It was a cold night in Boston, and the valets were taking forever, so two neurobiologists got to talking about a fitting topic: pain.
Bruce Bean and Dr. Clifford Woolf, both professors at Harvard Medical School, were vexed by the struggle to come up with viable new painkillers. The therapies of yesteryear dimmed pain but could cause numbness and immobility. Opiates could be addictive. There have been new kinds of painkillers, but they have come with safety and efficacy issues of their own.
“We just started talking about whether there was some novel way that we could selectively target pain-sensing neurons,” Bean said, and the two parted ways with a mutual challenge.
That conversation, between shivering scientists outside a now-defunct French restaurant, set in motion a decade-long quest to build a better neuroscientific mousetrap. And it has now resulted in Nocion, a nascent biotech company that just raised $27 million in venture funds to carry out the idea.
The plan is still to treat pain, but first Nocion wants to prove its scientific principles in another common and tough-to-treat scourge: chronic cough. It’s a disorder that hasn’t seen a new drug since 1958, and it sends about 30 million Americans to the doctor each year.
“The unmet need is massive,” said Dr. Peter Dicpinigaitis, director of the Montefiore Cough Center in New York. “What folks don’t realize, even doctors, is that cough is the single most common reason why people in the United States seek medical attention.”
Nocion won’t be the first to break that 60-year drought, as there are rival cough medicines already nearing approval. And the company’s science, as yet untested in human trials, could amount to more of a disappointment than a breakthrough.
But Nocion believes Bean and Woolf’s discoveries offer a new way of thinking about agitated neurons, one that might lead to treatments for cough, pain, itch, and inflammation. First, however, the company will have to prove that its scientific serendipity can translate into human medicine.
Years before Bean and Woolf turned their attention to cough, they were delving into the machinery of sensation.
Neurons are encased by gatekeepers called ion channels. When nothing is amiss, those gates stay shut. But when there’s external stimulation — like an injury — the gates open and let sodium ions flood in, a process that leads the neurons to fire sensory signals to the brain.
Decades-old anesthetics like lidocaine work by shutting off those ion channels entirely, a process that can reliably relieve pain. The problem is that they also block the neurons responsible for detecting touch and moving muscles, making them impractical for many uses.
Bean and Woolf wanted to find a way to target only nociceptors, the sensory neurons responsible for pain and itch, while leaving healthy neurons alone. That’s what led them to take a page from Greek mythology.
The pair discovered a class of Trojan horse molecules. Like lidocaine, they were ion channel blockers, but they had a positive charge that made them inactive in times of cellular peace. However, once an injury came and the channels flung open, that charge let the molecules trick the cell’s defenses, slip through the gates, and silence the neuron before it could fire its pain signal.
“That was the novelty of the idea,” Woolf said. “Use the biology of the cell as a means to an end.”
Bean and Woolf’s interest in cough came, like the valet encounter, by happenstance. A postdoctoral researcher in Woolf’s lab at Boston Children’s Hospital happened to be friends with a scientist working under Dr. Bruce Levy, who runs pulmonary and critical care at Brigham and Women’s Hospital. While Bean and Woolf were toiling on the biological underpinnings of pain and itch, Levy had been focused on cough. When all three got together, they landed on the question that would unite their work and give Nocion its first focus: Is cough not just the itch of the airways?
“That was the aha moment that all the work Bruce Bean and I had been doing could be translated to not just the symptom but the response, which is cough,” Woolf said. “And Bruce [Levy] clearly understood the unmet need there and brought that whole knowledge to us.”
That led to a series of mouse experiments in which those molecules reliably silenced nociceptors in the lung and significantly reduced airway inflammation. That’s also when it became clear this could be a business.
By 2015, the trio’s work had attracted the attention of Dr. Tom Beck, executive partner at the Fidelity-affiliated F-Prime Capital. Julie Grant, a partner at the venture firm Canaan, joined the fold months later, and the two holed up in the back of F-Prime’s Boston office to hammer out just how the work of Woolf, Bean, and Levy could give rise to an actual company.
By 2018, Nocion was a five-person company grinding out its medicinal chemistry in rented space at LabCentral, a Cambridge, Mass., co-working space. Richard Batycky, who co-founded a company that successfully developed an inhalable medicine, took the reins as CEO and found an immediate pleasant surprise.
“One of the first things we did — which usually doesn’t happen — is we were able to reproduce the founders’ data,” Batycky said with a laugh. “I mean how many times do you get in and you’re like, ‘I can’t get the experiment to work’? This was not that.”
That’s no accident. Woolf, Bean, and Levy held onto their idea a little longer than academics tend to do, and that meant using grant money to pay outside researchers to kick the tires on their science.
“The founders did it themselves before we even showed up, which is a testament to how they think,” Grant said. “They want products that are going to work. It’s not about their ego.”
Nocion expects to stretch its $27 million funding round, led by F-Prime and Canaan, all the way into human trials. Batycky divides the sum into thirds: $9 million to finish its chemistry work, $9 million to prepare preclinical evidence for the Food and Drug Administration, and the rest to test Nocion’s first cough drug in the clinic.
The plan is to start with acute conditions, like persistent cough following a viral infection. That should allow for smaller studies that could give Nocion a fairly quick answer to whether its approach is working, Batycky said.
Meanwhile, Merck is working through a late-stage trial with a drug called MK-7264, which, if successful, could win approval in 2020. But Merck’s drug has had problems with specificity in the past. In a mid-stage trial, the treatment succeeded at relieving cough but also wiped out the sensation of taste for some patients. If that side effect persists, Nocion’s future therapy could have a competitive advantage.
If Nocion succeeds in cough, the company has ambitions tracking back to Woolf and Bean’s earliest conversations. Nociceptors are widespread throughout the body, and if a souped-up lidocaine can prove its worth, it could lead to treatments for pain, inflammation, gastrointestinal disease, and women’s health, Grant said.
“There is so much potential with this platform,” she said. “I look forward to them pursuing partnerships for the therapeutic areas we’re not pursuing on our own.”
Meanwhile, Woolf, Bean, and Levy are still very much in the picture. They have monthly meetings with the company they seeded, and each has a spot on Nocion’s scientific advisory board.
“When we were looking for investors, something we made quite explicit was that we didn’t want to just pass over the technology and then forget about it,” Woolf said. “It’s still our baby, and we want to do our best to enable it and to see the progress.”