VAYHIT2 shows disease-modifying potential of ianalumab for ITP

The primary analysis of the phase III VAYHIT2 trial shows the treatment potential of ianalumab when combined with standard-of-care eltrombopag in individuals with primary immune thrombocytopenia (ITP) requiring second-line (2L) treatment after failure of first-line (1L) corticosteroids.

“Most adults presenting with newly diagnosed ITP will relapse following 1L corticosteroids and ultimately develop chronic disease,” said Dr Hanny Al-Samkari from Massachusetts General Hospital, Boston, Massachusetts, US, at ASH 2025. “These patients often require indefinite administration of maintenance ITP therapies such as thrombopoietin receptor agonists (TPO-RA) to prevent bleeding and achieve satisfactory disease control.”

“We also recognize that the longer the ITP duration, the more complex the autoimmune phenotype becomes and the more challenging the disease is to treat,” Al-Samkari continued.

Given the central role of autoreactive B cells in the pathogenesis of ITP, the B-cell activating factor (BAFF) signalling pathway is a prime and previously untapped therapeutic target in this disease, he added. “This pathway is critical in the activation, maturation, proliferation, and survival of the autoreactive B cells driving ITP.”

A BAFF receptor antagonist, ianalumab targets B cells via a novel dual mechanism of action. [J Rheumatol 2025;52:244] “When used in combination with the TPO-RA eltrombopag relatively early in the ITP disease course, ianalumab may provide durable disease control without an ongoing requirement for chronic maintenance therapy,” Al-Samkari said.

The study enrolled adults with primary ITP who had an inadequate response or relapsed after 1L corticosteroid therapy (± IV immunoglobulin), platelet counts <30×10⁹/L, and were naïve to 2L treatment and had a clinical indication for it. A total of 152 participants (mean age 42 years, 65 percent women) were randomized 1:1:1 to daily eltrombopag plus four once-monthly IV infusions of ianalumab 9 or 3 mg/kg or placebo for 16 weeks. An 8-week eltrombopag tapering period ensued thereafter. [ASH 2025, abstract LBA 2]

VAYHIT2 met its primary endpoint of time to treatment failure (TTF), which was significantly longer in both ianalumab arms vs the placebo arm (median 13 vs 4.7 months; hazard ratio [HR] 0.55; p=0.021 [9 mg/kg] and median not reached vs 4.7 months; HR, 0.58; p=0.023 [3 mg/kg]).

The key secondary endpoint of stable response at 6 months (SR6) was also met. More patients achieved SR6 with the investigational vs placebo regimen, be it with the higher (62 percent vs 39.2 percent; p=0.023) or lower (56.9 percent vs 39.2 percent; p=0.035) ianalumab dose. Of note, SR6 platelet count measurements were obtained while patients were still on eltrombopag and during tapering.

Other endpoints

At 6 months, response (platelet count ≥50×10⁹/L without rescue or new ITP treatment) rates were higher in both ianalumab arms than the placebo arm (73.5 percent [9 mg/kg] and 54 percent [3 mg/kg] vs 48 percent). A similar pattern was observed for complete response (platelet count ≥100×10⁹/L without rescue or new ITP treatment; 55.1 percent and 40 percent vs 26 percent).

At the end of eltrombopag tapering, PROMIS-Fatigue* scores across all treatment arms dropped, with the most pronounced effect observed with ianalumab 9 mg/kg. According to Al-Samkari, reductions in this score indicate less fatigue.

Week 25 saw fewer bleeding events in both ianalumab arms (10.4 percent [9 mg/kg] and 12.2 percent [3 mg/kg]) vs the placebo arm (20 percent).

Safety profile

The rates of grade ≥3 study drug-related adverse events (AEs) were low in both ianalumab arms (8 percent [9 mg/kg] and 4 percent [3 mg/kg]).

“Most serious AEs were adjudicated to be related to the underlying ITP. One serious AE (grade 1 palpitations) in the ianalumab 3-mg/kg arm was deemed treatment-related,” noted Al-Samkari. “No on-treatment AEs led to discontinuation of study drug or resulted in death.”

The frequency and severity of grade ≥3 infections were similar across arms (4, 2, and 2 percent for ianalumab 9 mg/kg, ianalumab 3 mg/kg, and placebo, respectively). All infusion-related reactions were mild to moderate in intensity.

The incidence of grade ≥3 neutropenia was higher with the higher ianalumab dose (14 percent vs 6 percent); however, Al-Samkari noted that these were transient, lasting only a few days to a few weeks on average, and did not require additional treatment.

He added that ianalumab had a very minimal impact on immunoglobulin G levels.

Early intervention

“We hypothesized that early intervention with ianalumab may provide a disease-modifying effect, such that the typical natural history of ITP is ameliorated in a significant proportion of patients,” said Al-Samkari. “[Our study shows that] a short course of ianalumab with eltrombopag induced disease control [in this patient setting].”

When combined with eltrombopag, ianalumab significantly prolonged TTF, improved SR6, reduced fatigue, facilitated eltrombopag tapering and discontinuation, and maintained safe platelet counts without requiring additional ITP or rescue therapy. Ianalumab was also well tolerated, with no increase in the risk of infection compared with placebo, noted Al-Samkari.

“[Taken together, our findings suggest that] ianalumab may be disease-modifying when used early in the course of ITP,” Al-Samkari concluded, calling for longer-term follow-up to validate its disease-modifying effect in primary ITP.

Other VAYHIT studies evaluating ianalumab as 1L (VAYHIT1) and third-line (VAYHIT3) treatment for primary ITP are underway.