Addiction risks from opioid drugs come from their targeting of receptors found primarily in the central nervous system. Other pathways are associated with pain, but many research efforts to hit them have fallen short of yielding viable drugs. SiteOne Therapeutics is one of a growing number of companies trying to treat pain with novel non-opioid approaches. With a lead program on track toward a proof-of-concept Phase 2 test next year, the startup on Wednesday announced the closing of $100 million in financing.
The research of South San Francisco-based SiteOne focuses on sodium channels, which are membrane proteins that transmit electrical signals. Just as a building has wiring throughout its structure, sodium channels are electrical wiring for the body, said SiteOne CEO John Mulcahy. These channels are found primarily in the peripheral nervous system, so a drug that hits them is less likely to spark the addiction problems caused by drugs that address central nervous system targets. The human body has nine sodium channels that conduct electrical impulses in the body. The two channels that transmit pain signals are NaV1.7 and NaV1.8.
“They’ve been known since the 1990s, but there’s been a major technical challenge, and that challenge has been identifying chemical matter, small molecules, that can target both subtypes,” Mulcahy said. “It took a long time for the chemistry to catch up, and now we’re there.”
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All of the sodium channels are closely related, and early research efforts found it difficult to target the channels that transmit pain signals without also hitting the other channels, Mulcahy said. Even if a drug successfully blocks NaV1.7 or NaV1.8, hitting the other channels as well can spark unwanted effects to nerves, skeletal muscles, or the heart — safety issues for any drug.
The company furthest along in sodium channel-targeting drug research might be Vertex Pharmaceuticals, which is focusing on treating acute and neuropathic pain. Vertex’s most advanced pain program is suzetrigine, a small molecule designed to selectively inhibit NaV1.8. This drug was developed for acute pain, defined as pain lasting less than three months. Suzetrigine is currently under FDA review; a regulatory decision is expected by Jan. 30.
While both NaV1.7 and NaV1.8 transmit pain signals, there are differences. NaV1.7 is like a light switch that turns pain on or off, Mulcahy said. NaV1.8 is more like a dimmer switch, so a drug that hits this channel could turn down excessive pain to normal levels. In some ways, hitting NaV1.8 is a better approach to pain management because the ability to feel some pain serves a protective function, Mulcahy said. For example, when you touch a hot stove, pain tells you to pull your hand away. SiteOne does have NaV1.8 research, but its lead program, STC-004, is designed to selectively block NaV1.7.
SiteOne traces its origins to Stanford University, where Mulcahy, the company’s scientific co-founder, researched toxins that target sodium channels. The company’s technology, licensed from Stanford, identifies small molecules that are highly selective modulators of these channels. The technology also identifies binding sites and designs small molecules that can target them. Mulcahy said this approach enables SiteOne to identify molecules that are extremely selective to the NaV1.7 and NaV1.8 channels. The startup’s name refers to the binding site that enables its drugs to be selective to NaV1.7.
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SiteOne quietly emerged with a small amount of funding 10 years ago. Since then, the company has been mostly stealthy. In 2017, Amgen led a $15 million Series B investment in the startup, a deal that came with an R&D alliance focused on developing NaV1.7 inhibitors for acute and chronic pain. Mulcahy said this Amgen collaboration was productive, but it ended when the pharma giant exited neuroscience research in 2019.
The research from the Amgen alliance lives on under a new collaboration agreement struck with Vertex in 2022. Financial details were undisclosed for this deal, which made SiteOne responsible for early preclinical development and the Boston pharma company responsible for clinical testing and commercialization. Mulcahy declined to elaborate about the status of the research, saying details are not public. But he added that Vertex’s suzetrigine is not part of this collaboration, nor is SiteOne’s STC-004, which is wholly owned by the startup.
The selective targeting of sodium channels could have applications beyond pain. The “wiring” of these channels throughout the body interfaces with many tissues and organs. One potential area of research is the drugging of sodium channels to treat cough, which Mulcahy likens to pain in the lungs. Coughing is the way that lungs respond to noxious irritants, he explained. A sodium channel-targeting drug could offer a new way to treat cough.
“We are certainly able to begin to explore that,” Mulcahy said. “This is one of the challenges with pain as an indication, [making] strategic decisions about what to prioritize.”
Novo Holdings led SiteOne’s Series C round. Other participants in the company’s latest financing include OrbiMed, Wellington Management, Mission BioCapital, and BSQUARED Capital along with earlier investors in the company. Much of the new capital will go toward the planned Phase 2 test of STC-004. But first, a Phase 1 data readout for the molecule is expected in the first quarter of next year.
Illustration: Anastasia Usenko, Getty Images
