TEV-408 Phase 2a Celiac Signal Is Real But Pivotal Distance Remains Vast

Teva's Anti-IL-15 Antibody Shows Positive Phase 2a Results in Celiac Disease

Teva Pharmaceutical Industries Ltd. announced positive topline results from its Phase 2a study of TEV ‘408, an investigational anti-IL-15 monoclonal antibody, in adults with celiac disease. The study met its primary endpoint, demonstrating statistically significant and clinically meaningful prevention of gluten-induced intestinal damage versus placebo at week 8. TEV ‘408 was well-tolerated with no new safety signals. This outcome supports TEV ‘408's potential as a "pipeline-in-a-product" for multiple diseases, including celiac disease and vitiligo, and strengthens confidence in targeting the IL-15 pathway to reduce immune-driven intestinal damage. The study enrolled 50 adult participants on a gluten-free diet who underwent a six-week daily gluten challenge.

• The Phase 2a study of TEV ‘408 successfully met its primary endpoint, showing statistically significant and clinically meaningful prevention of gluten-induced intestinal damage in celiac disease patients. Measured by the villous height-to-crypt depth ratio (Vh:Cd), the LS mean change from baseline was -0.43 for TEV ‘408 compared to -0.88 for placebo, resulting in a treatment difference of 0.45 (95% CI: 0.06, 0.84; p<0.05). This demonstrates the drug's ability to mitigate the core pathological effect of gluten exposure.
• Beyond the primary endpoint, TEV ‘408 also showed a favorable effect on intestinal inflammation, as indicated by a lower increase in the density of intraepithelial lymphocytes (IELs) compared to placebo (treatment difference of -27.23, 95% CI: -39.67, -14.79). Additionally, participants treated with TEV ‘408 reported lower gastrointestinal symptom scores, assessed using the Celiac Disease Symptom Diary (CDSD), a patient-reported outcome, suggesting an improvement in daily quality of life.
• TEV ‘408 was well-tolerated in the study, with no emerging safety signals observed to date, reinforcing its potential for further development. These positive results for celiac disease, combined with encouraging Phase 1b results in vitiligo, validate TEV ‘408 as a "pipeline-in-a-product" opportunity. The drug, which received FDA Fast Track designation for celiac disease in May 2025, targets the IL-15 pathway to address immune-driven inflammation and damage in multiple conditions.

Addressing the Unmet Needs in Celiac Disease Treatment

Despite significant advances in understanding its pathophysiology, Celiac disease (CeD) remains without a single FDA-approved pharmacological treatment, leaving patients dependent on a demanding dietary intervention with well-documented limitations. The breadth of unmet need spans from the inadequacy of the gluten-free diet (GFD) as a sole management strategy to the absence of effective options for severe disease progression.

• No FDA-approved pharmacotherapy exists. The only recommended course to alleviate CeD-induced symptoms is abstinence from all gluten-based products. While several clinical trials are actively developing pharmacological approaches — including AT-1001 (Larazotide acetate) and IMGX-003 (Latiglutenase) — none has yet achieved regulatory approval.

• The GFD is nutritionally inadequate and burdensome. Gluten-free products are considered of lower quality and poorer nutritional value compared to gluten-containing counterparts. The GFD is associated with micronutrient deficiencies including iron, folate, vitamin B12, vitamin D, zinc, and copper, as well as increased consumption of foods high in fat, added sugars, and total calories, raising the risk of obesity and a poor microbiome. Patients also face psychosocial burdens including anxiety, social isolation, and disordered eating.

• Mucosal recovery on GFD is incomplete in a substantial proportion of patients. Despite adherence to a strict GFD, 25.5% of patients in one study showed persistent villous atrophy after at least 12 months. Severe mucosal damage at diagnosis (Marsh 3c lesions) and elevated anti-gliadin antibody levels were identified as independent risk factors for failure to obtain mucosal recovery. Longer time with clinical manifestations before diagnosis was also associated with worse histological outcomes.

• Persistent symptoms occur even with mucosal recovery. Many CeD patients suffer from persistent symptoms despite a strict GFD and recovered intestinal mucosa. Low fiber intake was identified as a factor that may predispose patients to persistent symptoms, and the association between symptoms and mucosal inflammation was described as "more complicated than previously thought."

• Refractory celiac disease (RCD) lacks standardized treatment. Approximately 5% of patients with CeD do not respond to a GFD and progress to RCD. RCD type II carries a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. In the German registry, overall mortality among RCD patients was 26%, with a clear dominance in RCD type II patients (47%). A wide range of diagnostic and therapeutic measures was used across patients, underscoring the absence of standardized management protocols.

• Investigational therapies have shown limited or variable efficacy in trials. In a dose-ranging study of Larazotide acetate, the primary efficacy outcome — the urinary lactulose/mannitol (LAMA) fractional excretion ratio — was highly variable in the outpatient setting, and the difference in LAMA ratios between the Larazotide acetate and placebo groups was not statistically significant. Only some lower doses appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

Positive Phase 2a Outcomes for TEV ‘408 in Celiac Disease

Several recent clinical studies have evaluated investigational therapies for celiac disease (CeD), spanning enzyme-based, permeability-modulating, and immune-tolerizing approaches. The studies below represent a cross-section of phase 2 and exploratory trial data, each targeting a distinct mechanism in CeD pathogenesis.

• Latiglutenase (Phase 2, NCT01917630; published 2017): This double-blind, placebo-controlled, dose-ranging study enrolled 494 patients with symptomatic CeD and villous atrophy (villous height:crypt depth [Vh:Cd] ratio ≤2.0), randomized to placebo or 100, 300, 450, 600, or 900 mg latiglutenase daily for 12 or 24 weeks. In the modified intent-to-treat population, there were no differences between latiglutenase and placebo groups in change from baseline in Vh:Cd ratio, intraepithelial lymphocyte (IEL) counts, or serologic markers (anti-tissue transglutaminase-2 and deamidated gliadin peptide antibodies). All groups had significant improvements in histologic and symptom scores, indicating no efficacy advantage over placebo.

• Larazotide Acetate (Exploratory, double-blind, randomized, placebo-controlled; published 2013): This study enrolled 184 patients on a gluten-free diet (GFD), randomized to larazotide acetate (1, 4, or 8 mg three times daily) or placebo during a 6-week gluten challenge (2.7 g/day). No significant differences in lactulose-to-mannitol (LAMA) ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1 mg limited gluten-induced symptoms as measured by the Gastrointestinal Symptom Rating Scale (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005), and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups.

• TAK-101 (Phase 2a, randomized, double-blind, placebo-controlled; NCT03486990 and NCT03738475; published 2021): TAK-101 — gliadin encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles — was evaluated in 33 patients with CeD who completed a 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs. placebo (2.01 vs. 17.58, P = .006). Vh:Cd deteriorated in the placebo group (-0.63, P = .002) but not in the TAK-101 group (-0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). TAK-101 reduced changes in circulating α4β7CD4 (0.26 vs. 1.05, P = .032), αEβ7CD8 (0.69 vs. 3.64, P = .003), and γδ (0.15 vs. 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations, and no serious adverse events occurred.

Teva's IL-15 Success: A New Chapter for Celiac and Autoimmune Therapies

The recent positive Phase 2a results for Teva's investigational anti-IL-15 monoclonal antibody, TEV ‘408, mark a potentially pivotal moment for patients living with celiac disease. For individuals with this immune-mediated enteropathy, the only current management strategy is a strict, lifelong gluten-free diet (GFD). However, studies indicate that many patients continue to experience symptoms and even mucosal damage despite their best efforts, highlighting a significant unmet need for non-dietary therapeutic options. The success of TEV ‘408 in preventing gluten-induced intestinal damage offers a promising new avenue, validating the interleukin-15 (IL-15) pathway as a critical target in celiac pathophysiology.

This development is particularly noteworthy given the historical challenges in this space. Previous attempts at non-dietary interventions, such as latiglutenase, have not demonstrated efficacy in improving histological or symptomatic outcomes. Even another anti-IL-15 antibody, AMG 714, while showing some symptomatic amelioration, did not significantly prevent mucosal injury in a similar gluten challenge study. TEV ‘408's ability to achieve statistically significant and clinically meaningful prevention of intestinal damage suggests a potential differentiation or optimized targeting strategy. This strengthens Teva's broader 'pipeline-in-a-product' vision, as IL-15 is also implicated in other autoimmune conditions like vitiligo, where it plays a role in maintaining tissue-resident memory T cells. Targeting the IL-15/CD122 axis in vitiligo is an active area of research, with the potential for durable repigmentation.

However, the path forward is not without considerations. The current study focused on preventing damage in a gluten challenge setting, which differs from reversing established villous atrophy or managing chronic symptoms in patients already on a GFD. Future trials will need to explore TEV ‘408's efficacy in these broader patient populations. Nevertheless, the positive data provide a strong foundation for advancing TEV ‘408, potentially offering a much-needed therapeutic adjunct or alternative that could significantly improve the quality of life for celiac patients and expand treatment paradigms for autoimmune diseases.