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.
Https://onlinelibrary.wiley.com/doi/full/10.1111/jocd.15903
"Results
Based on the surface under the cumulative ranking curve estimates obtained from multiple efficacy endpoints, regimens with the highest likelihood of achieving percent reduction in SALT scores, as well as a minimum 90%, 75% or 50% reduction in SALT scores are (in alphabetical order) baricitinib 4 mg once daily (QD), brepocitinib 60/30 mg QD, deuruxolitinib (CTP-543) 12 mg twice daily (BID), ritlecitinib 200/50 mg QD, ruxolitinib 20 mg BID and tofacitinib 5 mg BID. In contrast, dupilumab subcutaneous injections administered weekly and apremilast 30 mg BID were less likely to be effective. Discontinuation due to any adverse event was the least likely with oral JAK inhibitors, and more likely with dupilumab and apremilast.
Conclusions
Our results support the conduct of high-quality comparative trials to determine whether JAK inhibitors are more effective and safer than PDE4 inhibitors."
Spot on Aber.
I must admit I didn't expect the price to drop to this level during a no-news period, but it has provided a welcome top up opportunity for both my kids' Junior ISA's. Every cloud and all that.
This is in no way share trading advice to others!
ATVB
Https://www.healio.com/news/rheumatology/20230713/brepocitinib-superior-to-placebo-in-reducing-psoriatic-arthritis-signs-symptoms
"“Brepocitinib is a JAKi with selectivity for [tyrosine kinase 2 (TYK2)] and JAK1 over JAK2 and JAK3,” they added. “TYK2 inhibition by brepocitinib provides greater blockade of IL-12 and IL-23 signaling compared with JAK1 inhibition alone; this reduces production of IL-17, one of the major effector cytokines in the pathogenesis of psoriatic disease.”"
All eyes on how well our TYK2 / JAK1 inhibitor gets on in comparison....
PS. Great post Laz.
ATB
https://www.sciencedirect.com/science/article/abs/pii/s0006295223002666
"abstract
acute promyelocytic leukemia (apl) is a hematological disease characterized by the expression of the oncogenic fusion protein pml-rarα. the current treatment approach for apl involves differentiation therapy using all-trans retinoic acid (atra) and ****nic trioxide (ato). however, the development of resistance to therapy, occurrence of differentiation syndrome, and relapses necessitate the exploration of new treatment options that induce differentiation of leukemic blasts with low toxicity. in this study, we investigated the cellular and molecular effects of mk-8776, a specific inhibitor of chk1, in atra-resistant apl cells. treatment of apl cells with mk-8776 resulted in a decrease in pml-rarα levels, increased expression of cd11b, and increased granulocytic activity consistent with differentiation. interestingly, we showed that the mk-8776-induced differentiating effect resulted synergic with ato. we found that the reduction of pml-rarα by mk-8776 was dependent on both proteasome and caspases. specifically, both caspase-1 and caspase-3 were activated by chk1 inhibition, with caspase-3 acting upstream of caspase-1. activation of caspase-3 was necessary to activate caspase-1 and promote pml-rarα degradation. transcriptomic analysis revealed significant modulation of pathways and upstream regulators involved in the inflammatory response and cell cycle control upon mk-8776 treatment. overall, the ability of mk-8776 to induce pml-rarα degradation and stimulate differentiation of immature apl cancer cells into more mature forms recapitulates the concept of differentiation therapy. considering the in vivo tolerability of mk-8776, it will be relevant to evaluate its potential clinical benefit in apl patients resistant to standard atra/ato therapy, as well as in patients with other forms of acute leukemias."
atb
Https://www.pharmexec.com/view/biotech-survival-story-companies-bear-down-lean-years
Well worth a few minutes of ones time with a coffee or beer in hand. IMO
Have a great weekend all.
Ha ha, more likely a wooden spoon award for over a decade of 'Headstrong Stubbornness & Tunnel Vision'.
Seriously though, I feel our time is almost here Krone, I really do.
ATVB
CHK1 inhibition in combo...., the National Cancer Institute no less:
New analysis reveals potential effective drug combinations for treating lung cancer:
https://ccr.cancer.gov/news/article/new-analysis-reveals-potential-effective-drug-combinations-for-treating-lung-cancer
"The results showed that, although synergy between drugs is rare overall, there are some combinations that could lead to more effective treatment of lung cancer. For example, a combination of CHK1 inhibitors and WEE1 inhibitors was particularly effective across many cell lines tested in this study. WEE1 inhibition can suppress tumor cell proliferation and sensitize cells to the effects of DNA-damaging agents, while CHK1 inhibitors work by preventing damaged cells from continuing through their cell cycle as they divide and replicate. This discovery suggests that many lung cancer patients could potentially benefit from this dual therapy.
Other drugs that were found to be particularly synergistic with a second drug include Poly-ADP-Ribose-Polymerases (PARPs), which interfere with the repair of double-stranded DNA breaks. These drugs were found to be synergistic with decitabine and zebularine, which are known to induce demethylation of DNA. MEK inhibitors and drugs targeting the PI3K pathway also appear to be good candidates to combine with other drugs.
The analysis by Nair and his colleagues also revealed important insights into what makes a drug synergistic in the context of lung cancer. In general, drugs that target multiple pathways tend to be more likely to be synergistic with other drugs. Additionally, two drugs that target a shared pathway or that target similar protein-protein interactions tend to be more synergistic together than drugs that do not.
Notably, the NCI researchers partnered with researchers led by Craig Thomas, Ph.D., at the National Center for Advancing Translational Sciences (NCATS) to help validate the top most promising combinations in an additional screen, and additional work was done to cross-reference this new dataset with genomic and transcriptomic data from humans using the Cancer Genome Atlas (TCGA). “As a result, this dataset is a great resource for other researchers to explore,” said Nair, noting that it lays the groundwork for researchers to begin testing these newly identified drug combinations in animal models. “It’s a huge data source — possibly the largest of its kind — and that, together with the insights gained from its analysis, are the key contributions of this work.”
ATB
Https://www.biopharmadive.com/news/johnson-johnson-protagonist-psoriasis-drug-results/684921/
"The overall numbers approach or exceed what was observed with Tremfya and are “setting new efficacy/safety bars” for oral therapies in psoriasis, wrote Jefferies analyst Roger Song in a note to clients.
Though it’s difficult to compare drugs across trials, the results also look favorable to mid-stage data that Takeda presented earlier this year, added another Jefferies analyst, Stephen Barker. Yet, shares of Protagonist fell more than 30% when summary results were first disclosed on Monday, as the “market may have had higher expectations,” he wrote.
The findings still give companies like Ventyx and Alumis, which are developing newer TYK2 drugs, “a shot at superior oral efficacy,” wrote Stifel analyst Alex Thompson.
Ventyx shares climbed more than 20% between Monday and early Wednesday."
Eyes on the prize LTH's.
ATB
Https://www.bloomberg.com/press-releases/2023-07-05/mhra-grants-marketing-authorisation-for-opzelura-ruxolitinib-cream-for-the-treatment-of-non-segmental-vitiligo-with-facial
Opzelura^® is the first approved treatment in the United Kingdom (UK) to
address repigmentation in non-segmental vitiligo
Phase 3 data supporting the approval show treatment with ruxolitinib cream resulted in improved facial and total body repigmentation, sustained and continued improvements with longer duration of treatment
Vitiligo affects around 1 in 100 people in the UK
ATB
Indeed Krone, Ventyx investors are certainly confident too:
www.evaluate.com/node/18989/amp
"JNJ-2113 appears better than established oral psoriasis drugs, based on a cross-trial comparison using 16-week data from the phase 2 Frontier-1 trial, presented today. But it has fallen short of the “biologic-like” efficacy that Johnson & Johnson wanted to see; J&J has previously said JNJ-2113 would have to match the efficacy of its injectable anti-IL-23 psoriasis product Tremfya to justify further development. The asset’s originator, Protagonist Therapeutics, has borne the brunt of the disappointment, with its stock slumping 28% on concern that J&J might cool on the project. The small biotech will receive $50m milestone on the start of phase 3 trials, and news on that front is now keenly awaited to calm jitters. Though disappointing for Protagonist and J&J, the readout has been a clear positive for Ventyx Biosciences. The group is up 21% as investors believe the way is now clear for its Tyk2 inhibitor VTX958 – one of biotech’s most valuable unpartnered assets – to distinguish itself as a promising oral when its phase 2 Serenity PsO trial reads out this year."
ATB
Https://www.frontiersin.org/articles/10.3389/fmed.2023.1217147/full
"Unfortunately, the SLE community has witnessed a multitude of failures of phase 2 and 3 clinical trials (61). However, during the last two decades we have also witnessed drug development that has resulted in licenced drugs (12). Recent advancements concerning JAK inhibition have yielded promising results for the treatment of autoimmune diseases. By targeting pro-inflammatory state-mediated signalling, these small molecules offer several advantages over biologics, such as oral administration, potentially lower costs, and a broad spectrum of mode of action that includes targeting multiple cytokines simultaneously. Importantly, JAK inhibitors including tofacitinib, baricitinib, and deucravacitinib have shown potential for treating SLE. Among them, the inhibition of TYK2 emerges as a promising therapeutic strategy due to its interference with key cytokines underlying lupus pathogenesis. We are cautiously optimistic about the results of the phase 3 trials of deucravacitinib for this challenging disease."
Https://www.hcplive.com/view/review-upadacitinib-crohns-disease-jak1-inhibitor
Brucey bonus:
Effective treatment of refractory alopecia areata in pediatric patients with oral abrocitinib:
https://onlinelibrary.wiley.com/doi/10.1111/jocd.15896
ATB
Https://www.redjournal.org/article/S0360-3016(23)00615-6/fulltext
"Purpose
There is an urgent need for biomarkers and new actionable targets to improve radiosensitivity of triple negative breast cancer (TNBC) tumors. In this paper, we characterized the radiosensitizing effects and underlying mechanisms of combined Aurora kinase A (AURKA) and CHK1 inhibition in TNBC.
Methods and materials
Different TNBC cell lines were treated with AURKA inhibitor (AURKAi, MLN8237) and CHK1i (CHK1i, MK8776). Cell responses to IR were then evaluated. Cell apoptosis, DNA damage, cell cycle distribution, MAPK/ERK and PI3K pathways were evaluated in vitro. Transcriptomic analysis was performed to facilitate the identification of potential biomarkers. Xenograft and immunohistochemistry were carried out to investigate the radiosensitizing effects of dual inhibition in vivo. Finally, the prognostic effect of CHEK1/AURKA in TNBC samples in TCGA database and our center were analyzed
Results
AURKAi (MLN8237) induced overexpression of phospho-CHK1 in TNBC cells. Addition of MK8776 (CHK1i) to MLN8237 greatly reduced cell viability and increased radiosensitivity compared with either control or MLN8237 alone in vitro. Mechanistically, dual inhibition resulted in inducing excessive DNA damage by prompting G2/M transition as cell with defective spindles, leading to mitotic catastrophe and induction of apoptosis after IR. We also observed that dual inhibition suppressed the phosphorylation of ERK, while activation of ERK with its agonist or overexpression of active ERK1/2 allele could attenuate the apoptosis induced by dual inhibition with IR. Additionally, dual inhibition of AURKA and CHK1 synergistically enhanced radiosensitivity in MDA-MB-231 xenografts. Moreover, we detected that both CHEK1 and AURKA were overexpressed in TNBC patients and negatively correlated with patients’ survival
Conclusions
Our findings suggested that AURKAi in combination with CHK1i enhanced TNBC radiosensitivity in preclinical models, potentially providing a novel strategy of precision treatment for patients with TNBC."
ATB
Janus kinase inhibitors in systemic lupus erythematosus: implications for tyrosine kinase 2 inhibition:
https://www.frontiersin.org/articles/10.3389/fmed.2023.1217147/full
https://www.nature.com/articles/s41467-023-39528-9#sec8
"one of the most striking outcomes of our analyses is that synergistic combinations are mostly sp**** and thus highly context specific. this is in line with the findings recently reported studying a large drug combination screen of breast, colorectal, and pancreatic cancer cell lines84. interestingly, some of the top synergistic combinations identified in the present work were also present in other cancer types studied in the jaaks et al. study84. of note, synergy between chk1/2 inhibition and wee1 inhibition is common across models from diverse tumor types. more generally, we find that combining drugs that are not active as a single agent almost never yields synergy. in addition, combining two drugs tends to render single agent resistant cell lines responsive rather than further sensitize already sensitive cell lines. furthermore, sensitive cell lines rarely become super-sensitive, as combination effects mostly fall within the minimum viability levels observed for their individual components across all cell lines. while this could potentially correspond to limited efficacy of combination of agents that are not efficacious on their own, exceptionally sensitizing combinations can be found. in addition, synergism might more broadly provide benefit by allowing context specific activity of lower drug doses than used with single agents. the mutational status of major cancer genes is not highly predictive of synergy, as observed in other studies. finally, synergy is more likely to emerge from targeting a single pathway or two interacting pathways, than by targeting two completely distinct pathways or functional modules of the cell. this finding is aligned with previous reports based on studying genetic perturbations in lower organisms74. one potential model explaining these findings is that when two combined drugs target sufficiently independent cellular functions then the highly evolved and robust ****eostatic control of the cellular system prevails.
there is still considerable debate over what is synergy. several competing models, that nevertheless often yield congruent conclusions26 are used to qualify and quantify synergy. here, a synergy scoring based on statistical independence akin to the broadly used bliss model was used. we and others have previously demonstrated that this model is indeed valid to study viability outcome upon combinatorial treatment35,85. nevertheless, it is often pointed out that this type of modeling can in some instances assign synergy to cases of self-additivity. it is important to note that this counter intuitive outcome is limited to a small number of drugs. examination of the relationship between self-synergy paradox and dose response shows that the drugs concerned have very steep dose response curves. "
As expected to be fair, but noteworthy all the same.
"Just a few weeks after its approval in the UK, Bristol-Myers Squibb’s new oral psoriasis therapy Sotyktu has been recommended for routine NHS in England and Wales."
"Sotyktu (deucravacitinib) can be used only in patients whose symptoms have not responded adequately to other systemic treatments, including ciclosporin, methotrexate, and phototherapy, or are unable to tolerate those therapies.
According to the guidance, doctors should also “consider stopping” treatment with Sotyktu after 16 to 24 weeks of treatment if there have not been sufficient improvements in PASI scores, and cheaper options should be considered if appropriate.
The list price of deucravacitinib is £690 per 28‑tablet pack before VAT, but BMS has agreed to supply the drug to the NHS at a confidential discount.
Laura Stevenson, deputy chief executive at patient advocacy group the Psoriasis Association, welcomed the decision, pointing out that psoriasis affects over a million people across the UK “and, for some, it can have a significant life impact.”
“It is therefore hugely important for the community to have access to a variety of treatments, including new therapies such as deucravacitinib,” she said.
The NICE decision is a positive step in BMS’ rollout of the drug around the world, as it chases down a peak sales target for the drug of around $4 billion a year. The Scottish Medicines Consortium (SMC) has not yet issued a decision on the drug, but is in the process of reviewing it."
https://pharmaphorum.com/news/bms-sotyktu-cleared-nhs-use-psoriasis
Maybe, just maybe, Thoth2 was bang on the money regarding Tyk2 inhibition in Alzheimer's & much of the humankind's autoimmune & inflammation issues.
Cracking bit of science in video form, easy to follow and understand, worth the ten minutes of your time (imo).
https://www.youtube.com/watch?v=RPQbhr0Xv1s
ATB