Invent: Life Sciences

Invent: Life Sciences Episode 3
Speakers: Stuart Lowe, Rabia Khan, & Anne Horgan
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Stuart: It's a sobering fact that even with modern medicine, genetics, and chemistry, only 15% of proteins within the human body are considered druggable. This means that even if we can determine the gene responsible for a disease, chances are we won't be able to target the aberrant protein causing the issue. This has become a problem for those developing small molecule drugs.
In the pharmaceutical industry, there's a desire to go beyond the traditional compound X acts on protein Y and achieve a more nuanced effect on the underlying biology.
For over 30 years, biologics had seemed to hold all the answers, targeting cell specific receptors to offer a different path towards treating disease. However, biologics tend to have a more complex manufacturing and delivery route than small molecules.
So, could a different approach to these small molecules open up a wider application space? And what benefits might this bring to cash strapped healthcare systems?
Join me, Stuart Lowe, as we plug in to Invent: Life Sciences, a podcast brought to you by technology and product development company, TTP.
Today, we ask, can new classes of drug target reinvigorate drug discovery and provide better medicines to patients?
The use of small molecules to relieve pain and treat disease dates back to the use of plants and herbs by the ancients. The pharmaceutical industry was built upon the development and industrialization of small molecules. However, many conditions we'd still like to treat are considered to be undruggable.
In order to understand how drugs have been developed from small molecules and where the limitations lie, I spoke with Anne Horgan, a partner at Cambridge Innovation Capital.
Anne: My name is Anne Horgan, I'm a partner at Cambridge Innovation Capital. We are a VC firm that invests in IP rich businesses in both deep tech and life sciences.
So, perhaps to give you a little bit of background, I am an organic and medicinal chemist by training, and I did the usual PhD postdoc and then worked in a small company here in Cambridge, which was my first proper job. And that was about making small molecules for therapeutic purposes.
I then moved on to tech transfer and worked for Cancer Research UK, or as it was called then Cancer Research Technology, which was the tech transfer arm now Cancer Research Horizons.
And then moved into investment about 10 years ago. First for Sofinnova Partners, a firm based in Paris, and then a smaller firm called AdBio Partners doing company creation and seed financing in France primarily. And about two years ago, I joined CIC.
Stuart: That's a really nice description of your journey. And I think we're actually going to touch on all of those points. I just want to take you back to the beginning and think about small molecules. So, why did you get into small molecule discovery and what are small molecules all about?
Anne: Well, I guess when you like sciences very much, you have a couple of options. One is an obvious one, which is being a chemist, making the molecules. The other one is being a biologist, which is more about testing these molecules and understanding the biological rationale behind this.
And the last piece is actually giving the molecules and being a medic. So, out of these three, chemistry was the one that interested me the most. And I've always liked to do experiments in lab, so I guess it was a good match.
Stuart: And what about small molecules as an industry? So, when did people first realise that a small molecule could be used as a therapeutic?
Anne: So, that dates back quite a bit. So, small molecules have been the main tenet of what we use for pharmaceutical intervention for many a year. And actually, when I was growing up in the 80s, you didn't have much of a choice. If you needed a drug, you either got an injectable or a small molecule.
So, these have been around for quite some time, and they have made a very strong impact in patient's life.
What has changed and evolved since is of course, newer modalities that have come to the fore first with antibodies that came into the scene, and then newer modalities, which I'm sure everybody has heard about.
So, gene therapy, cell therapy, and then moving on, we now have got some newer modalities, which are back to small molecules but using them in a slightly different way. And I think that's what we're going to talk about more today.
Stuart: So, why did small molecules kind of fall out of favour? Is it right to say that they fell out of favour?
Anne: I would not necessarily say that they fell out favour. I think they've always been there; they've always been helping patients and in some cases, curing diseases, certainly in other cases, making sure patients get better.
So, they didn't really fall out of fashion, but perhaps they were eclipsed a little bit from the limelight by these newer modalities. And of course, they all have a role to play, and I think everybody's very excited to have an arsenal that's growing by the decade, pretty much in having small molecules.
Then antibodies, we are now able to use oligos and RNAs where everybody's familiar with RNA these days, after COVID.
So, I think having more modalities to arsenal means we can target different diseases and different biological systems in a manner that wasn't possible before. And using small molecules in novel ways, I think is a natural evolution.
Stuart: So, you talked a little bit about targets. So, small molecule normally has a target, which it acts upon. And perhaps we're seeing the emergence of new targets, which we haven't even considered before as drug targets.
So, how does that happen? How do you get from a scientific discovery about a particular receptor or target and how does that turn into almost like a drug discovery program or a doctor by the industry?
Anne: That's an interesting one you see, because biology is what spurs everybody on. And let me get an example for you, which is not a small molecule example per se. So, when we used to have small molecules and I'm thinking about cancer therapy here.
For a long time, patients were treated with surgery and then after that people were treated with radiotherapy when X-rays were discovered and being used in that manner.
So, for a long time we were just basically cutting people open or zapping people. And then small molecules came to the fore. And that was discovering that certain small molecules at least can preferentially kill cells that divide fast. And that meant that cancer cells would be much more susceptible than others.
And we ended up having this era of chemotherapy that was around the 80s, and that was already a big step forward. But at the end of the day, this is really quite and selective in an approach, it's a bit of a blunt instrument, although it saved lives.
Stuart: You end up with big side effects.
Anne: You do. So, it's between cutting people and zapping people, you end up sort of poisoning people to some extent. And then moving forward, then that's when the targeted side of things happened, which you're referring to.
And a really neat example is when scientists started to understand the role of growth factors. And that's where targeted therapy is starting to move to, is that we can inhibit growth signalling with targeting a particular biological entity.
What happened then is that in the 80s, again, the discovery of the HER2 receptor, which is the human epidermal growth factor, receptor 2, that was found to be of expressed and driven in the development and progression of certain types of breast cancers.
And that was actually kind of a breakthrough, but it took about 14 years for the first drug to be developed against HER2, which is an antibody everybody knows, which is called Herceptin. And that has really revolutionised the treatment of breast cancer. In the past, if you were diagnosed with this type of breast cancer, it was pretty grim.
Stuart: Because actually, the HER2 positive was the more aggressive form.
Anne: Absolutely, absolutely. And these days, if you are treated with a HER2 antibody, Herceptin or others, then your chance of survival is around 90%. So, we went from pretty grim prognosis to something which is really quite striking.
Stuart: That’s a pretty big impact.
Anne: It's massive. I certainly know if I ever get diagnosed with this kind of cancers, that if there is something that can help move from some tragic news to something that can be in most cases handled, then that's, I think absolutely massive on patients' lives and their family lives.
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Stuart: As Anne's example demonstrates, the industry's approach to drug discovery can change rapidly when our fundamental understanding of disease biology improves.
And so, a lot of the progress in recent years has been driven not by small molecules, but by antibodies and their ability to regulate cellular processes by interacting with cell surface receptors.
However, the discovery of new biological targets means that small molecules are reemerging as effective drug candidates due to their specific mechanisms of action. To find out more about these new approaches, I spoke with Rabia Khan, founder and CEO of Serna Bio.
Rabia: My name is Rabia Khan, I'm a geneticist by training. Bit of background about me. I was born and raised in a developing country, Pakistan, and then moved to Canada, did an undergraduate degree in genetics, and went on to do a PhD and an MBA.
And my love for genetics really comes from the fact that the human body is made up four letters, ATGC, and those four letters define everything that we are.
Moving on from that, I went on to work at a company called Science Scape, actually, that then rebranded as Meta, which built a knowledge graph on the biomedical literature and was acquired by the Chan Zuckerberg Biohub.
A little-known fun fact Is that that name Meta for Facebook actually comes from that Toronto company.
Stuart: Does it really?
Rabia: It does, yes.
Stuart: No way.
Rabia: Which I think is really exciting. Looking back, that's not where you thought that would go. We were building a knowledge graph to build a Twitter like feed for scientists, and that's where it landed.
I actually wanted to then go back to the bench. I really missed the science and moved to the UK, did a postdoc on IPS derived macrophages, and met a phenomenal woman, Jackie Hunter, who was the CEO at BenevolentAI at the time.
And they also had a knowledge graph on the biomedical literature, as you might know, and that was my step into drug discovery.
Jackie hired me, I worked with Jackie on their GBM program, their AMD program, and fell in love with the intersection of computational methods as well as drug discovery.
It felt like the place where we could really make an impact to some of the most significant challenges, the challenges that I'd seen in Pakistan, mental health, dengue and so on.
And then was recruited into Sensyne Health, working at the intersection of computational methods again, but actually in this instance, patient data. The company Sensyne had a unique business model around taking NHS patient data, anonymizing it and using it to run in silico clinical trials, which was fascinating.
Stuart: Oh, really? That's really cool. And we quite often in the UK talk about the potential of the NHS as a massive data source. Because it's a single payer, single health system with a massive population.
Rabia: Yes. I think one of the hardest things I've had to do in my life is work with trusts where they're already resource constrained to get data out of databases. We did succeed, it was incredibly difficult. We actually deployed algorithms during COVID to support clinical decision making.
I was always in love with drug discovery, and I wanted to go back to my calling, which is biology. And at Benevolent, I was frustrated that we couldn't target the majority of targets that I found interesting.
I would go to our chemist and say, “This is the gene that I think is most important,” and they'd say it's undruggable. And I started thinking about, “Why don't we just target RNA, this seems so trivial.”
Stuart: What's the significance of RNA in this story between genetics, disease, and drug discovery?
Rabia: So, DNA makes RNA makes protein, we know this. In fact, 70% of the genome, we believe to date, may not make protein, at least in the classical sense, it only makes RNA. So, there's a large amount of biology that is transcribed into RNA, not translated into protein by the classical sense.
So, if we just think about sheer target space, I believe that targeting RNA opens up a large target base that we haven't been able to modulate. And any company that is either small molecules, ASOs, SI, or any other modality has access to that larger target space.
And from my perspective, 30 years from now, even 20 years from now, I think we're going to have more RNA targeting companies than we have protein targeting companies.
Stuart: Oh, well, yeah. And I suppose if you just take that ratio of transcription RNA to proteins, that would make sense, right?
Rabia: I think so. I think it's a function of probability.
Stuart: So, I can understand if there's a maladapted protein or a mis performing enzyme that you could look to inhibit that or block it somehow. How would the mechanism of actin work with a RNA targeting medicine?
Rabia: I love that question. Let me tell you why. First of all, the first RNA protein targeting drug was approved, risdiplam, it targets splicing. So, there are so many mechanisms that we can go after if we can modulate RNA.
We can interfere with pre mRNA to mRNA processing. In the world of splicing, that opens up all the splicing in oncology as well as splicing disorders. But what I find most beautiful about small molecules targeting RNA, and we see this even at Serna, is you can have a gradation of effects.
So, you can increase translation, maybe 20%, maybe 50%, you can decrease translation. And with complex disorders, ASOs and SI, they can be binary. It's a knockdown, PROTACs is a knockdown.
Whereas with small molecules, you can increase translation, you can decrease translation, you can affect splicing, you can affect RBP binding, RNA binding proteins. And most exciting to me, which I think we're just beginning as an industry to look at, is target the long non-coding RNA and microRNA.
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Stuart: It's surprising to hear that so little of the human genome is actually used to directly code proteins. In fact, it's only recently that much consideration has been given to the role of this so-called junk DNA.
As Rabia pointed out, we find in fact that much of the genome is coding solely for RNA and we're still exploring and understanding the role of these RNA molecules. It's in this regard that small molecules with their ability to target RNA could be important in controlling disease.
Scientists such as Rabia are investing in the technology in the hope that small molecules will drug the undruggable. But what does this mean exactly? Anne explains.
One of the things that we hear a lot about in the industry is drugging the undruggable, but what do you mean by undruggable? What do people mean by undruggable?
Anne: Yes. I think that that's the right way to start. What do we actually mean by this? And perhaps we need to go back one step even further and thinking about how small molecules usually work.
They tend to work with the protein of interest in that they will bind to the catalytic site of that particular protein of interest. And if it's not the catalytic site, it might be another site that has been identified, but which accommodate small molecule binding, that would be the allosteric site.
And the way the small molecule interacts with that protein of interest that either inhibits its activity or it does something to it from a direct perspective. However, a lot of proteins certainly are quite difficult to target with this conventional approach. It can be because there is not a real site where a small molecule can bind.
That can be for a number of reasons. There may be some shallow pockets, which may be active sizes which are broad and really undefined in terms of looking at a good fit with a small molecule.
So, in this way, they're intractable and they have been certainly identified as causes of diseases, but they have not really been targeted per se, by small molecules because we can't find a good fit.
Stuart: Can you give an example of an undruggable target? Something where they haven't been able to find the right sort of pocket?
Anne: There are actually many, maybe I should just give you a note of ideas. So, out of all the proteins that we know, I've seen some numbers around 15% only have been drugged so far with the rest haven't been deemed undruggable.
So, as you can imagine, a lot of … and I'm going back to cancer here, but a lot of oncogenes that we know about, which have been targets of excellence for research and trying to have some silencing approaches and not yet translated into some small molecule or even antibody approaches.
So, there are certainly plenty there. I could give you quite a few examples, but I think we might end up spending the whole podcast talking about lists. But here, hopefully that gives you an idea of the extent.
Stuart: Yeah. That's an enormous number actually, that's a huge proportion. Does it feel like we are able to do something about this now? Is there a new approach that's come up?
Anne: I think there's several approaches, actually. There are different ways of uncovering novel sites, which would be amenable for small molecule actions. And there are a number of companies that do this very well.
One that comes to mind is a company called HotSpot Therapeutics in the U.S. Another approach is not trying to modulate the proteins function, if you like, but knowing that if you do take it out of the system altogether, then you achieve your therapeutic purpose.
Stuart: So, some kind of like a search and destroy mission?
Anne: A little bit, that's right. As long as you can search and destroy selectively, then the intent here is that you should have a strong therapeutic impact. And that's very much what we see with this whole field, which is exploding at the moment of targeted protein degradation where one is not trying to modulate a function, but just sticking the protein out altogether.
Stuart: So, how does that work?
Anne: So, there are two different classes of molecules broadly speaking in that respect, which we know will interact with the whole body's own degradation machinery. Some of them are called proteolysis-targeting chimera or PROTACs, and the other ones are called molecular glues.
The concept behind it is very much similar. The whole idea is to utilise the cells own degradation machinery for selectively degrading a protein of interest.
The way PROTACs do this is very elegant, actually, is to have a bifunctional molecule. One end of it finds the protein of interest, and the other one is a ligand for the degradation machinery. And the two bits are being put together with a linker.
So, sorry, that's not the most technical definition but that's a bit more of a chemist's image in one's head.
Stuart: No, it paints a picture. It paints a picture.
Anne: And the way this this works is that you end up having a molecule which is bigger than the usual small molecules that one would typically think of in terms of therapeutics.
But you do have this bifunctional aspect, which means that you induce either chemically speaking, you tag your protein for degradation or in terms of molecular glue, it's a question of inducing proximity between your protein of interest and the degrader.
Stuart: And because you've got this additional protein degrader involved, then you have a bit more diversity in what you can target. Is that how it works?
Anne: Absolutely. And it's been a number of papers out there. One which was published maybe a year or so ago, and the title was the — instead of druggable genome, it was the PROTACtable genome. I think that that tells you everything.
Because theoretically as long as you can find a way of recruiting the relevant degradation machinery, which is working for that particular protein of interest, and in theory you could apply this very broadly.
Stuart: Oh, I see. So, actually it's the bifunctional nature. So, you don't necessarily have to be super specific on the cleft that you're looking for. But because you also have to get the right degradation enzyme in as well, it gives you kind of two shots for specificity then.
Anne: Broadly speaking, yes.
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Stuart: The range of potential applications for small molecules certainly seems to be growing. It's no wonder they've received such interest in the last few years, given that small molecules might allow us to target the 85% of proteins deemed undruggable.
Technologies such as targeted protein degradation are giving drug developers more opportunities to address the undruggable space. But considering the benefits these approaches bring, why weren't they pursued sooner? Why is interest increasing now?
I asked Rabia why her specific application of small molecules had risen in popularity within the last few years.
Why don't you think that RNA as a target has been explored particularly intensively before, or hasn't been explored intensively before?
Rabia: That is such an excellent question. Actually, most investors and even partners will ask you what keeps you up at night? What's the thing that you're worried about? And there's many answers to that question, but the one answer I keep coming back to and I've asked people at various RNA conferences is why haven't we done this before?
It's obvious 70% of the human genome, small molecules, we've been working with them for a while.
Stuart: There's some nice ingredients there.
Rabia: Right. So, this seems pretty straightforward. And so, where's all the drugs? We've got risdiplam, where is it? Where is everything? Tons of money is flowed into this industry.
And so, I don't know, I think any kind of new modality takes time to de-risk and understand what is the fundamental challenges. So, a very simple example I can give you is if you're targeting link RNA, the homology between human and mice is decreased than the protein coding genome.
Stuart: So, it's harder to actually do those preclinical studies.
Rabia: Could be is one example. The second example is how do you think about off-target profiling? So, when you're thinking about a kinase and you want to build a kinase inhibitor, you go to Eurofins or any other company and buy a kinome panel. What do you do when you want to target RNA?
Stuart: Yeah, you can't necessarily access that sort of panel.
Rabia: Well, you can run a kinome panel and I think that's great, but that doesn't tell you what other RNA your compound is binding to. So, we've had to build a lot of our own assays in-house to answer those questions.
Stuart: So, you've built your own kind of RNA that you can test upon?
Rabia: Absolutely. Well, you got to answer the question. When someone comes to you and says, “How do you know it's not binding to anything else?”
First, I would think about it and say, “Well, you could do the following assays.” And then I thought, “Well, how do we do this?” We run a kinome panel. Well, what's the equivalent there? So, we've built those in-house.
Stuart: So, you guys are really pioneers. So, you're building the tools that people will use in the future in this industry.
Rabia: That to me is why we say we're a data engineering biotech. Because we are really building data sets and tools to power our programs forward, or at a minimum, begin to answer the questions that we would answer in a classical protein-based program.
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Stuart: As Rabia points out, new modalities such as these have a steep hill to climb when facing regulators and clinical trials. Inventing new techniques for drug development can be risky and expensive, but the resulting tools can be shared to other stakeholders within the industry and academia, pulling everyone forward.
Exploring and analysing all of the RNA structures that scientists are interested in is a big ask, especially for one company. And so, it's inspiring that a CEO, such as Rabia can see that there is value in collaborating with others to tackle this challenge.
RNA targeting isn't the only exciting modality offered by small molecules. As Anne mentioned earlier, proteolysis-targeting chimeras or PROTACs for short offer their own set of compelling possibilities.
But what does the future for this modality look like? I asked Anne about PROTACs and their relevance in modern drug development.
Where is this all going? Where do we see the future for PROTACs therapies?
Anne: There's a number of ways to respond to your question, I think, and perhaps to give you a lot of idea about the level of excitement in the field, because I don't think I've mentioned this before. Clinical trials are of course, one thing. One of the metrics we look at.
Another metric is also with regards to publications. And just out of interest, I plugged in, put in degradation and put in degrader in PubMed, and you get close to 2000 hits since 2022.
Stuart: Oh, my goodness. Okay.
Anne: So, you can see the amount of excitement in that field, and of course, some of which are reviews, some of which — but I think it shows how vibrant the ecosystem is. And I think perhaps the third metric is the level of investment which has gone into this particular field.
And here thinking through the VC lens, when you think before something like 2017, before 2018 for sure, there was about 300 million that were invested in that space, which was coming mostly from private financings.
Past 2018, then there's been nearly 3.5 billion generated from public equity financing and public financing. So, you do have this sort of excitement and push towards developing this particular type of modalities and exploring every aspect of what they can do.
And that's the link, perhaps the second aspect to your question, and the excitement in my mind comes from the fact that we've only scratched the surface with PROTACs. There are so many things that we can do with this particular approach.
There are plenty of degradation machinery. One can go after these E3 ligases. There's also a lot of validated pathways which have been targeted but we could go a lot beyond that.
What's been really exciting is that PROTACs was just the beginning of what's been now referred to as the TAC family. You've got DEPTAC, which are targeting ubiquitination, you've got AUTAC which are going for autophagy, ENDTAC looking at degradation for endosome partners, RIBOTAC and I can go on and on.
So, as you can see, that was the start of something much larger. And very recently there's a paper that was published from Cambridge academic who is talking about degradation through small molecules of RNA.
So, moving towards different spheres where perhaps 20 years ago we would not have thought about these kinds of approaches.
Stuart: I know it is a different way of thinking that's being able to — opens up a lot of opportunities. I suppose, you kind of look at it on the other hand and think about potential threats.
The U.S. passed the Inflation Reduction Act 2022, which removed to parity in exclusivity rights between small molecules and biologics. What impact, if any, are you seeing this having on investment?
Anne: Yes, absolutely. See, that's something that's generated quite a lot of press and quite a few comments and certainly a number of slightly heated LinkedIn exchanges that one can see.
I think the difficulty is that nobody quite measures what really is going to be the impact of the IRA. Everybody's trying to measure or to understand. But at the moment, it still is quite hard to get any opinions or read anything which is really either data-driven or strongly rational to help understand what the impact might be. There's a lot of emotion that goes into it.
The study has been a few pharma CEOs who have come out publicly and mentioned that it would have an impact on how they prioritise their pipeline and how maybe biologics would be prioritised versus small molecules.
What we need to really understand is that the IRA provides Medicare the right to negotiate the price after a certain period of time. And that's not for every drug, that's for a select number of drugs as well.
So, there's, I'm sure quite a lot in the details that I certainly I'm not sufficiently familiar with to really comment.
But I wonder whether A, there's going to really be the financial impact that the U.S. government would be hoping for when they pass this act, which encompasses other pillars, by the way, it's not just about the process molecules.
Stuart: It's got a bit of everything in it, doesn't it?
Anne: It's got a few pillars absolutely. So, it's all about trying to curb inflation and reducing federal government budget deficit. So, the price of drugs is one end, but they also have got about investing into domestic energy production, promoting clean energy. So, it's got quite a lot of things shoved into there.
The question is from the industry perspective of small molecules and therapeutics in general, what really is going to happen? I think that's perhaps something to watch out for in the press.
And there are various webinars. I think there's some schedule throughout very regularly and some opinions being given. So, hopefully, we'll get more clarity on this. But certainly, it's something that has been flagged and may be of concern in the future.
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Stuart: The statistics that Anne shared clearly demonstrate the level of interest surrounding small molecules and their applications. And it's not just the science that excites investors, it's also the potential to leverage a technology that is cheaper to manufacture and more accessible.
Healthcare providers and governments are being confronted with rising costs for new therapies, particularly in the cell and gene sector.
And so, having lower cost treatments in the arsenal might help to alleviate pressure on the overall healthcare budget. I asked Rabia for her comments on the cost of small molecule-based treatments.
I'm going to characterise you as a small molecule company for a moment, just bear with me. You are never going to sell your product for a million dollars a dose, like some of the more recent cell and gene therapy that have excited the headline writers.
So, do you think in the future that we need to think about cost, do we need to think about distribution in how people access these drugs? And you've kind of answered this already, but just do a bit of a compare and contrast for me on the promise of cell therapy versus the cost.
Rabia: I'm not an expert in health economics, but what I can tell you is based on my own personal experience. If we think about complex disorders, I’m thinking about Alzheimer's, I’m thinking about dementia, and I'm thinking about public healthcare systems, the NHS, I don't see a world where we have a million dollars at pop for Alzheimer's as a solution.
Stuart: And that puts pressure on those companies, cell therapy companies to bring costs down. Sure. So, there's going to have to be some sort of interplay. So, in fact, small molecules are going to have to be part of the solution, because the cost base there is much lower.
Rabia: I believe so. I believe the cost base there is much lower, the mechanism of administration. So, as someone who I'm involved with my father's healthcare, he's not the best. And so, if you think about the economic cost of taking a patient into a hospital and the impact on the people around them. So, you have to have someone who can go with you. The social impact of having someone who's ill and having to go spend even four hours every other day.
So, he's on dialysis into a hospital. I think these are non-trivial things. We frequently spend a lot of time thinking about the biology and the really exciting science and forget about the impact on the human, the impact on their families.
And so, what I have seen small molecules do, again, going back to being raised in a developing country, you're not going to get complex cell gene therapies into the majority of the world where sometimes we have load shedding, the generators are powering hospitals, the freezers are off.
And yes, that's not the largest market, but across Asia, China, we've got a third of the world's population. Over time with India's GDP, I think surpassing the UK, you've got markets there that are quite large and growing and yes, I think people will go for the best therapy.
And anything that's curative will trump anything that's preventative. But if we can get as good as, or better, then any other modality, I think small molecules win.
Stuart: That's an interesting perspective. And I think the storage is a very good point. A lot of the small molecules, you don't really need to worry too much about the refrigeration.
Rabia: Or the training of the medical community. I'm thinking, are we running gene editing and cell and gene therapy in Pakistan? That's pretty complex and maybe Pakistan's not the right place.
I'm sure China can do it. I'm sure India can do it. But again, if you can reach the same efficacy with a small molecule, well that's just easier.
Stuart: I think that will definitely come into the equation. If you're putting two up against each other, equal efficacy and one's cheaper than the other, why wouldn't you? So, I suppose there's an imperative on companies like yours to kind of spread your wings quite broadly and find out what indications you can go for.
Rabia: And where we would have a competitive advantage. So, that's why I was saying, I don't know if we're a small molecule RNA company or an RNA company, or we're just a company that will focus on therapeutic areas where we do have a competitive advantage.
Stuart: So, if we have some competitive advantage, we've got some really nice small molecules coming through, what can we do to accelerate the discovery and development of such molecules?
Rabia: I'm going to be really selfish and say we should increase funding towards RNA small molecule companies and partnerships. So, one of the challenges that I've seen is that we've bucketed this industry into one category. So, it's an RNA small molecule industry.
And if you draw the analogy, no one is going around saying, “These are small molecule protein companies.” And so, I remember speaking to someone and I was like, “Oh, we're doing it,” and he is like a senior head of R&D at a pharma company.
And I was like, “We do RNA small molecule targeting.” And he's like, “Yeah, we've already partnered with one of those companies.” And if you think about, you can dissect proteins into kinases, GPCRs, degraders of kinases.
And so, we are not as an industry thinking about RNA small molecule in the same granularity as we are around some of the other aspects. So, we can differentiate splicing companies from translation inhibition, from link RNA, and even within those companies, there's a tremendous amount of diversity.
So, the first thing we can do is, I would argue, change the way we speak about this space and start talking very specifically about the differences so we can increase the funding, increase the partnerships that are there.
Stuart: And so, people are getting more targeted.
Rabia: Yeah. People get more targeted. So, if you want a portfolio of RNA small molecule companies, you can say, “I've got a splicing company in my portfolio. I've got a translation inhibitor, and by the way, I've got two translation inhibitor companies. Because one is phenotypic screening, and one is target-based.”
And that's a very fluffy answer, but I think if we can begin to dissect that space into those subcategories, then more companies will thrive.
The other area that I think is exciting, which is the use of generative AI in small molecules generally, and these large libraries like billion level libraries.
So, Atomwise has done an amazing job. They can screen trillions of compounds with the click of a button. How do we begin to adopt those technologies into our space? That to me is another really exciting space.
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Stuart: Small molecules have a lot going for them. They're cheap to produce, easy to administer, and don't have to be stored in cold conditions. This ensures that they will continue to play a central role in healthcare provision across the globe. But how can these new modalities reach their full potential?
Well, as Rabia pointed out, with greater exposure and understanding of the technologies, the more they'll become legitimised in the eyes of academics, industry, and regulators. So, what will the immediate future look like for small molecules? I asked Anne for her thoughts.
What's making you optimistic about the future of small molecules? Or are you optimistic about the future of small molecules maybe?
Anne: I just think I'm phrasing that. Yes, I am optimistic about the future of small molecules. I'm optimistic because, well, firstly, I have a little bit of bias. I'm a chemist at heart and small molecules have been such a staple in this therapeutic arsenal. I'm pretty convinced they're here to stay.
So, I am optimistic, and I think the way that we are finding new uses of small molecules or sometimes just being very clever about how we deploy them. And I think going forward in a lot of fields, we are going to see more and more combination approaches.
And whilst in people's minds, combinations are often thought of as perhaps more molecules that are being combined, it's not necessarily the case. It could be different therapeutic modalities which are being combined, or it could be a question of sequential treatment for patients which already happens in certain indications.
I think they're here to stay. And a nice thing about small molecules is that we do understand them pretty well. We know how to make them; we know how to store them. We know how to distribute them. And we certainly have learned a lot of the properties just because we've been handling them for many a decade.
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Stuart: Small molecules are an excellent example of the life sciences looking to its past to determine its future. While the pharmaceutical industry was built on small molecules, they've been somewhat eclipsed by the rise of biologics in recent decades.
Lately, however, scientists have rediscovered the potential of this technology and have invested in its future.
Although drug discovery may have been limited to targeting the small fraction of proteins that were considered druggable, the examples we've heard today are testament to the broadening of application space in small molecule science.
From RNA targeting to PROTACs, it's clear that we're only seeing the tip of the iceberg with what small molecules have to offer. Life scientists are standing at the forefront of this renaissance.
Companies such as Rabia’s are seeking to open up new markets for small molecules, and the statistics Anne shared with us demonstrate that investors are seeing its potential too.
Thank you to Rabia and Anne for sharing their stories and insights.