麻豆传媒

An investigational anti-CD38 monoclonal antibody (CM313) rapidly increased platelets in immune thrombocytopenia (ITP) patients to levels sufficient for preventing bleeding, a small single-arm Chinese study showed.

In the phase I/II trial of 22 ITP patients who had previously received multiple therapies, all but one patient had two or more consecutive platelet counts of at least 50 × 10⁹ per liter during the 8-week treatment period, meeting the study's primary outcome. The median time to that threshold was 1 week, and the median cumulative response duration was 23 weeks.

Additionally, adverse events (AEs) with the anti-CD38 drug were mostly low-grade and infusion related, reported Lei Zhang, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and colleagues.

"CM313 was safe and showed rapid and sustained efficacy in 95% of the patients," they concluded in their paper.

ITP is an autoimmune disease characterized by autoantibody-mediated platelet destruction, with clinical manifestations that "predominantly include cutaneous and mucosal bleeding, the severity of which is contingent on the platelet count and which may carry life-threatening risks," the researchers explained.

Most fatal bleeding events occur in patients whose platelet counts fall below 30 × 10⁹ per liter, and durable platelet response of at least 50 × 10⁹ per liter on multiple assessments is a common benchmark for regulatory approval. In this study, 14 patients (64%) achieved a durable sustained platelet-count response with CM313 (at least 50 × 10⁹ per liter in six of the final eight measurements).

Preclinical research has suggested that the novel anti-CD38 targeted therapy "induces potent killing of tumor cells through Fc-receptor–dependent mechanisms and has a favorable side-effect profile," said Zhang and colleagues, in explaining the rationale behind the study. "We propose that eliminating short-lived plasma cells and long-lived plasma cells with the use of CM313 could become a new strategy for treating ITP."

The enrolled a total of 22 ITP patients, all of whom had already been treated with thrombopoietin-receptor agonists, glucocorticoids, and intravenous immune globulin.

Patients had a median age of 36 years, 73% were women, and their median duration of ITP was 27 months. At baseline, the median platelet count was 12 × 10⁹ per liter, with 45% having a platelet count below 10 × 10⁹ per liter. Participants had received a median of four different previous therapies for ITP, and 36% and 18% had undergone treatment with rituximab and splenectomy, respectively.

After screening, patients underwent an 8-week treatment period (CM313 administered intravenously once a week at a dose of 16 mg/kg) followed by a 16-week follow-up period. Concurrent therapy with either thrombopoietin-receptor agonists or glucocorticoids was allowed.

The primary outcomes were safety and documentation of two or more consecutive platelet counts of at least 50 × 10⁹ per liter within 8 weeks after the first dose of CM313.

A total of 18 patients (82%) responded (complete or partial responses) to CM313 at week 8, increasing to 19 patients (86%) at week 12. By week 24, there were still 14 patients (64%) in response. Zhang and colleagues also found that CM313 achieved responses in three of the four patients with a history of splenectomy, in all eight patients with a history of failure on rituximab, in those who relapsed, "as well as in patients who were negative for glycoprotein autoantibodies."

The percentage of patients with bleeding decreased from 68% at baseline to 5% and 10% at weeks 8 and 24, respectively.

Researchers also looked at changes in immune function in order to better understand CM313's mechanism of action. "In line with previous findings with daratumumab [Darzalex], CM313 infusion effectively suppressed the proliferative function of lymphocytes and reduced serum IgG levels, which indicates its ability to down-regulate autoantibody production by clearing plasma cells and thus maintain a long-term response," they wrote. "The attenuation of platelet destruction and the restoration of the platelet count may gradually return the state of immune activation to equilibrium."

Sixteen of the 22 patients (73%) had at least one AE, and most of these events were grade 1/2 in severity. The most common AEs were infusion-related reactions (32%, all grade 2), most frequently chills (23%), nausea (23%), and increased blood pressure (14%). All infusion-related reactions were resolved while patients continued to receive CM313 infusions.

Other common all-grade AEs included upper respiratory tract infections in 32%, asthenia in 18%, and hyperuricemia in 14%. "Although the number of severe infections was limited, patients might benefit from intermittent intravenous immune globulin infusions, given the potential risk of severe infection," the researchers noted.

Zhang and colleagues acknowledged their study had several limitations, including the fact it was nonrandomized and noncontrolled. They also pointed out that the prophylactic use of glucocorticoids could affect the time to onset of treatment effects and the efficacy of CM313.

"Moreover, an assessment at the 16-week follow-up showed that immunoglobulin levels had not recovered in some patients, which highlights the need for an extended follow-up period to provide a comprehensive assessment of the safety of CM313," they added.

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