A quarter of cancer patients don’t respond to targeted therapies. This biotech wants to help them.

The more progress we make in precision medicine, the more edge cases we discover. Cancers once thought to be a single disease turn out to have a variety of different causes – and to require a range of different treatments. At JP Morgan this year, pharmaphorum caught up with Zach Hornby, the CEO of Boundless Bio, a company focused on oncogene amplification, an under-studied genetic driver in cancer.

pharmaphorum: Tell us about Boundless Bio. What's your core focus and what's your differentiator?

Zach Hornby: The company was formed to address one of the key unmet needs in oncology, which is patients whose tumours are driven by what's called an oncogene amplification. Over the last 30 years or so, we've had this precision medicine revolution, where lots of targeted therapies have been developed. These drugs work extremely well for patients with certain types of genetically-driven tumours, specifically patients who have gene fusions or point mutations. These patients do very well with targeted therapy, whether those are small molecules or monoclonals; these can be life-extending drugs.

However, there's another sort of genetic driver, which is oncogene amplification. Instead of a mutation in the sequence of their gene, these patients simply have too many copies of the gene. This is quite common - about 25% of all cancer patients. What we found is that those same targeted therapies that work well for fusions or point mutations, when given to patients with amplifications, no longer work. These patients have no standard of care, statistically worse survival, and more aggressive disease.

pharmaphorum: And these cancers present similarly, but they have different causes?

Zach Hornby: They could be any tumour type, really. But when they do the genetic sequencing, they'll say, "Oh, instead of a mutation of EGFR, you actually have 20 copies of EGFR." That's where an EGFR inhibitor that would otherwise work for a mutation doesn't work for the amplification. This has been an emerging clinical phenomenon over the past couple of decades. People were perplexed by why these patients with amplifications were deriving no benefit. Our scientific founders started devoting their careers to understanding the biology of these patients and why their tumours were not responding.

They made a unique discovery over the past 10 years, which is that, when these amplifications were detectable, especially when there were a lot of copies, it was frequently DNA that was not on chromosomes.

So, like, you'll remember from high school biology, you learn about like Mendelian genetics and the 23 chromosomes, and that's where your genome sits. Well, it turns out in cancer there's this shadow genome of these little circles of DNA that break off of the chromosomes and these little circles are fully functional, they can encode one or more full length genes. They independently replicate, independently transcribe.

Those little circles are called extrachromosomal DNA (ecDNA). Our company was formed in 2018 to take advantage of this emerging understanding of this cancer-specific biology and ecDNA. We aim to understand how these things form, function, replicate, transcribe, and move around, and how they drive cancer. Our goal is to identify ways to intercept that biology, mitigate or inhibit it by identifying novel targets that we can drug. That's what we've been doing for the past six years - building out a platform to identify novel targets and make drugs to help these patients with amplified cancer.

pharmaphorum: How far along are you in addressing this? Is your platform targeting one cancer at a time, or is there a general template for modifying existing treatments to affect amplifications?

Zach Hornby: It's always a continuum because we're advancing our knowledge. We currently have two programmes that have entered the clinic and a third one that we hope will enter the clinic next year. We're actively testing different mechanisms, drugs, and targets. Our approach is tissue-agnostic, meaning we're not focused on where in the body the tumour is growing, but on the genetic driver and whether these circles are present.

pharmaphorum: What do you have on the agenda? Any recent news or things you're looking to announce next year?

Zach Hornby: Our first clinical programme, BBI355, is an oral CHK1 inhibitor. We should read out data from our Phase 1b component by the end of this year. We're looking for preliminary proof of concept and anti-tumour activity. This could indicate that we have a real drug and help prove our hypothesis, giving credence to our approach and the value of our platform. Another milestone is a preclinical programme with a novel target that has never been disclosed publicly. We anticipate declaring a development candidate by mid-year, initiating IND-enabling work to enter the clinic next year.

pharmaphorum: How common are these amplifications?

Zach Hornby: They're quite common - about 25% of all tumours. It varies by tumour type, with some of the most aggressive tumours like glioblastoma, sarcoma, and oesophageal cancer being highly enriched for these amplifications. About 25% of cancers have any kind of amplification, and about half of those have these specific circular ones. A study in Nature last November found ecDNA in 17% of 17,000 patients' tumours.

pharmaphorum: What's the relationship between ecDNA and amplification?

Zach Hornby: ecDNA is one of the primary causes of amplification, but not the only cause. There can be cases where there are multiple copies of the gene on standard chromosomal DNA. Usually, if ecDNA is present, it's because the tumour has chosen it for its advantage, creating more copies of something beneficial to the cell.

pharmaphorum: Anything you've seen or heard since you've been here [at JP Morgan] that's interesting to you?

Zach Hornby: I'm always interested in innovation and happy when companies provide data updates or progress in their studies. I think what's important that we've seen a little bit of this year is that you need a healthy capital-raising environment because this science is risky and expensive, so, we need a supportive environment to fund it. To the degree that there has been some nice M&A that provides return to investors, and then it rewards them and they can recycle that capital back in, but also then have an appetite to continue to take risk - that's obviously just a critical component of our industry. So, it has been nice to see some of that.

Jonah Comstock: What I'm hearing is that M&A seems focused on later-stage deals due to patent cliffs, and the trend is towards fewer and bigger deals. Has that been your experience, and how does it affect you as a smaller, earlier-stage biotech?

Zach Hornby: I mean, I've been in the industry for 25 years now, so the industry goes through cycles. There're times when there's just more aggressive and more preponderance of capital than others. There're times when it's all late stage, like you alluded to, because people are filling patent cliffs, but at some point it's about supply and demand, and if that supply is depleted because there's only so many late-stage companies, but the demand still exists, then the pharma companies have to start acquiring earlier, more risky assets. So, I think it waxes and wanes. I never see it as a permanent state of existence. All you can do is maintain relationships, keep working on good data, be capital efficient, and make disciplined cuts to buy yourself time until the cycle shifts.

Jonah Comstock: Another thing I've heard is that companies don't get sold; they get bought. It's driven by what big pharma is looking for. You're in something of a niche, right?

Zach Hornby: It's a niche now because it's brand new, esoteric biology, but it's becoming more prominent. So far, we’re the first or most advanced company, but it certainly is gaining a lot of attention in academia. There have been multiple Nature publications - in fact, in November last year there were four concurrent Nature publications on this and it was the cover feature [of the journal]. It's going to be one of the plenary addresses at a major upcoming conference in the Spring. There's going to be an international ecDNA devoted conference in June in London. So, I think it may not remain a niche for too long.

About the interviewee

Zachary (“Zach”) Hornby is currently CEO, president, and a director at Boundless Bio, a clinical stage, next-generation precision oncology company. He is also a director at Radionetics Oncology. Prior to joining Boundless Bio, Hornby was chief operating officer at Ignyta, where he oversaw development of the company’s portfolio of four clinical stage therapeutics and was the team leader for the company’s lead programme. Prior to joining Ignyta, Hornby served in roles of increasing responsibility across business development, marketing, new product planning, finance, and regulatory affairs at Fate Therapeutics, Halozyme Therapeutics, Neurocrine Biosciences, and Transkaryotic Therapeutics (“TKT”; now the Human Genetic Therapies division within Takeda/Shire), and was a life sciences consultant at L.E.K. Consulting. Hornby holds BSc and MSc degrees in Biology, with a concentration in Neuroscience, from Stanford University and an MBA from Harvard Business School.