Industry Matters: Nessan Bermingham on Triplet Therapeutics and the keys to startup success.

Nessan Bermingham is a serial biotech entrepreneur and investor having founded multiple Life Science companies, most notably Intellia Therapeutics “one of the top 10 biotech start-ups in 2014” and a “Fierce 15 biotech company”, Triplet Therapeutics and Korro Bio. At Intellia, Nessan led the company from concept through partnering deals, multiple financings and an IPO prior to its second anniversary. He served as president and CEO from inception until December 2017. Intellia’s work has led the field of genome engineering showing the first in vivo systemic delivery of CRISPR Cas9 for the potential curative treatment of ATTR, an inherited genetic disorder.

Currently, Bermingham is an Operating Partner at Khosla Ventures where he focuses on Life Science companies with a particular emphasis on nucleic acid editing, novel delivery systems, gene & cell therapy, novel target identification and data analytics for drug discovery and development. He is also currently Chair of F-star, Executive Chair of Korro Bio and Triplet Therapeutics.

Triplet Therapeutics is a biotechnology company developing transformational treatments for patients with repeat expansion disorders (REDs) – a group of more than 50 known genetic diseases including Huntington’s disease, myotonic dystrophy, spinocerebellar ataxias, fragile X syndrome, and familial amyotrophic lateral sclerosis (ALS) – leveraging insights from patient genetics. Triplet designs and develops potential therapeutics for REDs using its proprietary approach, which enables the Company to develop a single oligonucleotide targeting the DNA Damage Response (DDR) pathway to potentially treat multiple REDs.

Nessan Bermingham set aside time to discuss Triplet Therapeutics with SCINQ as well as some of the factors needed for biotechnology startups to not only survive but also succeed.

What role do triplet repeat disorders play in disease?

Historically when you think about triplet repeats orders for things like Huntington’s Disease or myotonic dystrophy and spinocerebellar ataxias are probably the best known – there’s probably over 50 of these in existence. It’s an expansion of the repeat at the DNA level that effectively drives the disease itself. 

For example, take Huntington’s disease. In a gene called HTT, you’ve got an expansion of the CAG trinucleotide repeat that over, let’s say, 35 to 40 times in an impacted or affected individual. It was believed that that was the be all and end all, but what was very clearly shown over time was that the repeat – at let’s say, 40 CAGs – actually grows as the individual ages. That repeat gets longer and longer and longer, such that at the point when a patient dies, you’ve got to repeat that’s over 1000 CAGs. It’s grown from that, say, 40 repeats to 1000. That’s what actually drives the growth of that repeat over time. Ultimately, it hits a certain threshold, whereby it leads to cellular toxicity.

The other thing we also knew from population analysis or patient analysis was that you have individuals that are born with exactly the same number of repeats. But the age of onset of disease can vary significantly. One may have an age of onset of 20 years of age and the other one may have an age of onset of 60 years of age. That is a 40 year difference, even though they were born with exactly the same number of repeats. When you look at the progression of disease, for the early onset individual, it’s rapid but for the late onset individual, it’s not. 

There’s a tremendous amount of work that was done to actually try and identify what elements of the genome impact the age of onset and progression. What was identified was a pathway called the DNA damage response pathway. Effectively, very specific members of that pathway have been identified for potential therapeutic intervention. 

In essence, what’s happening in these individuals is that increase in the CAG for Huntington’s destabilizes the DNA. When the DNA is actually unwound and opened up to be read to make RNA and when it goes to actually rebind together – to reanneal – it’s a bit like two pieces of Velcro, where they don’t align quite right. When that happens, it forms a little loop in the DNA, and the DDR pathway effectively repairs that loop by cutting the bottom strand, stretching that loop flat, and filling it in. 

Where is the problem? Is it at the cellular or genetic level? Is it with the DDR pathway? 

It’s really at the level of the repeat. If I look at your DNA, you probably have about 20 repeats in there, but if I look at an individual who’s going to get Huntington’s disease, they may have 35, 40, 45 repeats in there. That change between repeats is enough to destabilize that region of DNA so that, similar to the Velcro, you’ve got the potential, when you put the two pieces of DNA back together to re-anneal, you get this loop actually forming. 

They misalign so you end up getting little blips or loops forming in the Velcro, when you put them on top of each other. Whereas, if you’ve got two small pieces, they’ll align and anneal pretty easily.

Does the genetic code around the loop throw off whatever enzyme is employed in the DDR pathway?

Imagine that you are getting this loop not being formed correctly in the DNA. When it goes to rebind, it forms this loop, because you got a misattachment, or misrealignment of the DNA. Because think about it, you’ve got CAGs that are, let’s say, 50 of these all in a row. On the bottom strand of DNA, you’ve got the equivalent GTCs that will bind to it. 

You need 50 of them to bind to each other, to actually make linear double stranded DNA. The repeat actually doesn’t bind. Instead of binding to its equivalent on the negative strand, it binds five CAGs further down. Because of this, the numbers one to four, effectively, are looped out right in the DNA. 

You get this looping within the DNA. And the DDR pathway identifies this loop and says, whoa, something’s wrong with the DNA, we need to fix this. When it sees this loop, the machinery comes in, and basically cuts one strand of the DNA, not the loop strand, but the other strand that it’s bound to. It basically straightens that kink in the DNA out. Then it just fills that gap. 

Whatever number of CAGs were actually in the loop, in this case was four, it actually fills those CAG ‘s and on the other strand. If you stop the DDR pathway from recognizing this, what actually happens is the DNA is opened again, because it’s been transcribed to make RNA. When it reanneals, the probability is very high that it will reanneal properly the next time around.

What is TTX-3360?

That is an antisense oligonucleotide that we’ve been developing to target one member of the DNA damage response pathway — the DDR pathway —called MSH3. MSH3 is a unique target in the fact that when you think about DNA damage and really targeting that pathway, you want to be sure that you’re not compromising that pathway such that it is not doing repairs or repairing DNA that actually is really critical that you repair. 

Think about cancer. Think about double stranded DNA breaks. When you think about the DNA damage response pathway, there are multiple components within it. There are actually multiple proteins that form complexes. You want to ensure that you’re targeting one member that does not compromise the integrity of the pathway itself for repairing damage that actually could be pro-oncogenic, for example. 

You spend a lot of time trying to figure out what is the right target here and interestingly, there’s MSH3, that by targeting it, you actually do not compromise that DNA damage response pathway where it’s responding to other injuries or other damage to the DNA that takes place.

How does it work?

Antisense oligonucleotide? 


Basically, it binds to the RNA for MSH-3 and prevents that RNA from making protein. What you’re doing is you’re reducing the amount of that protein that’s present within the cell, such that when the protein complex is being formed, there’s not enough of the protein of MSH-3 to be able to actually form that complex.

How far along is development? Are you close to entering clinical trials?

We’ve been developing this program for a few years. We’ve moved it into IND enabling studies that’s really looking at overall safety, tolerability of the drug, and overall efficacy as we think about reducing the level of the protein within the cell. We’ve been working with the intent of building that data package, as we think about moving it into the clinic in the near term. 

Our expectation has been that we move into the clinic this year. I would say I think it’s an important component to be aware of, when you look at this class of therapeutics, there certainly has been data that’s coming out both last year and this year, around the efficacy and overall safety of antisense oligonucleotides.

What diseases are being targeted?

The interesting thing is that this DDR pathway seems to actually be involved in, if not all 50, in a large percentage of these indications. It is possible that MSH3 targeting is relevant, not just for Huntington’s disease, but can potentially impact a multitude of different diseases. 

If we think about therapeutic approaches to triplet repeat disorders, historically, treatment really has been a kind of bespoke approach where, effectively, we’re building therapeutics on a disease basis. 

Okay. Let’s, let’s take how other companies are going about treating Huntington’s disease? How does triplets’ approach differ from theirs?

Most, if not all, companies target the repeat itself. For a long time, it’s been believed that by targeting the repeat, you actually can prevent disease progression and potentially onset. 

Human genome wide association studies in patients very clearly shows that it’s a two step process for disease. Step one is the increase to, let’s say, 40 repeats in the individual at the point where they’re born. The second step is the expansion of that repeat as the individual is aging over time. 

Just targeting the repeat itself, at the RNA level, which is what most, if not nearly all of them are doing, does not deal with the primary insult, which has taken place at the DNA level. That repeat, we would expect, will continue to grow, even though you’re impacting the RNA and the repeat at the RNA level. 

In many cases, because basically, these individuals have a copy with an expansion and a copy that’s normal. They’ve got one of each.

Treatments are really hitting Huntington as a protein, overall. And Huntington is actually a very important protein when you look at overall cellular survival of neurons, synaptic plasticity, and various other aspects. 

You’re balancing trying to prevent the toxicity of the repeat. You also want enough protein in the cell to allow you to actually have the cell function correctly and appropriately. That’s part of the challenge for us. We’re basically preventing that expansion from taking place. You’ve already got the first hit, you need to destabilize DNA. 

We believe that by preventing the further expansion of that we’re preventing that toxicity of the expanded repeat from actually presenting within the cell. You have a normal expression of the Huntington’s protein, so that normal function is maintained within the cell itself. 

Switching gears, Triplet Therapeutics is your third company and you are involved in a fourth. Can you discuss what the difference has been between starting your fourth company and starting your first?

Starting with the first company, you haven’t done it before. It’s learning in real time as you’re building the company and frankly, making mistakes, right? You learn from those mistakes, though I think that every company is different. 

I think you learn with each company, the trajectory of the company’s growth, the focus of it, and the macroeconomic situation. If you think about trying to start and grow a company today versus two years ago, there are very significant differences. I have a couple of companies that I’m seeding right now that we’re getting up and going at Khosla Ventures, where I’m a partner now. I would say the environment is very different compared with where we were two years ago. 

So there’s a lot of differences between the first company and today’s company. 

On the positive side, as we think about the last 20 years, we’ve learned a tremendous amount. As we think about the developments that have taken place within biotech, there are developments from a more fundamental understanding of biology driving disease, so the toolbox that’s been built or continues to be expanded. That allows us to start to dissect disease biology and also develop novel therapeutics. 

siRNA is a great example, as are ASOC, antisense oligonucleotides, and obviously, CRISPR Cas-9. The subsequent generations to the primary CRISPR Cas-9 has really opened up an understanding for us and also a therapeutic modality that is now proving itself at the clinic.

Again, all of these are giving us insights into disease, disease, biology and point of intervention to the point where you look at the COVID vaccine and how quickly the industry was able to pivot on that, start to sequence understand what the primary target should be, and then actually affecting that vaccine, and then manufacturing and distributing it. 

A lot happened in the last 20-25 years within this business. That makes building companies more sustainable and more targeted, as we think about the application. Where things have gotten, I think, probably more challenging is when we think about the pure volume of companies. There are a lot of companies now that’s been built in the space. Considering the infrastructure resources required to support a company, it’s non-trivial. 

How do we expand our capabilities to support these companies, both from a capital infusion standpoint, mentorship, focus, clinical development, space, hiring needs. I would say that, as we look at the industry overall, there has been phenomenal growth which has been great. 

What makes a company investable for you?

I think it very much depends on the state that you’re investing in, to be honest. When you think about a seed investment or a Series A, you’re effectively looking at the vision, right? What is the vision for the company? What’s the overall philosophy for building the company? And really, how is it different? 

If you’re looking to build the next PD1 inhibitor, I think that that’s more challenging, just because the competitive landscape out there is actually really quite broad. It will be very difficult to differentiate yourself in the marketplace and the value proposition, both from a patient standpoint, and from an investor standpoint, arguably isn’t there. 

So it’s really kind of turning around and asking, What are the unique selling points? What is the uniqueness of the overall approach of the company? Now you’re getting into the company that you’re envisioning building. Then you get into the team. I think a lot of it does come down to the team and the vision that the team has both both for the founders, and the actual seed sort of management teams, how they want to build a company, how they are actually able to announce that story, their understanding of drug discovery and development and an understanding of the challenges associated with that. 

It’s really kind of mapping out how you go from concept on a piece of paper to actual execution and what resources need to be put in place. I think having a basic understanding of data is absolutely critical, really understanding the data that’s coming in. 

Biology is extremely complex but our assumptions tend to be very simple. As data comes through, it’s being ready to analyze that data in a sort of pragmatic fashion. Utilize what the data is telling us, as we think about modifying, and developing our overall research plan, and path to the clinic.

Now, what we’ve seen historically, is that for large platforms, invariably the first few years consists of trying to determine what the platform actually can do and what it cannot do. Once you define what it can do, you understand the framework of the application from a therapeutic setting. I think where we’ve made mistakes historically has been assuming the platform can do everything, that it can cure all diseases. It’s taken us a few years to realize that actually, that’s not the case. A drug is actually good at x. We now need to identify and understand the indications that x is applicable to, and steer away from the diseases that other therapeutic approaches may be more relevant for.

Those are just some of the factors. But really, it does come down to the people. It comes down to the vision and then the execution. 

The final one factor is capital conservation. We’re obviously seeing that today. You need to be very clear about your use of proceeds, the use of your capital and being very judicious in how you’re deploying it, and staying focused. 

I think for a number of us, you know, this is our third cycle that effectively we’ve gone through. It’s part of the industry that you have these cycles of highs and cycles of lows. We always need to think about building our companies, understanding that, while everything may be great now, things can change tomorrow. We should build our companies with that in mind. 

There are a lot of startups around that have very similar ideas. Some survive, most do not. Why do some fail while others succeed? Is it a matter of execution?

Vision and execution… Execution is it. At times, it can seem very straightforward to put a vision out and generate interest around it. The execution and being very clear about the execution and your confidence in that execution is really the driver and determinant of success. This includes letting the data take you where it needs to take you, running the right experiments, not being afraid to do that, doing the right business development deals to access technologies that are relevant to you… all of those are absolutely critical. 

This interview has been edited for clarity and length.

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