SiteOne Therapeutics was passed over by investors for years. Now, it has backing from Novo Holdings and others, and plans to use the cash to obtain "proof of concept" for its medicines.

Almost 15 years ago, in the midst of an opioid epidemic that would kill more than half a million people in the U.S., a startup formed with the aim of creating new, non-addictive pain drugs.

This goal could have been seen as noble. But for most investors, it was far too risky. Pain research was known to be exceedingly difficult and, even if successful, any resulting products would have to compete in a healthcare system that opioid makers had already gamed.

The startup, SiteOne Therapeutics, has stayed afloat in the years since mostly through small grant funds. Yet, in a major reversal of fortune, it recently began to receive a huge influx of investment. The company on Wednesday announced the closing of a $100 million fundraising round, and plans to put the cash toward human studies designed to show its drugs work as intended.

"Pain has really been out of favor in the industry up until very recently," said John Mulcahy, SiteOne's cofounder and CEO. "Now is the time to add additional resources to really ramp things up."

SiteOne's research focuses on a kind of protein that's embedded, by the thousands, in the perimeter of cells. Aptly named "ion channels," these microscopic tunnels allow cells to communicate with one another through the rush of electrically charged particles. They are essential. Without them, our bodies wouldn't be able to move muscles, sense surroundings or fight against germs.

These functions also make ion channels attractive targets for drug researchers, who have already found ways to use them to combat seizures, infections, and problems with the heart and blood pressure. And over the past couple decades, technological advances have led to a better understanding of these proteins, such that some pharmaceutical companies now believe the field will, before too long, produce new treatments for pain, epilepsy, depression and many more neurological conditions.

Vertex Pharmaceuticals, which is currently worth more than $120 billion, proved how valuable this research can be through a series of drugs that transformed cystic fibrosis treatment by improving the function of chloride ion channels.

The Boston-based biotechnology company also spent years developing its own non-opioid pain medication. The drug acts on "NaV1.8" -- one of the nine known types of sodium channels -- and has demonstrated in a few medium to large clinical trials the ability to significantly reduce multiple kinds of pain, from chronic nerve pain to acute pain. Vertex this spring asked for approval in the acute setting, and analysts expect the Food and Drug Administration to oblige before the end of January.

SiteOne has a complicated relationship with Vertex. Its lead program also regulates NaV1.8, meaning the companies may one day be competitors. Yet they are also working together on a different non-opioid pain drug that targets the "NaV1.7" sodium channel.

More broadly, Vertex exerts an almost gravitational force on SiteOne. How the former moves through testing and, potentially, selling its pain drug directly affects the latter. This dynamic played out in SiteOne's latest funding round, which was led by Novo Holdings, the controlling stakeholder of Ozempic-maker Novo Nordisk.

According to Ken Harrison, a senior partner at Novo Holdings, the firm had kept an eye on SiteOne pretty much since it formed in 2010. After years of waiting, the firm finally decided to invest late last year, partially because of promising early data from SiteOne, but also because Vertex had established a pathway to successfully develop these kinds of drugs.

"The Vertex data were very compelling ... multibillions in market cap were added in a single day when they press released their Phase 2 and Phase 3 data sets," Harrison said. "If the Vertex data did not exist, would we have invested? I don't know, actually."

Harrison added that, having been in contact for years, Novo Holdings was impressed by the SiteOne team's candor and scientific rigor. "They would only put something in the clinic that they thought was worth it," he said. "That means a lot, that sort of truth-seeking behavior."

The firm naturally still did due diligence. It searched around for other companies developing NaV1.8 drugs and found sparse pickings. It also weighed the potential commercial challenges. SiteOne would have to contend not only with a large, deep-pocketed rival in Vertex, but a market where inexpensive opioids are favored by insurers and remain entrenched in certain pain treatment plans.

The few payers Novo Holdings has spoken to understand the problems with opioids and the need for new, non-addictive pain medications, according to Harrison. "But when it comes to pricing and the market realities payers will face with these drugs coming out, honestly I don't know," he said. "Commercially, Vertex is going to pave the way here for everyone."

SiteOne's new funding round also saw participation from OrbiMed, Wellington Management, Mission BioCapital and BSquared Capital, as well as existing investors. The company previously raised $15 million in 2017 through a Series B round led by Amgen. The two drugmakers had partnered on SiteOne's NaV1.7 program, but that agreement fizzled in late 2019 when Amgen exited neuroscience research.

SiteOne expects the latest haul to get it through "proof-of-concept" studies in both acute and chronic pain. A Phase 1 trial evaluating its lead drug in healthy volunteers kicked off in the middle of this year, and should produce data before the end of March. Mulcahy said data from acute pain testing should come in the first quarter of 2026, whereas the chronic pain work will "take a bit longer."

Like Vertex, SiteOne intends to show its drug can treat acute pain first by assessing it in people who just underwent either a "tummy tuck" surgery or a bunionectomy. The company hasn't fully decided where to begin in chronic pain, Mulcahy said, though diabetic neuropathy would be "the most logical place to start."

Harrison notes that, historically, venture capitalists viewed chronic pain as a more rewarding indication. "That is likely still the case," he said, "but this is a very unique time to be thinking about the acute pain market as well, because of the recognition across the board, especially with physicians, that non-opioid alternatives are needed and we don't have enough [research] activity."

SiteOne isn't alone in chasing Vertex. Latigo Therapeutics, a California-based biotech created by the venture firm Westlake Partners, is developing a NaV1.8 therapy directed at acute and chronic pain. Latigo debuted in February, equipped with $135 million in funding and some of the scientists who were laid off when Amgen left brain drugs behind.

"Novo's investment thesis is that this is perhaps a horse race with two or three competitors, but one in which every horse can win," Harrison said.