TAK-101 was well tolerated and prevented gluten-induced immune activation in patients with celiac disease, according to a study in Gastroenterology.
Investigators reported their findings regarding the safety, tolerability, pharmacokinetics, and efficacy of TAK-101 from the induction of gliadin-specific T-cell tolerance in patients with biopsy-confirmed celiac disease, during these phase 1 and phase 2a studies.
Phase 1 was a first-in-human safety and dose escalation study conducted from January 2018 to May 2019, in which patients received TAK-101 (0.1-8 mg/kg up to a maximum of 650 mg). It included 23 patients (aged 18-75 years) with celiac disease, and all patients participated in the study to completion.
Phase 2a was a randomized, double-blind, proof-of-concept study conducted from January 2019 to July 2019, in which patients received TAK-101 (8 mg/kg, up to a maximum of 650 mg) on days 1 and 8 and then underwent a 14-day oral gluten challenge. Phase 2a included 34 patients (aged 18 to 70 years; TAK-101, n = 16; placebo, n = 18), and 33 patients (97.1%) completed the study.
In phase 1, TAK-101 was well tolerated at doses up to 8 mg/kg after single and repeated intravenous administrations 7 days apart. The most frequently reported adverse events were mild to moderate flushing, headache, back pain, and fatigue.
In the phase 2a placebo group, ex vivo gliadin peptide stimulation of peripheral blood mononuclear cells (PBMCs) after 6 days of the oral gluten challenge led to a nearly 10-fold increase, compared with baseline in mean interferon (IFN)-γ+ spot-forming units (SFUs)/106 PBMCs (baseline mean IFN-γ+ SFUs, 1.98; day 20 mean IFN-γ+ SFUs, 19.56). In the TAK-101 group, the gluten challenge–induced gliadin-dependent T-cell response was reduced by about 90% (baseline mean IFN-γ+ SFUs, 3.08; day 20 mean IFN-γ+ SFUs, 5.09). The mean change from baseline was 17.58 SFUs for placebo compared with 2.01 SFUs for the TAK-101 group (P =.006).
In the phase 2a study, gluten-related gastrointestinal disorders were the most common adverse events reported during dosing and included abdominal distention or pain, diarrhea, flatulence, nausea, vomiting, and abnormal gastrointestinal sounds.
After the oral gluten challenge, the villus height to crypt depth ratio (Vh:Cd) decreased from baseline in the placebo group (mean change from baseline to day 29, −0.63; P =.002). In the TAK-101 treatment group, Vh:Cd was not significantly decreased (mean change from baseline to day 29, −0.18; P =.110).
TAK-101 had no effect on ex vivo T-cell proliferation and was not associated with clinically meaningful changes in vital signs, routine clinical laboratory test results, or serum cytokine/chemokine levels.
The researchers noted that their studies had a small sample size and were of limited duration, and the longer-term effects of TAK-101 were not fully evaluated.
“TAK-101 demonstrated a favorable safety profile and efficacy in patients with celiac disease through inhibition of T-cell activation and possible reduction in the deterioration of Vh:Cd following the gluten challenge,” the investigators concluded. “These findings support further clinical development of this novel immunotherapy for celiac disease and other antigen-specific immune diseases.”
Disclosures: This study was sponsored by COUR Pharmaceuticals Development Co. and supported by Takeda Pharmaceuticals International Co. Some of the study authors reported affiliations with pharmaceutical companies, including COUR Pharmaceuticals Development Co. and Takeda Pharmaceuticals International Co.
Kelly CP, Murray JA, Leffler DA, et al. TAK-101 nanoparticles induce gluten-specific tolerance in celiac disease: a randomized, double-blind, placebo-controlled study. Gastroenterol. Published online March 12, 2021. doi: 10.1053/j.gastro.2021.03.014