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An investigational selective spleen tyrosine kinase (SYK) inhibitor was well tolerated and induced durable responses as second-line therapy for primary immune thrombocytopenia (ITP), a small randomized from China showed.

Of 16 patients treated with oral sovleplenib at the recommended phase II dose of 300 mg, the main efficacy endpoint was met by 10 patients (63%, 95% CI 35-85) through 8 weeks, reported Renchi Yang, MD, of the Blood Diseases Hospital in Tianjin, China, and colleagues.

In the trial's placebo group, just one of 11 patients (9%, 95% CI 0-41) met that endpoint, which was defined as a platelet count of at least 30 × 10⁹ platelets per L and doubled from baseline at two consecutive visits without rescue therapy, the researchers detailed in .

During an open-label period that included an additional four patients who crossed over from the placebo group after 8 weeks, the overall response rate (one platelet count of at least 50 × 10⁹/L) was 80% with the 300-mg dose, with a durable response rate of 40% through 24 weeks.

Subgroup analysis demonstrated a "consistent response" to 300-mg sovleplenib, regardless of previous thrombopoietin or thrombopoietin receptor agonist use, Yang and colleagues said, suggesting the drug at this dose "could be a promising treatment option for patients who received previous thrombopoietin or thrombopoietin receptor agonist treatment."

SYK signaling is pivotal in phagocytosis-based, antibody-mediated platelet destruction in adults with ITP, the study authors explained, and thus is a potential target in an attempt to modulate the balance between platelet destruction and production in these patients.

In 2018, the as the first SYK inhibitor for primary ITP patients with an insufficient response to previous therapy. But while fostamatinib demonstrated a response rate of 43%, the durable response rate was just 18%, noted a by Maria Lozano, MD, PhD, of the Universidad de Murcia in Spain, and the non-specific SYK inhibitor was associated with several off-target side effects, resulting in a high proportion of patients needing dose reductions or interruptions.

"Considering that increasing the specificity of SYK inhibitors could ultimately improve safety and efficacy and allow unequivocal conclusions to be drawn about the prospects of this class of drugs for patients with primary immune thrombocytopenia, more selective agents are being investigated in clinical trials," wrote Lozano. Agents that include sovleplenib -- a small molecule, potent, selective SYK inhibitor.

In the current trial, one of the 16 patients on sovleplenib 300 mg required a dose reduction during the 8-week randomized period and two stopped therapy during the subsequent open-label period.

Despite the encouraging data in the trial, Lozano said questions remain, including whether non-Asian adults with primary ITP will benefit from the therapy, and whether sovleplenib if approved and widely available would work in patients intolerant to fostamatinib, and vice versa. (A is currently ongoing to confirm the efficacy and safety of sovleplenib as second-line therapy for patients with primary ITP.)

"Another question to be evaluated," she said, "is whether the use of inhibitors directed against this kinase requires specific monitoring in individuals with some carcinomas, given that SYK exerts tumor suppressor properties in cancers such as melanoma, breast, and gastric carcinomas."

Study Details

For the current study, 45 adults were randomly assigned to receive 100 mg to 400 mg oral doses of sovleplenib -- also known as HMPL-523 -- or placebo during an 8-week, double-blind period, which was followed by a 16-week open-label period with sovleplenib. The trial was conducted at nine hospitals in China.

Eligible patients were ages 18 to 75 years, had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1, and had primary ITP for more than 6 months. Patients had not responded or relapsed after first-line treatment or had poor response or postoperative relapse after a splenectomy.

Median age of participants was 40 years, and 60% were women. The median number of previous anti-primary ITP therapy lines was five in the sovleplenib groups and four in the placebo group. Ten of 34 patients (29%) in the sovleplenib groups received concomitant anti-primary ITP therapy after baseline, versus five of 11 patients (45%) in the placebo group.

In addition to the results reported for the 300 mg and placebo groups, the main efficacy endpoint was met by three of six patients (50%) each in the 100 mg and 200 mg groups, and two of six patients (33%) in the 400 mg group.

Durable responses -- defined as four or more of the last six scheduled visits with a platelet count of at least 50 × 10⁹ platelets per L -- were seen in five of 16 patients in the continuous sovleplenib 300 mg subgroup, and three of four patients who crossed over from placebo.

During the 28-day safety evaluation period, two grade ≥2 treatment-emergent adverse events (TEAEs) occurred in the sovleplenib groups (hypertriglyceridemia and anemia). During the 8-week placebo-controlled period, the most frequent TEAEs were an increase in blood lactate dehydrogenase, hematuria, and urinary tract infection (21% with sovleplenib vs 9% with placebo). Most events were mild or moderate in severity and required no treatment discontinuation.

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