Member Info for Burble

C7

Two latest additions to the board are definitely a positive sign for me. Dr O'Bryan-Tear as CMO, to me is an addition that is greatly needed. As we move more things into the clinic (SCIB1, Modi-1, Covidity) having somebody who understands the fine details here is definitely necessary. To me it should help smooth many of the risks this has by having somebody who knows the system, understands the paperwork that needs to be filed and has a track record of doing this in a way that produces results that the market/pharma want to see. The correct design of a trial does a few things. It not only validates your product, but also answers the broader questions you want to ask. A badly planned trial, can hamper recruitment or it can make it difficult to accurately get a read out at the other end. The CMO brings experience directing clinical development strategies and plans, they also manage relationships between key investigators and those involved in the trial. In doing so, this frees up time for the commercial side to be looking for partners/deals and the scientific side to build on the research. As we move into the clinic, knowing where the strategy and direction of the clinical aspects is going means we should save money and time moving things forward under this guidance.

Dr Miller also to me complements well, especially given the guidance as to which way to move things from a clinical perspective. Modi-1 to me is a case in point. A trial with 4 arms, means 4 potentials for success. If you see important gains in one arm, you may decide to prioritise that further and leave the other two parked for the time being. Dr Miller with his clinical, surgical and pharmacological experience should give us a better insight into how best to design trials to get read outs that benefit the company and the patients alike.

Both I think will help unlocking the recruitment issue we have with trials. Understanding the inclusion and exclusion criteria better, should mean the exclusion criteria is appropriate for the trial we are running. Their experience to me is necessary to ensure that we are able to move forward, by having the broadest pool of potential candidates put forward for the trial, without excluding people unnecessarily. Whilst at the same time, not including people who ultimately won't benefit but would contribute to poor read out of results.

Remind me was SCIB1/Keytruda still using Ichor? If so I wonder whether that was part of the problem for recruitment.

RP

My apologies, I read your comment the wrong way.

Again, depends on the system. The post-doc in the lab I used to work in used to develop nanoparticles for the delivery of peptides inside cells. His work built alternating layers of individual components together. So you'd start with component 1 and your cargo, you'd mix them, then agitate them for a few hours, then take these and wash them in a number of different solutions. Then place them in component 2. You'd repeat this, a number of times until you produced an encapsulated cargo with a number of different layers on the outside. I would assume lipid nanoparticles are easier to work with as they form lipid bilayers (e.g. the bubble analogy), encapsulating their cargo. The downside is they're less stable. In the lab when working with lipofectamine, you have to make it and use it within a relatively short space of time (20 minutes) for it to work. I would assume that's because the lipid bubbles fuse over time and so don't hold their shape properly. The protein ones were definitely more stable, the post-doc I used to work with could make them on day 1, then store them for days/weeks/months dependent on conditions.

For a visual, if we imagine the lipid membrane of a cell to be like that of a bubble. You want your peptide delivery system to interact with the surface of that bubble and fuse with it, without causing the bubble to pop. Normally the cell membrane prevents large molecules from transporting across, so you have to find a mechanism to do that. This is either done by causing transient holes in the cell (electroporation), or developing a mechanism to allow the fusion to happen (lipid nanoparticles are similar to the membrane) or peptide nanoparticles (can interact with the membrane and fuse with it but not rupture the system).

Visually this video shows essentially what we are needing to do to get our plasmid into cells.
(h ttps://youtu.be/BRe9M1lF4Hs?t=301) the white bubble is our plasmid filled nano particle, the clear bubble is the cell. We want to be able to fuse the two, not rupture the cell and deliver the contents inside.

RP

It's less the protein system interacting with the plasmid DNA, more that you need the peptide delivery system to interact with the surface of a cell and cause fusion of the two. There are a range of different set ups, but the high positive charge is probably the most understood. Basically, high charge peptide, interacts with negatively charged groups on the surface of the cell membrane. This induces binding to the cell, aggregation and subsequent entry of the nanoparticle and the cargo into the cell.

RP

No need to apologise!

I'm unsure given the limited information. For peptide delivery, a GMP certified Contract Manufacturing Organisation would most likely need to be the ones involved in the manufacture of GMP grade peptides. As we have limited details as to the exact formulation of this delivery mechanism, it may be the same company making the plasmid and the peptides or it may be another. It won't be Scancell directly as I would assume they are not GMP licensed or have the scale-up to do this in house with the QC steps involved in making medical grade materials. So definitely an outsourced company.

With lipid nanoparticles (at lab scale), you basically mix a set ratio of your LNP and plasmid together. Incubate it and then add directly to cells. Now I would assume that there are more complexities to doing this with human delivery, as it would probably need stabilising reagents and other constituents which go along with that to ensure that once manufactured it has a shelf life, is sterile, is medical grade. Again, unsure without having more details as to the final constitution of the peptide based nanoparticles, it might be as simple as the LNP method above, or it might need some more additional steps to ensure that you get your end product that is fit for delivery into humans as part of a trial.

Bermuda,

Nothing should be a stupid question - so feel free to ask away. Generally proteins and DNA are better stored at higher concentrations. So we would usually store our DNA plasmids frozen at a high concentration, but in small aliquots. You would take an aliquot out of the freezer, dilute it further to your desired concentration with any additives you needed and then use. As such, you could easily manufacture and store, then formulate later. We would make a batch of plasmid and dilute in ultrapure water, then use this for all bacterial work. The same batch of plasmid, would be diluted in lipid nanoparticles (lipofectamine was the brand) for use in human cell culture.

The main thing you want to do is formulate it in a sterile environment and consistent between batches. Hence, you most likely would formulate then store for biologics, rather than make a big batch, store that and then formulate. Though I guess this is also is dependent on how you design the manufacturing pipeline - one way may be far more costly than the other. Either way, if the end to end process is done to GMP standards then I can't see a problem with either.

Hi Bermuda,

I was meaning more the active pharmaceutical ingredient (i.e. the DNA plasmid) as I would assume that this was formulated with a carrier solution for delivery by the Ichor device. Obviously, dependent on the storage conditions and delivery method this most likely will change. LNP and protein delivery methods will have shorter term storage, or different storage conditions than a pure DNA construct. However, without seeing what these are in detail we cannot comment on what those will be.

In the past two decades we have seen three novel coronavirus outbreaks - MERS, SARS and COVID-19. Had countries had a vaccine sat waiting that had broad coverage, it would have been contained to the outbreak epicentre and not spread.

I had a bit of an epiphany last night. If SCIB1 has a usable shelf life of 5 years, Covidity will be the same. The fact (and I do hope it’s proven) that Covidity gives lasting protection for many coronavirus strains, strengthens the case further for long term use of this. As a backup for governments around the world in long term storage for if another coronavirus strain comes along. Furthermore, imagine down the line if further work is done on developing the Immunobody platform further into a pan-flu style vaccine. So many possibilities and opportunities for up front use or for long term stockpiling of a DNA based vaccine.

I’m dipping in and out! Juggling work deadlines with this on in the background.

Nice to hear they’re still engaged with the global biotech....

What was the general feeling about the modi peptides?

For me this was one of the key issues that stood out for me from Sally's presentation. Modi-1 is made up of three separate peptides. Two were formulated without much problem, the third has proved to be a PITA both in manufacture and solubility. Whilst the presentation suggested that this solubility had been overcome, to me it suggests the development of moditope may not be as plain sailing as many had expected. Considerable amount of work will have been done to try and solubilise this, especially with a solvent which is applicable for use in the clinic. If this is the case for other moditope peptides, then this will prove a bottleneck. The other risk is in the long term stability studies of this. If the peptide does not remain in solution after manufacture, this could prove a problem when it comes to clinical trials, scale up and marketability. I would be interested to see how the team are trying to mitigate this as a problem going forwards.

My second point, TCR side of things LD stated 8/24 screened with no response. This technology may need to wait for trials. I'd like to know whether this is definitely going to be parked or not? For me there is a worry that this will continue and be spending money/staff time and yield 24/24 failures, when this time and finances used to better effect moving other things forward. Obviously, once Modi-1 trial gets going, by all means do the TCR side of things. But I would like to hope this was put on the back burner for the time being.

More information coming out about the role T-cells play in cellular immunity to Covid-19.

https://www.birmingham.ac.uk/university/colleges/mds/news/2020/11/covid-moss-cellular-immunity.aspx

c7/Ivy

Did you see my post yesterday regarding the new strain of Covid circulating in Scotland? That’s also worrying more closer to home

It's at 6.05 in the Pro active investors video for anyone who is interested.

Also on II, your friend would have had to submit a response to the open offer corporate action request a few weeks back. Of the top of my head I cannot remember the date that it was pushed to the platform, but it was relatively quickly after the OO was announced. Then your friend would have had to respond with whether they wanted to take up their allotment of shares and apply for further additional shares by 23:59 23/10/2020. These were admitted to trading today so unfortunately he has missed the boat on that one.

This paper (it is a pre-print, hence has yet to be certified by peer review) has just been uploaded.
https://www.biorxiv.org/content/10.1101/2020.11.04.355842v1

In summary, a new strain of Covid-19 which contains an N439K mutation on the spike protein has emerged in patients seen in Scotland and is spreading. The hypothesis is that this forms an additional salt bridge bond between the ACE2 receptor and the virus spike protein, resulting in enhanced binding. The mutation shows viral fitness similar to wildtype or slightly improved, as well as similar virulence levels to wildtype.

More importantly, it seems that when evaluating the binding of patient derived antibodies (polyclonal) and a panel of patient derived monoclonal antibodies a reduction in binding was seen to this variant. Grafting the Covid-19 spike protein into a pseudovirus (wildtype or this mutant form) and then testing it against the patient derived monoclonal antibodies showed neutralisation of the spike protein containing this mutation was significantly diminished. Important take home 'This included diminished neutralisation of some of those in clinical development.'

The paper finishes with this take home message 'Although SARS-CoV-2 is evolving slowly and at present should be controllable by a single vaccine (Dearlove et al., 2020), variation accumulating in the RBM could put this at risk, especially for individuals with a moderate Ab response to vaccination or infection. While we only report on evasion of antibody-mediated immunity here, it would be surprising to us if similar changes are not observed to evade T cell immunity and innate immunity. '

This mutation has also been reported in the paper https://www.cell.com/cell/pdf/S0092-8674(20)30877-1.pdf which also reported reduced neutralising effect from mAbs.

These results are important for SCLP and Covidity in so far as targeting the more conserved N protein as well as the S protein provides some redundancies in the system which should help prevent immune escape for emerging Covid-19 mutations. Whilst many are saying that the current vaccines are producing a T-cell mediated response alongside the antibody response, it would be interesting to see how they stand up to a changing landscape if they have only vaccinated against the spike protein, rather than a number of viral components.

Bermuda,

Yes that is true, the lack of funding has hampered Scancell's move forward very much so (and is similar to many other small companies). I just hope that with this extra funding there is thought into how best to spend it to maximise the scientific output. A detailed project management, with key milestones to reach and with risk/reward balanced would be nice to see. After all Lindy is the one in the know on the science and what will take the time, where easy wins for data are. We shall see. I'm not fussed though, if this takes two years to come to fruition, the wait will have been worth it if the results we have seen in the lab are mirrored in the clinic.

Other company is Ilika (IKA) a company focussing on solid state batteries. Their most recent investors presentations have a full road map of all the things they needed to do for the next few years.

https://youtu.be/gcgsSZ067qc

If you look at 6m30 of this video you see a detailed timeline of all the things they need to do to move through to project ramp up. Earlier at 1m49 they show the markets that their product would fit.

To me this is the level of detail that I think SCLP should be going into. It’s easy to digest, especially for non-technical people. You would be able to see potential markets, the size of these etc and where our immunobody, moditope, Avidimab, TagMAbs etc fit. Then understand what the timeline for each of these products to get through trials or to market are.

I don't know about you all, but I am really looking forward to the presentation on Monday. I hope we see a proper timeline laid out for how SCLP wish to spend the money they now sit on. It would be good to see some proper targets with sensible timelines for how they wish to achieve these. Comparing SCLP to how one of the other companies I am invested in, is a bit like chalk and cheese. The other company has a clear strategy mapped out over the next 5 years, broken down into separate work streams. This is where I think the SCLP board have demonstrated a weakness at times. With Redmile on board, I hope to see a refreshed more purposeful presentation.

Does anyone else have any thoughts?

To lay my cards on the table. I have voted for.

Yes I stand to gain financially if we can advance platforms quicker and in parallel with the help of Redmile. But to me that isn't what drives me to invest in this company. For me, the drive is the fact that I believe in the science and believe in the fact that many many patients will benefit from any one of the SCLP platforms moving forward into trials and beyond. Without funding we are in a state of paralysis, we are in essence moving sideways. Adding new technology, but not really adding to the proof that this technology works in patients.

I sadly have contact with patients going through their cancer treatments day in, day out. Many survive, sadly many don't. It would be hypocritical of me, not to vote for. For me I truly believe the patient should be our focus. I know many people are in this purely for financial reasons, and they have every right to think this way. But for me, I cannot knowingly vote against something which could transform this company into bringing therapies to the clinic quicker and has the power to prevent or at the very least minimise friends, family and other human beings suffering.

It's a yes from me. My hope is the funds are spent in the most logical and cost effective manner to move forward as many platforms as possible, into the clinic and beyond. I have my doubts at times as to whether this board are able to stick to their timings or not, but I believe Redmile now may help focus minds a bit more.