Parsaclisib safe, effective for some CAD patients in Phase 2 trial
Therapy made to suppress enzyme that activates immune cells that fuel AIHA
Parsaclisib, an experimental oral therapy from Incyte, safely and effectively increased levels of hemoglobin in about half of people with cold agglutinin disease (CAD) in a small Phase 2 clinical trial, a study shows.
Data from the study (NCT03538041), which included people with other forms of autoimmune hemolytic anemia (AIHA), showed greater hemoglobin responses among those with warm AIHA, the most common form. Hemoglobin is the protein in red blood cells that transports oxygen.
Reductions in markers of red blood cell destruction, or hemolysis, fatigue, and the need for blood transfusions appeared to be generally similar between types of AIHA, however.
“Parsaclisib was well tolerated and resulted in substantial improvements in [hemoglobin] response at week 1, with durable responses through the extension period [up to about two years],” the researchers wrote.
The study, “Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study,” was published in the American Journal of Hematology. It was funded by Incyte, which is developing the therapy.
AIHA is a group of autoimmune diseases where the immune system produces self-reactive antibodies that attach to red blood cells, marking them for destruction. The disorder can be classified as warm AIHA, CAD, and mixed AIHA, depending on whether the antibodies are active at warm or cold temperatures, or a combination of both.
In all the types, antibody-induced hemolysis results in anemia, which refers to low numbers of red blood cells or low hemoglobin levels that limit the delivery of oxygen to the body’s tissues.
The goal of AIHA treatment is to reduce hemolysis and anemia, increasing red blood cells and hemoglobin levels.
How does parsaclisib work on CAD, AIHAs?
Parsaclisib is an orally available molecule designed to potently and selectively suppress phosphoinositide 3-kinase (PI3K) delta, an enzyme involved in the activation and growth of self-reactive B-cells, the immune cells that wrongly produce the antibodies that drive AIHA.
The trial enrolled 25 adults with AIHA (56% women, median age 63) at sites in the U.S., Austria, France, and Italy. Sixteen patients (64%) had warm AIHA, six (24%) had CAD, and three (12%) had mixed AIHA. About a third (36%) needed at least one blood transfusion in the previous year and 24% had been hospitalized due to AIHA. All had failed to respond to previous treatments, most commonly rituximab (76%) and prednisone (72%).
At the start of the study, or its baseline, the participants’ mean hemoglobin levels were 8.9 g/dL, below the normal range.
The study enrolled a first group of 10 patients, mostly with warm AIHA, who started treatment with 1 mg of parsaclisib daily for 12 weeks, or three months. If their hemoglobin didn’t increase significantly by week 6 or if they still needed a blood transfusion, their dose was increased to 2.5 mg daily.
After reviewing early results from at least six warm AIHA patients in the first group, enrollment was opened for the second group, which included 15 patients who started on 2.5 mg of parsaclisib daily. This group was intended to include more CAD patients and to see if the higher dose had greater clinical benefit.
Seventeen patients who showed benefits from the treatment after 12 weeks chose to enter an extension period to continue on parsaclisib. They were followed for about three months after the last dose.
Goal: Complete or partial response to parsaclisib
The study’s main goal was to see how many patients had a complete or partial response between weeks 6-12 without having received a blood transfusion in the previous week. A complete response meant hemoglobin reached 12 g/dL or higher, while a partial response meant hemoglobin reached 10-12 g/dL or increased by 2 g/dL or more from baseline.
Nearly two-thirds of the patients (64%) had a complete or partial response to parsaclisib, with response rates being better in warm AIHA patients (75%) than in those with CAD (50%) or mixed AIHA (33.3%). More than half the patients (52%) responded within a week and the responses were sustained into the extension period, with the number of patients achieving complete responses increasing.
Over time, there was a general increase in the proportion of patients who achieved a level normalization of markers of hemolysis, with no major differences between all the patients and the group of warm AIHA patients. Up to two patients needed a blood transfusion during the study. None needed a transfusion in the extension period.
The participants also reported reductions in fatigue at six weeks that were sustained at week 12. Again, there were no major differences between all the patients and the warm AIHA group.
All the patients had adverse events. These were deemed potentially related to parsaclisib in 11 (44%) patients, and most commonly included diarrhea, dry skin, itchy rash, and rash. One patient died of respiratory complications after COVID-19 that weren’t considered related to treatment.
“These data suggest that parsaclisib may be an effective strategy for managing AIHA,” the researchers wrote.
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