Totality of Evidence

STIMUFEND® (pegfilgrastim-fpgk): Established biosimilarity to Neulasta® (pegfilgrastim)
 

Proven structural, functional, and clinical similarity1,2
 

STIMUFEND is FDA-approved based on the totality of evidence supporting its biosimilarity to Neulasta.
 

Confirmed bioequivalence to Neulasta1
PK parameters confirmed bioequivalence from post-dose
Graph showing confirmed bioequivalence of STIMUFEND to Neulasta
Chart showing PK paramater comparison between Stimufend and Neulasta

Arithmetic mean (SD) pegfilgrastim serum concentration time profiles after a single dose of pegfilgrastim in healthy subjects.

 

PD parameters confirmed bioequivalence over 16 days from post-dose
Graph showing confirmed bioequivalence of STIMUFEND to Neulasta over 16 days from post-dose
Chart showing PD paramater comparison between Stimufend and Neulasta

Arithmetic mean observed ANC-time profiles after a single dose of pegfilgrastim in healthy subjects.

  • STIMUFEND was assessed in healthy subjects in a double-blind, randomized, 2-sequence, 2-period, 2-treatment, crossover Phase I study (NCT03251248)1
  • 240 subjects received both treatments and were included in the PK/PD analysis sets
  • Primary PK endpoints were AUC from time zero to the last sampling time, AUC from time zero extrapolated to infinity, and Cmax
  • Primary PD endpoints were Emax and AUE from time zero (pre-dose) to time to last quantifiable concentration for ANC
  • For all primary PK/PD parameters, the 90% repeated confidence intervals of the geometric means ratio of STIMUFEND to Neulasta were entirely within the equivalence range (80%-125%), confirming bioequivalence1

 

Study population1
Inclusion criteriaExclusion criteria
  • Healthy males and nonpregnant females
  • Aged ≥18 to ≤55 years
  • Body mass index ≥18.0 to ≤29.9 kg/m2
    In good health*
  • Provide signed informed consent
  • Signs or symptoms of COPD
  • Smoking >10 cigarettes/day
  • Prior exposure to any CSF or growth factor 3 months (84 days) before randomization
  • Prior exposure to therapeutic mAbs targeting the bone marrow or blood cells
  • Exposure to mAbs not affecting bone marrow or blood cells was allowed before screening†
  • Blood (≥500 mL) or plasma donation within 3 months (84 days)
  • Stem cell or bone marrow donation within 12 months (336 days) before screening

Patients who were positive for anti-PEG antibodies at screening could be included in the study.1

*Based on comprehensive medical history, physical examination, vital signs, and clinical laboratory tests.
†If mAbs discontinued >3 months (84 days) or 5 half-lives (whichever was longer).

  • STIMUFEND was assessed in healthy subjects in a double-blind, randomized, 2-sequence, 2-period, 2-treatment, crossover Phase I study (NCT03251248)1
  • 240 subjects received both treatments and were included in the PK/PD analysis sets
  • Primary PK endpoints were AUC from time zero to the last sampling time, AUC from time zero extrapolated to infinity, and Cmax
  • Primary PD endpoints were Emax and AUE from time zero (pre-dose) to time to last quantifiable concentration for ANC
  • For all primary PK/PD parameters, the 90% repeated confidence intervals of the geometric means ratio of STIMUFEND to Neulasta were entirely within the equivalence range (80%-125%), confirming bioequivalence1
Study population1
Inclusion criteria
  • Healthy males and nonpregnant females
  • Aged ≥18 to ≤55 years
  • Body mass index ≥18.0 to ≤29.9 kg/m2
  • In good health*
  • Provide signed informed consent

Exclusion criteria

  • Signs or symptoms of COPD
  • Smoking >10 cigarettes/day
  • Prior exposure to any CSF or growth factor 3 months (84 days) before randomization
  • Prior exposure to therapeutic mAbs targeting the bone marrow or blood cells
  • Exposure to mAbs not affecting bone marrow or blood cells was allowed before screening†
  • Blood (≥500 mL) or plasma donation within 3 months (84 days)
  • Stem cell or bone marrow donation within 12 months (336 days) before screening

Patients who were positive for anti-PEG antibodies at screening could be included in the study.1

*Based on comprehensive medical history, physical examination, vital signs, and clinical laboratory tests.
†If mAbs discontinued >3 months (84 days) or 5 half-lives (whichever was longer).

 
Similar immunogenicity to Neulasta2

Immunogenicity with ADA rates at any time after the first dose of 2 single doses2

Chart showing similar immunogenicity of STIMUFEND and Neulasta
Chart showing comparison of ADA rates between Stimufend and Neulasta

 

‡Upper limit of the exact one-sided adjusted 95% CI: 6.25. Confidence interval (CI) determined using Clopper-Pearson method.

  • STIMUFEND demonstrated non-inferiority to Neulasta with confirmed immunogenicity rates of 8.9% and 9.5% respectively
  • The immunogenicity and safety profiles of STIMUFEND were demonstrated in healthy subjects in a double-blind, randomized, parallel-group, Phase I study (NCT03251339)2
  • A total of 336 subjects were randomized and treated
  • Primary endpoints were confirmed treatment-induced ADA-positive status and confirmed NAb status to pegfilgrastim from predose until the end of study
  • STIMUFEND demonstrated non-inferiority with Neulasta with confirmed immunogenicity rates of 8.9% and 9.5%, respectively2
  • No filgrastim-specific neutralizing antibodies were detected in either treatment group2
Study population2
Inclusion criteriaExclusion criteria
  • Healthy males and nonpregnant females
  • Aged ≥18 to ≤55 years
  • Body mass index ≥18.0 to ≤29.9 kg/m2
    In good health§
  • No known hypersensitivity to any component of either pegfilgrastim product
  • All subjects were required to comply with the contraception requirements specified in the clinical study protocol
  • Provide signed and dated written informed consent
  • Signs or symptoms of COPD
  • Smoking >10 cigarettes/day
  • Splenomegaly (spleen size >13 cm in the craniocaudal dimension by US)
  • Prior exposure to any CSF or growth factor 3 months (84 days) before randomization
  • Prior exposure to therapeutic mAbs targeting the bone marrow or blood cells
  • Exposure to mAbs not affecting bone marrow or blood cells allowed before screening
  • Blood (≥500 mL) or plasma donation within 3 months (84 days)
  • Stem cell or bone marrow donation within 12 months (336 days) before screening

 

§Based on comprehensive medical history, physical examination, vital signs, and clinical laboratory tests.

If mAbs discontinued >3 months (84 days) or 5 half-lives (whichever was longer).

  • STIMUFEND demonstrated non-inferiority to Neulasta with confirmed immunogenicity rates of 8.9% and 9.5% respectively
  • The immunogenicity and safety profiles of STIMUFEND were demonstrated in healthy subjects in a double-blind, randomized, parallel-group, Phase I study (NCT03251339)2
  • A total of 336 subjects were randomized and treated
  • Primary endpoints were confirmed treatment-induced ADA-positive status and confirmed NAb status to pegfilgrastim from predose until the end of study
  • STIMUFEND demonstrated non-inferiority with Neulasta with confirmed immunogenicity rates of 8.9% and 9.5%, respectively2
  • No filgrastim-specific neutralizing antibodies were detected in either treatment group2
Study population2

Inclusion criteria

  • Healthy males and nonpregnant females
  • Aged ≥18 to ≤55 years
  • Body mass index ≥18.0 to ≤29.9 kg/m2
  • In good health*
  • No known hypersensitivity to any component of either pegfilgrastim product
  • All subjects were required to comply with the contraception requirements specified in the clinical study protocol
  • Provide signed and dated written informed consent

Exclusion criteria

  • Signs or symptoms of COPD
  • Smoking >10 cigarettes/day
  • Splenomegaly (spleen size >13 cm in the craniocaudal dimension by US)
  • Prior exposure to any CSF or growth factor 3 months (84 days) before randomization
  • Prior exposure to therapeutic mAbs targeting the bone marrow or blood cells
  • Exposure to mAbs not affecting bone marrow or blood cells allowed before screening
  • Blood (≥500 mL) or plasma donation within 3 months (84 days)
  • Stem cell or bone marrow donation within 12 months (336 days) before screening

Patients who were positive for anti-PEG antibodies at screening could be included in the study.1

 

§Based on comprehensive medical history, physical examination, vital signs, and clinical laboratory tests.
If mAbs discontinued >3 months (84 days) or 5 half-lives (whichever was longer).

 
Highly similar safety and tolerability profile
 
Lickliter et al: Phase I PK/PD trial
Most common TEAEs (>5% of subjects)
  • Adverse events with STIMUFEND were consistent with the administration of Neulasta1
  • TEAEs were generally mild to moderate in severity and were self-limiting1
  • Clinically significant splenomegaly# (Grade 1 or 2): STIMUFEND (n=3); all resolved spontaneously with no further study drug administered1

#Rare cases of splenic rupture have been reported following administration of filgrastim or pegfilgrastim; therefore, the spleen was monitored throughout the study.

Wynne et al: Phase I immunogenicity trial
Most common TEAEs (>5% of subjects)
  • TEAEs were generally mild to moderate in severity, self-limiting, and resolved without sequelae2
  • Both instances of splenomegaly (Grade 1 and 2, respectively) resolved spontaneously, and the patients completed the study2

||All events considered related to study drug.

ADA, antidrug antibody; ANC, absolute neutrophil count; AUC, area under the curve; AUE, area under the effect-time curve; Cmax, maximum concentration; COPD, chronic obstructive pulmonary disease; CSF, colony-stimulating factor; Emax, maximum observed effect; FDA, US Food and Drug Administration; mAb, monoclonal antibody; NAb, neutralizing antibody; PD, pharmacodynamic; PEG, polyethylene glycol; PK pharmacokinetic; SD, standard deviation; TEAE, treatment-emergent adverse event; URTI, upper respiratory tract infection.

Important Safety Information

Contraindication

  • Stimufend (pegfilgrastim-fpgk) is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products
  • Reactions have included anaphylaxis

Splenic Rupture

  • Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim products
  • Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain

Acute Respiratory Distress Syndrome (ARDS)

  • ARDS can occur in patients receiving pegfilgrastim products
  • Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Stimufend
  • Discontinue Stimufend in patients with ARDS

Serious Allergic Reactions

  • Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim products
  • The majority of reported events occurred upon initial exposure and can recur within days after the discontinuation of initial anti-allergic treatment
  • Permanently discontinue Stimufend in patients with serious allergic reactions

Use in Patients with Sickle Cell Disorders

  • In patients with sickle cell trait or disease, severe and sometimes fatal sickle cell crises can occur in patients receiving pegfilgrastim products
  • Discontinue Stimufend if sickle cell crisis occurs

Glomerulonephritis

  • Has occurred in patients receiving pegfilgrastim products
  • Diagnoses based on azotemia, hematuria, proteinuria, and renal biopsy
  • Generally, events resolved after dose-reduction or discontinuation of pegfilgrastim products
  • If suspected, evaluate for cause and if cause is likely, consider dose-reduction or interruption of Stimufend

Leukocytosis

  • Increased white blood cell counts of 100 x 109/L have been observed
  • Monitoring of complete blood count (CBC) during Stimufend therapy is recommended

Thrombocytopenia

  • Thrombocytopenia has been reported in patients receiving pegfilgrastim products. Monitor platelet counts

Capillary Leak Syndrome (CLS)

  • CLS has been reported after G-CSF administration, including pegfilgrastim products
  • Characterized by hypotension, hypoalbuminemia, edema and hemoconcentration
  • Episodes vary in frequency, severity and may be life-threatening if treatment is delayed
  • Patients with symptoms should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care

Potential for Tumor Growth Stimulatory Effects on Malignant Cells

  • G-CSF receptor has been found on tumor cell lines
  • The possibility that pegfilgrastim products act as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim products are not approved, cannot be excluded.

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer

  • MDS and AML have been associated with the use of pegfilgrastim products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

Aortitis

  • Aortitis has been reported in patients receiving pegfilgrastim products. It may occur as early as the first week after start of therapy
  • Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count)
  • Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue Stimufend if aortitis is suspected

Nuclear Imaging

  • Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results

Most common adverse reactions

  • Bone pain
  • Pain in extremity

Indications and Usage
Stimufend is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.
Stimufend is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome).

Limitations of Use
Stimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.
Please see Stimufend Full Prescribing Information.
Stimufend Injection: 6 mg/0.6 mL in a single-dose prefilled syringe for manual use only.

 

 

References:

  1. Lickliter J, Kanceva R, Vincent E, et al. Pharmacokinetics and pharmacodynamics of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta in healthy subjects: a randomized, double-blind trial. Clin Ther. 2020;42(8):1508-1518.e1.
  2. Wynne C, Schwabe C, Vincent E, et al. Immunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta® in healthy subjects: a randomized, double-blind trial. Pharmacol Res Perspect. 2020;8(2):e00578. 
Indications

Stimufend is indicated to:

  • Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia
  • Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome)

Limitations of Use


Stimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.