# Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study

W. Barcellini, F. Pane, A. Patriarca, I. Murakhovskaya, Louis Terriou, M. T. Desancho, W. T. Hanna, L. Leopold, E. Rappold, K. Szeto, et al.

► To cite this version:

W. Barcellini, F. Pane, A. Patriarca, I. Murakhovskaya, Louis Terriou, et al. Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study. American Journal of Hematology, 2024, Am. J. Hematol., 99 (12), 10.1002/ajh.27493. hal-05157740

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RESEARCH ARTICLE

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WILEY

# Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study

Wilma Barcellini<fnref n="1" /> ID | Fabrizio Pane<fnref n="2" /> | Andrea Patriarca<fnref n="3" /> | Irina Murakhovskaya<fnref n="4" /> |

Louis Terriou<fnref n="5" /> | Maria T. DeSancho<fnref n="6" /> ID | Wahid T. Hanna<fnref n="7" /> | Lance Leopold<fnref n="8" /> |

Erica Rappold<fnref n="8" /> | Ke Szeto<fnref n="8" /> | Shaoceng Wei<fnref n="8" /> | Ulrich Jäger<fnref n="9" /> ID

**Funding information**

Incyte

**Abstract**

Autoimmune hemolytic anemia (AIHA) is a group of acquired autoimmune disorders characterized by red blood cell hemolysis. In a phase 2, open-label, multicenter study, adults with warm AIHA, cold agglutinin disease, or mixed-type AIHA were administered once-daily 1.0 or 2.5 mg parsaclisib (selective phosphoinositide 3-kinase δ inhibitor) orally for 12 weeks, followed by an extension period. Dose increases (for AIHA worsening) or decreases (for tolerability) were permitted. Primary efficacy endpoint was the proportion of patients with complete (≥12 g/dL hemoglobin [Hgb]) or partial (10–12 g/dL Hgb or ≥2 g/dL increase from baseline) response at any visit during weeks 6–12 not attributable to transfusion. Among 25 enrolled patients (median age, 63 y), 16 (64%) achieved a partial or complete Hgb response during weeks 6–12. Responses were observed by week 1 in 52.0% of patients with incremental improvements during weeks 6–12 and sustained responses during the extension period. Responses were higher among patients with warm AIHA versus other types (75.0% vs. 44.4%). Clinically meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue scores were observed at weeks 6 and 12. All patients had treatment-emergent adverse events (TEAEs), most commonly diarrhea (32.0%) and pyrexia (28.0%). Grade ≥3 TEAEs occurred in 13 patients (52.0%). TEAEs considered possibly related to treatment occurred in 11 patients (44.0%). No dose reductions were required; six patients (24%) discontinued for a TEAE. In summary, parsaclisib was well tolerated and resulted in substantial improvements in Hgb response at week 1, with durable responses through the extension period.

**Clinical trial registration:** This trial was registered at [ClinicalTrials.gov (NCT03538041)](https://ClinicalTrials.gov).

1 | INTRODUCTION

Autoimmune hemolytic anemia (AIHA) is a group of rare, acquired autoimmune disorders characterized by autoantibody-mediated hemolysis of red blood cells (RBCs) and anemia due to insufficient

compensatory RBC production.<fnref n="1" />,<fnref n="2" /> The overall incidence of AIHA is 1–3 per 100 000 per year, and the prevalence is approximately 17 per 100 000.<fnref n="3" />⁻<fnref n="6" /> AIHA is usually classified by the thermal characteristics of the autoantibodies present (warm or cold [cold agglutinin disease (CAD)]), although mixed and atypical presentations are also possible.<fnref n="7" />

This is an open access article under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2024 Incyte Corporation and The Author(s). *American Journal of Hematology* published by Wiley Periodicals LLC.

<footnote n="1">¹Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy</footnote>

<footnote n="2">²Department of Medicine and Surgery, University Federico II of Naples, Naples, Italy</footnote>

<footnote n="3">³University of Eastern Piedmont and AOU "Maggiore della Carità", Novara, Italy</footnote>

<footnote n="4">⁴Albert Einstein College of Medicine/ Montefiore Medical Center, Bronx, New York, USA</footnote>

<footnote n="5">⁵Université de Lille, Inserm, CHU Lille, Centre de Référence des Maladies Autoimmunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), INFINITE-Institute for Translational Research in Inflammation, Lille, France</footnote>

<footnote n="6">⁶Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA</footnote>

<footnote n="7">⁷University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA</footnote>

<footnote n="8">⁸Incyte Corporation, Wilmington, Delaware, USA</footnote>

<footnote n="9">⁹Medical University of Vienna, Vienna, Austria</footnote>

<footnote>**Correspondence**
Ulrich Jäger, Medical University of Vienna, Department of Medicine I, Division of Hematology and Hemostaseology, Währinger Gürtel 18-20, A-1090 Vienna.</footnote>

<footnote>Email: ulrich.jaeger@meduniwien.ac.at</footnote>
Warm AIHA (wAIHA) comprises 60%-70% of AIHA cases,¹,⁸,⁹ and approximately 50% of wAIHA cases are characterized as primary disease, in which hemolysis occurs without associated disorders.⁹,¹⁰ Although recent guidelines provide recommendations on treatments for AIHA, there are no approved treatment options for wAIHA.¹,¹¹,¹² Management approaches for primary wAIHA include supportive care, corticosteroids, rituximab, and splenectomy¹²; however, these therapies are often limited by disease relapse, infusion reactions, and infections.¹

Phosphoinositide 3-kinase δ (PI3K-δ) signaling contributes to autoimmune disease through the activation and proliferation of self-reactive B cells, which results in increased autoantibody production, antigen presentation to autoreactive T cells, and the production of a milieu of inflammatory cytokines.¹³ Inhibition of PI3K can also contribute to autoimmune phenomena, cytopenias, transaminitis, pneumonitis, or colitis.¹⁴,¹⁵ Risk factors for the induction of autoimmunity include younger age and earlier line of therapy.¹⁵ Parsaclisib is a next-generation, oral, potent, and highly selective inhibitor of the class IA PI3K enzymes that is approximately 20 000-fold selective for PI3K-δ over other isoforms.¹⁶ In a 12-week analysis of patients with primary AIHA, parsaclisib (1.0 or 2.5 mg once daily [QD]) was generally well tolerated and resulted in normalization of hemoglobin (Hgb) levels.¹⁷ Here, we present long-term data from a phase 2 clinical trial evaluating the efficacy, safety, and pharmacokinetics (PK) of parsaclisib for the treatment of primary AIHA.

## 2 | METHODS

### 2.1 | Patients and study design

This phase 2, open-label, multicenter study evaluated the efficacy and safety of parsaclisib in patients with primary AIHA (NCT03538041) at eight study centers in Austria, France, Italy, and US. Eligible patients were aged ≥18 years with a diagnosis of wAIHA, CAD, or mixed-type AIHA, based on the presence of hemolytic anemia and serologic evidence of anti-RBC antibodies detectable by direct antiglobulin test (DAT; wAIHA: DAT positive for immunoglobulin G [IgG] or IgG plus C3d; CAD: DAT positive for C3d only, with cold agglutinins of I specificity; mixed: DAT positive for IgG and C3d, with coexistence of warm autoantibodies and high-titer cold agglutinins). Additional key inclusion criteria included active disease following ≥1 prior treatment for AIHA, no evidence of a lymphoproliferative disorder or other autoimmune-related underlying conditions (e.g., systemic lupus erythematosus), Hgb values of 7-10 g/dL at screening, and willingness to receive *Pneumocystis jiroveci* pneumonia (PJP) prophylaxis during the study (e.g., trimethoprim-sulfamethoxazole, atovaquone, dapsone with or without pyrimethamine, and pentamidine; selected by investigators). Patients were excluded from the study if they had an absolute neutrophil count of <1.5 × 10⁹/L, a platelet count of <100 × 10⁹/L, or laboratory values indicative of impaired liver (Child-Pugh Class C or alanine aminotransferase or aspartate amino transferase ≥2 times the upper limit of normal) or renal (estimated

creatinine clearance <45 mL/min) function. Patients who received rituximab within 3 months of baseline visit or immunosuppressive therapy (e.g., high-dose corticosteroids [>20 mg/day]) within 28 days of baseline visit were also excluded. Concomitant, stable use of low-dose corticosteroids (i.e., maximum dose of prednisone 20 mg/day or equivalent) was permitted throughout the study.

Enrolled patients received oral parsaclisib for 12 weeks at a starting dose of 1.0 mg QD (cohort 1) or 2.5 mg QD (cohort 2; Figure S1). Target enrollment in cohort 1 was 10 patients, with ≤3 patients with CAD or mixed-type AIHA to reflect the distribution of AIHA subtypes in the general population.¹⁸ Patients in cohort 1 who received a starting dose of 1.0 mg QD were eligible for a dose increase to 2.5 mg QD starting at week 6 if no meaningful clinical response was achieved (i.e., ≥2 g/dL increase in Hgb from baseline) or transfusions continued to be required. Cohort 2 enrollment was permitted following a review of efficacy and safety data through week 6 of ≥6 patients with wAIHA in cohort 1. Target enrollment in cohort 2 was 15 patients, with approximately five patients with CAD and ≤8 patients with wAIHA; this distribution was intended to further evaluate patients with CAD and account for higher baseline variability in wAIHA subpopulation from cohort 1. In both cohorts, dose reductions to 1.0 mg QD were permitted at any time for tolerability issues.

Patients who completed the 12-week initial treatment period and were deriving clinical benefit from parsaclisib (investigator's judgment) were eligible to enroll into an extension period wherein they could continue to receive oral parsaclisib QD. Following the last dose of parsaclisib, patients entered a 12-week follow-up to evaluate the safety and durability of response.

This study was conducted in accordance with Good Clinical Practice guidelines, provisions of the Declaration of Helsinki, and applicable local regulations. Study protocols were approved by all relevant institutional review boards or ethics committees. Before enrollment, all patients provided written informed consent.

### 2.2 | Endpoints and assessments

The primary efficacy endpoints were the proportion of patients who achieved a complete response (CR) or partial response (PR) in Hgb at any visit during weeks 6-12 that was not attributable to RBC transfusion. A CR was defined as a Hgb value ≥12 g/dL not attributed to transfusion effect (i.e., no transfusions in the prior week). A PR was defined as a Hgb value of 10-12 g/dL or a ≥2 g/dL increase from baseline not attributed to transfusion effect. Safety was also a primary endpoint. Incidence and severity of treatment-emergent adverse events (TEAEs) were assessed throughout the study and graded for severity using Common Terminology Criteria for Adverse Events v5.0 criteria. Adverse events of special clinical interest (AESIs) related to parsaclisib included colitis, cytomegalovirus (CMV) infection, diarrhea, exfoliative dermatitis, febrile neutropenia, herpes simplex, intestinal perforation, PJP, pneumonia, pneumonitis, rash, and varicella zoster virus infection.
Secondary endpoints included the proportion of patients attaining a CR or PR during postbaseline visits, proportion of patients attaining a ≥2 g/dL increase in Hgb from baseline, mean and change from baseline in Hgb, proportion of patients requiring transfusions, proportion of patients achieving normalization of Hgb and hemolytic markers (haptoglobin, lactate dehydrogenase, reticulocyte count, total bilirubin, and direct and indirect bilirubin), change in daily prednisone use, PK, and mean and change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale. During the treatment period, Hgb responses were assessed at baseline and during treatment period study visits (weeks 1, 2, 4, 6, 8, 10, and 12). During the extension period, Hgb responses were assessed at each study visit, which occurred at least every 8-12 weeks. Follow-up was continued monthly to assess Hgb responses for 3 months after the end of treatment. FACIT-F assessments were completed at baseline and weeks 6 and 12 of the initial treatment period and during the follow-up period. FACIT-F is a 13-item questionnaire that assesses patient-reported quality of life (QoL).¹⁹ Patients were asked to rate the severity of their fatigue symptoms over the past week from 0 to 52, with higher scores indicating improved QoL; a ≥3-point increase (i.e., improvement) in FACIT-F indicates a minimal clinically important difference for patients with anemia.¹⁹

## 2.3 | PK analyses

During the initial 12-week treatment period, blood samples for PK analyses were collected predose during study visits at weeks 1, 2, 8, and 12 as well as 1, 2, and 4 h postdose at weeks 2 and 8. Plasma concentrations of parsaclisib were determined using liquid chromatography-tandem mass spectrometry.

## 2.4 | Statistical analyses

All patients enrolled in the study who received ≥1 dose of parsaclisib were included in efficacy and safety analyses. Nonresponder imputation was applied to primary efficacy endpoints. The PK analysis included all patients who received ≥1 dose of parsaclisib and had ≥1 postdose PK sample. Data were summarized using descriptive statistics. Response among the subgroup of patients with wAIHA were evaluated post hoc. The data analysis cutoff was February 24, 2022.

# 3 | RESULTS

## 3.1 | Patients and study disposition

A total of 25 patients were enrolled in the study (cohort 1, *n* = 10; cohort 2, *n* = 15) and received ≥1 dose of parsaclisib. The median age of patients was 63 years (range, 22-91 years); a slightly higher proportion of patients were female (56.0%). More patients had wAIHA (64.0%) than CAD (24.0%) or mixed-type AIHA (12.0%). Baseline demographics and disease characteristics for patients with wAIHA as well as the overall study

<table><caption>TABLE 1 Patient demographics and baseline clinical characteristics.</caption><thead><tr><th></th><th>Overall population (N = 25)</th><th>Patients with wAIHA (n = 16)</th></tr></thead><tbody><tr><td>Age, median (range), year</td><td>63.0 (22-91)</td><td>59.5 (22-91)</td></tr><tr><td>≥65 years, n (%)</td><td>11 (44.0)</td><td>5 (31.3)</td></tr><tr><td>Female, n (%)</td><td>14 (56.0)</td><td>5 (31.3)</td></tr><tr><td>Race, n (%)</td><td></td><td></td></tr><tr><td>White</td><td>23 (92.0)</td><td>15 (93.8)</td></tr><tr><td>Black</td><td>1 (4.0)</td><td>1 (6.3)</td></tr><tr><td>Other</td><td>1 (4.0)</td><td>0</td></tr><tr><td>Type of AIHA, n (%)</td><td></td><td></td></tr><tr><td>wAIHA</td><td>16 (64.0)</td><td>16 (100)</td></tr><tr><td>CAD</td><td>6 (24.0)</td><td>-</td></tr><tr><td>Mixed</td><td>3 (12.0)</td><td>-</td></tr><tr><td>Disease duration, n (%)</td><td></td><td></td></tr><tr><td>&lt;2 years</td><td>12 (48.0)</td><td>8 (50.0)</td></tr><tr><td>2-5 years</td><td>3 (12.0)</td><td>3 (18.8)</td></tr><tr><td>&gt;5 years</td><td>10 (40.0)</td><td>5 (31.3)</td></tr><tr><td>Received ≥1 transfusion in the past year, n (%)</td><td>9 (36.0)</td><td>6 (37.5)</td></tr><tr><td>Prior splenectomy, n (%)</td><td>3 (12.0)</td><td>2 (12.5)</td></tr><tr><td>Prior therapies, median (range)</td><td>2 (1-6)</td><td>2 (1-6)</td></tr><tr><td>Prior therapies,<sup>a</sup> n (%)</td><td></td><td></td></tr><tr><td>Rituximab</td><td>19 (76.0)</td><td>12 (75.0)</td></tr><tr><td>Prednisone</td><td>18 (72.0)</td><td>13 (81.3)</td></tr><tr><td>Azathioprine</td><td>4 (16.0)</td><td>4 (25.0)</td></tr><tr><td>Cyclophosphamide</td><td>2 (8.0)</td><td>2 (12.5)</td></tr><tr><td>Intravenous immunoglobulin</td><td>2 (8.0)</td><td>2 (12.5)</td></tr><tr><td>Concomitant prednisone, n (%)</td><td>13 (52.0)</td><td>11 (68.8)</td></tr><tr><td>Hgb, mean (SD), g/dL</td><td>8.9 (0.8)</td><td>8.7 (0.9)</td></tr><tr><td>FACIT-F subscale, mean (SD)</td><td>31.1 (13.2)</td><td>30.8 (13.2)</td></tr></tbody></table>

Abbreviations: AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; Hgb, hemoglobin; wAIHA, warm autoimmune hemolytic anemia.
ªPrior therapies received by ≥2 patients in the overall population are reported.

population are shown in Table 1. Mean (SD) levels of Hgb at baseline in the overall population were 8.9 (0.83) g/dL. In the year prior to study enrollment, nine patients (36.0%) required ≥1 transfusion and six patients (24.0%) were hospitalized for AIHA. All patients had failed prior therapy, including rituximab (76.0%), prednisone (72.0%), and splenectomy (12.0%).

Among the 25 patients who received ≥1 dose of parsaclisib, 21 patients (84.0%) completed the initial 12-week treatment period (Figure S2). During the initial 12-week treatment period, the median treatment duration was 85 days (range, 7-99 days), and the median daily
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**FIGURE 1** Proportion of patients with a response (A) during the initial treatment period at any visit from weeks 6 to 12. (B) Each visit of the initial treatment period. (C) Each visit of the extension period. AIHA, autoimmune hemolytic anemia; CR, complete response; Hgb, hemoglobin; PR, partial response; wAIHA, warm autoimmune hemolytic anemia.</figcaption></figure>

*Patients initially received 1.0 mg starting doses of parsaclisib; 8 of the 10 patients assigned to the 1.0 mg dose at baseline switched to the 2.5 mg dose during weeks 6–10. †Following review of efficacy and safety data at week 6 from ≥6 patients in cohort 1, patients were enrolled and received 2.5 mg doses of parsaclisib. ‡Visits during the extension period were conducted every 8–12 weeks; data for visits with ≥10 patients are shown. [Color figure can be viewed at wileyonlinelibrary.com]

dose was 2.4 mg/day (range, 1–3 mg/day). Treatment was discontinued by four patients (adverse events [AEs], n = 2; patient withdrawal, n = 1; lack of efficacy, n = 1). Among the 10 patients in cohort 1, eight switched to the 2.5 mg dose between weeks 6 and 10.

A total of 17 patients enrolled in the extension period. As of the analysis cutoff, the median treatment duration (including the initial 12-week period) was 402 days (range, 21–938 days), and the median (range) daily dose was 2.3 (1–3) mg/day. Nine patients discontinued during the extension period (AEs, n = 4; lack of efficacy, n = 4; physician decision, n = 1). As of the analysis cutoff, eight patients were continuing parsaclisib treatment.

## 3.2 | Efficacy

Overall, 16 patients (64%) achieved a PR or CR at any visit during weeks 6–12 (Figure 1A). Among these 16 patients who responded, 8 patients achieved a CR (32.0% of the overall population). A slightly higher response rate was observed among patients who initiated treatment with a dose of 2.5 mg compared with those who initiated treatment with a dose of 1.0 mg (66.7% vs. 60.0%, respectively; CR rates of 40.0% vs. 20.0%). A higher proportion of patients with wAIHA had a response compared with other types of AIHA (75.0% [12/16] vs. 44.4% [4/9]); 50% of patients with CAD (3/6) and 33.3% of patients with mixed-type AIHA (1/3) had a response. Responses were observed by week 1 (52.0%) and were sustained over weeks 6–12 with incremental improvements in CR generally observed (Figure 1B). Response rates were ≥80% among patients who continued administration of parsaclisib through the extension period (Figure 1C).

Increases in mean Hgb levels were observed as early as week 1 and continued throughout the treatment period (Figure 2A). At week 12, mean (SD) Hgb levels of 10.9 (2.1), 11.5 (2.3), and 9.6 (1.0) g/dL were observed in the overall, wAIHA, and CAD populations, respectively. Mean Hgb levels remained stable throughout the extension period in the overall and wAIHA populations (Figure 2B). Among the eight patients who switched from the 1.0 to 2.5 mg dose between weeks 6 and 10, improvements in Hgb levels were observed with seven patients following the dose increase.

The proportion of patients attaining a ≥2 g/dL increase in Hgb from baseline increased from 16.0% at week 1 to 43.5% at week 12, primarily among patients with wAIHA (Figure S3A); proportions were maintained throughout the extension period (Figure S3B). There was a slight increase in the proportion of patients who achieved normalization of Hgb and hemolytic markers, such as total bilirubin, during the 12-week treatment period (Figure S4A) and extension period (Figure S4B). Similar results were observed among patients with wAIHA (Figure S4C,D). During the initial treatment period, ≤8% of patients (i.e., ≤2 patients) required a transfusion at any study visit. At the time of data cutoff, no patient required a transfusion in the extension period.

Improvements from baseline in FACIT-F scores were evident at the first assessment at week 6 and were sustained at week 12 (Figure S5A,B). Mean (SD) improvements from baseline at week 6 in the overall
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**FIGURE 2** Hgb values during (A) the initial treatment period and (B) the extension period. BL, baseline; Hgb, hemoglobin; wAIHA, warm autoimmune hemolytic anemia. *Visits during the extension period were conducted every 8–12 weeks; data for visits with ≥10 patients are shown. Source: This figure was previously published as part of an abstract submission to the European Hematology Association 2022 annual meeting (Barcellini W, Murakhovskaya I, Terriou L, Pane F, et al. Long-term efficacy and safety results from an ongoing open-label phase 2 study of parsacisib for the treatment of autoimmune hemolytic anemia. *HemaSphere* 2022;6(S3):187–188). [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>

population and patients with wAIHA were 7.6 (10.4) and 6.9 (10.3) points, respectively.

Among the 13 patients (52.0%) taking prednisone QD at baseline (wAIHA, n = 11; CAD, n = 1; mixed-type AIHA, n = 1), 2–4 patients decreased their prednisone dose at each study visit during the initial treatment period, and 1 patient had an increase in prednisone dose at week 1. Five patients with a history of long-term prednisone use were able to discontinue prednisone entirely (three during the treatment period and two during the extension period). Of these patients, four had wAIHA and one had mixed-type AIHA.

<table><caption>**TABLE 2** Summary of TEAEs throughout the treatment and extension periods.</caption><thead><tr><th>n (%)</th><th>Overall population<br>N = 25</th></tr></thead><tbody><tr><td>Patients with ≥1 TEAE</td><td>25 (100)</td></tr><tr><td>Most common TEAEs<sup>a</sup></td><td></td></tr><tr><td>Diarrhea</td><td>8 (32.0)</td></tr><tr><td>Pyrexia</td><td>7 (28.0)</td></tr><tr><td>Headache</td><td>5 (20.0)</td></tr><tr><td>Rash</td><td>5 (20.0)</td></tr><tr><td>Peripheral edema</td><td>4 (16.0)</td></tr><tr><td>Cough</td><td>3 (12.0)</td></tr><tr><td>Nausea</td><td>3 (12.0)</td></tr><tr><td>Neutropenia</td><td>3 (12.0)</td></tr><tr><td>Pain in extremity</td><td>3 (12.0)</td></tr><tr><td>Vomiting</td><td>3 (12.0)</td></tr><tr><td>Worsening AIHA</td><td>3 (12.0)</td></tr><tr><td>Patients with ≥1 treatment-related TEAE</td><td>11 (44.0)</td></tr><tr><td>Most common treatment-related TEAEs<sup>b</sup></td><td></td></tr><tr><td>Diarrhea</td><td>2 (8.0)</td></tr><tr><td>Dry skin</td><td>2 (8.0)</td></tr><tr><td>Pruritic rash</td><td>2 (8.0)</td></tr><tr><td>Rash</td><td>2 (8.0)</td></tr><tr><td>Patients with ≥1 serious TEAE</td><td>9 (36.0)</td></tr><tr><td>Most common serious TEAEs<sup>c</sup></td><td></td></tr><tr><td>Acute respiratory failure</td><td>2 (8.0)</td></tr><tr><td>COVID-19 pneumonia</td><td>2 (8.0)</td></tr><tr><td>Hypernatremia</td><td>2 (8.0)</td></tr><tr><td>Worsening AIHA</td><td>2 (8.0)</td></tr><tr><td>Discontinuation due to a TEAE<sup>d</sup></td><td>6 (24.0)</td></tr></tbody></table>

**Note:** One patient developed severe acute respiratory distress leading to death within 30 days of the last dose of study drug; this event was not considered by the investigator to be related to treatment. This event was not reported as treatment-emergent because of late reporting and unknown last dose date.

Abbreviations: AIHA, autoimmune hemolytic anemia; CMV, cytomegalovirus; TEAE, treatment-emergent adverse event.

<sup>a</sup> Occurred in ≥3 patients (≥12%).

<sup>b</sup> Occurred in ≥2 patients (≥8%).

<sup>c</sup> Occurred in ≥2 patients (≥8%). Additional serious TEAEs in one patient each include amoebic dysentery, aortic thrombosis, bacterial sepsis, *Campylobacter* colitis, COVID-19, CMV infection reactivation, diabetes insipidus, diarrhea, Enterococcal infection, fall, femur fracture, interstitial lung disease, invasive ductal breast carcinoma, pneumonia, *Pseudomonas* infection, psoriasis, staphylococcal sepsis, and tibia fracture.

<sup>d</sup> Diarrhea occurred in two patients (8.0%). All other TEAEs resulting in discontinuation occurred in one patient each (amoebic dysentery, aortic thrombosis, *Campylobacter* colitis, CMV infection reactivation, COVID-19 pneumonia, non-Hodgkin lymphoma, pneumonitis, staphylococcal sepsis, and thrombocytopenia).

## 3.3 | Safety

All 25 patients reported a TEAE (Table 2). Diarrhea, pyrexia, headache, and rash were the most common TEAEs, occurring in 8 (32.0%).
7 (28.0%), 5 (20.0%), and 5 (20.0%) patients, respectively. Diarrhea was mild or moderate in severity in most patients; one patient had grade 3 or higher diarrhea. All events of pyrexia, headache, and rash were mild or moderate in severity. Grade ≥3 TEAEs occurred in 13 patients (52.0%), most commonly worsening AIHA (n = 3), neutropenia (n = 2), and COVID-19 pneumonia (n = 2). Discontinuations and interruptions due to TEAEs occurred in 6 (24.0%) and 11 (44.0%) patients, respectively; no patients required a dose reduction of parsaclisib.

TEAEs considered by investigators as potentially related to treatment occurred in 11 patients (44.0%). Most treatment-related TEAEs occurred in one patient; diarrhea, dry skin, rash, and pruritic rash each occurred in two patients. Nine patients (36.0%) reported ≥1 serious AE; acute respiratory failure, worsening AIHA, COVID-19 pneumonia, and hypernatremia each occurred in two patients. Diarrhea, CMV infection reactivation, and psoriasis, each occurring in one patient, were serious AEs considered by investigators as possibly related to treatment. One patient had an acute respiratory distress event leading to death within 30 days of the last dose of study drug; this event was not considered by the investigator to be related to treatment. Approximately 6 weeks prior to this event, the patient was hospitalized because of COVID-19 pneumonia and had grade 1 acute hypoxemic respiratory failure secondary to COVID-19.

Regarding AESIs, in addition to the cases of diarrhea and rash discussed above, one patient had pneumonia and one patient had pneumonitis. No cases of colitis, new CMV infection, exfoliative dermatitis, febrile neutropenia, herpes simplex, intestinal perforation, PJP, or varicella zoster virus infection were reported. No clinically meaningful changes in vital signs or electrocardiograms were observed throughout the study. Most treatment-emergent shifts in immunologic or chemistry laboratory values were to grade 1 or 2.

## 3.4 | PK

All 25 patients were evaluable for PK. At week 1, mean (SD) predose plasma concentrations of parsaclisib were 23.0 (23.4) and 44.9 (40.3) nM for the 1.0 and 2.5 mg dose levels, respectively. Predose concentrations of parsaclisib were generally consistent from week 1 to week 12 at each dose level, and a steady state was reached at or prior to week 1. At week 2, maximum observed plasma concentrations of parsaclisib ($C_{max}$; mean [SD] of 99.3 nM [30.0] and 213 nM [91.4] for the 1.0 and 2.5 mg dose levels, respectively) were reached approximately 1 h after oral administration. The levels of exposure to parsaclisib at week 2 and week 8 were similar for patients at the same dose level (Table S1). The increase in parsaclisib exposure was approximately dose proportional.

## 4 | DISCUSSION

This phase 2 study is the first trial to evaluate oral administration of parsaclisib, a PI3K-δ inhibitor, for the treatment of primary AIHA. Parsaclisib resulted in a partial or complete Hgb response in the majority (64.0%) of patients during the 12-week initial treatment

period, with responses higher among patients with wAIHA (75.0%) versus other types of AIHA (44.4%). Responses were evident as early as week 1 and sustained during 12 weeks of treatment. At week 12, more than half of responses were complete. Efficacy was also seen in improvements to Hgb levels, hemolytic markers, and clinically meaningful improvements in FACIT-F subscores at week 12; responses were similar among all patients and those with wAIHA. Durable responses were observed among patients who continued to receive parsaclisib during the extension period.

Parsaclisib was well tolerated throughout the study, and no dose reductions of parsaclisib were required because of TEAEs. Discontinuations of parsaclisib because of a TEAE occurred in six (24.0%) patients; this will be closely monitored in future studies. The most common TEAEs were diarrhea, pyrexia, headache, and rash, most of which were mild or moderate in severity. Most serious TEAEs were not considered by investigators to be related to treatment. PK data indicate that responses were dose proportional across the dosing interval; a steady state of both dose levels was reached by week 1. Of note, although no cases of PJP were reported, PJP prophylaxis should be considered when evaluating the benefits and risks of parsaclisib treatment.

During the study, patients were permitted to take concomitant stable, low-dose corticosteroids (i.e., ≤20 mg/day prednisone [or equivalent]) and could taper at the discretion of the investigator. At baseline, approximately half of patients were taking daily prednisone. Dose reductions of prednisone occurred in some patients throughout the study and only one patient had a dose increase during the 12-week treatment period. Notably, five patients with a history of long-term prednisone use were able to discontinue prednisone entirely. The potential combined effect of corticosteroids with parsaclisib warrants further investigation. In the current study, the relatively small sample size and the variation in prednisone doses and treatment schedules prevented the development of any conclusions regarding synergy between corticosteroids and parsaclisib.

The rapid Hgb response observed in this study suggests that the mechanism of action of parsaclisib may be partially independent of autoantibody inhibition, which typically takes weeks to months for an observable effect. AIHA has a complex pathogenesis involving an imbalance of regulatory T cells as well as alterations of cytokine networks and monocyte/macrophage function.⁴ Possible alternative mechanisms of parsaclisib in AIHA include inhibition of B-cell proliferation¹³ or inhibition of PI3K-δ-mediated T-cell function.²⁰ It is also possible that macrophage activity may be involved given that PI3K signaling has been linked with macrophage function.²¹⁻²³

Although this analysis was not powered to evaluate treatment effects on different subgroups, it is notable that patients with wAIHA had high response rates (75.0% [PR, 25%; CR, 50.0%]). These data suggest parsaclisib targets wAIHA more effectively than other forms of AIHA, possibly owing to greater interleukin-6-dependent B-cell activation in the pathophysiology of wAIHA.²⁴ At variance, CAD is accompanied by a low-grade clonal B-cell lymphoproliferative disorder,²⁵ which may be less susceptible to immunomodulation.

Given that most patients with AIHA (approximately 75%) have a chronic, relapsing disease course,²⁶,²⁷ there is a pressing need for
improved treatments, especially for patients who relapse after first- or second-line therapy and thus may have limited treatment options. The response rates observed with parsaclisib in this study are close to those observed with rituximab and higher than those observed with other immunosuppressants, such as cyclophosphamide and cyclosporin, which may have safety concerns.¹⁸ Although rituximab is a common second-line therapy for wAIHA and recommended as a first-line therapy for CAD,²⁸ it has several drawbacks. Rituximab is not available worldwide, nor is it always reimbursable for patients; however, availability of biosimilars is expected to improve access and decrease cost.²⁹ Duration of response in CAD is relatively short,²⁸ and patients frequently relapse.³⁰ Regarding other treatment options for AIHA, splenectomy is not recommended as an early-line treatment because of their risks for bacterial infection and thrombosis and are explicitly contraindicated for patients with CAD.²⁸ The complement inhibitor sutimlimab³¹ is an approved treatment for CAD, although it acts on the pathogenic mechanism of complement-mediated hemolysis rather than inhibiting autoantibody production. In a post hoc analysis of a recent phase 3 study, the spleen tyrosine kinase inhibitor fostamatinib demonstrated durable Hgb responses in patients with wAIHA from North America, Western Europe, and Australia.³²

Regarding study limitations, the overall study design had a relatively small sample size and enrolled a heterogeneous patient population with multiple AIHA types. Although this study population reflected the different types of AIHA present in the overall population, the study was not designed to evaluate efficacy among subgroups. Analysis of the subgroup of patients with wAIHA was performed post hoc, which limited the comparisons that could be made regarding efficacy among AIHA subgroups. Furthermore, this study did not include a comparator arm, and the treatment period with parsaclisib was relatively short for some patients, although other patients were treated for >2 years.

In summary, parsaclisib normalized Hgb levels and was well tolerated in patients with AIHA. Partial and complete Hgb responses with parsaclisib were observed as early as week 1 and sustained throughout the initial treatment period and extension period. Overall, these data suggest that parsaclisib may be an effective strategy for managing AIHA, particularly those with wAIHA for whom there is currently no approved treatment.¹¹

## ACKNOWLEDGMENTS

Medical writing support was provided by Emily Mesev, PhD, from The Curry Rockefeller Group, LLC, a Citrus Health Group, Inc., company (Chicago, IL), and was funded by Incyte Corporation (Wilmington, DE).

## FUNDING INFORMATION

This study was funded by Incyte Corporation (Wilmington, DE). Study sponsor was involved in the design of the study, data collection, analysis and interpretation of data, and the development and decision to submit this manuscript for publication.

## CONFLICT OF INTEREST STATEMENT

W.B. has served as a consultant for Agios, Alexion, Apellis, Biocryst, Bioverativ, Incyte Corporation, Momenta, and Novartis and has

received lecture fees and/or congress support from Alexion, Incyte Corporation, Novartis, and Sanofi. F.P. and W.T.H. have no disclosures to report. A.P. has served as a consultant for Alexion, Incyte Corporation, Novartis, Sanofi, and Sobi and has received lecture fees and/or congress support from Alexion, Incyte Corporation, Novartis, Sanofi, and Sobi. I.M. has served as a consultant for Alexion, Apellis, Bioverativ/Sanofi, Momenta/Janssen, and Novartis. L.T. has served as a consultant for Alexion, Novartis, and Sobi. M.T.D. has served as an advisory board member for Pharmacosmos and is a member of the American Society of Hematology practice guidelines panel for anticoagulation in COVID-19. L.L., E.R., K.S., and S.W. are employees and shareholders of Incyte Corporation. U.J. has served as a consultant for Incyte Corporation, Janssen, Novartis, Roche, and Sandoz; has served as an advisor to AbbVie, Annexon, BMS/Celgene, Gilead, Incyte Corporation, Janssen, Miltenyi, Novartis, Roche, Sandoz, and Sanofi; has received lecture fees from AbbVie, BMS/Celgene, Gilead, Incyte Corporation, Janssen, Novartis, and Roche; and has received institutional research support from BMS/Celgene, Gilead, Novartis, and Roche.

## DATA AVAILABILITY STATEMENT

Incyte Corporation (Wilmington, DE, USA) is committed to data sharing that advances science and medicine while protecting patient privacy. Qualified external scientific researchers may request anonymized datasets owned by Incyte for the purpose of conducting legitimate scientific research. Researchers may request anonymized datasets from any interventional study (except phase 1 studies) for which the product and indication have been approved on or after 1 January 2020 in at least one major market (e.g., US, EU, JPN). Data will be available for request after the primary publication or 2 years after the study has ended. Information on Incyte's clinical trial data sharing policy and instructions for submitting clinical trial data requests are available at: https://www.incyte.com/Portals/0/Assets/Compliance%20and%20Transparency/clinical-trial-data-sharing.pdf?ver=2020-05-21-132838-960.

## ORCID

Wilma Barcellini https://orcid.org/0000-0003-1428-9944

Maria T. DeSancho https://orcid.org/0000-0001-9239-5131

Ulrich Jäger https://orcid.org/0000-0001-9826-1062

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## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Barcellini W, Pane F, Patriarca A, et al. Parsaclisib for the treatment of primary autoimmune hemolytic anemia: Results from a phase 2, open-label study. *Am J Hematol*. 2024;99(12):2313-2320. doi:10.1002/ajh.27493