PEGASUS key secondary endpoints

Noninferiority is a type of analysis that tests whether a new treatment is not worse than a comparator treatment by more than a specified margin.1

Transfusion avoidance (%)
and change from baseline in ARC met noninferiority2
Transfusion avoidance (%)2
EMPAVELI
(n=41)
35 (85%)
eculizumab
(n=39)
6 (15%)
Difference of mean values between EMPAVELI and eculizumab was 63%*.
(95% CI, 48% to 77%)
ARC (X 109 cells/L) change from baseline at Week 162
EMPAVELI
(n=41)
-136 (6.5)
eculizumab
(n=39)
28 (11.9)
Difference of mean values between EMPAVELI and eculizumab was -164.
(95% CI, -189.9 to -137.3)
*Difference in percentages and 95% CI were based on the stratified Miettinen-Nurminen method.2
Additional
prespecified
key secondary
endpoints
included LDH and
FACIT-Fatigue3
Additional prespecified
key secondary endpoints included LDH and FACIT-Fatigue3
Noninferiority was not met for the change from baseline in LDH level at Week 16. The data are descriptive in nature and collected for observation only. No formal comparisons can be drawn between the two arms and no conclusions can be made on the effect of EMPAVELI on this measure.3
The adjusted mean change in LDH from baseline was3:
  • -15 U/L in patients treated with EMPAVELI
  • -10 U/L in patients treated with eculizumab
Due to hierarchical testing, the change from baseline in FACIT-Fatigue score was not tested for noninferiority. The data are descriptive in nature and collected for observation only. No formal comparisons can be drawn between the two arms and no conclusions can be made on the effect of EMPAVELI on this measure. Patient-reported fatigue may be an under or over estimation, because patients were not blinded to treatment assignment.3
The change in FACIT-Fatigue score from baseline was3:
  • +9.2 points in patients treated with EMPAVELI
  • -2.7 points in patients treated with eculizumab
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Secondary endpoints and additional analyses
Normalization of lab values
Hb and ARC normalization were prespecified secondary endpoints in the PEGASUS study4
The data are descriptive in nature and collected for observation only. No formal comparisons can be drawn between the two arms and no conclusions can be made on the effect of EMPAVELI on these measures.
In prespecified analyses of the PEGASUS study at Week 16, Hb normalization was achieved in5:
  • 34% of patients taking EMPAVELI
  • 0% of patients taking eculizumab
    • In PEGASUS, mean Hb levels at baseline were 8.7 g/dL in both treatment arms2†
ARC normalization was achieved in5:
  • 78% of patients taking EMPAVELI
  • 3% of patients taking eculizumab
LDH normalization was a prespecified analysis in the PEGASUS study4
The data are descriptive in nature and collected for observation only. No formal comparisons can be drawn between the two arms and no conclusions can be made on the effect of EMPAVELI on this measure.
In this prespecified analysis of the PEGASUS study at Week 16, LDH normalization was achieved in5:
  • 71% of patients taking EMPAVELI§
  • 15% of patients taking eculizumab§
Normalization is defined as achieving the normal range for a given test based on the results that are seen in 95% of the healthy population. The normal range for a test may differ based on the group of people (eg, men and women) and value being measured.5
Hb normalization is defined as an Hb level at or above the lower limit of the gender-specific normal range, which is 12-16 g/dL for females and 13.6-18 g/dL for males.3
ARC normalization is defined as the reticulocyte level below the upper limit of normal range, which is 30-120 X 109 cells/L.3
§LDH normalization is defined as a lactate dehydrogenase level at or below the upper limit of normal range, which is 113-226 U/L.3
EMPAVELI was also studied in treatment-naive patients1
The results of PEGASUS are supported by 2 uncontrolled studies in patients with PNH who were not receiving a complement inhibitor: Study APL2‑202 (NCT03593200) and Study APL2-CP-PNH-204 (NCT02588833) (N=24). In both studies, patients were taking EMPAVELI for approximately 1 year.
Select inclusion criteria:
  • PNH clone size of ≥10%
  • LDH level ≥2x ULN
  • ≥1 transfusion in prior year
Increases in hemoglobin were observed in both studies
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Learn about the safety profile of EMPAVELI
SEE THE DATA
ARC=absolute reticulocyte count; CI=confidence interval; LDH=lactate dehydrogenase; FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy; Hb=hemoglobin; PNH=paroxysmal nocturnal hemoglobinuria; SE=standard error; ULN=upper limit of normal.

References: 1. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed February 8, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/non-inferiority-trial 2. EMPAVELI [prescribing information]. Waltham, MA: Apellis Pharmaceuticals, Inc.; 2021. 3. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384:1028-1037 4. Data on file. Apellis Pharmaceuticals, Inc., Waltham, MA. 5. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(suppl):1-16. 6. NCI Dictionary of Cancer Terms. National Cancer Institute. Accessed February 8, 2021. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/normal

Indication and Important Safety Information

INDICATION

EMPAVELI™ (pegcetacoplan) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

IMPORTANT SAFETY INFORMATION

EMPAVELI™ (pegcetacoplan) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

WARNING: SERIOUS INFECTIONS CAUSED BY ENCAPSULATED BACTERIA Meningococcal infections may occur in patients treated with EMPAVELI and may become rapidly life-threatening or fatal if not recognized and treated early. Use of EMPAVELI may predispose individuals to serious infections, especially those caused by encapsulated bacteria, such as Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B.

  • Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria.
  • Vaccinate patients at least 2 weeks prior to administering the first dose of EMPAVELI unless the risks of delaying therapy with EMPAVELI outweigh the risk of developing a serious infection.
  • Vaccination reduces, but does not eliminate, the risk of serious infections. Monitor patients for early signs of serious infections and evaluate immediately if infection is suspected.

EMPAVELI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the EMPAVELI REMS, prescribers must enroll in the program.

CONTRAINDICATIONS

  • Hypersensitivity to pegcetacoplan or to any of the excipients
  • Not currently vaccinated against certain encapsulated bacteria, unless the risks of delaying EMPAVELI treatment outweigh the risks of developing a bacterial infection with an encapsulated organism
  • Unresolved serious infection caused by encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae

WARNINGS AND PRECAUTIONS

Serious Infections Caused by Encapsulated Bacteria

The use of EMPAVELI may predispose individuals to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B (Hib). To reduce the risk of infection, all patients must be vaccinated against these bacteria according to the most current ACIP recommendations for patients with altered immunocompetence associated with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with EMPAVELI.

For patients without known history of vaccination, administer required vaccines at least 2 weeks prior to receiving the first dose of EMPAVELI. If immediate therapy with EMPAVELI is indicated, administer required vaccine as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis.

Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider discontinuation of EMPAVELI in patients who are undergoing treatment for serious infections.

EMPAVELI REMS

Because of the risk of serious infections, EMPAVELI is available only through a restricted program under a REMS. Under the EMPAVELI REMS, prescribers must enroll in the program and must counsel patients about the risk of serious infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated against encapsulated bacteria. Enrollment and additional information are available by telephone: 1-888-343-7073 or at www.empavelirems.com.

Infusion-Related Reactions

Systemic hypersensitivity reactions (e.g., facial swelling, rash, urticaria) have occurred in patients treated with EMPAVELI. One patient (less than 1% in clinical studies) experienced a serious allergic reaction which resolved after treatment with antihistamines. If a severe hypersensitivity reaction (including anaphylaxis) occurs, discontinue EMPAVELI infusion immediately, institute appropriate treatment, per standard of care, and monitor until signs and symptoms are resolved.

Monitoring PNH Manifestations after Discontinuation of EMPAVELI

After discontinuing treatment with EMPAVELI, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH levels along with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, dyspnea, major adverse vascular events (including thrombosis), dysphagia, or erectile dysfunction. Monitor any patient who discontinues EMPAVELI for at least 8 weeks to detect hemolysis and other reactions. If hemolysis, including elevated LDH, occurs after discontinuation of EMPAVELI, consider restarting treatment with EMPAVELI.

Interference with Laboratory Tests

There may be interference between silica reagents in coagulation panels and EMPAVELI that results in artificially prolonged activated partial thromboplastin time (aPTT); therefore, avoid the use of silica reagents in coagulation panels.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥10% of patients) with EMPAVELI vs. eculizumab were injection-site reactions (39% v. 5%), infections (29% v. 26%), diarrhea (22% v. 3%), abdominal pain (20% v. 10%), respiratory tract infection (15% v. 13%), viral infection (12% v. 8%), and fatigue (12% v. 23%).

USE IN SPECIFIC POPULATIONS

Females of Reproductive Potential

EMPAVELI may cause embryo-fetal harm when administered to pregnant women. Pregnancy testing is recommended for females of reproductive potential prior to treatment with EMPAVELI. Advise female patients of reproductive potential to use effective contraception during treatment with EMPAVELI and for 40 days after the last dose.

Please see full Prescribing Information, including Boxed WARNING regarding serious infections caused by encapsulated bacteria, and Medication Guide.