The next focusIR Investor Webinar takes places on 14th May with guest speakers from Blue Whale Growth Fund, Taseko Mines, Kavango Resources and CQS Natural Resources fund. Please register here.
Fantastic news, the board are nothing if not thorough. I think we can assume much is going on (as it should be of course!) behind the scenes regards our portfolio and protection of our assets.
Simply put, this groundwork will only add value & security to what is already an exciting and potentially very lucrative position.
What value will possible suitors place on the increasing patent protection I wonder.
SDC1802 still looks like the biggie to me.
ATB
Https://link.springer.com/article/10.1007/s11060-023-04372-w
"Conclusion: We identified CHK1 and PDGFRβ inhibitors that effectively target MB cells fueling treatment-refractory metastases. With limited research on effective therapies for Group 3 MB metastatic recurrences, this work highlights promising therapeutic options to treat these aggressive tumors. Additional studies are warranted to investigate these inhibitors’ mechanisms and recommended in vivo administration."
ATB
Https://www.mdpi.com/1422-0067/24/13/10488
"CHK1 Kinase Inhibitors
It can be implied that the anti-cancer effects of CHK1 inhibitors (CHK1i) may not differ much from ATRi, as they are part of the same signaling pathway. However, various studies revealing CHK1 overexpression or ATR-independent CHK1 activation in cancer make CHK1 an independent target for cancer therapy. UCN-01, a first-generation multi-target serine-threonine protein kinase inhibitor that also targets CHK1, sensitized p53-deficient cancer cells to DNA damaging agents [208,209,210,211]. Although it was not considerably potent, several Phase I/II clinical trials utilizing UCN-01 in combination therapies further highlighted the therapeutic potential of targeting CHK1. Subsequential development of CHK1i, such as SRA737 (formerly CCT244747) and prexasertib (LY2606368), have shown great promise in preclinical and clinical models. SRA737, a novel, potent and orally bioavailable CHK1i, has been shown to have single-agent efficacy in MYC-driven cancers, and in combination with IR, gemcitabine, irinotecan, and PARPi [212,213]. Recent Phase I/II trial data support further development of SRA737 in combination therapies [214,215]. Finally, prexasertib, a potent CHK1i, has been shown to induce antitumor effects through the induction of replication stress, checkpoint abrogation, DSB formation, and ultimately replication catastrophe [216]. Additional studies have shown synergistic effects of prexasertib when combined with olaparib in TNBC, ovarian, and gastric cancers and additionally with cisplatin in platinum-refractory cancers [217,218,219,220]. There are currently 19 completed and ongoing Phase I/II trials that are evaluating prexasertib as a mono- or combination therapy in p53-deficient, DDR-deficient, or CCNE1-amplified cancers."
ATB
Https://www.ejcancer.com/article/S0959-8049(23)00302-7/fulltext
"ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority."
Be great to see CCT245737 back in the mix and in the lab!
ATB
Couple of better links to the same piece...:
https://pubmed.ncbi.nlm.nih.gov/37343085/
https://www.science.org/doi/10.1126/scitranslmed.add7872
For the TLDR folks:
"Cells overexpressing BLM also exhibited similarly enhanced sensitivity to another specific CHK1i, SRA737 (36) (fig. S6B). Together, these data suggest that high BLM abundance in PARPi-resistant cells might predispose them to CHK1i treatment."
"We contend that patients with high mRNA expression of replication stress along with replication fork-related biomarkers should be considered for CHK1i-based therapy.
In summary, we demonstrated the therapeutic potential of CHK1i in a subgroup of BRCA-mutant HGSC, both in the preclinical and clinical settings, and reported that tumors with high dependence on replication fork stabilization may help identify patients for CHK1i irrespective of PARPi resistance, warranting further prospective validation. Ultimately, our comprehensive molecular assessment of pretreatment tumors will help to guide the development of more personalized treatment regimens and improve patient stratification in HGSC with BRCA mutation."
ATB
Morning Mafuta, I believe the FDA, much like our MHRA have serious backlogs, mainly caused by Covid, but also not helped by staffing shortages & cutbacks / under performing staff:
https://endpts.com/cbers-peter-marks-shares-pandemic-lessons-as-fda-continues-going-through-the-backlog/
PS. Indeed Brighty, I was thinking the same.
ATVB
Mentioned here a while back. They are man's best friend, theres two & a few about and a quick search shows an awful lot develop cancer:
"Sadly, it is estimated that about 25 percent of all purebred dogs die of cancer while 45 percent of those who live past ten years old will likely succumb to cancer. Cancers in dogs are very similar to human cancers and this has allowed the use of modern chemotherapies to treat dogs."
Food for thought as ever:
https://onlinelibrary.wiley.com/doi/10.1111/jvp.13187
"Results: The expression of total Chk1 has been found in different lymphoma/leukemia canine cells. The level of activated form of Chk1 (p-Chk1) increased after treatment of the cells with etoposide and decreased after inhibiting Chk1 with Chk1 inhibitors. The combine treatment with etoposide and the Chk1 inhibitors shows promising results by inducing high cell death level compared to etoposide alone.
Conclusion: The principal DDR kinase Chk1 is a promising target for the generation of new targeted anticancer therapies for lymphoma and leukemia in dog."
There's estimated to be 11 million pet dogs in the UK and 65 Million in the US...
ATB
Https://datadryad.org/stash/dataset/doi:10.5061/dryad.18931zd2s
"Using high-throughput drug screens, we identified ATR/CHK1 pathway inhibitors as cytotoxic, and further validated monotherapy activity of the CHK1 inhibitor (CHK1i), prexasertib, in PARPi-resistant BRCA-mutant HGSC cells and animal models. As a proof-of-concept trial, we conducted a phase II study of prexasertib in BRCA-mutant HGSC patients. The treatment was well-tolerated but yielded an objective response rate of 6% (1/17; 1 PR) in patients with prior PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of BLM, and CCNE1 overexpression or copy number gain/amplification were seen in patients deriving durable benefit from CHK1i. Our findings suggest replication fork–related biomarkers should be further evaluated for CHK1i sensitivity in HGSC."
Great weekend all.
Thought this worth a share, some might find this an interesting, plain English read in comparison to some of the science heavy pieces.
https://www.curetoday.com/view/one-step-closer-to-an-mpn-cure
ATB
Https://www.hematologyadvisor.com/home/topics/lymphoma/lymphoma-ptcl-golidocitinib-durable-anti-tumor-response-treatment-risk/
I know, I know, more Chinese data & research, but might bode well for SDC1802...
ATB
I would say that is a pretty fair assessment. When one removes any psychological & emotional attachment us existing investors have with Sareum, (especially those who have been here over a decade!) it is a pretty succinct snapshot of where we are at.
Imagine being a prospective investor, unaware of Sareum & the science - that piece is pretty fair as a way of alerting one to the potential returns/pitfalls here IMO.
This is drug discovery, cutting edge science, however compelling the data & research (of which I swamp this board with), there are always competitors looking to trump us and nothing is certain until Phase 3 & beyond.
We really are at the crossroads, and probably approaching the end game for the earlier investors in Sareum - getting our offerings in the clinic is really what it all boils down to; how we fare now is ultimately out of our hands.
As others have said, if SDC1801 sails through tox studies, you can bet your bottom dollar(pound) that SDC1802 wont be far behind it.
I will add though, I am mightily confident and very comfortable personally with my investment here.
Anyway, enough waffling from me, blame it on the nervous energy this Happy Hammer has, trying to kill some time before the biggest European night in our history for almost 50 years....
IRONS
ATB & GLA
Firstly, good morning Sad, yes I picked up on the slip too and it is indeed quite a big error - although, I have been digging a little into the latest JAK2i but that's for another day :)
Thanks again for your continued posts and thoughts, they are most informative.
An additional video on TLL018 from a second Dr:
Should JAKs be ‘Tyk’ed off? - https://www.youtube.com/watch?v=kd-ln4g74iQ
Quality is a little off, but she makes some good points and you get the gist.
Very exciting indeed for the future of our SDC molecules.
Several other links for the data hungry....
1.
A decent concise video for the non reading crew among us:
Upadacitinib in SLE - 30mg doses efficacious -
https://www.youtube.com/watch?v=eqnXUrgpWdM
2. - Some fascinating details on deuterated molecules - in fact deuterated SRA737 was used by Unai Banerji et al at the ICR ( https://repository.icr.ac.uk/bitstream/handle/internal/3278/3675E2E6-7B45-479B-904A-B748DE19CA05.pdf?sequence=5 ) and as SOG has confirmed here in the past the our SDC1801/2 both contain Deuterium.
Deuterium in drug discovery: progress, opportunities and challenges:
"Deuterium incorporation was initially believed to merely increase the metabolic stability of a compound, but it has become evident that the effect of this modification can go well beyond simple pharmacokinetic (PK) improvements to have a major impact on drug efficacy and safety."
"Overall, the clinical relevance of a potential deuterium switch approach is underscored by the existence of at least 15 compounds under clinical investigation. However, the use of deuterium has recently expanded beyond the improvement of already marketed drugs to become an integral part of the drug discovery process, in which it is often used at early stages to overcome PK shortcomings. Deucravacitinib, an allosteric tyrosine kinase 2 (TYK2) inhibitor approved for psoriasis in September 2022, is the first example of a novel deuterated FDA-approved drug. Here, deuterium incorporation avoids the formation of a non-selective metabolite and preserves the exquisite specificity of the parent drug for TYK2 over the other enzymes belonging to the Janus kinase (JAK) family."
ATB
TLL-018 (a JAK1/TYK2 agent) vs. Tofacitinib in RA
https://m.youtube.com/watch?v=NeKxnz8qFVc
A quite pertinent video from yesterday regarding the aforementioned TYK2/JAK1 inhibitor offering from our Chinese neighbours. TYK/JAKINIBS are hot hot hot.
No reading required for once... ;)
ATB
APOBEC3B coordinates R-loop to promote replication stress and sensitize cancer cells to ATR/Chk1 inhibitors:
https://www.nature.com/articles/s41419-023-05867-0
"Mounting evidence demonstrates that A3B is clinically significant in cancer. A3B overexpression was shown to confer resistance to drugs such as doxorubicin and tamoxifen [44, 45]. But on the other hand, A3B may enhance the sensitivity to immunotherapies. Studies have shown that patients with high levels of A3B are more likely to respond to immune checkpoint blockade [9, 46]. These apparently paradoxical observations highlight the fact that the function of A3B is fine-tuned in different contexts, and A3B alone is not sufficient to predict the overall benefits to patients. Perturbation of the ATR-Chk1 pathway induces deleterious consequences, thus can be exploited to treat cancer in which RS levels are always augmented because of oncogene hyperactivation [47, 48]. Accordingly, ATRi or Chk1i exhibit promising antitumor functions in pre-clinical models and are currently under evaluation in clinical trials [37, 49,50,51]. Our data revealed that both RS and sensitivity to ATRi elicited by A3B was dependent on R-loop formation because these effects could be largely alleviated by overexpression of RNASEH1. In this regard, A3B together with R-loop status could better define the level of RS and ATRi/ChK1i sensitivity."
ATB
Novel Therapeutic Strategies in the Treatment of Systemic Sclerosis:
https://www.preprints.org/manuscript/202306.0143/v1/
Direct .pdf https://www.preprints.org/manuscript/202306.0143/v1/download
"In spite of enormous progress in rheumatology and clinical immunology, the background of diseases is largely unknown and no specific therapy exists. The therapeutic approach to the disease is aimed to treat and preserve the function of internal organs, and this approach is commonly referred to as an organ-based treatment. However, in modern times data from the other branches of medicine may help to treat disease-related complications, making it possible to find a group of drugs to be utilized in the treatment of the disease. In this review, we present possible therapeutic options aiming to stop the progression of fibrotic processes, restore aberrant immune response, stop improper signalling from proinflammatory cytokines, and halt the production of disease-related autoantibodies."
Keywords;
Systemic sclerosis; treatment; Janus kinase inhibitors; fibrosis; anti-cytokine treatment
"Recent analysis of case reports and small uncontrolled trials showed the clinical benefit of JAK inhibitors in interstitial lung diseases associated with SSc. Keeping in mind many limitations from these studies, the results may indicate that targeting several cytokines with one drug may be a promising way to halt the progression of fibrosis and inflammation[100]."
SDC1801/2 will hopefully fit the bill.
ATB
The regulatory landscape of macrophage interferon signaling in inflammation:
https://www.jacionline.org/article/S0091-6749(23)00708-X/fulltext
"Abstract
The pervasive role of the innate immune system is established by interferons. Emerging research shows an underappreciated ability of macrophages to regulate and propagate interferon responses in infectious and autoinflammatory disease states. In this review, we will discuss recent findings demonstrating the immunomodulating effects of macrophage interferon signaling. Apart from provoking cellular antimicrobial defenses, interferons augment the inflammatory activity of macrophages. These immunological adaptations place the macrophage in the center of the interferon system and at the forefront of immunity. Consequently, macrophages are implicated in the pathogenesis of interferon-driven autoinflammatory disorders, like systemic lupus erythematosus. In these disease states, the recognition of immunogenic ligands triggers macrophages to adopt an inflammatory phenotype through interferon signaling. This will amplify immune responses, eventually leading to autoinflammation. A better understanding of the macrophage’s role in interferon signaling will support the future elucidation of novel targets amendable for clinical treatment."
Decent .pdf available to download on the page for those who are interested in digging a little deeper.
ATB
1.6.2023
https://www.nejm.org/doi/full/10.1056/NEJMc2303519
"Wang et al. hypothesize that treatment effects differed according to variant. However, we found the treatment effects were consistent across variants. The finding that TYK2 is not required for the antiviral activity of interferon lambda2 suggests that selective TYK2 inhibitors may preserve the antiviral function of the drug. However, the potential of such inhibitors to help counteract the cytokine storm phase of Covid-19 and provide clinical benefit in hospitalized patients should be ascertained first. The population that may receive baricitinib (i.e., inpatients) differs from our trial population. Moreover, the most common side effects that were observed in a recent clinical trial of a selective TYK2 inhibitor3 were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache, and diarrhea. Some of these effects could be of concern when treatment for Covid-19 is contemplated, although it is possible that cotreatment with interferon lambda could augment the antiviral response and decrease the incidence of these infections."
ATB
Https://www.marketwatch.com/press-release/polymyositis-pipeline-insight-companies-janssen-pharmaceutical-paean-biotechnology-kezar-life-sciences-roche-restem-viela-bio-bristol-myers-squibb-immunoforge-and-others-2023-05-26
"Brepocitinib is being developed by Priovant for the treatment of severe autoimmune illnesses that have few licenced treatments and in which simultaneous inhibition of TYK2 and JAK1 may be more effective than either inhibition alone."
ATB