Bio Brief | Weekly Recap: May 30, 2025

This week, biotech headlines were dominated by Eli Lilly’s $1B entry into non-opioid pain and iTeos’ full shutdown after anti-TIGIT setbacks. Read more for our insights.

Pain Without Addiction: Eli Lilly Bets Up To $1B on SiteOne Therapeutics

On Tuesday, Eli Lilly ($LLY) entered an agreement to acquire SiteOne Therapeutics in a deal worth up to $1 billion in milestone payments for STC-004, SiteOne’s experimental NaV1.8 sodium channel inhibitor targeting peripheral pain signals. While financial terms beyond the milestone value were not disclosed, the acquisition adds STC-004 to Lilly’s expanding non-opioid pain portfolio.

STC-004 blocks pain transmission at the peripheral nervous system level without engaging central opioid pathways, offering pain-relief without addiction or sedation. In Phase 1 trials, STC-004 showed strong tolerability and increased pain thresholds in healthy volunteers. Now entering Phase 2, Lilly is positioning itself as a competitive player in non-opioid pain therapeutics.

Lilly has quietly built a pain franchise around ion channel biology. STC-004 will join a portfolio that includes an epiregulin targeting antibody, a P2x7 receptor inhibitor, and a SSTR4 agonist (all in mid-stage development). As opioid lawsuits over addiction persist, the commercial and societal case for non-opioid innovation is stronger than ever before. Read the Deep Dive to learn more about the benefits of targeting the peripheral sodium channel pain pathway.

iTeos Therapeutics Shuts Down

On Wednesday, iTeos Therapeutics ($ITOS) announced that they would be officially closing their doors, just two weeks after terminating their development program for belrestotug after a lack of efficacy data from phase 2 trials in first-line NSCLC and metastatic head and neck cancer. iTeos and GSK ($GSK) had previously agreed to co-develop and co-commercialize belrestotug in 2021.

Despite cutting their lead program, shares of Iteos are actually up over 20% on news due to the announcement of a plan to return its $600m+ cash position back to shareholders and begin the sale of the remainder of its early-stage pipeline.

The hype for Anti-TIGIT mAbs like belrestotug in combination with anti-PD-1 antibodies has fallen off with the failure of Roche’s tiragolumab in NSCLC and the termination of Merck’s ($MRK) vibostolimab trials in 2024. The anti-TIGIT class has been plagued with lackluster efficacy data since 2022, which has ultimately led to iTeos trading at a significant discount to cash in recent years. A common feature? Active Fc function, which may deplete the very immune cells meant to fight cancer. Read the Deep Dive for more on the implications of Fc silencing and the future of anti-TIGIT immuno-oncology.

Under the Radar: Reprogramming Tumors

Actym Therapeutics, a private clinical-stage biotech based in Berkeley, CA, is quietly building one of the more unconventional platforms in immuno-oncology. The company’s STACT platform (Salmonella Typhimurium-Attenuated Cancer Therapy) uses engineered bacteria to deliver immunostimulatory therapies directly into the tumor microenvironment (TME).

Their lead drug, ACTM-838, is currently being tested in a Phase 1 trial for advanced solid tumors. It uses a weakened form of Salmonella bacteria to deliver two strong immune boosting agents – a STING activator and an IL-15 superagonist – directly into the tumor. The bacteria are designed to go where tumors grow and thrive in that environment. Once inside the tumor, they release immune-boosting agents right at the site.

The science is complex, but the goal is straightforward: solve one of immunotherapy’s biggest challenges. While immunotherapy has worked well in some cancers, many solid tumors remain “cold”, which means they resist or evade the immune system. Some treatments attempt to deliver immune boosters directly into tumors, but getting them there is difficult. Actym’s approach bypasses systemic delivery problems, using bacteria that naturally localize to tumors and activate only once inside. Read more below.

Deep Dive: Reading Between The Lines

The Opioid Reversal

Lilly’s $1B acquisition is not just about STC-004, but strategic positioning. With the FDA approval of Journavx (Vertex’s NaV1.8 inhibitor), non-opioid pain has shifted from speculative to competitive. Peak sales for Journavx are projected above $2.5B, and Lilly is ensuring a seat at the table. Although sodium channels are notoriously difficult to selectively target due to high conservation, targeting the NaV1.8 channel has proven to be effective. NaV1.8 channels are most expressed in pain-sensing neurons in the peripheral nervous system, helping prevent adverse effects compared to drugs that cross the blood-brain barrier.

Chronic pain remains a massive unmet need. The opioid crisis has created both regulatory urgency and commercial white space. As Lilly enters now, they are ensuring they won’t be locked out of this field, which may reshape its standard of care in the next decade. Whether STC-004 succeeds or not, this is Lilly’s bet on the future of pain therapeutics.

The Future of the Anti-TIGIT Ecosystem

FcγRs are a family of receptors encoded by the FCGR genes, which are expressed on immune effector cells such as macrophages, NK cells, and dendritic cells. These receptors bind to the Fc region of IgG antibodies, a subclass from which many monoclonal antibodies are derived, and can mediate antibody-dependent cellular cytotoxicity (ADCC). It is common for developers to silence the Fc region (Fc silencing) when it may be undesirable to trigger ADCC, particularly when the target antigen is expressed on beneficial immune cells.

That’s what makes the future of the anti-TIGIT class so interesting. The TIGIT receptor is typically co-expressed with PD-1 on exhausted T cells, as well as on regulatory T cells (Tregs) and natural killer (NK) cells. Many tumors over express CD155, which binds to TIGIT and suppresses the immune activity of these cells.

So far, clinical trials have focused on combination therapy using anti-TIGIT and anti-PD-1 monoclonal antibodies as first-line treatment in tumors with high PD-L1 expression. This presents a significant dilemma: tiragolumab (Roche), vibostolimab (Merck), and belrestotug (iTeos/GSK) all retain an active Fc region, meaning they could induce ADCC against the very immune cells intended to fight the tumor.

The rationale for retaining Fc activity was likely based on the hypothesis that depleting Tregs could enhance anti-tumor immunity. However, this approach may also lead to unintended depletion of cytotoxic T cells, which are essential for tumor clearance. With the failure of multiple Fc-active anti-TIGIT antibodies, the future of the class may rest with Arcus Biosciences ($RCUS) – which is conducting Phase 3 trials for domvanalimab, the most clinically advanced Fc-silenced anti-TIGIT antibody, following encouraging Phase 2 data.

Although investor sentiment has weakened around the anti-TIGIT space, upcoming data from domvanalimab in the next few years may have the potential to revive interest in this immuno-oncology class.

Actym’s Payload Delivery Advantage

Systemic immunotherapies activate the immune system throughout the body, often causing collateral damage to healthy tissues. Gene therapies also raise long-term safety concerns due to the risk of permanent integration into the host genome.

Actym’s STACT platform is designed to overcome both challenges. It employs attenuated Salmonella bacteria that are auxotrophic, meaning they are genetically modified to survive only in the tumor microenvironment (TME), where specific nutrients are present. These bacteria die off in healthy tissue, ensuring that therapeutic activity remains localized. Within the TME, they deliver two immune-stimulating agents and replicate to sustain continuous payload expression. The platform is fully biodegradable and avoids permanent genetic alterations, minimizing systemic toxicity.

In a conversation with a member of Actym’s team, we learned that this tumor-specific activation helps reduce the risk of widespread inflammation. This approach may be particularly valuable for immunologically “cold” tumors, such as pancreatic and colorectal cancers, where checkpoint inhibitors have been largely ineffective. Unlike single-use delivery methods such as antibody-drug conjugates (ADCs), which have shown promise in delivering chemotherapy and cytokine payload to tumors, the STACT platform enables ongoing payload production from within the tumor, potentially improving both the precision and durability of the immune response.