From Lab to Launch – Avoiding the Pitfalls of Drug Development

Hello, and a warm welcome to the latest edition of Conversations in Drug Development, brought to you by the team at Boyd's.

This podcast is for our fellow community of scientists and clinicians working in the wonderful world of cell and gene therapy and drug development.

Thank you for tuning in, and we hope you enjoy the conversation. So, welcome to the latest Boyd's podcast. My name is Neil Fish. I'm the Chief Business Officer at Boyd's, and the podcast is called Don't Do This at Home, How to Avoid the Perils of Drug Development. And I'm joined by Ami Patel. Hi, Ami. Hi, Neil. Good to be here with you. My name is Ami Patel in the U.S. Office of Boids, here to talk about the drug development process and the success.

Fantastic. Yeah. And between us, we've been doing this forever, haven't we? Yes. You're more than me. Yeah. Well, I've been doing it for almost 40 years, and we won't go into how long you've been doing it for. And I think between us, we've seen almost everything, haven't we? We have. So, you know, one of the first things we see is people basically coming in and they haven't got a plan. They actually haven't got the first idea of what they're doing.

So how can we help them? I mean, but also what shouldn't they be doing to start with? To really put it simply, honestly, you need a plan. Don't wing it. You need to go on a blackboard and sit down and decide exactly what is it that success looks like to you.

What are you looking to get out of in terms of the different milestones from an investor perspective and the regulatory milestones, and then map out the plan in detail in terms of all the different program aspects from beginning to end of whatever that milestone it is that you're looking for. It is too often that development, the optimization of the product.

The formulation development, This is done in a manner, I like to say this often, don't turn this into a PhD thesis where you are constantly just, oh, maybe if I do this, then it'll work. Or let me tweak this and it'll work. But what I really think is that it's really critical that you design every study that goes into the program.

You need to have a detailed map of different studies for preclinical, for proof of concept, what are the endpoints that you're looking for, what is the result of those studies, you are tying the success of your program development that you're looking for and have a decision tree around those experiments to progress the program in a positive manner. To sum it up, honestly, don't wing it. Have a plan. Have a decision tree.

Think about each different analytical aspects to characterizing success or the marker of what it is that you're trying to develop. And if an aspect didn't work, then try to have a meeting or a pause and try to dissect why it didn't work before just jumping into the next idea or the next experiment without proper thought.

I think that often in trying to be speedy with the drug development process early on, trying to meet some of the milestones to get to an investment phase, you overlook some basic development considerations that actually would get your drug killed very early on before you even get to the proper series a fundraising you want to have a designed plan and a program and a detailed design of experiment that leads you to a favorable

outcome for your milestones for regulatory and investor perspective yeah and i think also i mean you've got to be flexible haven't you because things are going to go wrong this is oh yes development is all about things going wrong isn't it? So you're going to need to advise that plan as well, aren't you? And you have to be willing to listen to those that have more experience and learn from that process.

It's a very good point. I mean, having these plans, it's really, really important, isn't it, to help if you're trying to raise money?

Because people are going to ask you questions about how long is it going to take and how much is it going to cost as well. And that's some of the things that we do very early on for our clients, where we develop a regulatory roadmap, a regulatory strategy. What does that look like? We help them with a product development roadmap. And that really is something that many of our clients have put into their pitch deck, and it actually raises their success. And so, Neil, now on to you.

You've taken a company from startup stage to a quoted company on the London Stock Exchange. Can you share insights on how you achieved that and things that work and didn't work, your learnings? Yeah. No, it was an amazing experience, I think is the first thing to say. And it was one of those things that, as I started my career, I had no idea where I was going to do this.

But circumstances about being made redundant in the 90s, and I met someone who had an idea for a company, and then two other people joined. And I think the very smart thing we all did at one point was to be humble enough and look at each other and say, we're not the CEO. We've never done this before. I mean, it was very obvious we'd never done this before. When we spoke to a venture capital firm, the first thing they wanted to do was replace all of us, which obviously didn't go down well.

And we actually, in the end, managed to get the company financed and floated.

But i think you know it's really important to not be proud to be you know to be humble about this and we we were really lucky to find a real superstar who just happened to be exiting after a mega pharma merger and he wanted to sort of have a crack at a young company and yeah i owe him so much for what he taught me and i know one of my colleagues does as well we worked together for 10 years with this particular person but and he had done it all from like preclinical

right the way through to getting an MA approved. And at every step, he was able to sort of point us in the right direction to plan. And frankly, you know, at that early stage, he taught us how to do it as well. Things went wrong all the time. And without him, the thing would have collapsed literally within months. So it was utterly critical to find someone who knows what they're doing.

And as the company grew and developed, you know, we needed more specialties like patent agents and clinical trial specialists. And the other clever thing we did was to run a virtual model. So we didn't go around trying to recruit hundreds of people because firstly, nobody would give us the money to do that anyway. But we subcontracted and had all these amazing sort of advisors and people who work with us. And for a small company that only ever had 17 people at its maximum.

It ended up running four clinical programs of which two were in phase three. But with all these advisors all around us who knew what they were doing and they could absolutely help us. It was quite amazing that the firepower and expertise that the company had. It was something I'm incredibly proud of. But the year before I started it, if you had told me I was going to be doing this, I wouldn't have believed you.

I didn't probably even know how to do it. It was one of those things, finding somebody who has the wisdom and the expertise and the knowledge to take you on that journey was incredible. And I think that's one of the things I love about Boyd's is that we actually now also do this with our clients. Within Boyd's, within our team, you know, we have a great many people who've done this now. And like you, I love working with the people who come in very early preclinical, need that plan.

And then we help them go, particularly sort of early preclinical to the end of phase two. We do a lot of our work with our clients. I think it's just such an exciting time and seeing them grow with their companies and learn, etc. A great many of them have never done this before, but they are so determined to do it.

And I feel quite humble talking to them as well because I know how difficult it is. Yeah, agreed. It is a proud moment when their products move to the next stage. And we can't tout about it publicly, but it is what keeps us going. Yeah. So one of the key things when we're doing development, obviously, is the CMC, the manufacturing side of everything we do. Because obviously, if you can't manufacture your product, well, you haven't got a medicine. It's as simple as that.

And I remember in the early days of my company, when we had our first development candidate, and we actually made it with mustard gas, believe it or not. That was a key part. And we kind of realized quite quickly, if we're taking this to market, we're not going to have to deal with tons of mustard gas to make this product. And in the end, we actually made a very simple process using an acid to join two chemicals together, which was fantastic.

So, I mean, what are the challenges you see with manufacturing particularly? And I think you nailed it. It's having a lab-based manufacturing process that is perfect and gives you the best data. But if it can't be translated during tech transfer for commercial stages, then that process will have to be redesigned. And so with that in mind, you want to always design the process with the goal of end in mind. What does this process look like outside your lab?

What we see on a daily basis here at Boyd's in terms of some of the early companies, especially in product development team, is that these are very early state startups, two to five team members, sometimes in an incubator lab space or they're in an academic or a hospital institution. They don't necessarily have all the ideal tools for initial drug development and proof-of-concept studies.

They have to make do with what is available. And with that in mind, they designed the process for the lab, but the minute it has to be transferred to a different lab or, you know, you want to scale it up and try formulating it at a CRO or a CDMO, then it does not work. It is not repeatable. And I think that's where the entire drug development, that initial R&D stage of drug development, that needs to be then repeated to make it work in that stage.

So very early on, you must think about what would the manufacturing process look like outside the lab? What does it need to look like? It is imperative that you have a protocol even during the R&D stages where you are documenting exactly how you are preparing your R&D formulation for be it delivery into mice or rabbits or whatever that in vitro model is that you're testing your therapeutic product in.

But you want to have a process that can be repeatable, not just in the lab, but outside your academic or your incubator lab in an appropriate GMP style tech transfer lab. One of my early roles during and after my PhD was at a preclinical CRO. I had a little bit of exposure to manufacturing at that time, and it was incredible how what was made in the lab and tested in the in vitro models, how the data had less noise, less variability.

But the minute that was manufactured at a large scale at a CDMO in a GMP facility, the same exact product, you would think that would have the same level of variability or results. It was not the same in a nutshell. It was too noisy. The data was too noisy. The variability was too high. The lot-to-lot variability was too high during manufacturing. And we had to then go back, try to minimize some of the factors that were causing that variability. And that does end up wasting a lot of time.

So if you build in the end in mind during your early manufacturing process development stage, build in the right CMC characterization parameters, you don't want the whole GMP tool, all the GMP tools for analytical characterization, but something that is good enough to give you the confidence that your process is working.

It's repeatable and can be transferred into another lab, another facility, and is robust enough to stand the challenges and still give you the same proof of concept data outside of that small lab scale formulation or product. That is the way to approach manufacturing from very early on. It might take a little bit more time in the beginning when you start with that approach in mind, but you will save a lot more time down the line.

And one of the things that always used to bemuse me is that the early stages, you don't actually want to make the products as pure as you can make it because you need the impurities for the toxicology. Yes. I've seen that, that people have made it so pure, right to start with, that later on, when they did change the process a little bit, they've got all these new impurities that, you know, they probably would have got with a dirtier process at the beginning.

I'm sort of using dirty in a sort of strange way there but there's the timing isn't it of how you improve that process and get rid of impurities and then understand the ones you've got and as you scale up isn't it agreed yeah so going back to what we were talking we talk about on a daily basis for the most part of your career you've been tasked with in licensing products and sourcing deals You still do this a lot at Boyd's when we're all doing due diligence and

preparing some of our clients for investor readiness. Can you emphasize a little on the key learnings from that experience? Yeah, I mean, I think one of the major ones always for me was to protect the invention. You would hope in today's world that everybody is smart enough and wise enough to at least file a patent before they go out and publish. And I say this because in the past, some of the world's biggest biopharma inventions were never patent protected.

You know these just weren't in the uk particularly the probably the most famous one is the underlying technology to produce monoclonal antibodies was never patent protected it was published and never protected and the number of drugs that were developed you have multi multi billion dollar drugs from that technology is it's probably quite frightening to think about but yes when i was doing a deal you know when doing deals i mean the patent

life is absolutely critical because first of all, you've got to get the product to market. And secondly, how much time have you got left to get the return on the investment you've put into the development? Ideally, when you're working with a patent agent, trying to get at least a composition of matter patent to start with, which is the highest level of protection you get, is critical. But then you go down a level of use patents and second use patents.

And in Europe, sometimes you can get market exclusivity, which runs for sort of longer than it does in the United States. And that can be quite useful as well. But there are also rare occasions when you don't need patent protection. Sometimes, you know, trade secrets can work really well. I mean, I think one of the famous examples, non-farmer, is Coca-Cola, which still has, I think there's still trade secrets on that and how it's made.

But, you know, I've seen companies with manufacturing processes that are very complicated or there's a particular trick you need and no one ever publishes anything, no one ever says anything. And that can work surprisingly well as well. So while patents are fantastic, there are other ways of protecting it. And I've seen some very big factories with literally rooms that you're not allowed in to see the magic trick. So it sounds a bit strange.

But I think in today's world, I mean, I think everybody sort of starting off knows that the moment they've got a sort of development candidate or a process that needs to be protected, they would at least be talking to a patent agent.

And ideally the sooner you can do that the better because how you plan your patent strategy you need to basically try to extend the patent life as long as possible to get the return on investment i mean when you talk you see published figures of how much does it cost to get a billion dollar drug to market is it a billion dollars is it two billion it's a big number and you need that exclusivity period to sell the product to be

able to get the return on investment but it doesn't seem to happen as much as it used to. I think everybody's learned the lesson, but it's something that's so easy to get wrong, particularly in this modern age of social media, et cetera, where all of these things count as disclosures, which can invalidate patents that you file. You've got to be so careful. Yes. And I think one of the things that we often see is that if the patent is not being used for the intended purposes.

Inventors can then also outlicense that and that can be another revenue stream that they can they can have if right, yeah no you've got a really good patent agent working for you you can be it sometimes amazes me how long you can get protection for you know can be a very very long time and and so certainly some of the more recent sort of blockbuster biological products the first wave of maps some of those had patent protection and they

called it evergreening you know they somehow managed to sort of re-patent it almost and extend the patent life to very long periods of time, as well as the challenges of actually making these types of products.

So at Boyd's I mean one of our big things you know we're very strong in the regulatory area you know we've got an amazing regulatory team so question is what shouldn't you do when you go and talk to a regulatory authority? Well, very basic. Don't upset them. Be humble. For the most part, regulators around the world are really keen to get some of these therapies approved. They are keen to work with the developers. They are trying to help the developers. That is their intent.

And it ties in with some of the goals and objectives that they have is to get some of these products approved and give access to the patients.

So with keeping that in mind, it is okay to push boundaries where there are no appropriate guidances when you have scientific data to support some of the pathways, regulatory strategies and pathways that you are seeking to do something novel from a perspective of looking at safety or efficacy or defining a new biomarker, which is not as commonly used in in clinical trials and in vitro studies.

But you do want to still realize and work hand in hand with the regulatory authorities, because at the end of the day, if you don't have their buy-in, if they don't agree with you, then you don't have a product. It's really as simple as that. And very often then, it is very rare that the regulators will leave you hanging and not give you insights on an alternate way to approach what you are seeking in terms of approval if they don't agree with your strategy.

So we like to say at Boyd's, and I am a strong believer in it from the experience throughout my career, is that don't be afraid of approaching the regulators as early as possible. Ask the questions. Know your product. frame the questions in a way that really just helps the regulators answer you as directly as possible. One of the biggest mistakes a lot of the clients that we see in some of these meeting requests to the FDA is that the questions are so vague and broad.

You don't really get much out of the communication with the FDA or the EMA or the MHRA, which we do routinely. So you want to also frame your questions correctly. You want to understand what is it that you're trying to get out of your communication with the regulatory agency. So they want to help you. They want to work with you. It is in their best interest and the patient's interest to get a therapy onto market.

And with that in mind, be humble, work with them, approach the authorities as early as possible in as many stages, get buying from them at every stage. And if there are ways where there are places where you don't agree on the first instant, we do this often. We don't always just take a no for an answer. We listen to them. We analyze, We work with the data and we say, what can we give more to get buy-in on what we are proposing? We go with additional data, additional scientific justification.

And sometimes the regulators do change their mind and they end up working with our proposed ways. So don't be afraid to push back also, but with the appropriate scientific justifications and data. But again, keeping in mind that you want to make sure that the goal is, the objective is to work hand in hand with them, use that strategy from beginning to end and to get to your regulatory milestones, which at the end of the day are very much tied to the investor milestones.

Yeah, no, I've seen over my career a number of examples where CEOs have basically picked fights with FDA or EMA. They're never going to win. I mean, they don't make the rules. I mean, FDA and EMA do that. You know, it's just a fight you're never going to win. And I absolutely agree with what you just said, that it's best to be collaborative, et cetera, because that's really the only way to go, isn't it? Yeah. Yeah, I agree.

I wanted to touch a little bit on the clinical development of some of the advanced therapies, especially that we work on. The clinical pathway for the small molecules is relatively, I wouldn't say simple, but relatively well-defined. But from a perspective of advanced therapies, cell and gene therapies for some of the rare diseases, can you shed some light on what role does the clinical strategy and the considerations play into drug development? Yeah.

Yeah, no, it's an interesting one. Yeah, the clinical development, obviously, to get the data you need to get the product to prove is critical. And a lot of the rare diseases, particularly with the advanced therapies, you're talking about really quite small patient populations to start with. That can be incredibly challenging to recruit in an ultra-orphan condition. So there's been an example recently in the UK of a company where there were only 10 patients in the UK.

And this particular company was trying to recruit those patients and i think they only got one or two and it took them so long to recruit eventually in the end of the day they ran out of money you've got to get this right there's a kind of a balance between having a say an indication that is rare enough but not too rare that you can actually do the study particularly also because there might be other companies also trying to recruit the same patients so yeah you

might not actually be on your own trying to recruit it can be quite competitive how it goes about that i think particularly also in europe this is something you've got to get really right and i've seen this done badly a couple of times i think that it's a truism that once you've launched a product you're probably not going to be able to put the price up very much that's just kind of the way europe works so you might have a product which might

have five indications let's say and and this is what we do at boyd a lot the question is which is the best indication to go for first and that's kind of a. Balance between the clinical benefit and particularly if it's a rare population but also, can you actually also recruit the study? And when we do these exercises, sometimes it actually turns out to be not the obvious one that is the best indication to go with first.

And I think also, yeah, so in clinical design as well, I think it's really important that you measure things which are clinically meaningful. I mean, that sounds obvious, but I think we've all seen plenty of studies that are measuring things which really don't have much value, actually, when you come to market the product. I think collecting that data, which can support particularly a pricing sort of strategy, et cetera, is so important.

And I think I particularly enjoy when we bring in the medics, the physicians on our team early on in these conversations, because they chime in in that first in human study synopsis that goes into the pre-IND meeting packages. And I still, I remember this very clearly. One of the clients had, going back to what you're saying about putting in a clinical endpoint in your protocol, just from experience of our physicians, they said, this is not going to work. It is very hard to get this data.

It sounds right on a piece of paper, on a protocol, but to execute this, it's not realistic. And I think at the end of the day, that that was removed. But building in that clinical strategy early on, having an idea of what that clinical trial or first in human study or what that patient population looks like. I think we also work very closely with patient advocacy groups, especially because we work on so many of the rare diseases and the orphan drugs.

It gives you the ability to understand what your patient population looks like and what are you going to be realistically able to recruit. And also to design the appropriate inclusion and exclusion criteria because sometimes you have a buy-in on a particular synopsis on a protocol for a clinical study from the regulators, and you're married to that. But then when you start to execute it, you realize that you can't necessarily decide

recruit those patients based on the inclusion-exclusion criteria that you have set out with. Yeah.

So, Ami, I think we're coming to the end of the podcast. I mean, I've really enjoyed that discussion. It's an amazing area we work in. I mean, there's so many, but there's also so many things that you can get wrong just because, for what it is, it's a complicated industry and there are many pitfalls, aren't there? So, I suppose the good news is Boyd's can help, really. Yes. And that's the part of the best part of working with you and Boyd's and the team alongside.

For me personally, it is that we go out there, listen to all these amazing innovations, what the developers are trying to do. And for the most part, we've been there, done that. And we get a lot of insights from our team. And we're learning something new every day. So, like you said, Boyd can pretty much help you navigate that complex pathway from beginning to end. And I like being a part of that. We hope you've enjoyed the podcast as much as we've enjoyed doing it.

And if you'd like to reach out and meet the Boyd's team, the Boyd's website is www.boydconsultants.com. And we hope to meet you sometime in the future. Bye-bye. Thank you, Neil. Bye-bye. Bye. Thank you for listening to Conversations. Music.