Exploring mRNA’s Potential

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Chris Spivey, editorial director, hosts a wide ranging discussion on the COVID-19 pandemic response, future government communications, and healthcare funding for mRNA with experts Dr. Kate Broderick, Chief Innovation Officer, Maravai LifeSciences and Dr. Tom Madden, President & CEO at Acuitas Therapeutics. Highlights include supply chain modalities, ensuring a fully trained manufacturing workforce, combining delivery with gene editing innovations, epigenetic approaches to modulate gene expression moving toward the clinic. We conclude with the huge potential for RNA expression of monoclonal antibodies and protein replacement applications.

About the speakers

Dr. Kate Broderick, chief innovation officer at Maravai LifeSciences has extensive experience and expertise in leading and liaising with multi-disciplinary groups from discovery and R&D to engineering and clinical teams. She brings strong and broad scientific expertise to TriLink Biotechnologies, which covers multiple areas, including gene delivery, medical devices, gene therapies for the treatment of various infectious diseases, cancer immunotherapies and vaccine development. Additionally, she has extensive experience with non-viral delivery systems for a wide range of vaccine targets and cancer immunotherapies.

Dr. Thomas D. Madden, president & CEO of Acuitas Therapeutics, is a world-renowned expert in the area of nanotechnology. Dr. Madden co-founded Acuitas Therapeutics in February 2009 and has guided the company into its position as a global leader through the development and application of lipid nanoparticle (LNP) technology. Acuitas Therapeutics partners with leading pharmaceutical and biotechnology companies and prestigious academic institutions around the world, providing its proprietary LNP delivery technology to enable new drugs based on nucleic acid therapeutics.

Pharmtech: So, thank you very much for making the time today to speak about an increasingly important topic, which is mRNA coming out from obscurity from a few years ago. We're very lucky to have two genuine experts in the field, and I'll let them introduce themselves.

Kate: Thanks so much, Chris. It's a pleasure to be here today and to join Tom in this exciting discussion. My name's Kate Broderick. I am the Chief Innovation Officer at Maravai LifeSciences. We are a San Diego based technology provider for developers in the field of nucleic acids. We are most associated with is the CleanCap technology, which was, of course, a component of the Pfizer-BioNTech vaccine. Prior to joining Maravai, I've spent my entire career as a nucleic acid drug developer. And so it's really exciting to be here today and to talk about this incredible technology and the power that it holds.

Tom: Good day to you both. Great to meet you, Kate. Looking forward to your comments and your thoughts. Like yourself, I am from the UK originally. Came out to do a postdoc at the University of British Columbia imagining I'd be there for a couple of years and never quite made it back. My background is in academia. I've worked in research at the University of British Columbia, held a position there for a number of years. The work we were doing had direct relevance to clinical applications, and so I moved into biotechnology. And I've spent almost all of my working life in development of delivery systems for a variety of new types of therapeutics. I think mRNA is now the most exciting opportunity to truly make significant advances in human health. I'm the president and CEO of Acuitas Therapeutics, which partnered with BioNTech and Pfizer to provide our delivery technology to them for the COVID-19 vaccine. And our team was incredibly proud of the accomplishments from that collaboration and for their opportunity to contribute to a solution to the COVID-19 pandemic. And so, again, delighted to be here, and looking forward to the conversation.

Pharmtech: Its been very interesting to see a platform go from, arguably a four letter word, on the investment side of things, to a household name. Is the question mark in the science community totally removed from mRNA as a working therapeutic platform?

Kate: I do think it is worth reminding ourselves that the general public didn't know anything about mRNA as a molecule until 2020, and now it's used routinely in your daily lexicon. And I do think that's quite an astounding thing that occurred during the last few years. From the perspective of scientific background, has the platform been proven out? I would say absolutely. I think none of us could have hoped to have seen the efficacy that we saw during COVID with the vaccines. It was startling, it was like a poster child for everything you want in an infectious disease vaccine. But I will hasten to mention, THAT is not carried through to the general public. Whilst everybody embraced it during a global pandemic, I think there are really worrying signs now that the public are starting to drift away from the power of the science, and that is a real concern for me.

Tom: Do I think it's a proven platform? Absolutely. One of the things we need to remember is mRNA is a natural molecule. Each of our cells is translating tens of thousands of copies of mRNA every minute. So, it's not as if we've come up with a new entity that we're then introducing to people, this is something that their body's recognizing, and they're used to dealing with. I do agree that there's a continuing need to educate the public, to educate regulatory officials and governments, who have the power over decision making relating to new vaccines or therapeutics, to ensure that the science message continues to be heard. Because I totally agree with Kate, I think the biggest challenge is in misinformation that is just rife out there in the- in the world.

Pharmtech: Do either of you have a way of reliably addressing public misconception or the politicization of this field?

Tom: The way I think of mRNA vaccines is that they're a much more elegant way in which we can train our immune system to be able to combat a potential infectious agent. In the past, we've simply taken attenuated virus, the whole attenuated virus or killed virus, injected that into our bodies, and then relied on the protective effect from that. Viruses contain all sorts of proteins and DNA or RNA. I consider mRNA vaccines as a simpler more elegant, and arguably safer alternative, to conventional vaccines. And conventional vaccines have demonstrated decades of safety. So, I think concerns over the new technology are truly overblown.

Pharmtech: I couldn't agree more. Look at the birth control issue, however. Settled science is still discussed in the public forum because there aren't enough strong voices able to, sort of overwhelm, that.

Kate: I think Tom's explanation is just spot on there. As you reflect on operation warp speed, what was achieved was absolutely phenomenal and incredible work. But when you listen to General Gus Perna, outlining retroactively, what did they do right, and what they did wrong, the number one thing they wish they'd done better, was the communication part of it. Of course, we all had so many things going on during the pandemic. But, you know, reflecting back, perhaps that was a miss for us, as the scientific community to go out there and really talk through exactly what Tom said. This is a natural molecule, this isn't something that's completely foreign to the body. But I do think that we as the scientific community need to own that. Maybe now's a good time to say that organizations like the Alliance for mRNA Medicine (AMM), which is an advocacy group, which has a lot of purposes really both in the scientific community but also for the general public, is we need. We need to make the public comfortable with RNA-based medicines, because this truly could change the face of healthcare. But if nobody or if only a small portion of the population are willing to take it, then the impact is really for nothing. And so I do think that that is something that perhaps at government level we should be taking extremely seriously.

Pharmtech: You talk about mRNA as a natural molecule, but we did tweak it, we used N1-methyl pseudouridine, for example, as a modification, which is a natural modification. But that is where some of the contending voices come in. They point to something like that as if it's a problem or a potential problem. On the science side, is there a way to explain to, let's say an astrophysicist or someone who doesn't know biology, why you have such a good comfort level with this platform?

Tom: Again as you say, even the modified nucleotides are modified nucleotides that are found in nature. I think you could also point to examples of vaccines generated with modified and unmodified mRNA constructs, and in fact the safety profile is probably even more favorable for the modified nucleotide construct. So, I think there is certainly a strong scientific basis for it. I think when we're talking about disinformation though, sadly the science is often trumped by fear. I echo Kate's comments that having a number of different companies trying to get out the message as to the safety and effectiveness of these types of therapeutics, that is far better achieved by an umbrella organization, a coalition like AMM, which can hopefully speak with a single voice. But also, as I say, I think we want to continue to educate scientists and regulators around the world. And again, I think one of the directions that AMM is intending to take, is to be an expert group or to bring together expert groups, who can advise on specific topics relating to these new types of therapeutics.


Pharmtech: Looking back at the pandemic on communication from the regulators, and from the big companies, they improved their ability to communicate, and were even talking to competitors. So, switching gears, from a manufacturing perspective, what sort of major obstacles or opportunities would you prioritize?

Tom: One of the areas where we're using mRNA is in the development of personalized cancer vaccines. It's an early clinical stage of development. There's some encouraging clinical data, but there's a great deal more work that's needed. So the challenge that provides is the exact opposite of the challenge we had with the COVID-19 vaccine. Not how can we make kilogram or ton quantities of vaccine, but how can we make very small quantities of vaccine suitable for individual patients? And so that's one of the areas where we're working and others are working is in trying to automate and miniaturize the manufacturing process so that we can, and I'd invite Kate to speak about this on the mRNA side, because you need to generate individual mRNA constructs that are patient specific and then formulate those into an LNP so that they can be administered to that patient in a very short period of time. Obviously, if you're a cancer patient, you don't want to be wasting any longer than absolutely necessary to receive the vaccine. So, that's certainly one area of focus and of challenge that I know a lot of people are engaged in. The other area obviously is being able to disseminate the manufacturer of vaccines in a wide number of countries. One of the problems we had during the pandemic is manufacturing sites were based in a small number of locations. And I think we want to ensure that countries have more access and control over vaccine supplies in the future. And so there's obviously a number of initiatives, looking as far as possible to automate the manufacturing process so that it can be available for more local distribution.

Kate: Tom is so right. I truly hope that in 5 to 10 years chemotherapy becomes something of a redundant treatment, and that we're looking really at much more bespoke tailored approaches to cancer. But to emphasize Tom's point, there was a beautiful study that came out of a large group in the UK called the TRACERx Study where they actually monitored people's cancers over time and fairly frequently. And, you know, within the matter of a month, some of these tumors had completely changed their neoantigen profile. So, to Tom's point, the need to have really unprecedented speed to make this, the promise of personalized vaccines prominent, I think it is absolutely key now. Many people, of course, scaled up during the pandemic, which is a major stride forward, for the field. I think now keeping those manufacturing plants warm, I think that's going to be a challenge, Fingers crossed that we don't have another global pandemic. I think an issue that was really pertinent during the pandemic was supply chain. There's a lot of work that needs to be done on the supply chain side, and certainly the US government's very keen on looking at modalities to do that. There are still a lot of elements that need to be tackled. Another interesting one, that might not occur, is that during the pandemic a major struggle for the manufacturers was having trained workforce. So, ensuring in some ways that perhaps we partner with academic institutions so that we're actually training the next round of manufacturers with a potential need for future pandemic preparedness. We need to think a little bit outside of the box, about the experience we went through, and what we can do to ensure that we have preparedness moving forward.

Pharmtech: Pain points present opportunities for doing a better job next time. Can you marry an mRNA platform to another technique, let's say gene editing or something like that?

Tom: Absolutely. We're working with a number of partners on a variety of gene editing approaches. There are two potential delivery options for gene editing, one is viral, one is non-viral. I think people are recognizing the advantages of a non-viral approach because you can redose patients, it's not a one-and-done therapeutic. And so, we are supporting a number of partners developing a range of gene editing modalities. What surprises me is how that field is growing, and how the technology around gene editing is improving, to avoid cutting, using base editing, prime editing, and so on. There are important ethical discussions around how and where gene editing therapeutics should be applied. Those are going on, and again, possibly an area AMM should consider engaging if you're not doing so already, because the delivery aspect is also critical there. But I think it's an area that has enormous potential. We're also working with partners, looking at a variety of epigenetic approaches to modulate gene expression. This whole field is extremely vibrant at the moment. There's a lot of nascent science that is moving towards the clinical. I think it's going to be a very exciting time over the next several years, particularly as we get more clinical data coming out, hopefully confirming the earlier studies demonstrating the utility of gene editing in particular applications.

Kate: I think Tom eloquently covered the editing profile, but I think as we're looking at the massive strides forwards that, for instance, Vertex is making towards the potential first approved product. But if I could play devil's advocate to that, if the public are having concerns about mRNA-based vaccines, you could extrapolate that they may have equally large, if not more concerns about things that could potentially edit their genome, really just coming back to that need for education. But on top of really the CRISPR editing applications, think about the potential for RNA-based expression of monoclonal antibodies. That is an enormous market that could allow us to utilize the power of monoclonals in places where, for instance, due to, just the environment, that would be impossible. So lets think through what the potential as a messenger this molecule could do. Protein replacements, another obvious application, the sky to some degree is the limit. But we do need to think about how we message this, pardon the pun, to those who would actually benefit from it.

Pharmtech: Beyond the vaccines, there's a lot of interesting uses. However, you would then need to get ahead of the public education part, because what is the point if people aren't going to, as you said earlier, accept this as a modality So, where would you head next if it were all left to you?

Tom: We generally work in sort of lockstep with our partners. So we are looking at where their clinical interest lies and trying to ensure that we support that. And I agree with Kate. I think recombinant, monoclonal antibodies have been incredibly important clinically and commercially, they can be challenging and expensive to manufacture. And I think the idea of using a messenger RNA, so simply encoded and have the patients generate the monoclonal antibody and glycosylate the monoclonal antibody themselves, I think is very attractive. And there are examples of these therapeutics in clinical development at the moment. I totally agree. I think we need to get ahead, of the public in terms of educating the public as to the potential benefits of this. There's an even bigger challenge when you're talking about gene editing or epigenetic modulation. And I don't think it's too soon, to give serious thought to, how can we ensure that there's a recognition of the clinical need. What are the patient populations that truly need these novel therapies, that have no other options available to them? And what are the safety studies that have been conducted and are being conducted to demonstrate that these therapies aren't going to change the gene line? So that science is going on, but I don't think there's any sort of conversation or there's very limited conversations happening with policymakers or regulators. They are occurring, but it hasn't risen to the level of the general public at this point.

Pharmtech: Are there any misperceptions or myths about mRNA that we could debunk in a quick way? Some of the adjuvants that were included in the vaccine evinced cardiac issues. I think that that was debunked. But there were a couple of others.

Kate: Well, Chris, yours is a perfect example. So it was debunked, but Elon Musk was just tweeting, or what you X-ing it now, or whatever you call it now, just recently about the young gentleman, the basketball player, - it wasn't direct that it was caused by the Covid vaccine, but there was definitely a, - but was it caused by the Covid? And that's a real problem. And I think, yourself, Chris, Tom and I could speak for the rest of the day about the, quite frankly, ridiculous notions that were tied to RNA-based vaccines. But whenever there's a grain of something, it's just being amplified. And certainly isn't helping when we have people like Mr. Musk putting that out on social media.

Tom: I think one of the things that is lost in the conversation is, even if there were some cross-reactivity between the spike protein and other components in the body, generally where we are seeing any safety signals from the vaccine, those are far more prevalent. Those same safety signals are far more prevalent in individuals infected by the virus. And that's lost in the conversation. The vaccine can't in any way, elicit to any extent, any of the side effects that you see with the virus. I think that's just an unrealistic expectation.

Pharmtech: Would you like to emphasize anything in particular or conjecture about something that you think would be of interest?

Kate: The future for mRNA-based or RNA-based therapeutics is so incredibly bright. I am at wonder at the potential of this platform and at the applications that we can have a meaningful benefit on. And I am so positive from a scientific perspective that that will be a reality in a fairly short manner of time. But I come back again and sorry for being a broken record, that I have major concerns about how we can do better at communicating the science in a meaningful way to the people who need to be convinced.

Tom: I completely agree with Kate. I think the versatility of the mRNA technology really lends itself to trying to address diseases which have historically eluded a vaccine approach, - malaria, HIV, tuberculosis, because we can express multiple different antigens, multiple variants of different antigens. As Kate mentioned earlier, we can rapidly adjust the constructs that we use, the antigens that we express to meet individual geographical requirements. There's a huge potential there to truly advance human health. But, as we've said before, I think the biggest challenge is misinformation, misperception as to what these vaccines are and what they can do. And I agree, people have to be willing to stand up and speak the truth and try, as I say, to be an advocate for this truly remarkable technology.

Pharmtech: A great emphasis, thank you, to finish on because FDA grasped onto the reconfigurability of the platform in a big way already. It's a genuine delight to talk to you both.