Member Info for Vander

Build and they will come!

https://ct.catapult.org.uk/news-media/manufacturing-news/research-highlights-uk-growing-manufacturing-industry

Horizon 2020 funding has also supported SMEs with GMP manufacture for virosomes/polymers/gold NPs

Look up maciviva, nanopilot and nanofacturing respectively

Yes maybe. Moderna are a midget compared to medimmune Moderna are spending 100s of millions USD per year on their research programme - you would think they may consider an alternative to their single liposome given the multitude of disease applications Btw patisiran was the first RNAi therapeutic to achieve global approval on 10th August 2018. It was delivered by liposome- it tracks to the liver where It inhibits synthesis of transthyretin It was given IV every 3 weeks for 18 months You have to show systemic safety with chronic dosing So far nuvec given subcutaneously and one off, but that is all may be needed for a dna vaccine. So far no safety issues in small animals

Btw we have now been collaborating with medimmune for 10 months. I thought the previous agreement was for them to agree a licence at any point within the 9months or 3 months subsequent. Delivery of their pDNA is a priority area of research for medimmune

The last rise was in response to the medimmune rns. The deflation related to uncertainty re timescale on how long ongoing research will take prior to a decision on a codevelopment agreement. The value of the product will not inherently change until we get that announcement Brexit worries did not help, though they are with us for days/months/years

In the papers today- same institute from which N4p patent hails- they used gold NPs
https://www.theguardian.com/science/2018/dec/04/scientists-develop-10-minute-universal-cancer-test

By the way the point of the post was that I am looking forward to the co-developed nuvec version We have got through a stage of the 3 outcome model of medimmune preclinical drug development (Go-stop-consider)

Nuvec has performed well with respect to immune response versus:
Lipofectamine (liposome produced by Invitrogen)- in vitro
In vivo-jetPEIA (polymer produced by polyplus transfection)- in vitro and in vivo

When the current version of nuvec is manufactured to cGMP standards, it should compete well with these two

However the optimised version of nuvec, co-developed with medimmune will need to compete well versus all methods of gene delivery
Will it combine with electroporation or be an alternative?
Will it compete with Moderna's current favourite NPL, N1GL, breaks out of the endosome 25 times as much as standard lipid nanoparticles (Mol. Ther. 2018, DOI: 10.1016/j.ymthe.2018.03.010).
- for this they 'screened 212 bioactive lipid-like molecules that are either enriched in vesicular compartments or modulate cell signaling'

The lesson: big companies are better at optimising nanoparticles than small ones

(BTW the rns 29/10/18 talked of studies to optimise the loading properties of nuvec- this will not take long to announce outcome
If they intend to optimise it by changing particle characteristic/component and correlating this with the basic cellular pathway for dna/rna delivery- this will take longer, and I would have thought also part of a long term package of data for the product

Yes. It’s difficult to know how seriously medimmune regard us, but they do not collaborate with every Tom, dick and Harry especially in a research priority area- it would make them look stupid N4p are very small and so our imagination may be that they are going down to the local diy shop for help with their science project. We could respect that in the local paper and watch Nigel present the findings in the town hall However the strange reality is that we are collaborating with one of the worlds largest Pharma companies with a massive newly opened research complex in Cambridge. We can research the findings in multi national newspapers and journals. Whether nuvec will attract attention to the wider investment community will probably depend on whether we get a contract with medimmune and more collaborations as a result

Hairy hat if you had said what is the point of wider research on big companies like Moderna and inovio prior to the recent rns, I could see your point. However the recent results are no longer inscrutable and low brow. The results are positive on all prespecified measures to a degree that they have earned a codevelopment project with medimmune. I agree that a contract still has to be earned but using medimmune resources to develop the product These far distant big companies are the same people that are collaborating with medimmune and one of their research priorities includes our product- it’s in publically available literature The problem is no one has heard of nuvec except us, medimmune and maybe, in the future their collaborators

I find the day to day share price here difficult to predict. For big Pharma the SP reacts precisely and purposively in response the results of lengthy clinal trials and associated commercialisation, with interpretation by industry experts Here the day to day SP movements responds more to hugh Wilson’s toilet habits than to actual positive results and announcement of collaborations Hopefully these aberrations will correct themselves with the passage of time

Btw I agree we should have constructive negative comments- ideally restricted to the company thoug Nuvec will not fail/ succeed based on Hugh Wilson

BTW if the delay had occurred in the context of negative results then we would have need slaughtered In this case the delay may have been due to the distraction of positive results and a codevelopment project with medimmune- we are on new level with those guys The Eu ncl programme required a large batch produced prior- it’s taken 3 months. Not sure if that is a delay. If we have GMP compliance and cta for trial ready product by sept 2019 that will be ahead of schedule

Artyth good to have some scepticism Not surprised re UoA delay. Change in r&d lead needed following positive results. We need a specialist in vaccine delivery and virology in charge Also difficult to start anything in Australia during holiday month December Eu ncl may have been slow to start Re leopards and spots: Different product and different efficacy results Same CEO but different people in charge of the science and manufacture

Today’s rns has given more detail of recent study outcomes and so has enhanced the scientific value of Nuvec This data forms the basis of the ongoing collaboration with medimmune. It outperformed an industry standard polymer- this information enhances its competitiveness and will increase the financial value of a future deal with medimmune or others The means of delivery is said to be a research priority for companies such as Moderna, and the area most in need of improvement. The medimmune codevelopment project will allow N4p to compete with multi-billion companies, at that level At present some of us find the scientific detail dull, and it will not hit home until a concrete deal is struck (it may fail, but the ducks are being lined up). Bigger challenges are due if it reaches human trials by which time we will have multi- bagged. We will probably get past large animal trilals -that depends as much on what nucleotide/ condition it is being used for. Medimmune are already in phase 3 human trials with the hsv vaccine for pre cervical cancer ie more advanced than anyone else for dna vaccines and there collaboration with Moderna is in phase 2. . Mymetics did not progress past 2 yrs with astellas because there were already two more advanced rsv vaccines with other companies and astellas gave up interest

This is a very fast growing area dependent on marginal gains This has performed better than an industry standard polymer on the key outcome measure of specific immune response to the OVA- the latter is used so that studies can be quantitatively compared. It has worked for both mRNA and DNA and data for peptide delivery in the next 6 months

Relax...deep breaths

Moderna have 600 employees- most scientists N4p need to get bigger or be taken over or fail

Hmmm. It looks like the delivery vehicle is a priority area for research and assessment may be more detailed than expected. On the plus side it is more likely to work further down the line

Here is a link to a good easy to read article (sept 2018) summarising the mRNA field, and associated companies inc Moderna, curevac, translate Bio etc.

Multiple applications inc vaccines, cancer therapeutics and gene therapies eg for Cystic fibrosis etc.
Moderna's most advanced phase 2 programme is with AZ.

https://cen.acs.org/business/start-ups/mRNA-disrupt-drug-industry/96/i35

Here is a snippet relevant to N4P:

The importance of delivery is not lost on Moderna. It’s the area with the most room for improvement and the biggest focus for the company’s chemists, Moore says. One proxy for success is how much mRNA escapes from endosomes, the cellular structures that ingest lipid nanoparticles. Moore says Moderna’s current favorite lipid nanoparticle, N1GL, breaks out of the endosome 25 times as much as standard lipid nanoparticles (Mol. Ther. 2018, DOI: 10.1016/j.ymthe.2018.03.010).
An even bigger long-term challenge will be getting mRNA into specific cells of the body. Lipid nanoparticles have a tendency to aggregate in the liver. That could make mRNA useful for producing therapeutic proteins and antibodies that are secreted from liver cells and circulated in the bloodstream. But getting mRNA therapies into other organs will require either direct injection into that tissue—as in AstraZeneca’s post-heart attack VEGF study—or fancy new control systems.

Translate Bio have patented the N1GL lipid nanoparticle manufacture

There are lots of articles out there- here's one for Mazik (Battle of the biotech unicorns)
https://labiotech.eu/interviews/curevac-moderna-biotech-unicorn-mrna/

WHO DNA vaccine guidelines 2007- old but still applies.
No 2 relates to nuvec. No 5 relates to medimune electroporation No 8 relates to the Gowans cytolytic dna.
I wonder if they will work in combination

1) complexing the DNA with polymers (enhances uptake, improves stability);

2) encapsulating the DNA on or within microparticles (assists uptake, presentation and stability); •

3) optimization of the codon usage of the gene encoding the antigen of interest (enhances expression); •

4) encoding a variety of T cell epitopes either instead of or in addition to a full size protein antigen (modulates the immune response by targeting T cell stimulation); •
5) optimizing administration, e.g. by particle-mediated delivery (gene gun) or electroporation (enhances uptake, modulates immune response); •
6) route of administration, e.g. mucosal versus parenteral (modulates the immune response); •
7)boosting with viral vectors or protein antigen following an initial priming with plasmid DNA (improves immune response);
8) co-administration of DNA encoding an immune stimulatory molecule (molecular adjuvant), e.g. a cytokine (improves immune response, modulates the immune response).