Antibodies Targeting the Tumor Necrosis Factor-Like Ligand 1A in Inflammatory Bowel Disease: A New Kid on the (Biologics) Block?

For almost 2 decades, biological agents such as tumor necrosis factor (TNF)-alpha inhibitors and later integrin receptor antagonists as well as interleukin (IL)-12/-23 inhibitors have dominated the treatment landscape for moderate-to-severe active inflammatory bowel disease (IBD) [1, 2]. It was only late in the 2010s when the first, new small molecules were approved. Among them are now different Janus kinase inhibitors and, recently, the first sphingosine 1-phosphate (S1P) receptor modulator [3]. Another S1P receptor modulator is currently under review for approval [4]. However, all those mentioned approaches show a limitation with respect to efficacy, which has been termed the “therapeutic ceiling” [5, 6]. Subsequently, there is a need for novel therapeutic approaches to develop more efficient treatments.

Three antibodies that target TL1A are currently in clinical testing. The structure of TL1A or TNFSF15 (TNF superfamily of proteins) shows similarity to other members of the TNF family of proteins [7, 8]. Discovered around 20 years ago, TL1A occurs in form of a type 2 transmembrane protein and in a soluble form (sTL1A). Under physiologic circumstances, it is almost never expressed [9]. Upon tissue damage, necrosis, or inflammation, it is expressed in different cell types such as macrophages, dendritic, as well as endothelial cells (shown in Fig. 1) [7]. It is also up-regulated when stimulated by TNF-A [7]. When TL1A binds to its receptor, the death receptor 3 (DR3), at least three different intracellular signaling pathways are triggered (shown in Fig. 2). The most important pathway results in a pro-inflammatory, survival-promoting cascade including activation of Map kinases (p38, JNK, ERK) and NFkappaB [10, 11]. TL1A-DR3 interaction co-regulates expression and production of cytokine (including TNF-A) downstream and influences the innate and adaptive immune system [3, 7].

Within the innate immune system, TL1A, synergistically with IL-23, contributes to the proliferation of innate lymphoid cells (ILC3). ILC3 play an important role in the regulation of mucosal immunity. In stimulated lymphoid cells, activation of the pro-inflammatory pathway outweighs the apoptotic pathways [7].

Within the adaptive immune system, TL1A, synergistically with IL-12 and IL-18, among others promote the secretion of pro-inflammatory interferon gamma (IFNγ) and TNF from T-cells [7]. As a consequence of this activation in mouse models, it has been found that TL1A overexpression induces ileitis, colitis, and exacerbates fibrosis [11, 12].

Clinically, in patients with IBD TL1A/DR3 are found to be markedly expressed in clinical samples of areas of inflamed mucosa [3, 13‒17]. Expression levels of TL1A in tissue samples of IBD patients were also found to correlate with disease severity [18, 19]. Among the cells that are directly activated by TL1A are also fibroblasts with consequently increased collagen production and resulting fibrosis [3, 12]. The latter is a common, difficult-to-treat complication in IBD [20, 21].

RVT-3101 is a fully human IgG1 monoclonal anti-TL1A antibody. RVT-3101 was tested in patients (n = 50) with moderate-to-severely active UC in a phase 2a open-label study (Tuscany) [16]. It was administered every other week intravenously and subcutaneously over a period of 14 weeks. The primary efficacy endpoint, endoscopic improvement (Mayo endoscopic sub-score = 0 or 1), was reached by 38.2%, which was significantly more compared to the expected placebo rate of 6%. Endoscopic remission was achieved by 10%. As this was a single-arm trial, authors compared actual results to a historic placebo response rate of 6%. This was the observed rate in TNF-A inhibitor-experienced participants in two tofacitinib trials performed in UC (Table 1) [16].

With regard to safety, 18 treatment-related events were reported. Four of them were serious adverse events (AEs). Most commonly observed was disease exacerbation and arthralgia (Tab).

A total of 82% of patients were tested positive for anti-drug antibodies. In 10%, drug-neutralizing antibodies were found. A total of 72% of the patients were TNF-A inhibitor experienced. In an analysis of trial participant tissue biopsies, an inhibition of inflammatory and especially fibrotic pathways was seen [22, 23].

Tuscany-2 is a consecutive phase 2b trial with n = 245 patients overall. Data from the 12-week induction course were released recently. Endoscopic improvement was seen in 40% and remission in 32%. Rates were slightly higher (56%, 41%) in patients that were tested positive for a predefined, but undisclosed, biomarker and that had been pretreated with a biological agent. Results were statistically significant compared to placebo. The dosing regimen and route of application had been modified to a monthly subcutaneous application. Three dose levels were tested. Topline data of the 40-week maintenance therapy (Tuscany-2b) are expected to be posted during the review process of this manuscript [24]. A study of the safety and efficacy in CD is currently ongoing, too (NCT05471492) [25].

PRA023 is another IgG1-humanized monoclonal antibody. Due to its biochemical structure, it is less susceptible to internal degradation processes. This feature is expected to translate into increased efficacy [26].

The Artemis-UC study is a phase 2 placebo-controlled, randomized trial performed in patients (n = 170) with moderate-to-severely active UC. Patients received four drug infusions over a 12-week period. The single primary endpoint clinical remission (modified Mayo Score) was met by significantly more patients in the PRA arm (26.5% vs. 1.5%) at week 14. 36.8% (vs. 6% in the placebo arm) showed endoscopic improvement. No serious AEs were reported.

In contrast to other recent clinical trials, around half of the patients in each treatment arm had not been exposed to advanced therapies. Therefore, the results need to be interpreted with caution. A companion diagnostic was used here, too. The aim was to identify patients who are genetically predisposed and express higher amounts of TL1A. It is hypothesized that these patients have a higher probability of response to the tested agent [27, 28].

In the Apollo-CD trial, PR023 was tested in patients (n = 55) with moderate-to-severely active CD open-label over 12 weeks. More than half of the patients (52.7%) had been treated with two or more biological agents before. Mean disease duration was 10.3 years.

Overall, 26% showed an endoscopic response (primary endpoint, defined as Simple Endoscopic Score-CD score ≥50%). 49.1% showed clinical remission (defined as Crohn’s Disease Activity Index [CDAI] <150 points). Response rates were significantly higher as compared to historical placebo response rates. A CD-specific algorithm that included predefined genetic markers designed to predict treatment response was said to be effective, too. No treatment-related serious AEs were reported [28, 29].

So far, data are lacking for the third TL1A inhibitor (TEV-48574). Three different doses are tested in a phase 2 study versus placebo (relieve UCCD) in patients (n = 280) with moderate-to-severely active UC/CD. The primary endpoint in UC is clinical remission (modified Mayo score ≤2 points) and endoscopic response in CD (at least 50% reduction vs. baseline in Simple Endoscopic Score for Crohn’s Disease). Expected completion is in 2024 (NCT05499130; NCT05668013).

Even though more treatment options have been added to the spectrum of advanced therapies in IBD, a number of patients still do not achieve remission. Safety concerns are also of increasing importance, given the reported increased risk of blood clots and rates of herpes zoster for tofacitinib and increased cardiovascular risk for tofacitinib and S1P modulators. This further limits the use of these small molecules in IBD [30, 31].

Anti-TNF antibodies are still a mainstay for the treatment of advanced, active IBD. However, no predictive markers exist, that could help in identifying patients that are likely to respond to an anti-TNF therapy. With antibodies against TL1A and their companion diagnostic, for the first time in the treatment of IBD, there could be the opportunity to choose a distinctive treatment option with the help of precision medicine. This would not only increase the likelihood of treatment success but should also help reduce the number of patients exposed to unwanted side effects of an ineffective agent [32, 33].

It is not possible to compare the efficacy data of the different anti-TL1A agents due to the different trial designs and the heterogeneous prior therapy experience of the trial populations. However, it is encouraging that significant response rates were reported in patients who were considered heavily pretreated. In the RVT-3101 UC trials up to 72% of the patients were anti-TNF antibody experienced. In the Apollo-CD trial of PRA023, 52.7% had been treated with two or more biological agents before. It will be interesting to see if patients with a history of failure to an anti-TNF antibody therapy will also show lower response rates to an anti-TL1A. It could be hypothesized that due to structural similarities of TNF-A and TL1A patients who do not respond or lose response to the inhibitors of the former share the same fate with the inhibitors of the latter. It is already known that with each subsequent anti-TNF-antibody therapy probability of treatment failure increases [34].

With regard to safety, no serious AEs or new safety signals were reported in these induction periods. However, safety evidence base is currently limited due to the short period of 12–14 weeks in the corresponding clinical trials. As with TNF inhibitors, the question could arise whether the TL1A inhibitors might bear tumorigenic potential. Theoretically, there might be a risk as the TL1A pathway also induces apoptosis, regulates programmed cell death and suppresses the proliferation of tumor cells [35]. Inhibition could interfere with this regulatory effect on cell proliferation. This concern may also be due to the fact that TLA1 was found initially as an angiogenesis inhibitor with the ability to suppress colonic tumor cell growth [36]. Besides, it has been shown that certain anti-mitotic chemotherapies rely on a functioning TL1A/DR3 pathway to exert their efficacy [37].

As with all new agents that interfere with the immune system a special focus will also be on viral and bacterial infections such as Herpes zoster and hepatitis B as well as possible infections with/or reactivations of Mycobacterium tuberculosis. Currently, there are no published data to define the inherent risk. However, in basic science studies, it has been shown that, in contrast to TNF inhibitors, inhibitors of TL1A are presumed to not induce immunodeficiency [38, 39].

Currently, it is unknown whether anti-drug antibodies will negatively affect the efficacy of the TL1A inhibitors. As they are large proteins they can provoke an immune response. In the Tuscany trial, at least 10% of patients were found to have drug-neutralizing antibodies [22, 23]. This rate is somewhere in between the rates seen with vedolizumab, ustekinumab, and golimumab (1–19%) and TNF inhibitors such as adalimumab (up to 54%) and infliximab (up to 83%) [40, 41]. With regard to an isolated rate of 10% seen in one trial with one agent, it is too early to estimate whether this will be a major burden along the path to approval. It can only be speculated whether this rate is associated with the high number of biologic-pretreated study participants.

It is also unclear whether these findings, if replicated for the other tested agents, translate into decreasing efficacy over time. Long-term extension studies with the mentioned compounds are ongoing. First long-term safety data of TL1A inhibition are expected to be available while this manuscript is in the review process. What is a little worrisome is the fact that this pathway is involved in apoptosis [7]. Possible effects will probably only be visible years after initiation of therapy.

So far, no detailed data are available on whether anti-TL1A inhibitors are effective in patients with TNF-inhibitor inadequate response/failure. In theory, they should be effective as they work more upstream in the cytokine cascade [42]. This was also proven clinically as many patients were pretreated in the abovementioned induction trials.

Currently, it is also unclear whether the response to TL1A antibodies will be exclusively biomarker-driven. In an animal model of rheumatoid arthritis TNF inhibition led to lower levels of TL1A, regardless of whether the mice were responders or non-responders [43]. Subsequently, it is not clear yet, whether lower TL1A levels always translate into a meaningful reduction of disease activity.

Sponsors have recognized that the route of administration and dosing intervals can be a crucial factor for or against choosing an agent. RVT-3101 is currently tested as a subcutaneous application instead of infusion. For PRA023 the proposed monthly dosing interval is certainly also favorable.

If approved, based on the advantages of a precision medicine approach, the assumed anti-fibrotic effect and acceptable safety profile, TL1A inhibitors could provide a valuable future treatment option for IBD.

Apart from IBD, also other inflammatory conditions could benefit from treatments based on TL1A inhibition. In a collagen-induced arthritis murine model of human rheumatoid arthritis, a reduction in bone erosions was found after TL1A inhibition, suggesting a beneficial role in rheumatic diseases [43]. For atopic dermatitis as well as for psoriasis, there are early data that point toward a possible role of TL1A as contributing to inflammation in the respective diseases. Also, in lupus erythematosus, ankylosing spondylitis and primary biliary cirrhosis, TL1A was found to be overexpressed [7, 44‒46]. Therefore, inhibiting this protein may potentially have beneficial effects on the respective diseases, too.

D.S. has no conflicts of interest to declare. G.R. has consulted to AbbVie, Arena, Augurix, BMS, Boehringer, Calypso, Celgene, FALK, Ferring, Fisher, Genentech, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions, and Zeller; has received speaker’s honoraria from AbbVie, Astra Zeneca, BMS, Celgene, FALK, Janssen, MSD, Pfizer, Phadia, Takeda, Tillots, UCB, Vifor, and Zeller; has received educational grants and research grants from AbbVie, Ardeypharm, Augurix, Calypso, FALK, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillots, UCB, and Zeller; and is cofounder and head of the Scientific Advisory Board of PharmaBiome.

This study was not supported by any sponsor or funder.

D.S.: idea, data collection, and writing of the manuscript. G.R.: writing and review.