The PIPER Phase 4 Study: Pathogen Inactivated Platelets

Entering Routine Practice

AABB 2021 VIRTUAL ANNUAL MEETING

PLENARY PAPER PL-4 AM21-33

MONDAY, OCTOBER 18, 2021 - 6:00 PM

Edward L. Snyder, MD, FACP

Yale University School of Medicine

(For the PIPER Study Investigator Group)

v. 1.9.1

Disclosures

• Study investigator Institutions received research support from CerusCorporation for trial conduct - no personal honoraria or equity were received

• Cerus investigators were employees of, and hold equity, in Cerus

Study Hypothesis and Design

• Phase 4 post marketing study of pathogen reduced platelets in routine practice

• Does transfusion of pathogen reduced (amotosalen-UVA) platelet components (PRPC) to Hem-Onc patients potentiate pulmonary injury including ARDS?

• Open label sequential cohort design with four matched primary therapy strata• Thrombocytopenic patients were enrolled into either CPC or PRPC study arm• Conventional PC cohort enrolled first at each site followed by PRPC cohort• 15 clinical sites participated • Non-study physicians ordered all platelet transfusions• Patients were enrolled in only one arm of the study• Trial included both pediatric and adult patients• Apheresis PRPC and CPC were suspended in plasma or plasma-PAS with ≥ 3.0 x 1011 platelets• FDA required platelet dose levels were met - PC doses were not measured at time of issue • Consent was oral or written as per institutional IRB

Study Parameters

• Population: Platelet transfusion dependent hematology-oncology patients

• Intervention: Amotosalen-UVA pathogen reduced platelet components (PRPC)

• Comparison: Conventional platelet components (CPC)

• Outcome: Treatment Emergent - Assisted Mechanical Ventilation (TE-AMV)

• Timing: Up to 21 days of platelet transfusion support with 7 days of safety surveillance after last study transfusion

Study Outcome MeasuresPrimary Outcome:

• Incidence of TE-AMV(intubation or tight mask w/PEEP ≥5 cm H2O) for PRPC compared to CPC

Secondary Outcomes:

• Incidence of TE-ARDS (Berlin Criteria) adjudicated by a blinded pulmonary expert panel

• Days to initiation of TE-AMV

• Clinically Significant - Pulmonary Adverse Events (CS-PAE) within 7 days of each PC infused

• Adverse events within 24 hours of each transfusion

• Serious adverse events within 7 days of each transfusion

• Acute transfusion reactions within 24 hours of each transfusion

• Use of PC and RBC for clinical care

• Mortality within 7 days of last transfusion

-Statistical Methods-

Primary endpoint of TE-AMV :

• Non-inferiority of PRPC cohort compared to CPC, w/2.3% margin for TE-AMV (mITT and PP)• H0 (null hypothesis): p PRPC - p CPC ≥ 0.023 vs. H1 (alternative hypothesis): p PRPC - p CPC < 0.023

• Multivariate sensitivity analyses for key outcomes w/ propensity score matching for key variables

Secondary endpoints:

• Stratified Cochran Mantel Haenszel (CMH) test (General Association) controlling for the four strata of primary disease therapy

• Continuous variables: p-values for treatment difference by ANOVA model including treatment and primary disease therapy as fixed effects.

• Categorical variables: p-values based on a stratified CMH test, unless otherwise stated, statistical significance was set at the two-sided 0.05 alpha level

Control (Conventional PCs, n=1223)Study Completion, n (%)

• Completed: 1194 (97.6)• Not Completed: 29 (2.4)

• Death: 29 (2.4)• Withdrawal of Consent: 0• Investigator Discretion: 0• Lost in follow-up: 0• Study Termination: 0• Other: 0

• Total: 1223 (100)

Test (Pathogen-Reduced PCs, n=1068)Study Completion, n (%)

• Completed: 1033 (96.7)• Not Completed: 35 (3.3)

• Death: 27 (2.5)• Withdrawal of Consent: 2 (0.2)• Investigator Discretion: 1 (0.1)• Lost in follow-up: 1 (0.1)• Study Termination: 0• Other: 4 (0.4)

• Total: 1068 (100)

Patient Disposition and Total PC TransfusedModified Intention-to-Treat Analysis

(n=2291)

Per-Protocol Analysis (n=2038)

5,277 PRPC 5,491 CPC

Patient Demographics and Primary Therapy

Parameter Total P Value

Cohort PRPC CPC -

Patients (n) 1068 1223 -

Mean Age ± SD (Years) 57.0±16.4 50.6±21.7 <0.001*

Male (%) 59.7 57.2 0.289

Any HCT 602(56.4) 603(49.1)

0.058Autologous 415(38.9) 371(30.2)

Allogeneic 187(17.5) 232(18.9)

Chemotherapy No HCT 466(43.6) 624(50.9)

• PRIMARY THERAPY STRATA WERE WITHIN 10% FOR PRPC AND CPC COHORTS

PC and RBC Transfusion Exposure (mITT and PP)

Modified Intention-to-Treat PatientsParameter Total P- Value

PRPC CPC

Patients (n) 1068 1223

PC TransfusedMean 4.9 ±6.1 4.5 ±5.1 0.046*

Median 3 2Days PC Support2

Mean 6.4 ±6.3 6.7 ±6.8 0.447Median 4 4

RBC Components TransfusedPatients: n

(%)639 (60) 716 (59)

Mean 3.0 ±2.7 3.3 ±3.1 0.146Median 2 2

PC use was slightly more for PRPC by mITT, but with large range consistent with minimal impact over days of PC support.

Distribution of PC Doses for PP

Cumulative Incidence of TE-AMV (mITT)

PRPC cohort had lower incidence of TE-AMVCu

mu

lati

ve In

cid

en

ce (

%)

Days from Platelet Initiation

CPC

PRPC

-Incidence of TE-AMV and ARDS (mITT)-Modified Intention-to-Treat Population

Parameter PRPC

n=1068CPC

n=1223PRPC vs. CPC

Treatment Emergent - Assisted Mechanical Ventilation and Platelet Component Exposure

1. Patients with TE-AMV: n (%) 31 (2.9) 56 (4.6) -1.7% (-3.3%, -0.1%)

2. Median days to TE-AMV >30 >30 0.076

3. Patients with TE-AMV-Pulmonary Dysfunction by Pulmonary Expert Panel: n (%) 18 (1.7) 38 (3.1) -1.5% (-2.7%, -0.2%)

4. Mean Days to TE-AMV after PC for 56 Patients with TE-AMV-PD by PEP 10.7 ± 1.2 6.1 ± 1.2 1.8 (1.0, 3.0)*

5.Incidence of Treatment Emergent ARDS for TE-AMV patients by PEP: n (%) 11 (1.0) 22 (1.8) 0.151

6. PC Use in Patients with TE-AMV for Pulmonary Injury by PEP (n ±SD) 22.6 ±22.1 13.6 ±9.2 0.493

7. Days of PC Support in Patients with TE-AMV for Pulmonary Injury by PEP (n ±SD) 14.8 ±7.0 14.1 ±7.2 0.632

• PRPC were non-inferior to CPC for the incidence of TE-AMV• Mean days to TE-AMV for patients with pulmonary dysfunction were longer for the PRPC cohort

Relative Risk of TE-AMV by Baseline Covariates (mITT)

• PRPC exhibited less risk for TE-AMV for: age <65, male, non-white, chemotherapy, prior pulmonary disease, and prior cardiac disease

Clinically Significant - Pulmonary Adverse Events

Parameter PRPC

(n=1068)

CPC

(n=1223)P-Value

Patients with Clinically Significant - Pulmonary Adverse Events (CS-PAE): n (%) 151 (14.1) 180 (14.7) 0.810

Patients with Serious CS-PAE: n (%) 67 (6.3) 85 (6.9) 0.705

PC Exposure in Patients with CS-PAE (n ±SD) 9.8 ±10.0 9.9 ±7.9 0.700

Days of PC Support in Patients with CS-PAE (n ±SD) 11.0 ±7.3 12.8 ±7.5 0.029*

• No difference in the incidence of CS-PAE

Relative Risk of CS-PAE by Baseline Covariates

• No increased risk of CS-PAE for exposure to PRPC compared to CPC• Reduced relative risk of PRPC for non-white patients

Adverse Events Modified Intention-to-Treat Population

Parameter – Patients with:PRPC

(n=1068)

CPC

(n=1223)PRPC vs. CPC

TOTAL ADVERSE EVENTS: n (%) 629 (58.9) 707 (57.6) 0.909

Serious Adverse Events: n (%) 277 (25.9) 284 (23.2) 0.219

Adverse Events Resulting in Death: n (%) 27 (2.5) 29 (2.4) 0.469

Any Adverse Events Related to Study PC: n (%) 90 (8.4) 119 (9.7) 0.277

Possible Transfusion-Transmitted Bacterial Infection: n (%) 0 4 (0.3) 0.072

Study PC Related Transfusion Reactions: n (%) 89 (8.3) 119 (9.7) 0.246

Study PC Related Serious Transfusion Reactions: n (%) 10 (0.9) 19 (1.6) 0.240

Study PC Allergic Transfusion Reactions: n (%) 32 (3.0) 68 (5.6) 0.006*

Study PC Febrile non-Hemolytic Reactions: n (%) 45 (4.2) 31 (2.5) 0.050*

Study PC Transfusion-Associated Circulatory Overload: n (%) 11 (1.0) 15 (1.2) 0.611

Hemorrhagic Adverse Events: n (%) 111 (10.4) 117 (9.6) 0.565

• No difference in AE, SAE, Transfusion Reactions, Hemorrhagic AE, and Mortality• Decreased allergic transfusion reactions with PRPC

Summary and Conclusions• PRPC were non-inferior to CPC for TE-AMV

• Cumulative incidence of TE-AMV was statistically less for PRPC

• Incidence of ARDS was low for both cohorts and less with PRPC

• No increased incidence of CS-PAE with PRPC

• No increase in RBC utilization with PRPC

• No clinically significant increase in PC utilization with PRPC

• No significant difference in safety

• Decreased incidence of allergic transfusion reactions with PRPC

Conclusion: PRPC demonstrated safety in routine clinical use with the benefit of reduced risk of Transfusion Transmitted Infection

PIPER Investigator Group• Edward Snyder – Yale University

• Allison Wheeler – Vanderbilt University

• Majed Refaai – Rochester University

• Claudia Cohn – University of Minnesota

• Jessica Poisson – Duke University

• Magali Fontaine – University of Maryland

• Ajay Nooka – Emory University

• Lynne Uhl – Beth Israel Deaconess Hospital

• Philip Spinella – St. Louis Children’s Hospital

• Mary Sehl – University of California, Los Angeles

• Joann Becker – Roswell Park Cancer Center

• Darla Liles – East Carolina University

• Thomas Coyle – Tri Health

• Maly Fenelus - Memorial Sloan-Kettering

• Michael Jang – Stanford University

Cerus Corporation:• Laurence Corash• Richard Benjamin• Jeanne Varrone• Jin-Sying Lin• Helen Peng• Kathy Liu• Stan Bentow