Pharma Giants Pour over $30B on TL1A/DR3: Next Game-Changer in Immunology?

April 24, 2025

 

A protein called TL1A (Tumor Necrosis Factor-Like Ligand 1A) is shaking up the immunology world, igniting a frenzied race among pharmaceutical heavyweights to develop therapies that target it. 

Over the past 1.5 years, deal activity involving TL1A has exceeded $30 billion, with companies like Merck , Roche , and Sanofi i placing bold bets—even on early-stage programs. Backed by promising clinical results, a unique mechanism of action, and the potential for biomarker-driven personalized treatments, TL1A could become a cornerstone for treating chronic inflammatory diseases. 

But as the spotlight shines on TL1A, a new contender is emerging: DR3 (Death Receptor 3)—TL1A’s receptor—which may hold the key to developing more durable and effective therapies. Leading this charge is Shattuck Labs, a biotech innovator advancing a first-in-class DR3-blocking antibody that could reshape the competitive landscape. 

Big Money Moves: Pharma’s Billion-Dollar Gamble 

The race to dominate TL1A therapies has triggered a wave of high-profile deals. Merck set off the frenzy in 2023 with its $10.8 billion acquisition of Prometheus Biosciences, Inc. , primarily to secure the mid-stage asset PRA-023. Roche followed with a $7.1 billion deal for Roivant ’s TL1A antibody, while Sanofi and Teva Pharmaceuticals partnered on an oral therapy with up to $1.5 billion in potential milestones. Even preclinical programs are attracting interest — AbbVie paid $150 million upfront to license a TL1A antibody from China’s Mingji Bio. 

Amid this frenzy, Shattuck Labs (NASDAQ: STTK) is carving out a niche by targeting DR3, the receptor for TL1A. Unlike competitors focused on blocking the transiently expressed TL1A ligand, Shattuck’s lead candidate, SL-325, directly inhibits DR3. This approach leverages DR3’s constitutive expression in both inflamed and non-inflamed tissues, potentially offering longer-lasting suppression of inflammation. With $90 million in cash and plans to enter clinical trials in 2025, Shattuck is positioning itself as a disruptor in the TL1A/DR3 axis. 

Chasing the Next Blockbuster: Who Will Lead the Race?  

  • Sanofi ’s Duvakitug: Positioned as a first-line oral therapy, it is projected to capture €2B–€5B in peak sales. 

  • Roche ’s RVT-3101: SVB analysts forecast $15B in U.S. sales alone, citing its extended durability and broad applicability across IBD subtypes. 

  • Global IBD Burden: With 10+ million patients worldwide and rising incidence, TL1A therapies could redefine treatment paradigms. 

  • The Sleeper Play—Shattuck’s DR3 Blocker: While TL1A dominates headlines, Shattuck’s SL-325 quietly holds disruptive potential. If clinical trials validate its durability and safety, the therapy could emerge as a go-to option for patients who fail TL1A agents—or even as a first-line treatment. Analysts also highlight DR3’s role in fibrosis and asthma, signaling broader commercial upside beyond IBD.

Why TL1A Matters: A Key Driver of Chronic Disease 

TL1A acts like a conductor for the immune system, directing inflammatory responses through its interaction with the DR3 receptor. When overactive, it fuels harmful processes in conditions like inflammatory bowel disease (IBD), asthma, and fibrosis by triggering the release of proteins such as IFN-γ and IL-13. Blocking TL1A/DR3 could calm this storm, offering a way to halt tissue damage and chronic inflammation. 

  • Biomarker-Driven Success: Prometheus’ PRA-023 targets TL1A-high patients, achieving 62% clinical remission vs. 22% placebo in Phase II. 

  • Beyond IBD: TL1A’s role in fibrosis and asthma opens pathways to expand into lung and liver diseases. 

  • Mechanistic Advantage: By blocking TL1A/DR3 signaling, these therapies disrupt NF-κB and MAPK pathways, curbing IFN-γ, IL-13, and other inflammatory drivers. 

Blocking TL1A has shown promise, but Shattuck argues that targeting DR3 may be a smarter approach. Here’s why: 

  1. DR3 Is Always There—TL1A Isn’t  While TL1A flares up transiently during inflammation, DR3 is constitutively expressed—meaning it’s present in both inflamed and healthy tissues. By blocking DR3, Shattuck’s approach could offer more durable suppression of inflammation by preventing immune cells from migrating to new areas of the gut. 

  2. Preclinical Edge  In animal models, deleting DR3 resolved inflammation more effectively than blocking TL1A. Shattuck’s lead drug, SL-325, a DR3-blocking antibody, binds with picomolar affinity (1.36 pM) and outperformed TL1A inhibitors in lab studies, blocking inflammatory signals like IFN-γ at 10x lower concentrations. 

  3. Safety First  In primate trials, SL-325 showed no adverse effects even at 100 mg/kg doses—a critical advantage over rivals like Merck and Roche, who face the challenge of managing immune-related side effects 

Shattuck Labs : The Underdog with a Big Idea 

While Big Pharma focuses on TL1A, Shattuck is betting its pipeline on DR3. The biotech’s lead candidate, SL-325, is designed to: 

  • Outlast TL1A Inhibitors: By targeting the stably expressed DR3 receptor, SL-325 could maintain suppression of inflammation even as TL1A levels fluctuate. 

  • Avoid Biomarker Dependency: Unlike Merck’s PRA-023, which requires patients to have high TL1A levels, SL-325’s mechanism could work across broader IBD populations. 

  • Pave the Way for Bispecific: Shattuck is already developing DR3-based bispecific antibodies, aiming to tackle multiple inflammatory pathways at once. 

With $90 million in cash and plans to start human trials in 2025, Shattuck is positioning SL-325 as a potential game-changer.  

“Targeting the receptor, not the ligand, gives us a unique durability advantage,” says CEO Taylor Schreiber M.D./Ph.D. , a veteran immunologist. “This could be the key to achieving long-term remission.”  

Global Innovation: China’s Growing Influence 

Chinese biotech firms are making significant strides in the TL1A space. Sinovac Biopharma is developing two candidates: one with enhanced potency and another that targets TL1A alongside a second inflammatory protein, LIGHT. Mingji Bio’s deal with AbbVie underscores global confidence in China’s research capabilities, highlighting innovations in antibody design.  

  • Sinovac Biopharma: 

    • GB20: TL1A monoclonal antibody with 10x higher in vitro activity vs. rivals, low immunogenicity, and a unique epitope. 

    • GB24: A dual-target TL1A/LIGHT antibody designed to tackle both inflammation and fibrosis in IBD. 

  • MingJi Bio: Partnered with AbbVie on a preclinical TL1A antibody, signaling global confidence in China’s R&D capabilities. 

The Road Ahead 

With IBD and fibrotic diseases on the rise worldwide, TL1A therapies could fill a critical gap left by current treatments, which often lose effectiveness over time. The combination of strong clinical data, biomarker-driven precision, and aggressive investment positions TL1A as a likely contender to join the ranks of blockbuster immunology targets like IL-17 and IL-23. 

The Bottom Line 

The TL1A/DR3 axis is no longer a scientific curiosity—it’s a $30 billion battleground. While Merck and Roche lead the TL1A charge, Shattuck Labs’s DR3 strategy offers a compelling twist. If SL-325 delivers in the clinic, it could shift the focus from transient ligands to steadfast receptors, mirroring the success of PD-1 inhibitors in oncology. 

For patients, this rivalry offers hope for more effective, longer-lasting treatments. 

For investors, it presents a high-reward race to own immunology’s next breakthrough.