Member Info for Burble

C11,

Remember with clinical trials once an amendment has been approved by a research ethics committee or the MHRA, it then has to be processed by individual site clinical trials managers and approval granted before it is allowed to cascade down through clinical teams.

This means it’s highly dependent on site clinical trials units and staffing time to make changes. Only once changes are approved can sites start recruiting patients.

We had an amendment approved in September 2019 for a trial across 20 sites, it took nearly till February (just pre-pandemic) to get it approved and through site systems across all sites.

Chester

There is a kind of blinkered view that mRNA is the way forward. That's where the money is and that's why the scientific talent is being drawn towards it.

I agree, we see it here in the UK. Vast amounts of money being put into mRNA technologies. I wonder whether we are putting all our eggs in a single basket and may live to regret that. One of the other striking things is the patent space in this area especially around lipid nanoparticle, ionisable lipids used in these. Many companies have patented these delivery systems and so hold huge sway over the entire modality.

In late stage cancer tumours Modi1 in monotherapy has found it difficult to mount enough of an attack to overcome the vastly mutated micro-biome. It would be very interesting to see how it performed at a much earlier phase of a tumours development.

I agree. The problem you have though is proving a phase 1, first in human compound is better than the existing treatments. Early stage patients have many more options and so from a risk profile, it makes no sense to try a new novel treatment. Hence Scancell have to prove it works in more difficult patient populations, before they have any hope in moving to earlier stage patients.

Do you agree that it's because Scancell are having to start with the most difficult stage cancers that we are flying so under the radar.

Partially (see comment above), but I also think many clinicians and researchers are cautious about DNA based vaccines due to the possibility of integration which in itself can cause cancers, hence their love for the transient mRNA vaccines. I also suspect on the moditope front a reluctance because it’s very novel - targeting stress induced post-translational modifications. Scancell will be the first.

I see GlymAbs having a lot of interest, especially if the platform can produce more antibodies against different targets. Avidimab, I see could have a lot of interest, but only if people see a value in using it on their own antibody therapeutics, if you take say a 80% performing mAb and make it work 82%, then no real point adding Avidimab. However if you have a great target but mAb only works say 50%, if you can get that to 80% with Avidimab, then it would be worth licensing.

I’m curious as to whether we will see licensing deals over the coming months/years.

Violin, I did not as I felt I wanted to prejudice answers. I thought alluding to DNA vacccines would maybe see whether SCIB1 was on the radar

I agree. It's interesting to see what somebody on the ground working with mRNA vaccines thinks when posed a few questions like this.

Some interesting take home points. As I have suspected, SCLP may be more under the radar than we realise/hope. I wonder if part of the reason moderna has gone after resectable melanoma is because they have access to clinical material to enable sequencing and neoantigen identification on. Without that, you would struggle to identify which targets to go after.

I have received a response back to the email I sent, which has some really interesting and insightful views.

Burble: We saw during covid that mRNA vaccines, due to their inherent stability issues require low-temperature cold supply chains. Do you think there is any potential in this space for us to move away from mRNA based vaccines and look at other nucleotide formats such as a DNA based vaccines which would require less of this end to end cold chain?

I am not sure we have optimized vaccines with the mRNA approach. It is certainly worth continuing to look at other approaches, but mRNA has features (safety, ease of development, built in adjuvants with lipid nanoparticles as well as inherent “danger signal” of free mRNA) that make it an excellent vaccine format.

Burble: Do you think we will ever have the opportunity to move towards a more ‘one size fits all’ approach with this type of cancer vaccine rather than needing to make a bespoke vaccine for each individual patient. From a manufacturing perspective this would help reduce cost and the time it takes to manufacture?

Maybe. I think we will be able to make better tumor specific antigen vaccines targeting shared antigens. Whether these are better than personalized neo-antigen approach will need to be sorted out in randomized trials. Life will be good if we have to run those trials, since it will mean that both approaches help people.

Burble: From a clinical perspective, what do you see as the challenges/opportunities within this space going forward?

Roll out is a challenge. Having useable tissue that yields high-enough quality mRNA and DNA to run the sequencing to inform vaccine development is not a given. This will be the biggest issue from an individual patient perspective. The manufacturing issue is overcome-able, but obviously it would be much easier to have an as effective, off-the-shelf vaccine with similar or greater efficacy.

Burble: My final question comes more from my own curiosity. Do we see recurrence in these patients, or do patients who respond well to treatment have long-term protection from metastasis due to the T-cells generated being on surveillance around the body for other metastases?

There are certainly patients who recur, but it seems that recurrences distantly are dramatically lower, suggesting that there is a better anti-tumor memory population of T cells generated.

Dalester - have done just that. Will see whether I get a response back.

So results and the investor presentation Tuesday next week!

Excited

I finally managed to get my hands on the following publication https://aacrjournals.org/cancerdiscovery/article-abstract/13/6/1278/726966/mRNA-Vaccine-Slows-Melanoma-RecurrencemRNA-Vaccine?redirectedFrom=fulltext titled 'mRNA vaccine slows melanoma recurrance'.

This looks at data from the phase IIb KEYNOTE-942 trial which combines moderna's mRNA-4157/V940 with keytruda (pembrolizumab). Briefly this vaccine consists of highly personalised nanoparticle-encapsulated mRNA molecules encoding 34 patient-specific neoantigens. 157 patients, following surgery were randomised 2:1 to receive the vaccine, every 3 weeks for a total of nine shots. At 18 months, the combination cut disease recurrence 44%.

What stood out was the following few quotes.

‘for the first time with a melanoma vaccine, we have randomised data showing a hit of benefit; past trials with different approaches – peptides, dendritic cells, viral vectors – all failed’ said Ryan Sullivan, MD of Mass. Gen. Hospital…’the question now is, are we seeing benefit because this vaccine serves as a nice adjunct to pembrolizumab, providing more T-cell populations with antitumor activity? Or is the key the mRNA platform itself, which seems to be fairly potent delivery system’.

Is Scancell flying beneath the radar? Are people being selective in what they’re quoting? Are people discounting DNA vaccines because mRNA vaccines are in vogue at the moment in this post-covid world?

Then there is a section which goes on to talk about the tumour mutational burden and its relevance to neoantigen vaccines. Where basically they say that TMB may not matter and this ‘could be due to immunodominance’…’whereby out of multiple neoantigens presented, immune responses are skewed towards just a few’….’the problem is there’s no good way to detect immunodominance and it’s still poorly understood’. The article then goes on to quote Jeffrey Weber MD from NY University’s Langone Medical Centre saying ‘bottom line, the number of neoantigens isn’t as important as having the right one’.

This makes me chuckle. Basically, Moderna is throwing the kitchen sink at each patient, taking 34 patient neoantigens, making each patient a bespoke vaccine, and hoping that one of them works and the patient’s immune system generates a potent T-cell response against this. If you choose the wrong ones, the patient gets no or limited benefit. Add to that the additional cost and time taken to produce.

Scancell on the other hand is an off the shelf, with multiple epitopes encoded within the SCIB1 backbone. Yes there is a skill in choosing the right antigens, but once you’ve done that once, you just make it in a large batch and deliver.

If we aren’t fully on everybodies radar….at what point do we start to be.

Dracula,

Yes SCLP is trialling a different method. The process of generating and using a CAR-T involve harvesting a patient's T-cells, then genetically modifying them in the lab to generate the T-cell. Then reinfusing this back into the patient where it gets to work tackling the patients malignancy.

In both the immunobody platform and the moditope platform, the T-cells are generated using the natural mechanisms that exist in the immune system. In the case of immunobody, the DNA platform is translated and transcribed into proteins which contain the appropriate cancer epitopes (targets). The immune system is presented with these and then generates T-cells against these targets.

In the case of moditope, short modified peptides are presented to the immune system which then generates T-cells against these targets.

So unlike CAR-T cells, you're not doing this in a lab. You're just using the patient's own immune system to do the job for you. So v.different. Therefore the news coming from the CAR-T world is interesting, but shouldn't really concern scancell.

Also did you know that statistically 6 out of 7 dwarves are not happy.

C7, good to hear from you! Life throws us all a curve ball at times, but I'm glad you're still with us! Fingers crossed that this is the year SCLP can turn a corner and you get to see the end game and how that plays out! Wishing you well. Burble

Following on from CWs post.

Also important to highlight of those 15 blockbusters coming off patent, seven are antibodies:

- humira - adalimumab

- keytruda - pembrolizumab

- stelara - ustekinumab

- opdivo - nivolumab

- xgeva - denosumab

- cosentyx - secukinumab

- entyvio - vendolizunab

So theoretically, if Avidimab were able to be incorporated into any of these and demonstrated to work better than the parent, these companies could potentially look to extend their patent life by producing a second generation therapy.

Https://www.thetimes.co.uk/article/ai-car-system-is-a-wake-up-call-for-drivers-and-investors-cwjfsw7km

TF

I agree with what you’re saying, but how do you get people to read an RNS. Youve got to entice them in.

Scope trial, to me sounds like something a company that makes medical equipment would release. Endoscope, microscope etc.

A single word or a handful could have changed that RNS and made it more interesting to people who maybe have no idea what Scancell is about (especially given we are listed as Scancell Holdings, not Scancell Pharma).

For me instead of ‘Update on scope trial’ any of the following would be an improvement.

- update on SCOPE melanoma trial

- update on SCOPE DNA vaccine trial

- MHRA approval granted for SCOPE trial

Or permutations of the above.

I don’t have time to read every RNS put out by every company. I read the ones which have a title that draws me in. If my interest is peaked, I start researching the company before making a decision to invest or not. Without good RNS title, I just gloss over them

‘

We have said this before, so often the RNS title does not fully reflect the information held inside. It doesn't need to be rampy but 'Update on SCOPE trial' does nothing to fuel interest in the company. As others say, detailed RNS titles could help support a higher share price..

for those people new to the board, can i just draw people's attention back to slide 20 and 21 of the 2022 agm presentation (https://www.scancell.co.uk/data/sites/1/media/docspres/agm-presentationnovember-2022_final.pdf).

we known scib1 is performing well in the scope trial with a current objective response rate of 85%, but patients eligible for this trial are limited to patients with hla-a2 (meaning only 40% of patients are able to join this trial and benefit from this treatment).

iscib1+ includes multiple epitopes which means that it can be used to treat all patients. it also includes sclp patented avidimab modifications which enhance the efficacy and also extend the patent life (making it more attractive to potential partners).

on slide 21, we see in mouse models after 21 days, scib1+ (without avidimab) has a demonstrable effect, with reductions in tumour volume. this is improved significantly further, by the addition of the avidimab modifications with iscib1+. i assume that the control is just the c56bl mice and not comparing this to standard scib1.

if you look at the right hand ******-meier survival curves, (again comparing scib1+ without avidimab to iscib1+ with avidimab) we see further improvements in survival of these mice. for reference, 50 days post tumour implant is equivalent to 5.5 years human time. also note that after a patient has been in remission for 5 years this is the time clinicians usually consider a patient to be ‘cured’.

so in summary: this news (and if this translates through to clinical benefit) regarding iscib1+ means

- increased potency

- increased efficacy

- greater patients able to benefit from this

- larger market size

- extended patent life

and like the original scib1 in trial this is:

- not a personalised medicine (which is a positive)

- an off the shelf product

- cheap to produce

- easy to store (doesn't need low temperature storage like mrna drugs)

- easy to deliver (needle-free).

Fantastic news! Ray, I was thinking the same. Clinicians know the results are good, they knew this was coming. Wouldn't surprise me if we get a recruitment completed for the iSCIB1+ cohort RNS sooner than their timelines. Hopefully their timelines are conservative and this proceeds quicker than previously. I know LD has previously said that the expanded patient eligibility criteria should speed up recruitment.

That's really good to see! Fingers crossed that we get some traction.

Sorry pressed post message too soon.

Meant to add this 'The company also noted at that time that it had received MHRA correspondence which paves the way to a test of iSCIB1 in the first quarter of their next year (May-July).'