There are no bad ideas in developing bioanalytical testing, says Jim McNally, CSO of BioAgilytix. Not all ideas will work, of course. But he has found that it is the outside-the-box ideas that often turn out to be the solution in challenging assay work. Dr. McNally speaks with The Chain about his background in bioanalytical testing and supporting clinical trials, the exciting future of cell and gene therapies, and the importance of setting precedent in bioanalysis of these new, life-saving therapies. It is an exciting time for gene therapy especially, and Dr. McNally shares how new immunogenicity data is getting us closer to bringing this therapy to more people.

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Taking Risks and Setting Precedent in Bioanalytical Assays for Cell & Gene Therapies transcript powered by Sonix—easily convert your audio to text with Sonix.

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Hannah:
You're listening to the Chain, a science podcast through we bring what is new and biologics and protein engineering to the community of scientists working in the field.

Hannah:
We discuss the latest developments with leaders who are on the front lines of cutting edge research. For more on the future of bio therapeutic drug development, check out Pegg's Boston summit. For more than 15 years, PEX Boston has been the premiere networking and professional development event for Biotherapeutics drug development, research and collaboration. This year, Picts Boston takes place virtually May 11th through 13th to browse the twenty twenty one agendas and to register.

Hannah:
Please visit Pegg's summit dot com. Today I'm speaking with Jim McNally, Chief Scientific Officer of biogenetics.

Hannah:
Welcome, Jim.

Dr. Jim McNally:
Thanks, Hannah. Good to be here. Good to talk to you today.

Hannah:
In your work, you often advise on emerging scientific developments and offer regulatory guidance. Can you tell me about your background in bio analytical essays and what started you on this path?

Dr. Jim McNally:
Sure, yeah, you know, I I started out just interested in science in general, went to school with the original intent of being a biomedical engineer, but found myself fascinated by immunology. I took an immunology course and fell in love with the topic, you know, eventually ended up in industry and going into industry.

Dr. Jim McNally:
I really had no clue about bio analysis.

Dr. Jim McNally:
I took my first job in a very small company where you did a little bit of everything, and I was essentially the company immunologist.

Dr. Jim McNally:
But when I joined Genzyme, I joined essentially a bio analysis group and as my first real exposure to developing assays for bio analytical testing. And that's where I got a real taste for it. It's incredibly rewarding to be part of generating the data that's supporting clinical trials. And when I saw that happening, and it was fascinating to me, it kind of took me down that path of bio analytical support. And then ever since then, I've been involved in that space. Every role in every company that I've been a part of, I've been playing around in the bio analytical space since then.

Dr. Jim McNally:
So incredibly satisfying sort of experience and journey for the career so far.

Hannah:
Is there an early case study that you can talk about now or the clinical trials in your early career when you were working in the space that you remember that really like click that for you?

Dr. Jim McNally:
Yeah. You know, again, sort of that first experience at Genzyme, one of the first assays that I worked on, and I was still at the bench working developing assays. I was asked to develop a cell based assay for pharmacokinetic analysis. This is not typical or at least certainly at that point in time, it was less typical to use cell based assays to try to measure drug. But we got a specific request. I was put to me, it was incredibly challenging. We had a lot of difficulties and then literally stumbled into a solution that solved all of the assay problems after working on it for months and just walked backwards into the solution. And it played out. It worked out, became an implemented assay. And I think it was one of those things that not only, again, sort of got me interested in cell resources and immunogenicity, but an element of just Problem-Solving. You know, it's my favorite thing to do in this. I love challenging assay work simply because of that sense of satisfaction when you either solve the problem or stumble into the solution.

Dr. Jim McNally:
Sometimes it's better to be lucky than good, I guess. And in that case, I was lucky. But I really enjoy sort of digging in and trying to work with complicated problems no matter where it is home and work.

Hannah:
So we need that kind of thinking and especially nice when you can stumble into it, as you say.

Dr. Jim McNally:
Absolutely.

Dr. Jim McNally:
It's one of those strange things where you try everything that makes sense and it still doesn't work. And then it's the crazy outside of the box, you know, barely has a chance of working solution that turns out to be that solution.

Dr. Jim McNally:
So now when I try to teach other people and work with people and in assay development and problem solving, it's you know, there are no bad ideas, you know, and you maybe that are all work, but the crazy ones sometimes are the ones that will will pan out for you. So.

Hannah:
That's definitely a scary thought, you know, going with the crazy, but yeah, you know, if it works. Yeah, activity sounds like it's really needed.

Dr. Jim McNally:
Yeah, there's that part of it. I think it's also in that specific example, it was sitting down and scrutinizing the data and not just the numbers that were coming from the ASAY, but how did you get there in this particular situation? It turned out that it was an asset that had tons of background problems and we tried all kinds of blocking reagents and inhibitors and and things to try to clean up the background this year. But what I stumbled onto was that actually during running the assay a couple of times, I screwed up. I, I, you know, as I said, it was a cell based assay and it involved senator fusing the plates to pellet the cells and then aspirating media off of it. And a couple of times I refused it. Too many times I went through too many cycles. And what I found out was that in the runs where I had done too many cycles of of the washes, it actually reduced the background significantly. And if you got above a certain threshold of the number of washes, the background was completely removed. So by screwing up, I ended up finding out that if you did more than whatever it ended up being something like more than four washtubs, you could magically make the background go away.

Dr. Jim McNally:
And it was literally just the mechanical act of washing the cells more frequently to get the background down. And if I hadn't made the mistake of not following the original procedure, I would have never found it. So I guess there's a lot of lessons buried in there. So often what we do with the assay work, you don't realize, you know, it works some days and other days it doesn't work and you try and try and try to isolate. Well, what did I do on that day that it worked versus the days that it didn't work? And I think too often we look for the more complicated answer because it's somehow more satisfying as opposed to on this day. I actually I kind of screwed up, but it resulted in something that had an impact on the asay and really tearing down. Here's what I did this day versus the other day. I can make a difference.

Hannah:
That's great knowledge and our mistakes and leading to innovation and looking towards innovation and sort of like the future frontier of biases, in your words, you've called it sort of the Wild West cell and gene therapy, if you could talk a little bit about that.

Dr. Jim McNally:
Sure. Yeah, it's, uh.

Dr. Jim McNally:
You know, the Wild West is exciting, I guess, for a lot of people, especially I think for scientists and and for me in the Wild West means a couple of things. First of all, they're both young spaces, right? So from drug modality, cell and gene therapy are relatively new compared to things like monoclonal antibodies that we've been working with for quite some time.

Dr. Jim McNally:
So that's exciting. We don't know the answers, we don't have decades and decades worth of experience and hundreds of candidates that have been out there and you've worked on before these these are news.

Dr. Jim McNally:
So you get a lot of new areas. They also have added in another sort of component of the Wild West, which is a bit of control, lawlessness, because they're novel modalities. You don't have a lot of guidelines that are set. And for the time analysis of this, we're using new platforms that we haven't used before or in typical bio analysis. If you think in the cell therapy space, for example, I'll come back to sort of the whole cell based pharmacokinetic gossip. You know, for for most Biotherapeutics piqué analysis is done with, like, binding assays to sort of standard platforms that are available. But in the cell-based space, we're now looking at analyzing an entire cell and trying to quantitate it. So you're relying more on flow cytometry, molecular approaches that haven't typically been used for quantitate drug and pharmacokinetic analysis. So we're trying to sort of apply pharmacokinetic guidelines to new platforms, new types of analysis, which can be intimidating for some people because they like having a path trend for them. You know, we develop and assay this way. You've validated a certain way, test your samples a certain way. But for other people, this opportunity is to do something different, take what we know from the previous experience, but apply it into these novel situations, these new platforms and new data sets. And it's pretty exciting. And I think for someone like me, I really enjoy being part of it to help set the precedent for how we should do this. I want to be part of the discussion of what makes sense for this type of analysis so that we can be as directed and focused on our efforts to move these things forward as quickly as possible. The powerful therapies that could benefit a lot of people. And the more quickly we can understand them and move them forward, the more everyone will benefit from it.

Hannah:
Sort of benefit outweighs the difficulty in taking risks when you say Wild West, something I think of too is like, oh, it's dangerous and it's something to consider, as I'm sure you do in these cases.

Dr. Jim McNally:
Yeah, sure. And, you know, I think, you know, for a bit of dramatic flair, the lawlessness is probably a bit over the top. Right. I mean, we're trying to operate within a certain space, but it's more the idea of, you know, the guidance is for how to validate certain assays have been out there for a while, you know, for like and assays. There is a very clear path of how to validate a legally binding assay for quantitate drugs. But there aren't the same clear paths for how do you validate a quantitative flow cytometry assay in a set of circumstances where let's say if you take carti therapy, the drug given to one patient is not exactly the same as the drug given to the other patient. They're both the same KARTI. But the actual base cell that's used to generate the party is different for some individuals. So by definition, the assay has to be robust enough, but also flexible enough to address all these different car t cells that are being generated inside of a larger box of that particular drug companies design for the car.

Hannah:
And as you know, there are long standing regulations in place. But how how does the cell and gene therapy, how does FDA approval sort of differ from other modalities at this point since it's so new or doesn't?

Dr. Jim McNally:
Well, it differs one, because you're in different a different wing of the FDA in Sieber instead of Ceder in those cases. You also have you know, in both well, let's say in a lot of cases for gene therapy and in most cases for cell therapy, you have patient populations that are desperate for these drugs. You're not going into a lot of normal volunteer studies. For example, you're headed right into the disease population, but especially with car t therapies, you're typically in people with sort of late stage oncology settings.

Dr. Jim McNally:
So the.

Dr. Jim McNally:
The flexibility to deliver a potentially life altering or life saving therapy allows you to move a little more quickly so the trials can be somewhat smaller and faster, moving and leaner. But then also on the flip side of that, because you don't know exactly what are the right things to measure in a cell therapy. You're doing a lot of characterisations, a lot of additional measures. You, for example, you're collecting samples, but they're part of an immunological characterization. But you don't necessarily know everything that you're going to measure up front until you start to see the facts and say, OK, well, we need to look for Cytotec cells versus cytokine secreting cells. And you can plan and theorize, but you're trying to adapt on the fly. And a lot of cases. And I think with the agency there and this is really true in almost all of my experiences with them, they're open to it. They're a place where if you go to them, have these discussions, engage them, be part of the discussion with them. They're they're looking for the best interest of the patient and the program because we all want to help people. We're all in the same game. So I think working with them is similar in that respect.

Dr. Jim McNally:
But in these new therapies, they're open minded, too. They're starting to see more data. They see more data coming from more sponsors.

Dr. Jim McNally:
Now as more people are submitting islands and executing clinical trials, spaces that they're learning and they're trying to help all of us learn based on their experience. You know, it's one of the things that I've found kind of in common between FDA and now having joined a zero. You see this breadth of experience across multiple programs and multiple companies because FDA sees all these submissions.

Dr. Jim McNally:
So they may be reviewing yours, but in the back of their mind, they know what they've seen in your competitors and comparable people that are in the same disease space and using the same modality.

Dr. Jim McNally:
So they've learned from that experience and they know that to ask for certain things because they're seeing it across the industry as a whole.

Dr. Jim McNally:
CRO has the same advantage. Right. You're you're you're working for a number of sponsors.

Dr. Jim McNally:
We see things broadly you can help while preserving the integrity of the information. We see a lot more than just that one company sort of singular focus on what they're working.

Hannah:
It sounds like everyone's learning together, which makes sense and a place, as you say, you're setting precedent.

Dr. Jim McNally:
Yeah, it's great. And there's so engaged at the industry level.

Dr. Jim McNally:
You know, people from Africa are part of the industry, working groups there. At the meetings, we used to go to meetings together and now we're all virtually out them.

Dr. Jim McNally:
But I mean, they're at scientific meetings, either speaking themselves, being part of the discussion, taking questions, engaging with people. And I really feel so lucky to have opportunities to interact with those folks. And and it's been a great experience.

Hannah:
You mentioned working groups, and I know you're a part of one that addresses immunogenicity and Biotherapeutics, so what's the goal of that group that you're a part of and what work do you do?

Dr. Jim McNally:
Yeah, so we actually just had a group meeting today. And part of what we do is it's organized under a and we're the immunogenicity discussion. And the idea here is, is that you've got a lot of people from from FDA and industry that are all sitting on the group. They try to organize the different aspects of immunogenicity for Biotherapeutics and work on helping being generating regulatory guidelines, being engaged with the agencies of FDA of a world wide with organizations to help set the guidance's so that we're all learning from each other's experience.

Dr. Jim McNally:
So this particular group is kind of an umbrella group for all these other subgroups in immunogenicity.

Dr. Jim McNally:
It's a really broad field, as you can imagine, and no one group could cover everything. But this is an umbrella that has smaller subgroups under it that address these little aspects of it.

Dr. Jim McNally:
So we're trying to coordinate that, make sure that one group is not running off and doing something different from what other groups are. We're trying to facilitate as much transparency as possible so that people across industry, if they want to join, if they want to be part of those discussions, they know who to reach out to. If you've got a particular area of interest, we can direct you to one of those subgroups to either get help or to be part of giving help to others.

Dr. Jim McNally:
And then also, I think, you know, we're trying to open the doors for the next generation of scientists, the people that are coming up in the industry.

Dr. Jim McNally:
The 10, 15 years ago when I wasn't on one of these groups and I was trying to figure out, well, who's making these decisions, you know, who's part of these discussions? And I found my way into them.

Dr. Jim McNally:
I started meeting people, networking with them, people from the agency, people from other companies became part of the group.

Dr. Jim McNally:
And now I see what the process is. And I'm kind of acutely aware of making sure that we have some continuity by bringing in young scientists with new ideas that are working in new companies, new modalities. To help us grow and then to be that next generation of leader for an industry.

Hannah:
Mm hmm.

Hannah:
Use that young brain power coming in and young experiencer, I'm sure, trained them and hopefully everybody that was in that discussion group this morning will love will lump them all and will all say they were young brain power. And then everyone can figure out who's the young and who's not in it because we have some seasoned investigators and turn the cameras on.

Hannah:
Well, that's great to hear that you're still able to me. I don't know if you did it virtually in the past or if you met in person, but this whole quarantine lockdown working from home is definitely complicated things. But in this space, it's great to hear that innovation and discussions are still happening.

Dr. Jim McNally:
Yeah, there's those discussion groups. Just because of the nature of people from different companies and from different regulatory agencies being on it have always been virtual. But I think the one thing that we do miss and a lot of us have have known each other for quite some time. We're we're all friends. You know, we when we went to scientific meetings, we would all see each other. We meet for drinks or go out for dinner together or take that opportunity to have a face to face meeting and just to see each other. And one talk about science, which everybody loves, but also, you know, all the different things that we enjoy doing outside of work. I'm truly friends and colleagues that I've enjoyed knowing for quite some time, and it has been difficult over this past year to only see them virtually now. I feel lucky that I do get to see them, but I miss the conversations at the bar after after all the presentations are over with. You know, that's that's part of the fun. There's a lot of brainpower there. Yeah. For more scientific discussions and just fun.

Hannah:
That's how I was going to say it. That's where the real scientific discussions happen.

Dr. Jim McNally:
People don't think so. You know, I, I have my my postdoctoral mentor used to telling me that he came up with some of his best ideas after about the second drink.

Dr. Jim McNally:
No, I don't know if that's what he seriously meant or if it was some sort of relaxation tool, but I think he is a brilliant guy. So I believe that's for sure.

Hannah:
He says it's true. Hopefully one day we'll be back together in person at these meetings.

Dr. Jim McNally:
And I think so I think we're not too far away. Right. I mean, we've got some help. We've got some vaccines out there. Right.

Hannah:
There is a small light now at the end of the tunnel. So we'll keep working towards that. And, you know, that small light, I guess. Well, obviously, getting back together with colleagues and friends at meetings and other places. But what else are you excited about, I guess, in this field as covid and anything like that affected it?

Hannah:
Or just going back to the newest modalities, what does the future look like and what gets you excited?

Dr. Jim McNally:
Well, I'll do the covid thing because I think it's almost it's a non scientific thing. To some extent, but I think we have found out that our technology really does allow us to do some of this remote work where you can be connected to people without actually having to be in the room with them.

Dr. Jim McNally:
So the rapid turnaround of data, information, the ability to have conversations, you know, has been a great advance as far as I'm concerned. I think that's the one plus that we can maybe get out of all of this. But I think in the you know what excites me most, especially in my favorite area at the moment, which is selling gene therapy in the gene therapy space, there has been a lot of discussion around pre-existing immunogenicity for gene therapy. There are a lot of gene therapy. Companies work using vectors where large percentages of the global population already has antibodies against that back. And the problem has always been a concern that one, there might be a safety risk, but also a lack of efficacy because people would already have antibodies. It would limit the ability of the gene therapy to perform its function because you have an immune response to it as soon as it's delivered and you would clear the vector out before it had a chance to have any efficacy. But they're starting to be some evidence. And one company in particular just released in December of last year, press releases of UNICOR, who's working in the hemophilia space, that they had enrolled patients in a trial and took everyone, whether they had pre-existing antibodies or not.

Dr. Jim McNally:
And as it turned out, the people with preexisting antibodies, no problem. The gene therapy work just as well as it did in the people that didn't have this pre-existing. So it's exciting one, because it's a topic that I've been talking about a lot at meetings and giving presentations on it to. I think it's a huge benefit. Gene therapy has such a powerful potential for changing people's lives. And if you consider how many people would be ineligible for receiving one because they had pre-existing antibodies to it without knowing whether it would matter or not, that would be a shame. I mean, truly desperate patient population that can benefit from this. And I think this type of thing kind of opens the door to a couple of things. One, again, making these therapies available to as many people as possible. But secondly, kind of the overall role of immunogenicity in how we interpret data from clinical trials. I think because it's such a new space, people worry about immunogenicity a lot.

Dr. Jim McNally:
But in this case, it says, you know, you can you can have antibodies against our drug and it's not necessarily a problem.

Dr. Jim McNally:
And and it's just one piece of the larger data puzzle as opposed to some big red flag that needs to be needs to be worried about. So much is still important. But again, you talk about light at the end of the tunnel.

Dr. Jim McNally:
It's a little light that I think opens the door to a lot of beneficial therapies, more data, more and more knowledge, and hopefully, like you said, getting it to more people. Absolutely. I really look forward to seeing how this field evolves going forward and just the path to that. You and others working right now on assays, sort of what that path becomes and the precedent, as you say. So this has been really exciting. And thank you so much for taking time today.

Dr. Jim McNally:
Oh, thank you. I appreciate it. Enjoyed talking to.

Hannah:
Thank you for joining us on The Change. Tune in next episode for more conversations about science, research and exploring the world of protein engineering.

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Cell-Based Assays

Learn how BioAgilytix provides the specialized large molecule insight and proven GLP / GMP knowledge needed to support a full range of cell-based assay (CBA) requirements.

Pharmacokinetics (PK) Services

See how our PK expertise complements our immunogenicity services by evaluating absorption, distribution, metabolism and excretion characteristics of a product.

Case Studies

Learn why we’re a trusted partner to 22 of the top 25 global pharma and biotech companies.

Tell Us About Your Project

What are your specific assay needs? Let’s schedule a conversation to review your
questions and requirements with one of our scientists.

SPEAK TO A SCIENTIST
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