Back to Boston

Our time at IndieBio & next steps at AstraZeneca

Nivien arrived at IndieBio in December with a novel target and initial venture funding. Since then, we’ve developed the first molecules that inhibit Hippo signaling, which may play a critical role in cancer’s resistance to treatment.

We’ve had positive and negative data, hiring successes and failures, novel discoveries and new IP. Now we’re moving back to Boston to work at the AstraZeneca BioHub. We officially start today and we have a lot to prove these next few weeks in order to advance our program.

It’s been 7 months since my last essay, but I’ll condense what feels like 7 years of learning into 7 short sections:

1. Colleagues

The primary catalyst for our return to Boston is AstraZeneca, which offered free access to lab space and equipment at the state-of-the-art BioHub. It’s an exciting opportunity to work with scientists from one of the best oncology teams in the world — and to save a lot of money on rent and equipment.

Our new home at the AstraZeneca BioHub.

We’ve continued our partnership with Reverie Labs, a ML company that uses convolutional neural networks to optimize therapeutic candidates. With Reverie’s custom-built models, we’ve explored the selectivity of our best molecules and completed high-fidelity IC50 predictions to guide next steps.

Another key partner has been Charles River Labs, a multinational CRO that made it possible for us to run industrial-scale drug discovery on a startup-scale budget. If you need an excellent CRO, I highly recommend their team.

2. Hiring & Firing

We recruited a veteran industry chemist and a postdoctoral cancer biologist in November. The chemist has been a star, but we had to re-hire our biologist after just a few weeks at IndieBio.

We didn’t recruit a replacement until we’d notified our first biologist. Then we moved fast, scoring 65 candidates and interviewing 27 scientists in 52 hours. We soon hired a senior cancer biologist from Houston Methodist (with prior postdocs at UCLA and the NIH) who has done solid work the past few months.

A few takeaways: Talk to every reference — listed or not. Personality and spirit are vital, but don’t let focus on culture outweigh core technical needs. When it doesn’t work out, be civil and empathetic but decisive: the show must go on.

3. Chemistry Fast, Biology Slow

We developed the first potent, selective Hippo inhibitors in 5 months with just $178K (faster/cheaper than industry standards), but our biological validation hardly moved beyond replicating proof-of-concept by our partners at Harvard.

Much of this is luck. We ran a high-throughput screen of 660,000 molecules, expecting to identify just one or two starting points for our med-chem and Reverie modeling. Instead, we got 248. So we were very lucky with chemistry.

An IC50 curve for one of our starting points. IC50 measures the concentration of a molecule required to inactivate 50% of a target protein or process. We went on to improve potency by an order of magnitude.

But when we ordered 20 siRNA clones to eliminate a target protein — at least a couple of which were expected to work — we struck out. An important cell line that supposedly had a double-knockout was a dud, as was its replacement (we got back our money, but not our time). We generated good data with another line that we created in-house, only for it to spontaneously die the next week. Antibodies went bad and a busted pipe flooded our lab:

El Día de la Inundación: No major losses, but we had to sacrifice a box of Kimwipes to the water gods.

We also made mistakes—with our biggest error in hiring. We selected a cell line that wasn’t well-suited for our experiments, ordered the wrong system for testing a hypothesis and fell behind our original—albeit ambitious—schedule. So it’s not entirely chance that our chemistry roared ahead under a 17-year industry expert while our biology suffered from experimental delays.

4. Demo Day

IndieBio ends with a pitch to over 700 VCs, reporters, and biotech enthusiasts, all live-streamed by TechCrunch, and Nivien got featured in Forbes.

The pitch only ran 7 minutes, but I spent about 7 hours practicing in the week leading up to Demo Day.

The structure of the event verged on formulaic (4 startups, including us, had “next-gen” on our banners) but the excitement was legit: while I’m sure that all of us will struggle and many of us will fail, a couple of the companies from our cohort really will change the world.

Our peers pitched everything from fungi-based “salmon” burgers and a new composite material that replaces the use of old-growth wood to a stem cell collection device and improved biomarkers for Alzheimer’s and Huntington’s.

A guitar made of Ekoa, a new composite developed by our friends at Lingrove.

After post-pitch glad-handing, the founders and the IndieBio team returned to the accelerator to celebrate with karaoke and impromptu speeches.

As the party wound down, my co-founder and I took a conference room and reviewed our next steps for Nivien into the early hours of the morning. On my way out, I saw another founder already back in the lab.

5. Fundraising

The top-line summary: we closed $600K on good terms, but need to run more experiments before raising a larger round.

The first time I pitched investors last summer, Nivien had no money, little data and less IP. While we could get through the door of the Boston VCs, mostly on technical merit and the reputation of our advisors, we never got close to a real investment. IndieBio’s willingness to take a risk on two young founders was a big part of our decision to move to SF.

By the time we started pitching this spring, we had initial funding, stronger IP and a demonstrated ability to develop therapeutic candidates with minimal burn. We closed several investments in just a couple meetings, but many other investors wanted more data on our new molecules.

A few pointers for other first-time entrepreneurs: Be honest, confident, and ask for feedback. Do your homework and only pitch VCs that invest in your space (we met several tech VCs who were excited to learn about cancer therapeutics but were never going to write us a check). “Too early” is a catch-all way for VCs to say “No” — and so is not getting back to you. As in dating, move on fast.

Turn down money from investors that you don’t trust or who won’t add value. Once you have investors, ask for advice and update them regularly, even if the news isn’t as good as you’d like: everyone wants to be kept in the loop.

6. Balance

Startups are tough, but life doesn’t (always) need to be. Even if there are weeks when you break 100 hours of work, it’s essential to balance that with exercise, community and new experiences. I’m not sure I believe in “burnout” per se, but I definitely believe in maintaining fitness, friendships and sleep.

Out in SF I tried hang-gliding for the first time — and a second. I explored the entire city, often on calls and twice when my girlfriend visited from Boston. I walked all of Ocean Beach with a housemate, debating FDA regulation and scouting the best site for my 22nd birthday—a sunset fire beneath the cliffs.

ft. My college roommate Joe.

7. What’s Next?

July and August will be focused on data generation and relationship-building. We face significant challenges as we investigate the validity of our molecules, as well as a lot of optimization before any human trials.

I’m optimistic about our experiments, but we’ve also run into a lot of negative or ambiguous results. It’ll be a tense few weeks as we replicate and analyze our data.

In the meantime, if you’d like to learn more about Nivien, the IndieBio Accelerator, or just want to talk biotech, feel free to connect.


This post is part of a series of short essays about entrepreneurship, venture capital, and translating scientific research into applied technologies. If you enjoyed reading this one, check out the others and feel free to get in touch!

Shout-outs to Sam Koppelman and Emi Gonzalez for smart edits.

Update: Nivien closed after 2 years. Read our story in The Washington Post.

Principal at RA Capital, on the boards of 7 biotech companies. Founder/CEO of Nivien Therapeutics. Australian-American. 50 countries and counting.