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From Journal of Thoracic oncology
Pimarily SCLC
Dec 2019 The SRA737 þ LDG
regimen mimicked the schedule currently being used in the clinical trial described above with or without anti–
PD-L1 on the third day of a weekly cycle. We did not observe a significant antitumor effect with any single agent treatments (anti–PD-L1, SRA737, or LDG), and only a moderately delayed tumor growth with combined
SRA737 and PD-L1 treatment (Fig. 4A). However, we observed remarkable tumor regressions when we combined SRA737 þ LDG with anti–PD-L1. All mice achieved some level of tumor regressions and 8 of 10 (80%) mice had complete tumor regressions which were sustained up to 60 days post treatment.
Here we show that the SRA737 þ LDG regimen in combination with anti–PD-L1 enhances dendritic cells in the tumor and leads to a decrease in pro-tumorigenic MDSC populations. Most notably, the establishment of the strong antitumor immune microenvironment observed when SRA737 is combined with low-dose gemcitabine opens an opportunity for a highly efficacious and tolerable treatment regimen with a potentially distinct mechanism from that
of standard chemotherapy or DDR inhibitors alone.
Further studies are warranted to determine if this approach would be beneficial with other chemotherapies, such as low-dose platinum-based doublets, in combination with ICB and DDR inhibitors. Whereas the RPP SCLC model used in the immune-competent animal experiments represents only part of the heterogeneity of
SCLC, our previous work with olaparib and prexasertib in combination with anti–PD-L1 suggests that our observations are more broadly applicable to SCLC.8,12,23 As with many other cancer types, pre-clinical studies are limited to only a few immune-competent models of SCLC, consequently further validation of the combinations described here, will likely need to take place in a clinical setting. Given that anti–PD-L1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 þ LDG regimen is well tolerated in clinical trials in SCLC (NCT02797977), our preclinical data provide a strong rationale for combining this regimen with inhibitors of PD-1/PD-L1 pathway in the clinic.
Food for thought.
GSK could have bought momo from sierra.
They stated they purchased Sierra for the momo primarily.
The target price was put at around 55 dollars a share. This is what GSK made an offer based on.
We can only deduce from this that GSK have their eyes on the Sierra pipeline and their expertise in developing compounds to take through to commercial stage.
Informal discussions would have been going on for many months before formal discussions took place.
Good posts put forward by many, Citizen79, Bobbler, James and HbD and others.
Regards
Termination of trial.
Would hazard a guess at financial issues especially comittment with the Momo. from memory Sierra were robbing the SRA737 cash pot to press ahead with momo. Around about 2 million dollars I believe cut back on SRA737.
EudraCT NumberFull title of the trialSponsor name2017-004927-56A Phase 1b/2, Open-label, Multicenter, Dose-ranging Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of SRA737 in Combination with Niraparib in Subjects with Metastatic Castration-resistant Prostate CancerSierra Oncology, Inc.
This study was prematurely terminated due to a change in the positioning of the clinical development pipeline for Sierra Oncology. The clinical trial was approved, but it was never started, no subjects were enrolled, and no clinical trial results are available.
A note i will add here is CHK1 is used in combo with LDG. Low dose gemcitibine as gemcitibine toxicity is high when used in higher dose with CHK1 inhibitors.
Masses of potential here. Effectively much more potential in combo. Much much more if we look at possibility with a TYK2 Jak1 cancer treatment. A question now exists of whether DDR will still need to be addressed when treating patients with ovarian cancer or similar forms of cancer that have known DDR pathways for example with a Tyk 2 inhibitor.
I believe it important as a whole not to think as inhibitors as one cure for all. It is in the contribution they can make in multi pronged attacks on cancer. This is where the true value lies I believe.
GSK are very heavily committed to development down this route. they are hell bent on research and development into IO ( Immuno Oncology). Certain inhibitors and treatments in combo will be required to maximise the potential for their already made treatments in clinical use and development.
Our SDC1802 is designed to be not only compatible with other treatments but also enhance their effectiveness when cancers develop resistance to earlier forms of treatment.
I would certainly not rule out a GSK sareum agreement of some sort with regards to our TYK2 Jak1 compounds. But we are a little way off and need indications of toxicity results in human trials. If results turn out as good as we have been led to believe then game on.
Beer oclock for me now.
Agree with you wholeheartedly on that one SCHeckler.
Only announcement by Sareum would be news of progress/planning of SRA737.
Interesting to see what GSK intentions are regarding Momo and pipeline development.
Difficult at the moment to put a monetary value on 515 and 737. it should be noted that SRA737 in combo worth certain other named inhibitors has now been patented. That will incresae the value of 737 and make up for some of the shortfall for lack of development over past 3 years.
regards
HotBlackDes - I do apologise in advance, it’s becoming a bad habit. Sorry! I don’t think we (as SAR shareholders) will get an RNS announcing the deal being voted thru. Unless any of us are signed up for *Sierra* alerts. Or GSK alerts. I think it’s more likely that the SAR BoD would “note” the action after the Sierra announcement (assuming it’s carried) or possibly not at all if they don’t feel it’s appropriate. Anyway, if it’s noted by SAR I’d expect it to be half a day or a day behind.
All IMvHO and happy to be proven wrong.
HBD , I am afraid way beyond my bandwidth , however I would say a lot more than was ever anticipated .
Yes looks like GSK have played a blinder .
Now it should be our turn soon .
Happy Days
Evening Sixth - your task now is to put some sort of valuation on 737!
Whilst we should get a 7am RNS on Friday to say the merger vote went through, I don't expect it'll give too much away about the route ahead unless GSK announces something specific right after the vote - I can't see GSK allowing a minority stakeholder to let the cat out the bag re the global market for 737 and how they got it for a song.
Exciting times ahead with GSK in the driving seat.
Great research work guys
Thanks for coming back with additional info, Citizen. There’s so much “noise” that something is definitely afoot!
Firstly, apologies as I've had one or two ales.
Note that Niraparib was shown to be effective/enhanced by SRA737 combination back in July 2018 here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154848/
At that stage, owned by Tesaro, originally a Merck product.
"Recently, within the past two months, Sierra Oncology has signed a clinical supply agreement with Janssen Research & Development, LLC. for access to TESARO’s ZEJULA® (niraparib). Sierra intends to evaluate its CHK1 inhibitor, SRA737, in combination with niraparib in the United Kingdom in patients with metastatic castration-resistant prostate cancer (mCRPC)."
Then in December:
https://www.gsk.com/media/5218/gsk-acquisition-of-tesaro-investor-call-slides.pdf
Sierra were going to trial SRA737 with Niraparib, but cancelled the trial once GSK owned Niraparib?
Maybe the plan all along, did they have funds to continue, or did GSK pull rank so to speak and plans changed.... we may never know.
But as James says, it's all very very interesting. Something is certainly afoot.
ATB
Celtic, the authors are what you might called pretty credible:-)
Amazing read bobbler. Stripped. ..... wowwwww . Eight out of nine lines.....amazing. ...
Published March 2020 but still a very encouraging read.
“Combined treatment with SRA737 and an experimental inhibitor of B-family DNA polymerases called aphidicolin stripped cancer cells of their ability to cope with DNA damage, and was more effective at killing them in eight of the nine cancer cell lines tested.”
https://www.icr.ac.uk/news-archive/two-pronged-attack-on-dna-repair-could-kill-drug-resistant-cancers
Citizen, one thing is for certain - something IS going on.
That's my thinking, maybe just a piece on Niraparib in general, updating periodically with info about combos, new studys and data etc.
I could be totally wrong though, someone with more nous than me will be able to confirm either way, we have some very knowledgeable folk here.
ATVB
Hi citizen,
Ahh, so it could actually be nothing of importance!
Afternoon James,
I believe SRA737-03 relates to this:
https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004927-56/results
click the "Summary Reports" link for a .doc showing why the trial never started.
ATVB
Very interesting.
To add further meat to the bones, try this...
Google sra737, go to Tools and filter the date frame to Past Month. Now, find the 3rd result down, which should be "Niraparib - Janssen/Merck/GlaxoSmithKline - AdisInsight". You'll see it was updated 9th June - 1 day after HBD's results revelation. The text snippet reads "with metastatic castration-resistant prostate cancer (mCRPC) (SRA737-03; ... tolerated dose and schedule of SRA 737 in combination with niraparib and to ...". Visit the result and you'll see no mention of SRA737. Nothing. Last update was June 2nd 2022. If anyone has a login, it might just unearth what WiP knows? Interesting indeed.
Interesting:
cisplatin = Bristol Myers
gemcitabine = Eli Lilly
Not sure if this has been posted before but the results were submitted for review for a third time on 8th June having twice failed the National Library of Medicine's QC process.
https://clinicaltrials.gov/ct2/show/results/NCT02797977?term=sra737&draw=2&rank=2
The National Library of Medicine QC review assesses for apparent errors, deficiencies, or inconsistencies.
The definition of 'Results returned after Quality Control review, is -
"The date on which the National Library of Medicine provided quality control (QC) review comments to the study sponsor or investigator. The sponsor or investigator must address major issues identified in the review comments. If there is a date listed for results returned after quality control review, but there is not a subsequent date listed for results submitted to ClinicalTrials.gov, this means that the submission is pending changes by the sponsor or investigator."
Might be nothing, might be something but I imagine the people at GSK are watching this one closely.