Teriflunomide, an oral dihydroorotate dehydrogenase inhibitor, in immune thrombocytopenia Free

IntroductionPrimary immune thrombocytopenia (ITP) is an autoimmune disease, posing a serious threat to human health as one of the most common bleeding disorders. Improving response rates and durability to current therapies remains an unmet need in relapsed/refractory patients. Teriflunomide, an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), has been shown to prevent the proliferation of activated immune effector cells and restrain aberrant immune system activity. Targeted inhibition of DHODH may prevent immune dysregulation and provide a novel treatment modality for ITP. Therefore, our study aimed to establish the recommended phase 2 dose (RP2D) and determine the efficacy and safety of teriflunomide in patients with corticosteroid-resistant or relapsed ITP (NCT06190145). MethodsThis is an ongoing prospective, open-label, phase 1/2 clinical trial (TEMPO-1). Eligible patients are adults with primary ITP who were resistant to corticosteroid treatment or who relapsed and had a platelet count <30×10^9/L or a platelet count <50×10^9/L with bleeding manifestations. Teriflunomide is administered as 7 mg orally once daily with dose adjustments for 24 weeks. A 3+3 design with dose escalation and dose expansion cohorts was implemented. Two dose levels (DLs) of teriflunomide are being investigated: DL0: teriflunomide 7 mg PO qd; and DL1: teriflunomide 14 mg PO qd. Stable doses of concomitant corticosteroids, immunosuppressants, and thrombopoietin-receptor agonists (TPO-RAs) are permitted. The primary endpoint is sustained response (SR), defined as a platelet count over 30×10^9/L and at least a 2-fold increase of the baseline count in the absence of bleeding and rescue therapy for at least four of the six weeks between weeks 19 and 24. The secondary endpoints include overall response, time to response, bleeding scores, and adverse events (AEs). ResultsAs of July 18, 2025, a total of 25 patients have been enrolled (9 patients for dose escalation, 16 patients for dose expansion). In the escalation cohort, 3 patients were at the starting dose (DL0) of 7 mg, and 6 patients were at the DL1 of 14 mg of teriflunomide. The median age was 46 years (range, 21-73), and males accounted for 56% of the sample. Patients had a median baseline platelet count of 12×10^9/L (range, 1-48×10^9/L), with a median duration course of 8.2 years (range, 0.6-45), and were heavily pretreated, with a median of 5 prior therapies, including steroids, TPO-RAs, IVIg, immunosuppressants, and herbs. Five patients (20%) in the study received teriflunomide monotherapy, and 20 patients (80%) received at least 1 concomitant ITP medication. Treatment-emergent adverse events (TEAEs), which were observed in 7 patients (28%), were all grade 1 or 2. The most frequently occurring TEAEs were elevated alanine aminotransferase, alopecia, hand tremble, erythema, and diarrhea. Bleeding episodes, measured using the WHO bleeding scale, were relieved by teriflunomide treatment. Teriflunomide was well tolerated across the doses, with no treatment-related SAEs.Since no dose-limiting toxicities (DLTs) were observed at DL0, dose reduction to DL-1 was not warranted. Additionally, no DLTs were observed at a dose of 14 mg, and the maximum tolerated dose has not yet been reached. The teriflunomide dose has not been escalated further on the basis of data from pivotal phase 3 trials in patients with multiple sclerosis (TEMSO, TOWER, and TOPIC), in which participants with a lower relapse rate and good tolerability profile received teriflunomide at 14 mg. Thus, a dose of 14 mg once daily was established as the RP2D for the dose-expansion phase. To date, 18 patients have achieved the primary endpoint across the doses, 10 (56%) of whom achieved an SR at the 24-week follow-up. For patients who responded to teriflunomide, the median time to response was 48 (IQR, 21-81) days, and the median peak platelet count was 76 (IQR, 53-119) ×10^9/L. ConclusionsTeriflunomide has demonstrated an acceptable safety profile and encouraging clinical efficacy in cases of relapse, ineligibility, or failure to respond to steroids among ITP patients and warrants further clinical evaluation. The dose-escalation portion of the study is complete, and enrollment continues at the RP2D of 14 mg daily for 24 weeks to confirm the treatment benefit.