly inflammatory autoimmune diseases."
"Priovant plans to announce topline results from the potentially registrational trial evaluating brepocitinib for the treatment of patients with systemic lupus erythematosus (SLE) in the fourth quarter of calendar year 2023. Priovant also expects to announce topline results from the Phase 2 POC study in non-infectious uveitis (NIU) in the first quarter of calendar year 2024 and topline results from the Phase 3 trial in dermatomyositis (DM) in calendar year 2025."
Interesting timelines & targets, very relevant to us; looking forward to getting our offerings up against the competition proper.
Will another of the big pharma fish look to snap up one or indeed two fully patented, distinct TYK2/JAK1 inhibitors with the potential in so many dieseases & areas.... I've invested on the belief they will... and that's without considering our CHK1i, the SKIL platform and associated molecules & data. As SOG and others have posted previously, the ongoing tox tests are of paramount importance to Sareum. This is make or break and the point for which long-term investors have stuck by the company for so many years, the science works or it doesnt, we offer potential treatments & alternatives to the market or we don't. The rest, much like the abundance of (recent vastly increased) green boxes here is just noise.
ATVB all genuine posters.
Https://www.nature.com/articles/s41375-023-01979-w
"In summary, hyperinflammation was resolved in most COVID-19 patients with ruxolitinib. The oral treatment was feasible in critically ill patients, application was safe without high grade or lasting adverse treatment associated reactions. Detecting the critical stage of hyperinflammation with COVID-19 inflammation score provides a tool for accurate preselection of COVID-19 patients and by that optimizes clinical benefit of ruxolitinib therapy."
Https://www.sciencedirect.com/science/article/abs/pii/S0304383523002598
Highlights
•RRM2 is overexpressed in GBM and associates with poor prognosis.
•Triapine inhibition of RRM2 sensitizes GBM to ionizing radiation treatment.
•Simultaneous RRM2 and CHK1 inhibition induce synthetic lethality in GBM.
ATB
A decent video for rhe TLDR crew ;)
As LTH's are only too aware, Deucravacitinib flopped in UC.... a splash of JAK1i is (as SOG has stated many times) needed.... oh and yes, we trumped Tofa many moons ago. (Paper can still be found if one looks hard enough)
ATB
https://www.hmpgloballearningnetwork.com/site/gastro/videos/david-rubin-md-jak-inhibitors-small-mighty
Many here will agree, TYK2 is indeed an exciting target!
Head of Business Development:
https://www.salary.com/job/neuron23-inc/head-of-business-development/j202302151727413985811
"Neuron23 Inc. is a clinical-stage biotechnology company focused on developing precision medicines for genetically defined neurological and immunological diseases. Neuron23 leverages recent advances in human genetics, combined with knowledge- and artificial intelligence (AI)-enabled drug discovery and biomarker platforms, to advance therapeutics for devastating diseases.
We are looking for an experienced business development leader to join a dynamic executive team in an exciting start-up environment. Neuron23 is working on two of the industry’s most exciting genetically-defined targets, LRRK2 and TYK2 and the candidate will be expected to hit the ground running, with strategic input on both of these programs. Reporting to the CEO, the person will actively lead efforts to create attractive partnership opportunities and execute deals that create and capture value from the company’s therapies in development. In addition, the candidate will be experienced engaging in corporate development activities (fundraising, IR, public market interactions) in partnership with the CEO and management team. "
ATB
(6) Commonly assigned U.S. application Ser. No. 16/559,077, filed on Sep. 3, 2019 discloses some dimethyl amino azetidine amide compounds useful as JAK inhibitors. In particular, the compound (S)-(3-(dimethylamino)azetidin-1-yl)(2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)-5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-6-yl)methanone (compound 1):
(7) ##STR00002##
is specifically disclosed in the application as a potent non-systemic pan-JAK inhibitor suitable for treating, preventing and/or delaying inflammatory respiratory diseases, including asthma and lung transplant rejection.
(8) To effectively use this compound as a therapeutic agent, it would be desirable to have a crystalline solid-state form. For example, it would be highly desirable to have a physical form that is thermally stable at reasonably high temperature, thereby facilitating processing and storage of the material. Crystalline solids are generally preferred over amorphous forms, for enhancing purity and stability of the manufactured product. However, the formation of crystalline forms of organic compounds is highly unpredictable. No reliable methods exist for predicting which, if any, form of an organic compound will be crystalline. Moreover, no methods exist for predicting which, if any, crystalline form will have the physically properties desired for use as pharmaceutical agents. Accordingly, a need exists for crystalline forms of compound 1.
SUMMARY OF THE INVENTION
(9) Provided herein is a crystalline hydrate of the compound of formula 1:
(10) ##STR00003##
(11) Also provided herein are pharmaceutical compositions comprising the crystalline hydrate of the disclosure, and a pharmaceutically-acceptable carrier.
(12) Provided herein is a method of preparing the crystalline hydrate of the disclosure, as well as methods of treating, preventing, delaying, and/or ameliorating diseases amenable to treatment with a JAK inhibitor, in particular respiratory diseases and lung transplant rejection.
(13) Also provided herein are uses of the crystalline hydrate form in medical therapy and in the manufacture of a formulation or medicament for treating, preventing, delaying, and/or ameliorating diseases amenable to treatment with a JAK inhibitor, in particular respiratory diseases and lung transplant rejection.
Anyway, enough from me - must've had too much coffee this morning!
ATB
(5) JAK-signaling cytokines also play a major role in the activation of T cells, a sub-type of immune cells that is central to many immune processes. Pathological T cell activation is critical in the etiology of multiple respiratory diseases. Autoreactive T cells play a role in bronchiolitis obliterans organizing pneumonia (also termed COS). Similar to COS, the etiology of lung transplant rejections is linked to an aberrant T cell activation of the recipient's T cells by the transplanted donor lung. Lung transplant rejections may occur early as Primary Graft Dysfunction (PGD), organizing pneumonia (OP), acute rejection (AR) or lymphocytic bronchiolitis (LB) or they may occur years after lung transplantation as Chronic Lung Allograft Dysfunction (CLAD). CLAD was previously known as bronchiolitis obliterans (BO) but now is considered a syndrome that can have different pathological manifestations including BO, restrictive CLAD (rCLAD or RAS) and neutrophilic allograft dysfunction. Chronic lung allograft dysfunction (CLAD) is a major challenge in long-term management of lung transplant recipients as it causes a transplanted lung to progressively lose functionality (Gauthier et al., Curr. Transplant. Rep., 2016, 3(3), 185-191). CLAD is poorly responsive to treatment and therefore, there remains a need for effective compounds capable of preventing or treating this condition. Several JAK-dependent cytokines such as IFNγ and IL-5 are up-regulated in CLAD and lung transplant rejection (Berastegui et al, Clin. Transplant. 2017, 31, e12898). Moreover, high lung levels of CXCR3 chemokines such as CXCL9 and CXCL10 which are downstream of JAK-dependent IFN signaling, are linked to worse outcomes in lung transplant patients (Shino et al, PLOS One, 2017, 12 (7), e0180281). Systemic JAK inhibition has been shown to be effective in kidney transplant rejection (Vicenti et al., American Journal of Transplantation, 2012, 12, 2446-56). Therefore, JAK inhibitors have the potential to be effective in preventing or delaying lung transplant rejection and CLAD. Similar T cell activation events as described as the basis for lung transplant rejection also are considered the main driver of lung graft-versus-host disease (GVHD) which can occur post hematopoietic stem cell transplants. Similar to CLAD, lung GVHD is a chronic progressive condition with extremely poor outcomes and no treatments are currently approved. A retrospective, multicenter survey study of 95 patients with steroid-refractory acute or chronic GVHD who received the systemic JAK inhibitor ruxolitinib as salvage therapy demonstrated complete or partial response to ruxolitinib in the majority of patients including those with lung GVHD (Zeiser et al, Leukemia, 2015, 29, 10, 2062-68).
(4) Asthma is a chronic disease of the airways for which there are no preventions or cures. The disease is characterized by inflammation, fibrosis, hyperresponsiveness, and remodeling of the airways, all of which contribute to airflow limitation. An estimated 300 million people worldwide suffer from asthma and it is estimated that the number of people with asthma will grow by more than 100 million by 2025. Although most patients can achieve control of asthma symptoms with the use of inhaled corticosteroids that may be combined with a leukotriene modifier and/or a long acting beta agonist, there remains a subset of patients with severe asthma whose disease is not controlled by conventional therapies. Cytokines implicated in asthma inflammation which signal through the JAK-STAT pathway include IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-11, IL-13, IL-23, IL-31, IL-27, thymic stromal lymphopoietin (TSLP), interferon-γ (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Inflammation of the airways is characteristic of other respiratory diseases in addition to asthma. Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumonitis, interstitial lung diseases (including idiopathic pulmonary fibrosis), acute lung injury, acute respiratory distress syndrome, bronchitis, emphysema, and bronchiolitis obliterans are also respiratory tract diseases in which the pathophysiology is believed to be related to JAK-signaling cytokines.
cont...
yes, i have some time on my hands..... this one is for the science heads:
quite interesting to have a look at theravance therapeutics, it might help gain insight into what sareum are trying to achieve, read-across should of course be taken with a large pinch of salt, but then again research is research!
https://www.theravance.com/our-pipeline
market cap of approx $550m, they certainly like applying for patents... but we can potentially glean data from them.
for example...
https://www.onscope.com/ipowner/en/owner/profile/1849168-theravance-biopharma-r-d-ip-llc.html
18.07.2023 - crystalline hydrate of a jak inhibitor compound:
"field of the invention
(1) provided herein is a crystalline hydrate form of a jak inhibitor compound useful for treating respiratory and other diseases. also provided herein are pharmaceutical compositions comprising such crystalline form, methods of using the crystalline form to treat, for example, respiratory diseases, and processes useful for preparing such crystalline form.
state of the art
(2) cytokines are intercellular signaling molecules which include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor. cytokines are critical for normal cell growth and immunoregulation but also drive immune-mediated diseases and contribute to the growth of malignant cells. elevated levels of many cytokines have been implicated in the pathology of a large number of disease or conditions, particularly those diseases characterized by inflammation. many of the cytokines implicated in disease act through signaling pathways dependent upon the janus family of tyrosine kinases (jaks), which signal through the signal transducer and activator of transcription (stat) family of transcription factors.
(3) the jak family comprises four members, jak1, jak2, jak3, and tyrosine kinase 2 (tyk2). binding of cytokine to a jak-dependent cytokine receptor induces receptor dimerization which results in phosphorylation of tyrosine residues on the jak kinase, effecting jak activation. phosphorylated jaks, in turn, bind and phosphorylate various stat proteins which dimerize, internalize in the cell nucleus and directly modulate gene transcription, leading, among other effects, to the downstream effects associated with inflammatory disease. the jaks usually associate with cytokine receptors in pairs as ****dimers or heterodimers. specific cytokines are associated with specific jak pairings. each of the four members of the jak family is implicated in the signaling of at least one of the cytokines associated with inflammation.
cont....
Good morning SOG, I wholeheartedly agree and thank you again for your continued insight and thoughts!
In addition, you may find the below interesting, as ever your opinion would be appreciated - some decent science to muse over, albeit not yet peer reviewed:
18.07.2023 - Community analysis of large-scale molecular dynamics simulations elucidated dynamics-driven allostery in Tyrosine kinase 2:
https://www.authorea.com/doi/full/10.22541/au.168969561.12631657/v1
direct .pdf: https://d197for5662m48.cloudfront.net/documents/publicationstatus/143830/preprint_pdf/6848a0216a10da4849fd159d07416da6.pdf
ATVB
Establishment of comorbidity target pools and prediction of drugs candidate for multiple sclerosis and autoimmune thyroid diseases based on GWAS and transcriptome data:
https://www.msard-journal.com/article/S2211-0348(23)00404-2/fulltext
"Results
We identified a pool of shared targets containing genes and pathways, including 46 common genetic susceptibility pathways and 9 common differentially expressed pathways, including JAK-STAT signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, etc. In addition, a total of 29 hub genes, including TYK2, JAK1, STAT3, IL2RA, HLA-DRB1, and TLR3, were identified. Drugs approved for treating MS or AITD, such as methylprednisolone, cyclophosphamide, glatiramer, natalizumab, and methimazole, can target the shared genes and pathways, among which methylprednisolone and cyclophosphamide have been shown to be beneficial for the treatment of the two diseases, indicating that these drugs have the potential to become a priority in the treatment of comorbidities. Moreover, drugs targeting multiple common genes and pathways, including tacrolimus, deucravacitinib, and nivolumab, were identified as potential drugs for the treatment of MS, AITD, and their comorbidities."
Also, good to see UK investment:
UK's Upperton wraps up £15M manufacturing expansion project:
https://www.fiercepharma.com/manufacturing/uks-upperton-cdmo-completes-ps15m-manufacturing-expansion-project
ATB
Https://pubmed.ncbi.nlm.nih.gov/37457579/
"Aberrant activation of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is common in systemic lupus erythematosus (SLE), conferring immune-mediated properties in target tissues. Multiple cytokines activate different combinations of JAKs and STATs to alter the cell fate of target tissue and induce end-organ damage. Thus, the simultaneous blockade of several different cytokines by small molecules acting downstream intracellular signalling has gained traction. JAK inhibitors have been approved for the treatment of several rheumatic diseases, yet hitherto not for SLE. Nevertheless, JAK inhibitors including tofacitinib, baricitinib, and deucravacitinib have shown merit as treatments for SLE. Tofacitinib, a JAK1/3 inhibitor, reduced cholesterol levels, improved vascular function, and decreased the type I interferon signature in SLE patients. Baricitinib, a JAK1/2 inhibitor, demonstrated significant improvements in lupus rashes and arthritis in a phase 2 and a phase 3 randomised controlled trial, but the results were not replicated in another phase 3 trial. Deucravacitinib, a selective tyrosine kinase 2 (TYK2) inhibitor, yielded greater response rates than placebo in a phase 2 trial of SLE and will be investigated in larger phase 3 trials. TYK2 is activated in response to cytokines actively involved in lupus pathogenesis; this review highlights the potential of targeting TYK2 as a promising therapy for SLE."
Https://academic.oup.com/humrep/advance-article-abstract/doi/10.1093/humrep/dead145/7224521?redirectedFrom=fulltext
"LIMITATIONS, REASONS FOR CAUTION
This was a preclinical study performed with human ovarian samples, and clinical research is required for validation.
WIDER IMPLICATIONS OF THE FINDINGS
These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients."
ATB