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Ouch!!!!.... I reckon Novartis would have been better off waiting for SFX-01's interim results for ARDS/ Covid-19...Gla ;-)

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The $1.35 billion deal recently signed by Novartis for a ARDS/Covid treatment still in clinical trial, has now received FDA fast track designation after the release of early interim results.....and so a striking example of SFX-01's potential value and prospects for ARDS/Covid, if positive data is observed. Gla ;-)

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Novartis Inks $1.35 Billion Deal with Mesoblast for Remestemcel-L for COVID-19 ARDS

Published: Nov 20, 2020

Novartis inked an exclusive worldwide license and collaboration deal with Australia-based Mesoblast to develop, commercialize and manufacture remestemcel-L for acute respiratory distress syndrome (ARDS), including when it is linked to COVID-19. The company plans to launch a Phase III trial in non-COVID-19-related ARDS shortly after closing the deal. The drug is currently being evaluated in a Phase III trial in COVID-19-related ARDS.

https://www.biospace.com/article/novartis-inks-deal-with-mesoblast-for-remestemcel-l-for-covid-19-ards/

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21/12/20

Mesoblast’s stem cell therapy fails to meet primary endpoint in COVID-19 study
Remestemcel-L was being studied in patients with COVID-19-related acute respiratory distress

Australian biotech company Mesoblast announced on Friday that its stem cell therapy remestemcel-L failed to meet the primary endpoint in a phase 3 COVID-19 trial.

Remestemcel-L was being studied in ventilator-dependent COVID-19 patients with moderate-to-severe acute respiratory distress (ARDS).

https://www.pmlive.com/pharma_news/mesoblasts_stem_cell_therapy_fails_to_meet_primary_endpoint_in_covid-19_study_1360353

Looks like someone close to the action has just picked up 900k shares on the cheap......all bodes well!!! Gl ;-)

3 x 300k buys just in...Gla :-)

Another recent deal on SHP2 that Evgen has under evaluation with Queen Mary University of London, has shown that SFX-01 inhibits activity of the non-receptor phosphotyrosine phosphatase, SHP2 (coded by the ptpn11 gene). SHP2 is thought to be a significant factor in some cancers and we have recently agreed to support work in well-renowned university to investigate whether SFX-01 has potential in a specific blood cancer disease.....endless UPside potential it seems...Gla ;-)

AbbVie pens cancer pact with U.S.-China biotech Jacobio

Jun 1, 2020

AbbVie has signed a new pact to focus on SHP2 inhibitors, which target a key node in cancer and immune cells, from early-stage biotech Jacobio Pharmaceuticals.

Under the deal, financials of which are not being shared, AbbVie nabs an exclusive license to the China and U.S. company’s SHP2 portfolio.

Jacobio will work on early global clinical trials of the two leading candidates out of this portfolio, namely JAB-3068 and JAB-3312, but now AbbVie will start covering R&D expenses.

https://www.fiercebiotech.com/biotech/abbvie-pens-cancer-pact-u-s-china-biotech-jacobio-pharma

Looking good and strong and still cheap as chips given the Transformational upside potential opportunity ahead. Gla :-)

That would be very nice Nolupus and i'd be very excited if Oncology and/or ARDS had been mentioned, sooner or later a Major player will come knocking....Gl ;-)

"reflecting evidence targeting SHP2 counters adaptive resistance to the red-hot approach to treating cancer."

10/12/20

Blood cancer target

Professor Philip Eaton at Queen Mary University of London has shown that SFX-01 inhibits activity of the non-receptor phosphotyrosine phosphatase, SHP2 (coded by the ptpn11 gene). SHP2 is thought to be a significant factor in some cancers and we have recently agreed to support work in well-renowned university to investigate whether SFX-01 has potential in a specific blood cancer disease.

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Genentech pays Relay $75M for cancer drug, plans KRAS combo

Dec 14, 2020

Genentech has struck a deal to license Relay Therapeutics' SHP2 inhibitor for $75 million upfront. The Roche subsidiary plans to combine the drug with its KRAS G12C inhibitor, reflecting evidence targeting SHP2 counters adaptive resistance to the red-hot approach to treating cancer.

Excitement about finally being able to design drugs that bind to frequently mutated oncogene KRAS has been tempered by early clinical data showing the limitations of the use of KRAS G12C inhibitors as single agents. The reactivation of the inhibited pathway, known as adaptive resistance, is one source of concern for KRAS drugs and other targeted therapies. Researchers at New York University School of Medicine found SHP2 inhibition may help by boosting G12C-I accessibility to mutant KRAS.

Relay has done its own assessments on the combination, reporting in its IPO paperwork earlier this year that it has shown the benefits of pairing a SHP2 inhibitor with a KRAS G12C agent in preclinical studies. The SHP2 inhibitor, RLY-1971, began phase 1 development in solid tumor patients earlier this year.

https://www.fiercebiotech.com/biotech/genentech-pays-relay-75m-for-cancer-drug-plans-kras-combo

Could Tier 4 last until we've all had jabs? Matt Han**** warns mutant Covid strain is 'out of control' and people in Tier 4 areas should behave like they are infected as he suggests tough new curbs could be in place until vaccine

Boris Johnson yesterday cancelled Christmas for 16 million people in England
PM moved London and south east of England into new Tier 4 to slow virus spread
New curbs sparked Tory revolt as furious MPs called for Cabinet resignations
Matt Han**** today warned that a new variant of coronavirus is 'out of control'
He suggested Tier 4 restrictions could be in place until the vaccine is rolled out

https://www.dailymail.co.uk/news/article-9072291/Tory-MPs-demand-clear-exit-strategy-nightmarish-cycle-lockdowns.html

These include chronic obstructive pulmonary disease (COPD), asthma, allergy, rhinitis, aging, diabetes mellitus, Helicobacter pylori infection, and subarachnoid hemorrhage (Table 1). The clinical trials provide extensive pharmacokinetics, pharmacodynamics, safety, and efficacy information [77] that can be extrapolated to COVID-19.

Notably, most of these trials have recommended cruciferous-free diets during the study period to minimize baseline noise and accurately detect the plasma and urinary levels of sulforaphane and its metabolites [86].

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(20)30165-6

However, these inhibitors alter the balance ACE/ACE2 and increase ACE2 levels, thus potentially increasing the number of docking sites for viral entry [42].

NRF2 deficiency is known to upregulate ACE2, whereas its activator oltipraz reduces ACE2 levels [43], suggesting that NRF2 activation might reduce the availability of ACE2 for SARS-CoV-2 entry into the cell (Figure 1).

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Sulforaphane

The isothiocyanate sulforaphane (SFN), originally isolated from broccoli, a cruciferous vegetable, as an inducer of the classical NRF2 target, NAD(P)H:quinone oxidoreductase 1 (NQO1) [76], is the most potent naturally occurring NRF2 activator, with well-documented antioxidant and anti-inflammatory effects [77].

The high bioavailability of SFN and its stabilized a-cyclodextrin-encapsulated version sulforadex (SFX-01) makes it an excellent candidate for alleviating excessive anti-inflammatory responses and protecting the lungs.

SFN has been found to be protective in animal models of respiratory disease, including an ARDS model in rabbits [78] and a hyperoxia-induced pulmonary injury model in mice [79].

It also limits RSV replication and virus-induced inflammation in the lungs of wild-type, but not NRF2-null, mice [80].

In HIV-1 transgenic rats, SFN increased GSH levels and the expression of NQO1, and restored the tight junctions between the alveolar epithelial cells [81].

In an in vitro model of influenza A infection, SFN reduced both viral cell entry and replication [82].

In addition, SFN suppresses HCV replication [83] and reduces HSV-1 virion production [29].

Interestingly, SFN inhibits nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein (NLRP) 1 and 3 inflammasomes (crucial innate immune components that shape host immune homeostasis) as well as pyroptosis, partly in an NRF2-independent manner [84].

Moreover, an interesting study conducted in smokers (a patient cohort with higher risk of lung infections, damage etc.) showed that SFN increased the expression of NQO1 in cells of nasal lavage fluid and, upon infection with live attenuated influenza virus, lowered the levels of IL-6 and viral load [85].

Sources of sulforaphane, including standardized broccoli extracts, dietary supplements, and encapsulated stabilized sulforaphane (Prostaphane and SFX-01) have been in numerous clinical trials for indications that range from lung disease to inflammatory diseases which are closely related to COVID-19 pathophysiology.

Can Activation of NRF2 Be a Strategy against COVID-19?

Antonio Cuadrado

Albena T. Dinkova-Kostova

Highlights

The host inflammatory response is a crucial determinant of disease outcome and correlates with disease severity in SARS-CoV-2-induced infection, for which there is no treatment to date.

Activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) promotes resolution of inflammation and, in parallel, restores cellular redox and protein homeostasis, and facilitates tissue repair.

NRF2 can be activated by pharmacological inducers that target Kelch-like ECH-associated protein 1 (KEAP1), the principal negative regulator of NRF2.

The available information on pharmacokinetics, pharmacodynamics, safety, and efficacy for the NRF2 activators sulforaphane and bardoxolone methyl (currently in advanced clinical trials for other disease indications) in humans makes them excellent candidates for testing in randomized clinical trials in COVID-19.

Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus.

The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials.

The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.

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SARS-CoV-2 Biology and Potential Crosstalk with NRF2

The SARS-CoV-2 genome encodes non-structural proteins (nsp) that are required for replication, structural proteins including spike (S), envelope (E), membrane (M), and nucleocapsid (N), and accessory proteins ORF3, 6, 7a, 7b, 8, and 9b that interact with the host cells [38].

The receptor-binding domain (RBD) located in the S protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) of host cells to allow viral entry (Figure 1) [39].

The use of ACE inhibitors/angiotensin-receptor blockers, which are widely prescribed to patients with cardiovascular pathologies [40], is currently being considered for COVID-19 (clinical trial numbersi NCT04311177 and NCT04312009 for the use of losartan) because angiotensin II, the target of ACE inhibitors, has vasoconstrictive, proinflammatory, pro-oxidative, and prothrombotic effects [41].

The ACE2 receptor appears central to the spread of Covid-19, and the research by one of SFX-01's lead investigators highlights the therapeutic potential of Nrf2 activators and influence over ACE2, and no doubt one of the compelling reasons why SFX-01 was selected for Covid-19 patient trials.....Gla Holders....Positive data will be transformational for all concerned. :-)

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What do we know about this new SARS-CoV-2 variant?

It’s been snappily named VUI-202012/01 (the first “Variant Under Investigation” in December 2020) and is defined by a set of 17 changes or mutations. One of the most significant is an N501Y mutation in the spike protein that the virus uses to bind to the human ACE2 receptor. Changes in this part of spike protein may, in theory, result in the virus becoming more infectious and spreading more easily between people.

https://www.bmj.com/content/371/bmj.m4857

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In the search for treatments for COVID-19, many researchers are focusing their attention on a specific protein that allows the virus to infect human cells. Called the angiotensin-converting enzyme 2, or ACE2 “receptor,” the protein provides the entry point for the coronavirus to hook into and infect a wide range of human cells. Might this be central in how to treat this disease?

https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928

Tier 4, a new variant rampant in London and the South East with a rapid intense rise in hospital admissions...the recruitment and assessment of the first 100 patients administered SFX-01 must be very close imho....the urgency of finding treatments to treat and alleviate the severe respiratory effects of Covid-19 has just gone up a notch...Gla holders...let's hope SFX-01 will have a part to play. ;-)

Buys or sells, strange trading activity as usual, but with the sp back into double figures, hopefully the very smart money accumulating....Roll on next week ( Christmas is coming ) and more of the same please...we could be in for a very Prosperous New Year with any luck. :-)

SNG's market cap back to £295m and rising on Covid alone......EVG's market cap is £13m on multiple disease targets.......any positive data from the first 100 patients administered SFX-01 for Ards/pneumonia in the Covid patient trial should see the gap in value close substantially with any luck, as well as other news that could drop at anytime on the rest of the pipeline that could also add significant value ....Gla ;-)

EARLY REPORTING FROM SFX-01's COVID-19 PATIENT TRIALS, just as soon as the first 100 patients are recruited and assessed.....it only took 17 days for SFX-01's lead investigator to recuit the first 100 patients to his Stop Covid trial, and so news on SFX-01's trial could be very close. Gla ;-)

10/12/20

9 patients administered so far with full results expected Q4 2021, although unblinded data will be reviewed after 100 patients!!! Gla ;-)

Up to the 7th of December nine patients had been recruited and depending on availability of COVID-19 patients and other patients with ARDS, data could be available in the final quarter of 2021. In addition, a Data Safety and Monitoring Board will review unblinded data after 100 patients have been treated with SFX-01 or placebo.

Good news for SNG...Gla ;-)

- SNG001 given Fast Track designation and IND cleared by the US FDA

- Phase III trial design adapted which will expedite results

- Phase III trial to commence dosing in UK imminently

Tocilizumab, also known as atlizumab, is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor

James D Chalmers
@ProfJDChalmers
·
7h
Important data on Tocilizumab in COVID19 just dropped in @NEJM

https://nejm.org/doi/full/10.1056/NEJMoa2030340?query=featured_home

Reduced progression to requiring mechanical ventilation/death composite but no effect on mortality.

Consistent with earlier trials suggesting reduced ICU admission
There is a signal here

Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia | NEJM
Original Article from The New England Journal of Medicine — Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
nejm.org

James D Chalmers
@ProfJDChalmers
·
6h
Two previous trials showed similar trends towards reduced ICU admission but nothing convincing on mortality

REMAP-CAP data apparently positive but not in the public domain
Hard to know if this is just "noise" across multiple trials or real benefit in a subset of patients
Show this thread

ps and just like Evgen's collaborator......"U-M has applied for patent protection"

Maybe no connection ontarget, but lots of similaraties......and no naming or detail of the STAT3 inhibitor in the article, one of the key pathways as well as Nrf2 that we know SFX-01 has potent activation , along with its ability to quickly cross the blood-brain-barrier......and so if not their's , then definitely something similar and not too long to disclosure imho.....Gl ;-)