Read a revised version of this essay in The Washington Post and follow-up essays by Derek Lowe (In The Pipeline) and John LaMattina (Forbes).
Two years ago, I met a professor at Harvard to discuss his new manuscript.
He’d identified a master regulator of systems in cells that stop several cancer drugs from working. When a scientist in his lab inactivated the regulator, the drugs destroyed pancreatic tumors — in mice.
The regulator — a signaling pathway called Hippo — had never been targeted in humans. With the professor, my co-founder and our advisors, we launched Nivien Therapeutics and filed our first patent on Christmas Eve in 2016 using a Harvard dorm as our business address.
We raised venture capital; recruited scientists; and designed, synthesized and patented the first molecules that potently inhibit a core component of the Hippo pathway. A top journal published the professor’s paper and scientists at UCSD revealed that our strategy may not only enhance treatment, but also act as a novel immunotherapy.
Suddenly backed by funding, patents and publications, I left Harvard one semester before graduation to lead our team at a new lab in SF.
We ran a barrage of experiments with partners on three continents to test our approach. I pitched Nivien to hundreds of scientists and investors at the IndieBio Demo Day. AstraZeneca invited us to join its state-of-the-art BioHub.
Then — after months of rapid chemical development and hard-won progress on the biology — we hit a brick wall of ambiguous and negative data.
Our basic hypothesis proved true. When Hippo is inactivated, the levels of key proteins that break down or export many drugs from cancer cells —rendering the drugs ineffective — are reduced.
But the magnitude of that benefit proved much less than we’d hoped, and our initially-positive results didn’t generalize beyond early proof-of-concept.
What would I say to the patients who had written to us?
“First of all, thank you for your cutting edge research with cancer treatment,” wrote one woman. “Recently, a dear 45 year old male friend was diagnosed with stage four pancreatic cancer. He did have a successful Whipple surgery with clean margins, but there is other involvement.”
Our chief medical advisor is a surgical oncologist at MGH with a PhD focused on pancreatic cancer. He does several Whipple surgeries a week and taught me the paradigm. While 5-year survival for stage four pancreatic cancer has hovered at 5% for decades, I knew just two words meant the writer’s friend would not make it to 50 — that final, fatal qualifier: “other involvement.”
She asked if we were offering any studies he could join.
“He is looking to start treatment ASAP… We who love him are desperate to see he gets a fighting chance at more years… With the wonderful write ups you are getting I’m hoping you are getting fully funded.”
Another note came directly from a patient.
“I am currently going through chemo for pancreatic cancer… As of now the treatment is working but its [sic] having severe side effects on my body. I was very intrigued by the research conducted by you guys.”
Most writers recognized the poor odds. They also saw an opportunity to help pursue a better standard-of-care: each request was matched by two offers of assistance. “I was wondering if I can be any help to the cause,” he concluded.
Other writers were nonplussed by common medical jargon, like “preclinical.”
“I’d like to chat with you about the realities of your potential therapy, and even what opportunities may exist for a preclinical trial evaluation,” wrote a tech executive two years into treatment.
“Preclinical” is prior to human studies, but it’s easy to be misled by how the media, and often biotech companies themselves, describe emerging science. All new discoveries take years to become new medicines, if they work at all, but even in scientific papers it can sound like a cure is just around the corner.
The “realities of [our] potential therapy” were that it was another Hail Mary against one of the most lethal diseases. Rereading an article about Nivien, I saw how easily a person with cancer could misinterpret the headline — and how I, like too many entrepreneurs, had not provided enough caveats when talking about the potential of our work.
It’s easy to accidentally generate the impression of an imminent win. Often, new biotechnologies really are revolutionary. Many companies, however, generate this impression intentionally, even when undeserved.
Raising money, recruiting people and building a movement around your mission almost demands irrational optimism, especially in failure-riddled drug development.
There is an allure and a danger to believing in something like this, giving it your all, and seeking to convince others to do the same while knowing the chances of success are lean. No one wants to commit to a marginal endeavor.
But employees want transparency. Investors want a fair bet. And patients, who know more than anyone, want honesty. They are not one-liners for your PR machines or slides for your pitch decks. Now, reading the latest and greatest biotech PR, I’m furious when I see overstated results and oversold potential.
“Treat humanity, whether in your own person or in the person of another, always at the same time as an end and never simply as a means.” —Immanuel Kant
I spent hours crafting replies to the letters. How to express reality without savaging hope? I scoured www.clinicaltrials.gov for new studies, of which there are always too few. I replied to each message, sometimes leading to exchanges that were emotional, devastating and inspiring all at once.
I had met several people with pancreatic cancer before launching Nivien, often at clinics in Boston. The father of a boy I hung out with one summer as a kid had set a record for survival in a particular clinical setting, then died when we were in middle school.
But once I left Harvard to work on Nivien, I spent most of my time at our lab and didn’t meet a patient in person for months. The one exception was during a biotech conference at Harvard, where I met a woman who had survived for years with stage four pancreatic cancer after many grueling rounds of chemo.
Then, during a visit home, after it had become clear that our program was unlikely to succeed, my Dad fell off a dock while helping a man tie up a boat.
Dad climbed out, glasses gone, and went inside to dry. The sailor lent me and my girlfriend his snorkeling gear and we went diving (unsuccessfully) to retrieve the glasses in the waning light. After it became impossible to see beneath the water, we returned the gear to the sailor and started to talk.
He was tanned, fit, and a movie producer whose films I’d seen. He was also dying of pancreatic cancer. He had heard about Nivien at a party and wanted to learn more. Shivering, I gathered the courage to tell him that we were in a tough spot. Nowhere near as tough as his, I thought.
He took it well — much better than I had. It was cold, windy and darkening. I asked if he’d like to come home with my family for a hot dinner. He looked at the aftermath of the sunset and told me that he needed to move the boat to the lagoon before full dark, but that he’d call us when he was done. I gave him my number and watched him walk, alone, back to the end of the dock.
He didn’t come over for dinner. When I started this post over Thanksgiving, I didn’t know if he was still alive. But then we saw each other again, months later, last weekend. He’s in a clinical trial now and seems better off than many.
When I email newly-announced trials to people who’d written to me and they don’t reply, is it because they’re too busy, too sick, or already found one? It’s almost never because they got better. Is it because they’re already dead?
After I told our investors that we were done, helped our scientists find new jobs, and returned to Harvard for my final semester, I got one last message.
The writer’s Dad, it turned out, is only a couple years older than mine.
When we got the bad experimental results, we still had funding, a great team and a ton of goodwill.
If we had committed our remaining capital to further development, could we have reached some promising milestone, raised another round and eventually taken Hippo-targeted drugs into human trials?
Maybe. Would the benefit still have been meaningful to patients? Based on the data, it no longer looked that way.
I explored a few pivot opportunities, like a chemotherapy delivery device and a bioinformatics play. None were a good fit for our team or compelling enough to launch another full-fledged program. I’m still looking at alternatives while I finish my degree, but it’s pretty much over.
Did I expect this to happen? No. We wanted to build the next Genentech. But we also knew from the start that failure was the most likely outcome. 19 in 20 drug programs fail — after first-in-human trials.
I don’t regret trying. I’m proud of our work; that we took the shot in the first place. We turned an unpublished manuscript into the first good molecules against a novel therapeutic target, broke new ground in both the chemistry and the biology of an important biochemical system, and did it all faster and cheaper than industry standards despite our initial inexperience.
We ran the go/no-go experiment and the results were negative. No go. That’s how it goes.
As my one full summary of the past two years, this reflection came together with help from several friends and family. Thank you to Sam Koppleman, Laura Deming, Joe Kahn, Nelson Sigelman, Emi Gonzalez and my Mum and Dad for thoughtful edits and suggestions.
Thanks also to everyone who helped Nivien: our advisors, investors, partners and collaborators, as well as everyone else who supported us along the way.
Finally, thank you to my friend and co-founder Nikita Shah, who shared each step of the journey; to our head of chemistry Dr. Wenkui Ken Fang and our head of biology Dr. Dharmendra Singh, without whom Nivien could not have worked; and most of all to the patients, for their support, courage and perseverance.