What's Next for LNP Vectors and mRNA Vaccines?

1:02 
Hello, everyone. 

 
1:04 
I am Yuji Kasuya from Daiichi Sankyo. 

 
1:05 
Thank you. 

 
1:06 
We are now developing the LNP mRNA COVID-19 vaccines locally in Japan. 

 
1:15 
That is 3 almost three years behind the major LNP mRNA vaccine for COVID-19. 

 
1:23 
But I believe that to think about what's next for LNP vectors and mRNA vaccines. 

 
1:33 
So I believe I am not three years behind that topic. 

 
1:40 
So thank you very much the people of Oxford Global to discuss the what's next for LNP vaccines and thank you very much for all participants to share. 

 
1:56 
This time I would like to enjoy the discussion of the what's next for LNP vaccines. 

 
2:04 
I have working for drug delivery for more than 25 years. 

 
2:10 
The LNP and the liposomal formation is one of my life, job, life work and the other is research of antibody drug conjugate and then so I would like to start the next LNP formulations of next generation. 

 
2:36 
Thank you very much. 

 
2:38 
And would you give the Roger, would you give a self introduction? 

 
2:47 
Yeah, yes, thank. 

 
2:48 
Thank you very much, Yuji. 

 
2:50 
Good morning. 

 
2:50 
Good afternoon. 

 
2:51 
Good evening, everyone. 

 
2:52 
I'm Roger Adami, I'm the Vice President of Pharmaceutical Sciences and Business Development at Nitto Biopharma. 

 
2:59 
I'm based out of San Diego, CA, and I've been working here for almost a decade. 

 
3:05 
We work in Nitto Biopharma on LNP delivery systems and therapeutics. 

 
3:09 
So we have a number of products in the clinic and partnerships with large pharma as well as partnerships with biotechs in a variety of different arenas developing LNPs for systemic extra hepatic delivery to different organs. 

 
3:24 
So I'm looking forward to the discussion and happy to answer or discuss any topics the panellists would like to discuss. 

 
3:34 
So thank you. 

 
3:37 
OK, to discuss. 

 
3:41 
Oh yes, no, you just yes, thank you. 

 
3:43 
OK, thank you. 

 
3:45 
Thank you, Roger. 

 
3:46 
OK, so to start the discussion, I will, I would like to give you 2 slide showing the to facilitate the discussion. 

 
4:03 
This slide is showing the positioning of mRNA vaccines in delivery formulation. 

 
4:12 
Can you share the slide? 

 
4:16 
We see, we can see it. 

 
4:18 
We see. 

 
4:18 
Would you like to go to full screen mode, slide mode? 

 
4:24 
Sure, I will. 

 
4:28 
OK. 

 
4:31 
It's better I think. 

 
4:32 
Yeah. 

 
4:34 
Thank you. 

 
4:36 
OK. 

 
4:36 
This slide is showing the positioning of mRNA vaccines in delivery formulation. 

 
4:44 
First of all, we need a cargo for API and optionally the targeting moieties. 

 
4:54 
So for mRNA vaccines, Sorry, first of all, I'm not a native English speaker, so my speak is slow and I would like to ask you to speak clearly and slowly as far as you can. 

 
5:17 
OK. 

 
5:18 
So to select the cargo formulation, LNP formulation is selected for mRNA vaccines to think about the what's the next? 

 
5:33 
So we needed to consider the other cargo such as water soluble polymers, particles, micelles, sometimes exosomes. 

 
5:44 
So we do, we would like to discuss which cargo is better or LNP is better. 

 
5:55 
If you think about the net, what's next? 

 
6:00 
In addition, we can use the targeting moieties for LNP formulation. 

 
6:09 
Actually, the current LNP mRNA vaccines does not use the targeting moieties to think about the next. 

 
6:21 
We may use the targeting technologies for next LNP mRNA vaccines. 

 
6:30 
And also we have established in a drug delivery field the LNP formulations for mRNA. 

 
6:43 
However, the formulation technology is not limited to mRNA that can be applied to small molecules or nucleotide peptide proteins. 

 
6:58 
So we can develop the technology of mRNA, LNP mRNA technology to other API modalities. 

 
7:12 
Basically, the current LNP mRNA vaccines, the classical or conventional delivery system has been applied and that is proved successful even in the pH responsive lipid formulation. 

 
7:36 
So the concept is proposed about 30 years ago by Doctor Karis, Peter Karis, so that we establish the technology throughout development of LNP mRNA vaccines. 

 
7:57 
Then we should think about the to improve the LNP technology of next generation. 

 
8:12 
The next slide I would like to show you the key message for discussion. 

 
8:19 
The significant and detailed knowledge about LNP has been acquired through the development of LNP mRNA vaccines for COVID-19. 

 
8:33 
That delivery technology was well validated throughout this process. 

 
8:40 
The impact and usefulness and sometimes the limitation of the delivery system has been recognised widely in pharmaceutical research and development that is not limited among the drug delivery scientist. 

 
9:01 
The drug delivery technology isn't now the very major field of research in all our under the of pharmaceutics today discuss. 

 
9:18 
We have shown the discussion topics in advance as shown here and I would like to ask for all participants for some comments or questions for any of each topics. 

 
9:46 
OK, does anyone have a comment? 

 
9:50 
OK. 

 
9:51 
Sorry, Roger. 

 
9:52 
No thank you. 

 
9:53 
I was going to say the same thing. 

 
9:54 
Maybe we just open up to the panellists to see if there's any initial questions or topics for discussion that there's an interest in. 

 
10:01 
And if you do have a question, if you could introduce yourself and the company you're from that would be great. 

 
10:09 
Thank you. 

 
10:12 
Hi everyone. 

 
10:13 
I'm Shashank Pinnapireddy from CSL Behring and I had the nanoparticle research at CSL Behring. 

 
10:20 
I primarily had one question regarding LNPs for vaccines. 

 
10:24 
Why would you want to pursue active targeting? 

 
10:27 
What's the rationale behind that? 

 
10:32 
Yeah, thank you very much for your question. 

 
10:35 
So the your question is related to there's a need for more competitive drug delivery systems, OK, So by that is related to availability of mRNA when we inject the mRNA formulations. 

 
11:03 
So intramuscularly the very limited amount of mRNA is utilised and that leads to a protein expression. 

 
11:16 
So we needed to understand the availability of mRNA in each process. 

 
11:25 
That process include the recognition of the of nanoparticle by the targeted cells and also the LNP needs to be endocytosed into the cell. 

 
11:43 
The process is very that is much smaller than the 100%. 

 
11:54 
If we needed to, if we can successful in improving the ratio of endocytosis, the we can reduce the dose of the vaccines that leads to the cost reduction of the vaccine price and also after the endocytosis. 

 
12:17 
So the mRNA should be released into the cytosol. 

 
12:24 
The process also that there's a very low availability. 

 
12:31 
So if we improve the process of you know the endosomal escape of mRNA that also did these to the reduction of mRNA dose. 

 
12:46 
So by to achieve the improved availability we may need a active targeting technology that is a target of next research. 

 
13:04 
Yes, but usually for vaccines you would pretty, I mean pretty much always aim for an IM intramuscular delivery and we are not aiming for any specific organ here. 

 
13:15 
And how would a active targeting moiety help in a better endosomal escape? 

 
13:20 
I mean, it's more or less in there to the particle itself and not to the targeting moiety, right. 

 
13:31 
Yeah, I was going to comment that. 

 
13:32 
Yeah, I agree with your comment there. 

 
13:34 
I don't believe that in a vaccine it requires an active targeting moiety. 

 
13:39 
It is primarily an IM injection, at least at this stage. 

 
13:43 
So yes, I don't think that it would be necessary. 

 
13:46 
And ultimately the target of the vaccine is recognition of the expressed protein. 

 
13:50 
It's not so much the LNP itself. 

 
13:52 
And ideally you wouldn't want the LNP to necessarily induce the immune recognition. 

 
13:57 
Otherwise you might have consequences for subsequent re administrations or for next, you know, vaccines that you'd want to create. 

 
14:05 
So really, it's not so necessary. 

 
14:07 
And I don't think that there's a, at this stage of you that you would have to have active targeting. 

 
14:11 
The active is really for systemic therapeutics to really try and buy us away from the liver, ideally get to novel cells that wouldn't otherwise have a specific kind of, you know, passive tropism in the LNP. 

 
14:24 
So you can engineer, you know, reasonable amount of distribution to different target organs passively, but they get to very specific cell types. 

 
14:31 
That's where you'd look to go through an active modality. 

 
14:36 
So I'm not sure if it is a targeting active targeting, but if we can degrade the internalisation process and you know the endosome escape process by using the some bispecific molecules that can be used to the improving the bio availability of mRNA. 

 
15:10 
OK, thank you Roger for your comments. 

 
15:12 
Thank you. 

 
15:13 
Thank you very much for your question. 

 
15:15 
Can I make one comment, one topic, my name is Venkat from Takeda Pharmaceuticals, Boston, MA. 

 
15:26 
So I want to discuss about, I know these are good topics and the storage of the vaccines because of the storage limitations. 

 
15:36 
So these most of these LNP vaccines are not available worldwide. 

 
15:42 
So is there any companies or any researchers working to improve the LNP technology suitable for widely available throughout the world? 

 
15:56 
I can quickly answer. 

 
15:58 
In our company Netto Biopharma, we have lyophilization technology. 

 
16:02 
So we do create lyophilized LNP drug products that are significantly more stable even in some of the frozen that the current frozen generation of vaccines. 

 
16:14 
You know, as you're probably aware, remarkably, even under frozen storage, some of the mRNA can degrade. 

 
16:20 
But that's one approach to try to further enhance the stability and certainly the transportability of the drug products. 

 
16:28 
It makes it much easier to ship them around the world if they're not in a frozen form. 

 
16:35 
Yeah. 

 
16:36 
Instead of, you know, combining LNP with the some polymeric CPNs. 

 
16:43 
Does that help to improve the stability? 

 
16:49 
So if you have any comments about that approach, Yeah, thank you very much for Bank. 

 
16:56 
So we are very interested in that point. 

 
17:02 
First of all, the freeze dry formulation of LNP and the liposome. 

 
17:09 
We have a very long history of as you know the formulation research, we should apply the knowledge of freeze dry formulation of the liposomal formulation to LNP mRNA formulation. 

 
17:30 
So there is a we know that some several cryoprotectant protect the LNP aggregation. 

 
17:41 
So in the process of freeze dry and the reconstitution that however, what is important is acceptance criteria. 

 
17:55 
We should not we cannot completely avoid the some aggregation of the particle, but if we can control the extent of aggregation, that may be good to. 

 
18:13 
In the practical use, the acceptance criteria is dependent of the each product. 

 
18:21 
We should very careful evaluation to set the acceptance criteria and also the criteria is dependent on the application administration route. 

 
18:40 
We think if we apply the this formulation intramuscularly, the may be a severe control of particle size is necessary. 

 
18:55 
But some people are thinking about the, you know, the mucosal administration of vaccines. 

 
19:04 
They in the administration route, the acceptance criteria of maintenance of the particle size aggregation may be different. 

 
19:17 
So we should think about the to control the, you know, the particle size. 

 
19:25 
So we should think about the how the LNP is applied. 

 
19:31 
OK, thanks. 

 
19:34 
And Venkat, I'm not certain what you're considering as far as a polymeric excipient, whether that's something that you'd have in the bulk to help stabilise the LNP or something that you'd have complex to the mRNA directly to try to further stabilise it. 

 
19:47 
It really depends. 

 
19:47 
But I think in general there's you know, some, you know, reasonably traditional lyophilisation approaches that can significantly stabilise the particle. 

 
19:57 
We have particles now that. 

 
20:00 
Have more than five years stability in a lyophile format and yeah, that's a 2 to 8° storage. 

 
20:06 
So we know can confidently extrapolate possibly to even room temperature storage for a period of time. 

 
20:13 
And that's really the ultimate intent is to have something much more transportable, easily stored and obviously stabilising the mRNA in the vaccine use. 

 
20:24 
So do you have further elaboration on what you're thinking with the polymeric excipient? 

 
20:30 
You're. 

 
20:31 
Well, yeah, I think, you know, mostly the lipids have some limitations. 

 
20:37 
You know, most of these companies have specific IP for specific lipid and that is another, you know, you cannot use those lipids. 

 
20:47 
Mostly those are proprietary lipids and that's why people are exploring other options other than lipids. 

 
20:56 
Beyond lipids, combination of lipid polymer, other excipients might deliver not only to the specific cells. 

 
21:06 
Maybe we can attach targeting molecule because the polymer offers so many arms. 

 
21:12 
So you can load the targeting moieties and improve the selectivity and also the stability. 

 
21:19 
I know a few people are working in this area. 

 
21:22 
There's a professor in UPenn actually is interested in and there are a few companies in Boston area they are exploring these options, but they're far away from physical trials. 

 
21:34 
So whether they're successful or not, we don't know that yet. 

 
21:40 
Yeah, thank you. 

 
21:43 
Especially from you imagine a few concepts that I've already did not say deal with and since a few years, even decades ago. 

 
21:51 
It's to be honest, sometimes some of these concepts looks like quite complicated from the research side. 

 
21:59 
It might be very sexy. 

 
22:01 
It might be from, let's say from small studies, but you've also considered to manufacture them robust to large scale. 

 
22:08 
If you consider this, it becomes much more complicated to make a robust product. 

 
22:13 
I think we have to never forget the COVID situation with LNP was an urgent situation. 

 
22:20 
Maybe the world was in the phase. 

 
22:22 
Yeah, we have to find something and you have to pay for it finish to better debate was easy to get. 

 
22:27 
I would guess if we did this urgency is not there and just developing that your new vaccines on the let's say the regular regime that we have. 

 
22:36 
It could be that the word reacts differently. 

 
22:41 
Yeah, I understand that one. 

 
22:42 
Yeah, there's complexity involved. 

 
22:44 
You know, all these new concepts may not turn into your product. 

 
22:48 
Yeah, I understand that one. 

 
22:50 
But people don't then get the idea. 

 
22:54 
They are curious whether it work. 

 
22:57 
If it works, there's a big win actually. 

 
23:00 
So, yeah, in the 1st generation, the COVID vaccines had a spec for the mRNA at 50%. 

 
23:07 
So they didn't have to have such strong stability for the long term. 

 
23:11 
And I believe that was with the SEC methodology by the way to analyse for that stability with which is even more of a lenient approach. 

 
23:18 
It's not based on for example, CE or some kind of a fragment analysis. 

 
23:24 
So I think that yeah, that the vaccines were kind of a unique situation that had to kind of come into place very quickly. 

 
23:31 
But down the road then it'll be more traditional. 

 
23:33 
And in those limits, those specs would have to be set much higher than 50%. 

 
23:38 
In my understanding, FDA at the moment will accept 70% stability of the mRNA for the product. 

 
23:46 
So for you know the reconstitution of the LNP that is more stable compared with liposomal formulation. 

 
24:01 
In the liposomal formulation is it is difficult to reconstitute the shape the drug. 

 
24:13 
Drug leakage cannot be avoided. 

 
24:19 
However, in the case of LNP mRNA formulation that is a complex formation inside the LNP structure. 

 
24:31 
So we can maintain the structure of LNP mRNA, and the main target is a how the you know the particle, each particle can be, you know redispersed when we reconstitute it. 

 
24:57 
So do you have any, you know, additives or surface modification to avoid the aggregation and be generated each particle during the process of freeze dry and reconstitution? 

 
25:17 
This topic, if we break down this topic, the classical or classical formulation technology has may have the key we can combine the conventional formulation technology to this LNP mRNA formulation. 

 
25:41 
That's maybe some good solution. 

 
25:44 
Maybe do a good solution for freeze drives formulation of where LNP mRNA. 

 
25:51 
Usually it's not a huge problem for pegylated particles when you re suspend them. 

 
25:56 
And the main point of freeze drying for this is for the stability of the mRNA rather than the nanoparticle itself. 

 
26:05 
And like Rosa said, we also have similar processes in space in place for freeze drying of these particles. 

 
26:12 
And we didn't test them over years but or a few months. 

 
26:16 
And even at 4°, they are quite stable up until six months. 

 
26:21 
That's what we've tested upon freeze drying. 

 
26:26 
I was going to make a maybe general comment that from our experiences and we work with a huge variety of different systems, lipids, different compositions, including multiple types of RNA, DNA, oligonucleotides and mRNA. 

 
26:40 
And it's not from our viewpoint, there's no general global, you know, situation that says this is an, you know, in every case, for example, we don't, you know, we have plenty of liposomal, you know, unilamellar, multilamellar particles as well as LNPs, which are more of the unstructured internal sort of complexation of lipid to the RNA directly. 

 
27:01 
To me, that's what differentiates a lipid nanoparticle from a lipid liposome with the true kind of bilayer. 

 
27:08 
And what we see is it's more dependent really on the nature of the lipids. 

 
27:11 
So for example, if you have an unbound, ionizable non charged lipid, it more impacts that longer term stability because there's nothing really to, you know, hold it together. 

 
27:21 
There's no scaffolding, if you will, that the RNA can impart. 

 
27:24 
The RNA, you know, fundamentally acts as an internal type of scaffold to hold the particle intact. 

 
27:29 
And so depending on your lipid combinations, you could have a charged lipid where that intact, you know, scaffolding interaction through that ionic binding is very strong and the particle will definitely remain intact. 

 
27:42 
On the other hand, if you go ionizable, it can tend to more unravel and have less stability over time. 

 
27:48 
So I think those are scenarios. 

 
27:49 
There's no to me one absolute like, you know, LNPs have one property, or liposomal structures have a different. 

 
27:55 
It's more dependent in my experience with the nature of the system, the interactions between the lipids, the type of lipids and it gets very complex. 

 
28:04 
So you know, branched lipids, you know, it's single tail depending on the nature of the lipids length that the picture gets, you know more and more complex. 

 
28:14 
But just so if we are successful in a freeze dry and the reconstitution of just to maintain to regenerate the shape of LNP no aggregation. 

 
28:31 
So this means we can store the an appropriate conditions where the mRNA stability is maintained. 

 
28:46 
So to realise the freeze dried formulation. 

 
28:50 
So the to avoid the aggregation of LNP and to regenerate the each particle. 

 
28:59 
That is a key. 

 
29:01 
If we are successful, the mRNA stability is dependent on the temperature. 

 
29:08 
So if we are successful in the freeze dry formulation of the shape of LNP mRNA, we can set the two to 8° storage condition for mRNA. 

 
29:27 
Maybe one point, Roger, you mentioned the word complexity was LNP. 

 
29:32 
Certainly something which makes it a little bit more complex at all is the huge variety of excipient, let's call it that way that I need it. 

 
29:40 
So more or less everybody use a new lipid which at the end need somehow to be manufactured under GMP condition. 

 
29:49 
However, the point is we don't make lipids, but we make an mRNA. 

 
29:54 
This is API who then governs the corresponding biological, physiological response. 

 
30:00 
If you consider how many exhibits you have in the classical business, let's take liquid formulation, you have the excipients like citrate, so deployed. 

 
30:07 
This is really quite limited amount of the people who work with this and develop the drug around it. 

 
30:13 
The point that I see something in this field is a huge variety of lipids that are developed, tested. 

 
30:21 
Sometimes it's quite a bit complicated. 

 
30:24 
The people get lost in it and also they're basically everybody makes his own little bit of cause Academy IP around it clear. 

 
30:31 
But you will not really boost the field because a lot of people will not do it. 

 
30:36 
It's becoming a little bit complicated. 

 
30:39 
And then something also we have to think of cause we can have, you know, have some sexy ideas to make it fancy stains and some photos. 

 
30:48 
I think Shashank already mentioned some targeting here, targeting there. 

 
30:52 
But it is really our a is not better to have let's say a drug that is really available stable at a certain temperature that you can distribute in the world and go with that even if you may just 90% of efficiency, but at least you can use it worldwide. 

 
31:13 
Yes, that's very true that there's quite a bit of a competitive research on different lipids and I think the systems are somewhat complex at the moment. 

 
31:24 
I believe that the dominant sort of recipe, if you will that most people pursue is that for lipid composition. 

 
31:31 
And you know, two of the lipids are pretty general grass reagents, I would assume cholesterol. 

 
31:37 
And generally with the helper it could be, you know, the DSPC, DOP, it depends on which choice. 

 
31:43 
But then you have the PEG lipid and then your cationic proprietary lipid. 

 
31:46 
Generally that's really where I think there is that variety and diversity at the moment. 

 
31:51 
But the, those cationic lipids, I think you know, there are really a handful that I think have become the dominant sort of carrier systems, if you will, you know, MC-3 in the liver and then the more recent ones, the SM-102, ALC-0315 for, you know, the vaccines, those are the big branched ionizable lipids. 

 
32:12 
So it's not a huge universe, but certainly there's quite a bit of research. 

 
32:16 
We have our own proprietary lipids and by the way, we do licence them to other companies. 

 
32:21 
So if there's interest that's one of our business models here at Netto Biopharma's licencing LNP carriers as to the development of therapeutics and vaccines. 

 
32:34 
But yeah, I agree with the point. 

 
32:35 
I think it'll consult, I think this is still relatively early days in the whole scheme of things for the LNP arena. 

 
32:42 
I think of it, I always call it the Model T era of our field. 

 
32:47 
It'll improve dramatically and become quite, I think, sophisticated. 

 
32:51 
And the way I see that aspect is, you know, the vaccine world or the viral world has moved to strip away complexity from viruses to try to make a minimal virus. 

 
33:01 
But there's still a limitation and you know, some constraints they can have in terms of, you know, the size of the cargo, the repeat dose ability. 

 
33:09 
It's almost unheard of at this stage to repeat dose of viral vector. 

 
33:13 
And then on the LNP side, I see it the opposite, where it tends to incorporate more and more complexity, sort of approaching a virus, but not quite reaching that level and then ideally getting all the components and features you really need to deliver the cargo. 

 
33:28 
And so those two never will converge, I believe, in the centre to meet kind of an equivalent viral that, you know, gets stripped away down to a minimal vector or an LNP that gets complicated up to a viral style. 

 
33:40 
But I do think the LNP world is moving more and more like that's where the targeting comes in. 

 
33:44 
Now you're getting a protein corona that you're essentially conjugating to the surface of particles. 

 
33:50 
So it's getting more complex in that regard as well. 

 
33:54 
Yeah, I'm sorry, I cannot catch up the old discussions now this topic, but I have some personal thinking. 

 
34:08 
So the screening of LNP is very complicated and there is a, you know, the patent, the complicated patent, there are complicated patent in the situation what is important as a drug delivery scientist is to find the real is a useful technology. 

 
34:34 
Then we can to realise for commercialization we should make us a partnership and patent exchange or something. 

 
34:45 
I don't know. 

 
34:46 
But yeah, what is important is a practical technology. 

 
34:51 
The screening is like something like the screening of API. 

 
34:57 
The, you know, the 30,000 molecule, 1 of 30,000 molecules, we can find 11 API. 

 
35:08 
The screening of LNP is something like that. 

 
35:13 
What is important is to find the really the practical formulation technology we should seek for that. 

 
35:22 
OK, thank you very much. 

 
35:30 
Are there any other questions or other discussion areas that people would like to focus in on? 

 
35:37 
Oh, we'll discuss more about the route of administration. 

 
35:40 
Is it possible for oral delivery? 

 
35:44 
Ora, yeah, I'm very interested in it that is related, that's related to mucosal administration of vaccines that it's not a part oral absorption is not the necessary not possible. 

 
36:03 
So to realise the activity of oral mRNA vaccines that is a mucosal administration of mRNA vaccines. 

 
36:20 
So to reach, to deliver the surface of GI tract, we can, we have a lot of technology that is a capsule, conventional capsule which is enteric coating coated. 

 
36:37 
So the mRNA vaccine can be encapsulated in enteric coated capsule then we need a mucosal mRNA vaccine technology. 

 
36:52 
So that is a very the target of the next LNP vaccines. 

 
37:04 
Do you have any comments or some recent topics of mucosal mRNA vaccines using cationic repeat? 

 
37:17 
The repeat composition of the nature property of a cationic repeat should be different when we inject intramuscularly or on the trans that you know the mucosal administration? 

 
37:36 
Yeah, I think that's a great question about the oral and I think it depends on the systems. 

 
37:41 
I know in the oligonucleotide world that's being heavily explored for siRNA and that's, you know, that can be obviously very chemically stabilised. 

 
37:51 
It can undergo, as you were saying, you know, enterically coated to withstand the stomach acidity into the intestinal condition, but then it transports more directly through a direct conjugate. 

 
38:03 
So the for an LNP, I think that's the question you have is whether you could do oral for an LNP into the gut mucosa. 

 
38:10 
And through I agree that it's generally very challenging and probably there's a lot of lipidases and other kinds of components that could degrade and metabolise away these particles. 

 
38:21 
But on the other hand, the potentially could be some transporters that could be looked at as possible intra kind of intestinal delivery through, you know, kind of different. 

 
38:36 
I don't know that's an active area of research, but it's possible that down the road that might be an area of investigation. 

 
38:45 
But I think the main area right now is the oligo side where it's intended to more traffic directly as almost a small molecule kind of agent rather than through a nano particle maybe more also. 

 
39:01 
Well, if we could realise the oral or intranasal application of mRNA vaccines, that means we can avoid the injection. 

 
39:13 
This means the mRNA vaccines can be distributed widely in the global. 

 
39:24 
No injection is necessary and it might depend also if the intent is to have the activity in the intestinal mucosal cell line layer there or if your intent is to try and get systemic through oral. 

 
39:37 
There are some companies working on swallowable capsules that do effectively like a micro needle injection in the intestine. 

 
39:46 
And so that's another approach that some companies are investigating. 

 
39:50 
I haven't seen that necessarily applied in the mRNA context, but it is a neural macromolecular drug delivery approach. 

 
39:58 
So these are truly mechanical little capsules that have a little needle and would effectively give you an intestinal injection. 

 
40:08 
So I don't know if that solves the problem, at least for chemical delivery. 

 
40:16 
Thank you Roger for some very important information. 

 
40:27 
Any other comments or questions about the any of each topic so? 

 
40:43 
So about preparation, I would direct to propose that talk about the preparation for next pandemic some there is some interest in some of the participant. 

 
40:59 
So maintenance of the facility for manufacturing mRNA is necessary, but each pharmaceutical company it is hard to maintain the huge manufacturing facility for LNP formulation. 

 
41:24 
So that needs, you know, the specific facility, specific machines to form the. 

 
41:33 
I think on. 

 
41:34 
I think on a long run except for a research scale, it is not sustainable for the pharmaceutical companies to maintain LNP and MRI. 

 
41:42 
And almost always the answer would be outsource or go for CDMOs in this regard. 

 
41:47 
And there are quite a few nowadays, a lot actually than two years ago. 

 
41:54 
Yeah. 

 
41:55 
So if we think about you mean the CDMO in the points standpoint of CDMO, they also it may be harder to maintain the facility. 

 
42:08 
It's true. 

 
42:09 
It would be the same for them as well. 

 
42:11 
Yeah. 

 
42:12 
And also that is the case for, you know, the consumable. 

 
42:16 
But the thing is we should look at it that this way the CDMOs don't just cater to the pandemic or vaccine areas, they also cater to other areas for where LNPs are applicable. 

 
42:29 
So they're always making or manufacturing LNPs on a large scale or even if it's not for production, but also for scale up purposes for development. 

 
42:41 
And I don't think there would be a huge gap they would have so serious problem using so collaborating with CDMO. 

 
42:52 
OK, thank you very much. 

 
42:54 
And also as a pharmaceutical companies approach the use application that we need to enhance the art under the project that use this technology for you know that no pandemic, but some conventional vaccines and also we can develop other applications such as no vaccine that is oncology or some other field of disease. 

 
43:34 
So once we establish the LNP mRNA technology, manufacturing technology, we can go to the other therapeutic and prophylactic area field, then the facility can be activated by a multiple R&D. 

 
43:59 
So do you have any, do anybody have some interest or some comments about the application of LNP technology to other areas such as oncology? 

 
44:17 
Yes, you know, I was going to ask maybe if we could briefly, you know your interest or what areas you're working on in within. 

 
44:25 
Are you doing it for therapeutic applications in your company's vaccine or technology? 

 
44:33 
So Venkat, you mentioned your ticket is, are you developing the therapeutics? 

 
44:37 
Yes, we are mostly focused on therapeutics, not vaccines. 

 
44:42 
So the difference is LNPs for vaccines and therapeutics. 

 
44:49 
Vaccines maybe, perhaps you may need one or two shots, that's good enough and there's prophylactic. 

 
44:56 
Whereas for therapeutic you have to administer frequently maybe once in a month or yeah like that. 

 
45:05 
So repeated dose administration is critical, you know, in therapeutic area and toxicity is very important. 

 
45:13 
Lipid toxicity, LNPs the quality, the kind of LNPs the lipid composition is a critical therapeutic communications and of course the nature of the you know, the cargo and stability, all these other issues. 

 
45:29 
So the difficulty in therapeutic area is the lipid composition that is the critical. 

 
45:38 
So what about the dose? 

 
45:40 
The there is a big difference in the dose of yes, those also, yeah. 

 
45:46 
Dose encapsulation efficiency and stability all those are important formulation criteria, but in terms of the nature of the lipids should be extremely safe and it should be biodegradable and did not accumulate any organs and bio distribution is also important. 

 
46:09 
So in terms of vaccine all these is not necessary actually maybe one or two shots the most of the lipids used in vaccines are not suitable for therapeutic applications. 

 
46:23 
Definitely that's true for even from the physical chemical perspective because they are usually charged slightly and they are made in such a way to invoke immune responses at the site of injection at least. 

 
46:36 
Yeah. 

 
46:39 
And I think there's still a remaining body of learning in the systemic application of the mRNAs for therapeutic use because the, you know, the current application is primarily in the vaccine. 

 
46:50 
And even Moderna made a big strategic decision to focus primarily on the vaccine applications. 

 
46:56 
And it's not clear if that was strictly because of the complexity of the systems or the cost. 

 
47:00 
I know their doses are very low. 

 
47:03 
They were, you know, 30 and 100 microgram doses for the mRNA vaccines. 

 
47:07 
And then they even lowered it later for the boosters, at least Moderna did, I believe it was 50 micrograms, their final dose level. 

 
47:14 
But that's substantially lower than the therapeutic applications where generally these are being looked at it, you know, up to maybe a mg/kg, generally lower, but even 1 mg/kg is not out of the question in some of the applications Where I think the question still remains, at least in my mind is the nature and the immune stimulation of the RNA in an LNP that's intended for systemic cause. 

 
47:40 
The SI world is really controlled. 

 
47:43 
You have a duplex very small and chemically controllable API that you can eliminate the vast majority of small fragments and other things and just primarily have a very clean stable duplex form of the RNA. 

 
47:56 
The mRNA is a completely different starting point where you have quite a bit of fragmentation, quite a bit of small pieces that could really elicit, you know, very strong immune response. 

 
48:07 
I think those will be some of the challenges for longer term, you know, systemic applications is really ensuring that the circulating particle itself doesn't trigger it. 

 
48:15 
And that's I think been overcome. 

 
48:16 
We have a lot of programmes where we dose repeatedly for six months and we look at PK, we don't have any evidence of accelerated blood clearance. 

 
48:24 
So I think the LNPs themselves in the RNA cargo itself can be managed in the way that you don't have that. 

 
48:29 
I think it still remains to be seen just to what extent that those issues can be overcome for the mRNA world. 

 
48:35 
Yeah. 

 
48:38 
So I think those are some of the big challenges for the field moving forward and especially as they get larger and larger. 

 
48:45 
I know that there's a lot of emphasis now on programmable and self-replicating RNA, especially ones that have kind of a replica or replicates inserted. 

 
48:55 
They get quite large, even as high as 10 kilobases or bigger. 

 
49:00 
And then it becomes a very labile entity and very hard to work with to ensure you have the stability and it does not fragment, you know, there's just different layers of challenges. 

 
49:12 
I think that's another point. 

 
49:13 
It's just a general broad comment around the field. 

 
49:15 
I think from, you know, the RNA in the SI arena when it was small, could be standardised on a fairly common template where you could assume that the sequence could change. 

 
49:25 
But overall, the general physical properties of that RNA were the same mRNA. 

 
49:31 
Now on the other hand, is totally different secondary structures, different folding, different lengths and other properties. 

 
49:38 
So I think there's a very unique kind of case by case scenario. 

 
49:42 
So there's certainly no one-size-fits-all. 

 
49:44 
So even if you have a very good robust formulation for one RNA, you may truly have to tweak and optimise it and formulate differently for the other RNA. 

 
49:53 
And that could even be a case where your research looking at a distribution or activity through a reporter such as luciferase or GFP, and then you transition later to some kind of therapeutic construct. 

 
50:05 
And they're not necessarily similar in other factors. 

 
50:09 
So you almost have to go back to the drawing board to reformulate. 

 
50:12 
But the therapeutic construct sometimes substantially, sometimes just minor tweaks. 

 
50:19 
It just depends. 

 
50:21 
Yeah. 

 
50:22 
So in the case of LNP formulation LNP siRNA and LNP mRNA. 

 
50:30 
So there is a not so big difference between the formulation of the particle. 

 
50:36 
And however, if we apply the other technologies including lipoplex, water soluble polymers, the polymeric nanoparticles, there may be a big difference when we apply this technology to siRNA to or mRNA. 

 
50:58 
So because that is because of the big difference in the molecular weight length. 

 
51:03 
Yeah, this is a specific issue for each modality, siRNA and mRNA. 

 
51:20 
I think if we have a few more minutes, I was just going to bring up another topic. 

 
51:27 
I don't know if there's interest in the targeting side of things or you know, in the future of the field. 

 
51:33 
I think there's a lot of interesting technologies that have emerged recently. 

 
51:36 
What one that seems to be gaining some traction if you keep up with the latest and greatest is the PNP and that does not stand for polymer and nanoparticles anymore, which it used to. 

 
51:46 
Now it's the protein nanoparticles. 

 
51:48 
So that's even a new one where it's being essentially engineered and it's not necessarily an exosome either. 

 
51:55 
So these are proteins, I don't know if you've seen some of the publications, they have a specific protein, PEG 10 protein that's sort of a capsid style protein from a virus and it encapsulates an RNA that's very specifically designed to interact with that PEG 10 protein through the UTRs. 

 
52:12 
So there's a lot of new things in the horizon that really are kind of advancing. 

 
52:16 
I think those will be, by the way, equally fraught with their own challenges for immunogenicity, stability, size considerations, etcetera. 

 
52:25 
So I don't think there's going to be any trivial way to get around some of the issues the fields are facing. 

 
52:31 
But I think the LNP offers in my opinion, the most versatility and a true mimetic of natural systems. 

 
52:38 
I mean, in essence to me, I think of it as a synthetic exosome. 

 
52:42 
It doesn't have all the same protein components, but it's essentially a, you know, enveloped kind of particle. 

 
52:49 
So a lot, lots of things that are, I think very interesting. 

 
52:52 
I don't know if there's interest to discuss briefly. 

 
52:55 
Take a few minutes. 

 
52:57 
And those arenas any I think we have a handful of attendees still and any other areas of interest or chat, maybe we can just make some final comments then in I think we're approaching the hour about four minutes away. 

 
53:31 
So maybe Yuji would you like to start with some final words? 

 
53:37 
OK. 

 
53:40 
Thank you very much for nice information and some idea. 

 
53:48 
So yeah, I'm, I learned much about this. 

 
53:54 
What LNP and mRNA delivery system today? 

 
54:00 
Thank you very much for all top participants including the panellists and Roger. 

 
54:07 
OK, thank you very much. 

 
54:09 
And finally I would like to ask Roger as a closing remarks, is that OK? 

 
54:18 
Yes, thank you very much Yuji. 

 
54:20 
And yes, thank you to all the panellists and the questions and the interactive discussion. 

 
54:27 
I think it's a great, you know, great opportunity to get together with other individuals in the field to really share knowledge and learnings and try to bridge toward a new kind of therapeutic modality that, you know, frankly, I personally believe will become one of the dominant modalities in general just across the board. 

 
54:47 
When oral or lingos replace small molecule therapeutics at a genetic level, I think it's game over for every therapeutic approach. 

 
54:56 
It'll just be an oral oligo and injectable mRNA, maybe even oral mRNA. 

 
55:01 
So I think the field has a very exciting, you know, future. 

 
55:04 
I think as I said earlier, my view is it's still very early days, sort of the Model T era of the technology. 

 
55:11 
We'll certainly look down the road at what we've achieved as a field in 20-30, forty 50 years. 

 
55:17 
It'll be very different, but it's an exciting time to be part of it. 

 
55:21 
So, you know, hopefully we can continue these conversations and have some future opportunities to share learnings and thank you very much.