First in Human Episode #11 featuring Viswa Colluru

For episode 11, we chat with Viswa Colluru, CEO & Founder of Enveda Biosciences.  Listen in to find out the difference between TechBio and biotech. First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder & guest host Co-Founder, Andrew Brackin. Episodes launch weekly on Tuesdays & Thursdays.

Simon Burns: [00:00:00] Viswa, thank you so much for joining us on First In Human.

Viswa Colluru: Thank you so much for having me, Simon.

Simon Burns: To kick it off, congratulations on the fundraising announcement, great news.

Viswa Colluru: Thank you, it is somewhat of a rarity these days to get funded as a biotech company post Series A so, I’ll take that as a massive testament to what we’re building.

Simon Burns: That it is. Give us an instruction on your background and maybe touch on what it was like to close a fundraising round in a bear market.

Viswa Colluru: Happy to. Before we get started I’m founder and CEO of Enveda Bio. We are based on the thesis that nature is the best source of bioactive chemistry in the planet. In that it has spent about four billion years in evolution. And the fact that it is simultaneously both the most validated and untapped source of medicines, in that over 50% of medicines come from nature, yet 95% of nature is a chemical mystery.

Back when we started Enveda about three years ago, we had no idea how we were going to solve this problem, except that we knew we had to spend the next few years of our life solving it. So, it’s been a fun and exciting journey and this last round, as you asked, has been particularly exciting.

I think investors went from, “Hey, Growth at all costs,” and , “Build a long term mode for indefensibility,” and,”Build a Google of biotech,” to, “Hey, what are your assets, when is your first platform revenue going to come in?” And, I think Enveda was in a great position to show not just that the platform was able to deliver highly different shaded chemistry in the short term for problems that are very valuable and are widely acknowledged as valuable, but that we’ve built a team culture and a structure that is able to translate our platform output of assets quickly. And, at a rate that is demonstrably increasing over time.

So, as I told some of the investors I was talking to, as a drug discovery company, your number one rule is to have drugs. And since we have more than you would expect I think that’s ultimately what catalyzed it.

Simon Burns: Well, It’s really impressive, so congratulations, again. 

Viswa Colluru: Thank you.

Simon Burns: You’re one of the few companies in what can probably start calling the Recursion mafia.

Viswa Colluru: [laughs]

Simon Burns: You can tell us a little bit about what you think made Recursion so special and created this mafia that’s emerging. And second, as you thought about building your culture, what were some of the key elements you took from Recursion, what did you add to it? You guys are an interesting company and being so re imaginative in the drug discovery process.

Viswa Colluru: Yeah, lots of amazing lessons from Recursion. One of the main things that spurred the mafia, so to speak, is that we were encouraged to think first principles, before anything else. And I think someone recently posted on Twitter, of course, the world’s wisdom distilled into a website, just kidding, that every time a company fails there’s scar tissue because you are trying to avoid it. I think it may even be Paul Graham. And then someone took that and said, “Well, imagine the amount of scar tissue in drug discovery.”

Because, you have these large companies that are not set up to fail where individual career risk is taken by innovation, but that reward is shared. So, If you’re a VP at a large company, it is not in your best interest to do something that is against the grain of the culture of your company. as we started turning over the rocks in drug discovery, we realized that there are lots of incredible lessons baked into the best practice, but there’s also lots and lots of dogma.

Learning to quickly adapt to the former and then challenge the latter, I think is very important and that was maybe one of the first and most important lessons from my time at Recursion. Those that me and other Ex-Cursionauts probably took away. And then, a couple of others who I was reflecting on cause I knew this question was going to come is the idea that, we all speak vastly different languages and different disciplines.

We lived this reality at Recursion and we all have played Telephone, as young children, and it’s so obvious as you pass 10 kids, you have no idea what the first kid said. Now, imagine that you are playing Telephone in different languages how bad would that be?

And that is approximately the problem you have to solve as a founder, as you bring an ML engineer an AWS specialist a biologist who just graduated from a PhD or a Post-doc, and then a medicinal chemist who put 40 drugs in the clinic. And they all just don’t even know what they’re disagreeing about.

We took a page out of big tech and we said, “there’s lots of creator-customer relationships in such a company, and the people who can speak both languages are uniquely valuable. And let’s call those people product managers.”

Since day one, we had a product organization at Enveda and we said, “let’s make that translation a lot easier and actually start to tap into the collective superpowers instead of the collective dogma or disagreement.”

I’d say lesson number three is something I already talked about in my intro, but if [00:05:00] you’re a drug discovery company, whether you’re technology driven or not, but especially if you’re technology driven, you need to have drugs. 

If you can manage it, build your platform for yourself first, before partnering it out. Thanks to companies like Recursion that paved the way for being able to do this. At Enveda, we were able to, for the first three years say, “We’re not very interested in making our platform and approach be palatable to pharma. We’re just going to build the best national product, drug discovery company that can be built in the 21st century, and show that it can deliver substrate standing on the shoulders of billions of years of evolutionary intelligence.”

Simon Burns: Making sense of billions of years of that intelligence is no easy feat. First, how did you come about the process of thinking about leveraging this biodiversity and creating a map and second, how are you going about the execution of that?

Viswa Colluru: It was an interesting insight. It was prompted by my dad who once asked me, ” Why is biotech and drug discovery so difficult?” Because as a middle class south Indian boy the easy, well-trodden path is to just study computer science and go become a CEO in Silicon Valley. My dad was like what is this whole startup and why are you interested in solving this problem? 

He spent many years running a pharmacy in my south Indian town, and then actually did justice to his law degree and started a law practice. But I realized he had no science background. He had no context, and the question was so simple that it deserved a simple answer. I took a whole couple of days and I got back to him and I said, “Drug discovery is hard because things that work in the lab, don’t work in people.” That was the only way I knew to describe it to someone who was not in the industry. 

And, immediately as I framed the problem that way and I expected this response and that’s exactly what he said to me. He said, “What if you started with things that do work in people?” [laughs] And I said, “What are you talking about?” He reminded me that medicines from plants are not alternate medicine in India. In fact, as a pharmacy owner, he sold hundreds of thousands of doses over many years, and reminded me that as a young child, I had an episode of jaundice that was treated by a medicinal plant. In fact, there is no treatment of liver inflammation as we well know today, whether that occurs in a idiopathic form or NASH or in alcoholic liver disease. That really rung a bell.

Of course, my initial reaction was, “Well, none of that’s real. It’s hocus pocus, snake oil it’s not placebo controlled.” I realized whenever you make a summary judgment about something that you don’t really know, you’re wrong. That’s my number one takeaway from graduate school.

That’s when I discovered the very origin of the pharmaceutical industry, that’s how we found aspirin, metformin, morphine and quinine. And not only did they shape the pharmaceutical industry, but apparently the very contours of colonialism. Where British investor powers had to first fight to get the cinchona bark, so that they could have enough quinine, so they could pretreat their soldiers so they could take over South American colonies without getting malaria.

 I said, “Wow. It turns out these human priors area actually pretty powerful.” If you’ve ever heard of the Lindy Effect, I think it approximately goes something like, whenever you observe a phenomenon, you assume you’ve observed it at the half point. If something’s been a round for a thousand years, safe to say it’ll be around for a thousand more. I realized, if these priors were generated over thousands of years, then they probably will be around for a lot longer, why not harvest them?

That was the core insight. The next question was how do you go about actually solving this problem? Why has the industry stopped going after the next aspirin? And how do we tell that story?

Luckily for me, there was a company called GW Pharmaceuticals that had gotten a landmark approval for a drug called EPIDIOLEX. There were a lot of roots for that in Colorado, but the ancient roots went back thousands of years to India and China and the semi-modern roots to a paper published in the 1840s by a physician in the East India army.

 Just as I was thinking about this idea, this approval came about, and little did I know, but GW would go on to sell that national product without MOA and target information for 7 billion dollars to Jazz, three years later.

There are alot of really cool things I could dig into there, but it was enough for me that there was a company here that leveraged human priors and clinical observations to take what was known information and turn it into an asset about 180 years later.

 So I said, what will it take to do more and more of that? And that’s when I discovered the key problem which is you don’t really know how to search for new drugs in mixture of unknown compounds. And, the fact that most of nature is actually unknown compounds. I won’t walk through the full story here but over the course of several weeks and [00:10:00] months, I realized that, on average, 99% of a medicinal plant is unknown chemistry. About 75 to 80% of a tomato, which 2 billion people eat, every day, is unknown chemistry. And about 80% of the human blood is unknown chemistry. As in, if I took a vial of your blood and ran it through a mass spec, about 80% of the masses don’t have a confidently annotated structure. I was surprised because as a biologist, I thought chemistry was a solved science.

Of course, sequencing the human genome and the genomes of everything around us, it was a fantastic achievement, but we share 50% homology with a banana and 99% with an ape. And so I said, “Wow, why can’t we do to chemistry what we’ve done to biology? Let’s go about trying to solve this because it is already,” As I mentioned before, “The most prolific source of drugs and products known to man, but it also seems to be the most untapped.

So the third piece is, how do I go about executing it? The honest-to-God answer here is, I had no idea. [laughs] I just knew I had to solve the problem and I said, “What are the two, three big things I need to tackle here over the next six to twelve months? Who are the people who will help me tackle them? And cold email, show up at their office, do what it takes to get a meeting, get them excited about this and throw their hat in the ring, and get started.”

Simon Burns: I love it. If you ever need a second name, for whatever reason, IP or something, you can go with Lindy biosciences, I like that [laughs]

Viswa Colluru: [laughs] That’s definitely a good suggestion.

Simon Burns: I’d love to hear more about some of the regulatory challenges. You mentioned no MOA, no target, and you’ve done a lot of work in the more traditional, regulatory framework. What have you learned that’s different about working with natural products?

Viswa Colluru: There are a lot of unique challenges to natural products, which may have been roadblocks in the ’90s, and they’re the perfect problem, because you know the problems within the problems and you then say, “Okay, does today’s technology solve them?” 

Apart from the regulatory advantages, which I’ll get to, some of the primary challenges, the way we think about it and were able to distill from hundreds of hours of skeptical conversations with people in the industry is one the inability to prioritize lead-like structures.

 We know there’s probably tens of millions of unique compounds in nature, if not more and there’s a lot of very, attractive chemistry in there. But it is dispersed within a lot of chemistry that may not be attractive, the way we design or define orally available small molecules today. And we call this kind the chemical annotation problem. What are the needles in nature haystacks, so to speak, quite literally.

The second is, now you have a mixture of unknown compounds, how do you find the needle in the haystack but then, you know that it’s the needle that’s active, right? You have an extract, it has anti-cancer activity or it has neuroprotective activity, how do you get to the active molecule or the salicylic acid in the willow bark extract, which ultimately gave us aspirin?

And third is, if you’re able to then search through the space finding the molecule you think you’ll be able to modify, tweak, store safely, manufacture, then, you have to say, “Okay, it’s active,” now you have all of these things. But you then have to go out and actually get enough of this material to enable preclinical, clinical, and commercial development. Funnily enough, I think all three of these problems are imminently solvable and we’ve made massive progress, if not solving them entirely over the last three years.

 To solve the first one, we’ve built what I like to call the AlphaFold for chemistry. Using some of the same large language model of generative AI architecture as ChatGPT, we’re able to read mass fragmentation patterns of molecules, and predict properties and structure just like AlphaFold does that for amino acid sequences.

 Today, without needing to isolate, purify individual molecules and send them off to a lengthy NMR experiment, we can just say, “Hey, let’s do a mass spec experiment,” which can take 20 minutes for thousands of fingerprints and be able to chemically annotate that mixture.

The second piece is, we’ve solved that a number of different ways and built at least three distinct platforms but the short answer is: we break up the mixture into a few deterministic pieces, ask whether there’s a correlation of putative active molecule with the activity of that mixture and use good old fashioned statistics in addition to lab automation and metabolomics defined the active molecule.

What used to take weeks for a single project; you take a plant and you take a biological activity, we’ve reduced it down to the matter of days. In many cases, we can do the whole cycle in a week. And earlier this year, I challenged my team to industrialize this process. 

In a period of about three months, we found 100 completely new bioactive molecules from nature which I’m told is [00:15:00] equal to about the output of 10 or 20 academic labs from a whole year.

 And then, third , I don’t even need to pitch this but there’s enough VCs and founders who have built synthetic biology companies, where you can make more things. You can make things better or you can make better things. We use a slew of SynBio techniques to widen the funnel of the kinds of chemistry we can get at.

Now, when you have all of this, then you can say, great, you know given that humans have been exposed to. There’s a lot of data behind the use of these, can you actually safely begin human trials. Perhaps do some clinical development at risk, and we are fans of that pathway and exploring multiple ways to do this for both topical and oral products.

Simon Burns: Wow, that’s fantastic. I didn’t realize the skill, the output. It’s really remarkable. Founder-led Bio is having a moment we’re living through it, I feel like every week there’s, more talk of we’re going through this transition from-

Viswa Colluru: Yeah.

Simon Burns: – Studio models to the founder-led bio models. You have to be one of the few poster childs or, one of the many now poster children. Why do you think it’s happening now, and where do you think the founder-led bio movement is in five years?

Viswa Colluru: That’s a great question. Folks always ask me what is techbio and how is it different from biotech? So I’ll go ahead and define that first before riffing on where I think it’s headed. I’ve always learnt and thought about biotech is where biology is the technology, right? Classically Amgen and Genentech used cells to produce human arthropodan or human insulin. Biology was the technology that delivered medicine. Techbio is, deservingly the complete opposite of those two terms. It’s where some new technology, so laboratory or computational, drives the biology you pursue. This could be changing where you look in the chemical space, like Enveda. Or, how you integrate phenomic data into models of biology, like Recursion. It’s really cool and very different, from biotech. I like the fact that this is fundamentally driven by people who are techno-optimists.

Investors and stakeholders, who have seen how the internet has changed the way we communicate, order food or transport ourselves are saying, “What are other ways in which advances in software or hardware technology could affect the world?” As well as, people who are completely astute and focused on the business of drug discovery and biotech.

But going back to the founder-led bio movement, the distinct feature is that these are companies and founders who are building for the long term. For a long time, investors who were in the business of biotech built a certain model of where you go after a certain pathway or a group of assets or a set of indications. They may have an underlying common theme or maybe even a platform underneath them. But, they were largely built to sell. Like, when would this biotech company be acquired? How do we make it attractive initially for partnership and then later for MNA? A big difference is if I talk to my peers or if I look at my own self in the mirror, I’m not building Enveda to get an exit through MNA I don’t have one asset, I have a portfolio. I don’t have drug discovery, I have six industries in my hundred-year vision

 That’s, a combination of maybe this moment in technology, the incredible success that techno-optimist investors have had, even though the pessimists may now say all of that was because of extremely low interest rates, for the past 30 years. We’ll never know. But the truth is, people made a lot of returns and completely and fundamentally altered the way we live today.

 I’d say, why not? The more people who join the movement, the diversity of funders and founders who exist in this space means different ideas. Considering that we have 95% of diseases that don’t have an FDA approved treatment, I would say all comers should be welcomed, And we should question any and all assumptions use technology and good old common sense to solve it.

 Five years from now, I’m hoping we don’t talk about biotech and techbio as two different things, and we just talk about humanity and all of the different tools we have in our arsenal to find new medicines.

Simon Burns: I love that. Six industries. Wow, you’re keeping the bar low for yourself.

Viswa Colluru: [laughs]

Simon Burns: So at Vial, we think a lot about clinical trials and the technology applications to drive clinical trial efficiency. I’m sure you’re thinking a lot about how to drive efficiencies there, too. Where do you think the biggest impact can be for technology and trials?

Viswa Colluru: I think about the drug discovery process as three main stages. The first is identify the biology you want to pursue. Second is, drug that biology with some kind of modality. It could be a small molecule, an oligo, an antibody. And third is efficiently translate [00:20:00] once you have a drug candidate, most of the focus has been in techbio and applying tech to biology and drug discovery has been in one and two, folks have found it easy to say, “Okay, here’s the evolution of laboratory methods, here’s novel access to data and algorithms. I’m just going to do more of it, do it differently. I’m going to innovate on laboratory methods and find new biology.” Recursion is a great example the great generation of spatial transcriptomics and multiomics companies are an example there.

On the chemistry side, Enveda said let’s bring AI and machine learning to solve this problem of ” How do we access the chemistry that’s all around us?” Which has to be the most relevant place to find new medicines. You may have DEL companies that are approaching the same problem.

Companies like Wire are actually a minority in this space. No one’s asking, “How do we actually translate medicines into the clinic more efficiently?” A great example, we have assets in development for pain and itching and they are actively thinking about, “How do we run these trials efficiently?”

 I discovered that even though your Apple Watch is perhaps the most sensitive gyrometer you have on you that can detect an itch constantly, or at least an itch while you’re sleeping. You can’t actually use it in the trial. Because no one has validated the Apple Watch as a way to measure an itch. Unless Apple spends its money doing that, no one’s going to validate the Apple Watch, because they don’t own it.

There’s this almost perverse set of incentives that prevent the modernization of trials, and I like that while is it at least doing that for the executional and process oriented things but, boy, would I love to see a world where the Apple Watch tells you if you’ve walked enough or you get tired after walking or if you’ve itched.

Right now, and you’ll know this better than me, Simon, when we’re looking at endpoints, investigators tell us, “Oh, use something called NRS,” which is a patient just says how itchy they feel. I know, as someone who itches, like every human, that can be incredibly inaccurate. What I would absolutely love is a device that just tells me how many times someone woke up because they were itchy.

And the fact we don’t have that is a galling problem. But then, when I put my business hat on, as a sponsor that’s responsible to the board, I don’t want to take a risk and validate an instrument in addition to my therapeutic. I would love to hear from you, maybe, on how you’re thinking about this and where you see this space going.

Simon Burns: That could be a podcast on its own, but I totally agree with you, subjective endpoints are a huge challenge in driving a lot of innovation. In pruritus in particular, I think the lack of objective endpoints there is huge challenge. Let’s, work together. We’ll rid of NRS and come up with something else.

Viswa Colluru: Absolutely.

Simon Burns: Last question. Say you could talk to yourself three years ago and impart some wisdom on a younger Viswa building Enveda, what would you say?

Viswa Colluru: Lots of lessons learned along the way, I’ll share maybe three main ones. One is, you only need one yes. On average, you need one yes a year. One yes from an investor, one yes form a partner, and every time you get a no, realize that it’s probably a good thing.

I think as Jeff Bezos said in his congressional testimony, something that again in hindsight is brilliant, genius, because of its simplicity, he was like, “By definition innovation comes from unlikely places.” And every time you get a no, that’s a sign that most people don’t see the world the way you do. As long as you get one yes, keep moving forward.

The second is just take one step. Someone told me, as I was belaboring whether or not to start Enveda, “Life rewards you for what you do, not what you know.” The world is a complex space and many of us are trained as scientists and engineers and we like to analyze. Turns out we’ll never analyze beyond one degree of dependency. So, Just move forward, make the world a slightly less hazy place.

And the third is, invest in the process and not the outcome. Fall in love with building. View every opportunity and setback as a way for you to grow. As much as we would like to think we’re in control, we’re not. Outcomes are largely out of our control, so the thing we have is, “Well, I’m going to wake up and enjoy the challenge, of trying to create something out of nothing.” And that, in and of itself, is a victory.

Simon Burns: Thank you for the conversation today, I really appreciate it.

Viswa Colluru: Thank you, Simon.

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