New Diagrams for in vivo efficacy

[mattodd]

We need to generate better/new pix for the in vivo efficacy. Wiki contains some details.
MMV639565: we have the two inherited pictures. I don't think we have the original data.
MMV669844: we have data on the old lab notebook, including the original data points, so we can plot our own version. I've dragged the PDF here for simplicity.

• ACTION ITEM: Mat to ask MMV for original data behind MMV639565

9792.pdf

[mattodd]

Am in touch with Paul Willis about the original data, and which authors generated them (and therefore who ought ot be authors). Will update when clear.

[mattodd]

Update on the in vivo data. GSK generated the data on MMV639565 (also known as PF-06342505). The team has sent me the original report and the Excel sheets, and I'm just checking whether I can post those and/or submit with the paper SI.
Since we're including GSK data we need to send a late draft of the paper through GSK's "Data Integrity internal review", and when we mention the SCID mouse model in the Methods section we need to include the sentences "The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol. All animal studies were ethically reviewed and carried out in accordance with European Directive 2010/63/EEC and the GSK Policy on the Care, Welfare and Treatment of Animals."
I am checking which GSK authors need to be included.

• Check whether GSK MMV639565 Data/reports can be posted openly and included in paper SI
• Submit late draft of paper to GSK's internal review
• Add text re animal use to paper
• Include all relevant GSK authors.
• Check who generated the data on MMV669844 - we have the report, and the ELN entry says Swiss TPH, but this needs confirmation.

[mattodd]

Have asked Sergio Wittlin at SwissTPH whether he can track down who did the SCID study for MMV669844, and will report back. Original report now here.

Update 23/3/21 - email from Sergio providing essential info, which i'm clarifying.

[mattodd]

Update 29/3/21. Sergio has kindly provided an updated/more complete report for the in vivo evaluation of MMV669844, which I have uploaded here. He has approved this report being in the public domain and for it to be submitted as part of the paper's SI.

With this supporting data, Sergio is suggesting we do not plot the in vivo data together on the same graph because data were only taken at days 3 and 7 (that's just the way they ran the assay at the time - back when this assay was done the SCID mouse model was relatively new), and though it clearly shows efficacy, such a method is not typical. He's suggesting we include in the paper the statement:

"In an independent study performed at Swiss TPH, at day 7 post-infection, n=2 mice treated with a 4x 50 mg/kg p.o. dosing regimen of MMV669844 were parasite-free (>99.9% activity) compared to n=4 untreated control mice (see SI). The parasite detection limit in that study was 1 parasite in 10,000 erythrocytes (that is, 0.01%)."

I think this is fine, and I've added it to the paper.

He has also clarified authorship, which is for us to put into the acknowledgements section the following:

"We thank Ursula Lehmann, Christoph Fischli and Sergio Wittlin (Swiss TPH, Basel, Switzerland) for help with the SCID mouse data for MMV669844."

Again, this is fine by me and I've added this to the paper.

I need to add some of this to the wiki. DONE.

All that remains is the tweaking of the GSK curve, if we want to do that - there is perhaps less need if we're not merging two studies.

[mattodd]

The GSK assessment of compound MMV639565. Four files have been added to the Experimental section of the file repo here. Two reports for the compound and two spreadsheets. This allows us to re-draw the diagrams for in vivo evaluations if we want to. GSK have sent these reports and are happy with them being submitted along with the paper.

Interestingly the Pf potency is very good, whereas the compound appears not potent vs Pb... The same thing was found for (+)-SJ733 (https://www.pnas.org/content/111/50/E5455) which apparently shares the same mechanism of action (PfATP4). However, for the Novartis compound (again PfATP4), 100 mg/kg was efficacious (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335872/). We'll likely need a comment in the paper on this.

The GSK team have gotten back to me to say that they are happy to be included in the acknowledgements as "Therapeutic Efficacy and DMPK Group, GSK R&D, Tres Cantos, Spain"

[mattodd]

@edwintse - are the four GSK files above part of the SI list associated with submission? Just double checking.

We need the statement "We thank the Therapeutic Efficacy and DMPK Group, GSK R&D, Tres Cantos, Spain for the in vivo evaluations of compound MMV639565" in the acknowledgements if it's not there already.

Also @edwintse can you please check that when we mention the SCID mouse model in the Methods section that we have included the sentences: "The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol. All animal studies were ethically reviewed and carried out in accordance with European Directive 2010/63/EEC and the GSK Policy on the Care, Welfare and Treatment of Animals."? GSK requires us to say this.

Also a reminder that we need to send the preprint paper through GSK Data Integrity Internal Review - I'll do that when the above things are verified. I don't think this will slow submission.