Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show,

Dr. Sean Kane  00:32
hey, HelixTalk listeners. This is Dr. Kane. Before we get into today's episode, I want to let you know that we originally recorded this with Dr. Martin on November 23 2021 since that time, several things have happened, including moderna's Full FDA approval of Spike Vax, the mRNA covid 19 vaccine. We don't talk about that in the episode because we didn't know it at the time back in November, but I thought it was important that you the listener, know that this was recorded several months prior to it actually being published on HelixTalk.com and now, without further ado, on to the show. Welcome to HelixTalk, Episode 144, I'm your co host, Dr

Speaker 1  01:09
Kane, and I'm Dr. Patel. And in today's episode, we have a guest speaker to talk up and coming. Exciting thing the title of our episode is mRNA technologies and their implications in therapeutics, Q and A with Dr. Martin, so the sheer mention of the word mRNA kind of brings in the light of the, you know, covid 19 vaccine in the market. Dr. Kane, we have kind of recorded some covid 19 related episodes recently, but today's episode, we're not focusing on the vaccine so much we we instead want to dive in the depths of the science, the technology behind the mRNA and how it's here to reshape the future of therapeutics and healthcare in general. And in order to do that, we bring in the best of the best, Dr. Danielle Martin, a medical science liaison from moderna. Welcome to the podcast. Dr. Martin, thank you. Thank you so happy to be here at this point. Dr. Martin, would you like to share any disclaimer you have from moderna?

Speaker 2  02:12
Sure, because of what we will be discussing, I'm required to share moderna's forward looking statements and disclaimer. This is lengthy, so it has been posted on your website. HelixTalk.com in short, any statements I make in this podcast episode are not promises or guarantees of what to expect from moderna or mRNA medicines in general, and any statements are based on moderna's current expectations and speak only as of the date here, of

Dr. Sean Kane  02:38
Well, Dr. Martin, as Dr. Patel mentioned, you're an MSL for moderna, and I think from the audience's perspective, it might be nice if they could get to know you a little bit better. So could you kind of give us a sense of what your day to day life is like within moderna, and help the audience understand you a little bit more

Speaker 2  02:54
sure, of course, first, thank you guys so much for this opportunity to chat with you today. It's a pleasure to get the chance to talk to you and your audience about moderna and our mRNA technology platform. So as you stated, I am a medical science liaison or MSL at Moderna, and I cover the Midwest territory, and MSLs are typically individuals with a background in science and an advanced degree, including degrees such as PharmD, PhD or MD. Personally, myself, I have a PhD in microbiology and immunology with a background in virology, and so thinking of my role as an MSL, my primary role is to engage and build relationships with thought leaders and healthcare providers and share clinical data and answer any clinical medical questions. So a typical day for me includes making appointments to meet virtually with experts in the field give clinical presentations. So essentially, I am a resource to healthcare providers where clinical and medical information are specifically right now our covid 19 vaccine, mRNA 1273, however, I also speak to providers to learn about their thoughts on the data, so it's kind of a give and take relationship. And I asked them what they think is missing, as far as data gaps, their experience with the vaccine uptake and safety and any challenges that they're having in their clinical setting. And I take these insights that I learned in these conversations back to moderna to help guide future clinical strategy and help make a better and more useful product. So in a nutshell, my job is to build relationships, educate and learn, and as we know, product development should be collaborative, a collaborative effort between pharma, biotech, and those individuals in the healthcare setting, like healthcare providers who are using the product firsthand.

Speaker 1  04:48
This is very impressive. Dr. Martin, it sounds like you are kind of like the liaison between the health experts and the company and the you know, and the science behind it. So thank you for that introduction. Of what you do. You know, moderna has become a household name, but what most don't know about is the company's origin, history and its mission and vision. Can you please tell the audience a little bit about moderna, what it does as a company, when was it established, and what are their mission and vision?

Speaker 2  05:20
Okay, of course. So moderna was founded in 2010 and it is headquartered in Cambridge, Massachusetts. And since moderna is founding, they have pioneered the development of modified messenger RNA or mRNA medicines. And moderna's mission is to deliver on the promise of mRNA science, to create a new generation of transformative medicines for patients. So we are a leader in this space, and we have advanced more than 20 programs using modified mRNA technology into development. The mRNA platform is especially innovative more because it allows for the research and development of novel vaccines or therapeutics at a speed that was previously not feasible. So when utilizing this platform, drug products can not only be made at a faster speed, but also produced at a large scale as well, which is important, especially as we saw during this pandemic and moderna is committed to corporate social responsibility, which is very important to me personally, and we have demonstrated our efforts to be inclusive when it comes to studying our vaccines, and aim to provide effective and affordable vaccines and therapeutics to all populations. And this was seen, for example, in our phase three trial study for our mRNA 1273 covid 19 vaccine. And we refer to this study as the cove study, and in the study, 37% of enrolled participants were from communities of color, similar to the diversity breakdown seen in the US population. And this was a very intentional effort during the trial to make sure that the data collected from this study would represent people from all backgrounds and ethnicities.

Dr. Sean Kane  07:09
Dr. Martin as someone who teaches pharmacy students with respect to clinical trial design and interpreting clinical trials historically, this was a huge issue, and we're not going to get into it during this episode, but trials that were done in the 1990s were not appropriate in terms of the demographics of the US and things like that. So kudos to moderna and the team involved in that CO study for making it a more representative study. I think that's really important.

Speaker 2  07:33
Yeah, it was really important to me, especially a person from a diverse community. I really thought that that was really excellent.

Dr. Sean Kane  07:40
So in terms of the name, moderna, kind of clever name. It sounds kind of like a modern RNA. You know, everyone who's listening knows that. You know, covid 19 vaccines have this mRNA based technology in them from moderna and also from Pfizer. But really, mRNA, in terms of your company, moderna, it's a deep seated root of your company. It's literally in the name. So maybe we can talk a little bit more about the mRNA science behind the moderna mission and the therapeutics.

Speaker 2  08:08
Sure, sure. Yeah, the name is pretty unique. And from my understanding, it was initially mode RNA, until it was changed to moderna, and then the name is a playoff of modified RNA. And as many of your listeners probably know, mRNA is a naturally occurring cellular product that's produced in the cell, in our cells. So mRNA instructs the body to synthesize a specific protein, and it kind of acts as the blueprint, essentially. So mRNA medicines are a set of instructions, and these instructions direct cells in the body to make proteins to prevent or fight disease. So just to go through the process, mRNA enters cells and is used to produce viral antigen proteins from within the cell that include natural post translational modifications. And this process, it mimics the process by which natural viral infections occur, where and where information from a viral genome is used to produce a viral protein from within a cell, and this can potentially enhance the immune response, including an improved B and T cell response. Moderna has developed proprietary technologies and methods to create mRNA sequences that cells recognize as if they were produced in the body naturally. We focus on diseases where enabling targeted cells to produce or turn on one or more given proteins will enable the body to fight or prevent a given disease.

Speaker 1  09:36
You know, whenever I think about mRNAs, I like to geek out. I think that it's a pretty cool molecule and technology. You know, aside from this topic, Dr. Kane, the other day, I saw a license plate RNA DNA, and I'm like, Gosh darn it, that person beat me to it. But seriously, this this production of mRNA, and we know the science behind it, but how does Moderna take this science, start with one mRNA molecule, and transform it into drug innovation and development and create these advanced therapeutics. Can you describe a little bit more about the innovation to the development journey of such a development candidate, potential. MRNA molecule,

Speaker 2  10:23
sure, sure. Yeah. So when you're thinking about moving idea to development candidate, our mRNA research engine services moves new product ideas into the development candidate stage via our drug discovery efforts, and this includes an infrastructure to enable rapid supply of 1000s of pre clinical mRNAs for research involving in vitro, both in vitro and in vivo experiments, in order to accelerate programs from again idea to development candidate designation. So when our scientists come up with a new idea, an mRNA is designed for research and testing within days using, of course, proprietary systems, and our web based mRNA Design Studio is used to digitally design and order mRNA constructs to be used in pre clinical studies so existing proteins can be selected or novel proteins can be created from other sequences. So after this, the selected protein sequence is used to create an initial, optimized mRNA sequence using the sequence designer module. And this they can then tailor an entire mRNA from the five prime UTR, which stands for untranslated region, to the coding region, to the three prime UTR untranslated region, and the mRNA sequence is then further optimized using, again, proprietary bioinformatics algorithms. And so now we have the desired mRNA sequence that it can then be ordered through our digital ordering system, where further customizing to tailor specific properties can occur if that is needed, and the order is then submitted to our automated, high throughput production facility, where the mRNA constructs are then synthesized, and quality control assays, or QC assays, have been developed to ensure that these products are of high quality. So while the mRNA constructs are being synthesized, the scientists are on the other end, designing and planning their experiments and using a custom suite of design tools, a project management tool tracks the discovery projects and data results which are accessible and can be shared across the platform. And this helps accelerate the pace of understanding after the mRNA molecule advances to a developmental candidate, and from this point, a custom digital portfolio management tool can centrally coordinate timelines to move the development candidate through the process of in vitro and vivo experiments to get to the clinical trial stage.

Dr. Sean Kane  13:08
Dr. Martin, you kind of glossed over it, and I just want to highlight this a little bit. So this whole design phase that you were talking about going from tailoring your mRNA sequence to optimizing it, doing all this stuff. Did you say it was a web based interface in terms of designing that sequence?

Speaker 2  13:26
Yes, it is a web based so they're in, in that web based design studio, there are existing proteins that can be selected. As you know, essentially protein sequences are known where there's a big catalog and database where there's a list of different protein sequences, and if you know the protein sequence, then you can work in reverse and you know the mRNA sequence. So there are known protein sequences that can be selected from, and then there's also novel proteins as well that can be used to construct mRNA constructs as well.

Dr. Sean Kane  14:02
And I know I'm preaching to the choir here, but the fact that in 21 years, we've gone from the initial sequence of the human genome to now a web based interface to make a custom mRNA sequence that can then be studied in a clinical trial fashion, I think that 21 years going from beginning to end. That's pretty crazy. I don't I don't know if you share the same sentiment in terms of the rapidness of the technology and things like that.

Speaker 2  14:30
It is really remarkable. And I think that as more people understand it, when the questions arise of especially some of the questions that arose during the development of the covid 19 vaccines for the current pandemic. Of you know, how was this able to be done so quickly? Well, now we have so much information that's available. As far as knowing sequences and being able to design sequences based off of known protein sequences, it definitely is not. It's revolutionized medicine and science.

Dr. Sean Kane  15:03
And I mean, even on the pharmacy school side, you know, pharmacogenomics is a great example where we've gone from in a couple decades knowing not that much to knowing a ton about drug disposition based on pharmacogenetic characteristics and things like that. So this is really moving at the speed of light in terms of our understanding of the human genome and interactions with proteins and things like that. Totally agree. I did want to switch a little bit. So, you know, you kind of went through the process of basically how the mRNA sequence is designed in a on a web based interface, and then potentially how it's synthesized in a lab with quality control measures and things like that. I'm sure that's only part of the story, right? So just because you have the mRNA doesn't mean that it's ready to go in terms of, obviously, it's not orally bioavailable, so it needs to be injected. Can you tell us a bit more about kind of the delivery process to get that mRNA into a human being to exert its therapeutic effect? Sure.

Speaker 2  16:00
So delivery is really one of the three key steps involved in the mRNA platform. So mRNA is delivered via lipid nanoparticle, or LNP, is what I'll call it moving forward. And this LNP consists of multiple components, including an amino lipid, a phospholipid, cholesterol and pegylated lipid, a peg lipid. And each of these components is necessary for stability and efficient delivery of the mRNA cargo. The properties of the nanoparticles and therapeutic indications determine the administration route. So if the goal is to elicit an immune response, and like for example, in the case of vaccines, a local administration is optimal because resident antigen presenting cells are present in the skin and muscle, which can internalize and process mRNA encoded antigens. Furthermore, the vascular and lymphatic vessels of these tissues help antigen presenting cells and mRNA vaccines to center the draining lymph nodes to stimulate the B and T cell immunity.

Speaker 1  17:10
So Dr. Martin, I think this is very interesting. You mentioned a brief composition of the lipid nanoparticles, and I know along with the mRNA based vaccine, the lipid nanoparticle also is kind of becoming this growing and widely known word among the you know, scientific community, the science of drug delivery. In this case, the mRNA based, you know, therapeutic delivery is sort of like the essence of pharmaceutics, of what we teach students too, and we would love to know more about how these mRNA and lipid nanoparticles are co-formulated, because essentially this is together coming out to become a vaccine or a drug product. Would you be able to elaborate a little bit more on how the co-formulation occurs. Dr. Martin, sure, sure.

Speaker 2  18:03
So exactly. So, yes, the mRNA is encapsulated in lipid nanoparticles. So the lipid nanoparticle mRNA combination formulations are now commonly manufactured by rapid mixing. So the ethanol phase, which contains the lipid components, are mixed with the aqueous phase, which contains the mRNA molecules. And this mixing must be done under very specific conditions, like proper pH and flow rate. And the mRNA is susceptible to degradation. As probably a lot of your listeners may know, mRNA is very susceptible to degradation. I shouldn't understate that, and thus formulation buffer should be free of any ribonuclease contaminations. So the lipid nanoparticle mRNA composition formulations, they are then further purified to remove organic solvents and any residual components that may cause degradation of the encapsulated mRNA and the filtered and frozen lipid nanoparticle. MRNA formulations are then subject to a series of good manufacturing practices or GMP standard tests, including evaluation of physical parameters, for example, evaluating mRNA encapsulation, particle size, the charge, and other testing, such as sterility, bacterial endotoxins, particulate matter and just in general, other quality testing.

Dr. Sean Kane  19:34
So Dr. Martin, clearly, a lot more goes into mRNA based drug than just the mRNA, right? So, as you mentioned, the lipid nanoparticle, but also all the stuff that goes along with it that probably kind of flies under the radar a little bit with respect to many drugs that are approved on the market. And I think these mRNA based drugs are no exception to that. Correct, correct, definitely. So why don't we pivot a little bit to thinking more future-based, you know, clearly the COVID-19 vaccines have had a dramatic impact on this pandemic. But as you said, moderna was founded in 2010 where we didn't even think covid 19 was on the radar. So there must be other applications to, you know, mRNA based drug therapies that you can comment on, that maybe moderna has in the in the pipeline. Kind of the Sci Fi brain in me wants to know if chlorophyll based mRNA injections will be coming out at some point so I don't have to eat. I can just sit in the sun. I'm sure that's not on the pipeline. But maybe give us a better sense of like, what are realistic things that are likely to be seen either from moderna or, in general, from an mRNA based therapeutic approach,

Speaker 2  20:42
sure, sure. Well, I can't speak on the chlorophyll-based vaccines, obviously, but our development pipeline illustrates the progress we're making on moderna's clinical programs currently in development to create more mRNA medicines for a wide range of diseases and various conditions, and our pipeline focuses on several different modalities, including prophylactic mRNA vaccines, systemic secreted and cell surface therapeutics and exploratory modalities like Cancer vaccines, intra tumor, immuno oncology, localized regenerative therapeutics, systemic intracellular therapeutics. And there are currently nine prophylactic mRNA vaccines in our development pipeline now, and several prophylactic vaccines have been developed, including those targeting various viruses, which include RSV, flu and CMV. So focusing on CMV, for example, for a moment, CMV is a particular interest, because nearly one in three children are already infected with CMV by age five and an infant, CMV can cause really long term issues, some of those issues being hearing loss, developmental and motor delay, vision loss and seizures. Moderna CMV, mRNA vaccine has already undergone phase one and phase two trials in the US, and is in the process right now, actually in phase three, and we are proud to say now we have 37 programs in development, including 22 and ongoing clinical studies. So just to name a few more products in phase two or three trials, our RSV vaccine, Zika vaccine, and a personalized cancer vaccine and a VEGF-A for myocardial ischemia.

Speaker 1  22:37
Well, that sounds like a whole lot new and innovative use of mRNA technology, just even beyond the vaccine. But it's, it's very awesome to hear that this technology is going to be able to create vaccines for some of the viral diseases that we've had out there that you know, we haven't been able to find solutions for. So definitely very exciting. And now many of you here can relate to the following statement, but practicing as a healthcare provider in this super advanced era of biotechnology is super exciting, as we said earlier. Dr. Kane, 21 years and we are here. We have multiple protein sequences available. We're making mRNAs off of that. We're turning them into therapies, and we have seen the impact of mRNA based covid 19 vaccine on overall public health and healthcare. I mean, we have clinical data that these. You know, the science works in general. What is the future of this mRNA based therapy mean for our healthcare and healthcare providers.

Speaker 2  23:42
So it is a really an exciting time right now. There's a lot of innovation, a lot of great ideas, and mRNA science and technology is opening doors to approach diseases in a whole new manner. So HCPs will now have alternative therapeutics to address disease states that they couldn't address before in a way that they haven't had in the past. So for example, we are also applying our mRNA technologies I mentioned to the emerging field of immuno oncology. Also it's also referred as immunotherapy, and this therapeutic area involves harnessing the body's immune system to identify and kill cancer cells in the same way the immune system identifies and targets infection from pathogens. So one approach is to administer a cancer vaccine that encodes for peptides containing mutations found in that cancer, for example, to create a personalized cancer vaccine composed of Neo antigens that are unique to a patient's tumor, and Moderna's immuno-oncology programs are currently focused on two main areas, those areas being therapeutic vaccines and intratumoral immuno-oncology therapeutics. So just in a nutshell, mRNA technology has the potential to be used to develop therapeutics in various areas for very. Various modalities,

Speaker 1  25:02
you know, I think, I think that sounds very much like personalized medicine, you know, like to look at that patient specific Neo antigens and create a particular vaccine or drug for that particular patient. Sounds kind of like that car T cell therapy, Dr. Kane, and I think with that personalized medicine in general, the future of mRNA technology is sounds like limitless and bright.

Dr. Sean Kane  25:30
So, Dr. Patel, one thing that strikes me is how this is going to almost mandate a different way that the FDA approaches therapies like mRNA based therapies. You know, this is not the conventional drug approval process that we would see with methotrexate or cytarabine, but it's still really important for healthcare professionals and graduates to know everything about these therapies in terms of both these specialized preventative medicine therapies, but also therapeutic agents that literally are used in patient care as if it was a medication, because It is future healthcare providers are going to be the people involved in making decisions to start these therapies, to monitor the therapies, to talk to patients about these therapies. You know, this is an emerging field that's going to be really important for the future healthcare provider.

Speaker 1  26:15
And I 100% agree. You know, while the don't currently have so much focus in education world about these therapies, it certainly makes a case for lifelong learning and continuing education after graduation. You know, looking from research and development, production, regulatory standard standpoint, as we heard Dr. Martin say, how many people are involved behind, you know, developing a successful molecule. It really requires sort of a multi specialty approach, and kind of, you know, kind of reshapes the structure and organization of the traditional, you know, pharma companies or industries that we have known it so far. So it's gonna definitely take some realignment of learning, perhaps more Continuing Education and Lifelong Learning added to understand the therapy. And it certainly is an exciting time.

Dr. Sean Kane  27:10
Yeah, I would second that. I think that what's so important here is that this is going to be the future. Certainly we're still going to have our conventional therapies as well, but healthcare providers are going to be expected to know how to use and monitor these novel therapies, because they're going to be game changers for certain disease states. And I think that's really important and really exciting to think about. So for the listeners, if you want to see show notes from today's episode, you can access those at HelixTalk.com we're also on Twitter at HelixTalk, and I wanted to again, thank Dr. Martin for her participation today, she was an awesome person to have on to talk about moderna and mRNA vaccines and the future of mRNA technology. So again, thank you so much. Thank you so with that, I'm Dr. Kane

Speaker 1  27:53
and I'm Dr. Patel, and as always, study hard. And once again, thank you so much, Dr. Martin.

Unknown Speaker  27:59
Thank you so much for having me.

Narrator - Dr. Abel  28:01
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Narrator - ?  28:12
to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.