John Mulcahy, PhD, spent years as a neuroscientist studying natural toxins that bind to and inhibit sodium channels—a family of targets that has recently sparked interest from big pharma, such as Vertex Pharmaceuticals, and investors seeking non-opioid peripheral nervous system (PNS) pain treatments—before deciding to apply his knowledge of modulating ion channels to drug development and founding SiteOne Therapeutics with three professors ten years ago.
“Whereas most neuroscience companies are focused on the central nervous system (CNS)—brain and spinal cord—SiteOne is a bit different,” Mulcahy told Inside Precision Medicine. “By focusing on the PNS, we feel we have the opportunity to address pain and a number of other related conditions, which we call sensory hyperexcitability disorders, without the central side effects and risk of addiction of existing medications, things like opioids and gabapentinoids.”
Today, SiteOne announced closing a $100 million Series C financing to advance a portfolio of selective, small-molecule ion channel modulators in the PNS for pain and sensory hyperexcitability disorders like chronic cough and itch through human clinical proof of concept.
SiteOne’s technology was developed to discover highly selective modulators of ion channels, first focusing on voltage-gated sodium channels (NaVs). As with Vertex’s suzetrigine, SiteOne’s lead candidate, STC-004, selectively targets NaV1.8 for pain and related disorders. A separate program targeting NaV1.7, another PNS NaV, is being pursued in collaboration with Vertex.
“I think the industry as a whole made some very significant missteps with how it handled opioid pain medications, marketing, and prescriptions,” said Mulcahy. “I think where we are now with these non-opioid approaches to pain, we have an opportunity to, to a certain extent, do our best to make that right and do the right thing here for patients. That has kept us going at SiteOne over the years and motivates our team to push forward even to this day.”
The Series C financing will be used to advance SiteOne’s NaV1.8 program through clinical proof of concept in acute and chronic pain. It will also advance the rest of their pipeline, which comprises other ion channel modulators focused on the peripheral nervous system. Novo Holdings led the financing, with participation from OrbiMed, Wellington Management, Mission BioCapital, BSQUARED Capital, and existing investors.
Owning the action potential
According to Mulcahy, SiteOne started with NaV1.7 with a very different scaffold than everyone else interested in that channel, choosing to use a toxin scaffold that binds to a different site on the channel, the extracellular pore.
“We were trying to capitalize on a structural variation in NaV1.7, a pretty small structural variation of only two amino acids different from the other subtypes of NaVs,” said Mulcahy. “With a small team and limited resources, we were able to do that through this irrational strategy design and advance some extremely selective NAV 1.7 inhibitors and explore their pharmacology. That’s what got us started in this space.”
The same approach was applied to NaV1.8, targeting a selective binding site where there is a structural variation that distinguishes Nav1.8, in this case, from the other eight sodium channel subtypes, capitalizing on that structural variation to build “exquisite” selectivity for the subtype of interest over all the NaV subtypes. By targeting the family of NaVs in the PNS, Mulcahy said that SiteOne has been able to work towards a concept he calls “owning the action potential.”
“The action potential is the fundamental unit of electrical signaling in the PNS, and what we mean by ‘owning the actual potential’ is triangulating, targeting, and attacking it from different angles with different mechanisms of action,” said Mulcahy. “We feel this has the opportunity of providing eventually better efficacy than one mechanism alone.”
Mulcahy describes NaV1.7’s role in setting the threshold for action potential firing as a “light switch” that turns on or off the PNS. NaV1.8 inhibitors readjust the threshold for action potential firing when there’s hyperexcitability due to some damage, something more akin to a “dimmer.”
“NaV1.8 is the foundation of this approach, but we’re adding additional mechanisms on top of NaV1.8 going forward to build a competitive advantage,” said Mulcahy. “In some ways, targeting NaV1.8 is more desirable because pain has this fundamental protective purpose. You don’t want to turn it off completely so that someone could hurt themselves, for example, by touching a hot stove. You want to retain that normal level of sensitivity to noxious stimulus.”
Potent, speedy, and non-interacting
Since SiteOne is nowhere near being first to the finish line with a nonaddictive oral treatment for pain treatment with Vertex Pharmaceuticals on the verge of gaining FDA approval for suzetrigine (VX-548), with an established target action date of January 30, 2025, Mulcahy is focused on the requirements for being best-in-class. For SiteOne, this comes down to three differentiators. The first is delivering the maximum possible efficacy available with this mechanism to patients, and the second is achieving a rapid onset of action.
“You can’t leave any efficacy on the table, and you can’t leave a patient hanging there, waiting for an analgesic to take effect,” said Mulcahy. “The drug has to be rapidly absorbed and perceived as effective by the patient; otherwise, you risk losing them to things like opioids, and that’s obviously what we’re trying to avoid here—to transition away from opioids to this newer approach.”
The third is minimizing drug-drug interactions, which is a headache, given that pain accompanies so many other conditions. As Mulcahy put it, “You end up with a patient population that is on a variety of concomitant medications, so it’s really important that an analgesic be able to be taken with a variety of other drugs without interfering with them,” said Mulcahy.
Relatedly, while NaVs are mostly restricted to the PNS, they are relatively ubiquitous throughout, making it difficult to discover ways of targeting spatially selective areas of the body. So, taking a NaV modulator systemically, such as in an over-the-counter pill, would target the entire PNS. NaV modulators have to be injected to target localized acute pain, and this is likely the path that SiteOne will be the first to trek through because of the straightforward path to approval recently carved out by other companies. There are proof-of-concept models for soft and hard tissue models in abdominoplasty and bunionectomy, respectively.
The clinical testing landscape for chronic pain is far more complex and uncharted. According to Mulcahy, chronic pain is much more nebulous and segmented, so figuring out the chronic pain segments SideOne will operate in first is just a more complicated decision than acute pain. However, a new challenge awaits at the end of this journey: reimbursement.
“The other interesting dynamic has to do with the commercial adoption of these medications and, in particular, how reimbursement is going to play out,” said Mulcahy. “For a long time, there’s been this dogma that opioids are safe medications, and the patients are the problem. I think the science doesn’t support that. The science indicates that with every dose of an opioid, you’re increasing a patient’s risk of dependence and addiction. But where reimbursement lands will be an evolving story here as this technology begins to reach patients.”
Beyond pain
Mulcahy believes that NaV modulators provide therapeutic opportunities beyond pain. For example, there are remarkable physiological similarities in the C-fibers—unmyelinated nerve fibers that transmit information about deep, dull pain—that innervate the skin and the lungs. According to Mulcahy, that opens up looking at conditions like chronic cough and irritation.
Mulcahy said, “You’re not going to be able to achieve tissue selectivity where you could only target one part of your body over another. However, the upside is that, if you think about the PNS is this wiring that interfaces with almost every tissue organ in your body, when that tissue is damaged, a lot of the time that irritation manifests in pain. There are also other symptoms, like [irritation], that can accompany that damage.”
Mulcahy said it’s too early to comment on exactly which molecules SiteOne will advance for indications beyond pain. Even if SiteOne hasn’t made much progress in targeting NaVs and other ion channels in conditions related to hypersensitivity, they’re quite a bit closer to getting their foot in the door to a whole new world of indications.
“The total addressable market with the NaV mechanism is really broad and comprised of not only acute pain and chronic pain, but also there are potentially these other opportunities beyond pain that we aim to explore,” said Mulcahy. “So, as a small company, it’s very exciting, but at the same time, we have a lot of work ahead of us here to explore what we think is possible with this approach.”
