About Releuko

Releuko® from Amneal Biosciences

Releuko (filgrastim-ayow) injection is biosimilar to Neupogen® (filgrastim) and made entirely in the United States. 1

Filgrastim is a recombinant granulocyte colony stimulating factor (rG-CSF). It promotes neutrophil production in appropriate patients.

Product Info & Dosing
Releuko® from Amneal Biosciences

Indications

Releuko is a leukocyte growth factor indicated to6:

  • Decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anti- cancer drugs associated with a significant incidence of severe neutropenia with fever.
  • Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).
  • Reduce the duration of neutropenia and neutropenia-related clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation (BMT).
  • Reduce the incidence and duration of sequelae of severe neutropenia‚ (e.g., fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia.

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

Releuko® Robust Evidence1-5

Analytical, preclinical and clinical studies have demonstrated Releuko® is similar to Neupogen®1,2,4-7

Releuko® clinical comparability includes data from 112 subjects evaluated in 2 PK/PD studies and 134 subjects in 1 immunogenicity/safety study:

      1. Strong comparability PK package in HV clinical trials The PK similarity of both products was established.

      • Statistical analysis of the PK parameters demonstrated similarity between Releuko® and Neupogen®
      • Releuko® was generally well tolerated by healthy subjects
      • The safety and immunogenicity profile of Releuko® and Neupogen®was determined to be similar following multiple doses

      2. Strong Comparability PD package in HV clinical trials As a surrogate for clinical efficacy, PD similarity of both products was established:

      • Pharmacodynamic similarity of Releuko® versus Neupogen® was established for ANC (absolute neutrophil count) in two HV studies where bioequivalence was established1
      • Pharmacodynamic similarity was also established for CD341
References:
1. Releuko® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
2. Releuko® Product Quality Approval: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
3. Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.
4. Food and Drug Administration, FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry, 2015.
5. Food and Drug Administration, FDA. Draft Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, 2019.
6. Neupogen® Summary Basis of Approval – Scientific Discussion https://www.accessdata.fda.gov/drugsatfda_docs/bla/pre96/103353Orig1s000.pdf

Proven Similarity with Neupogen®1-5

Releuko® is a biosimilar filgrastim which has been developed with Neupogen® as the Reference Product (RP).

Multiple state-of-the-art analytical methods were applied to evaluate all quality attributes required of the biosimilar and confirmed analytical similarity between Releuko® and Neupogen®:

Primary Structure

The same amino acid sequence is confirmed in Releuko® and Neupogen®. 
In the figure below, the same set of twelve (12) primary peptides G1 to G12 are seen from the digestion of Releuko® or Neupogen® by Glu-C for peptide mapping, confirming that the primary structure of Releuko® and Neupogen® is the same.

Molecular Conformation

Similarity between Releuko® and Neupogen® in terms of molecular conformation was demonstrated as seen by identical Far-UV CD Spectra, and Intrinsic Fluorescence spectra.

Charge Variants

Cation-exchange analysis demonstrated that Releuko® and Neupogen® have similar content of acidic and basic forms.

Protein Content and Purity

Similar protein content and high purity was found in both Releuko® and Neupogen®.

Comparative Stability

Comparative accelerated and forced degradation studies have shown a similar behavior and degradation profile of Releuko® and Neupogen®.

References:
1. Releuko® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
2. Releuko® Product Quality Approval: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
3. Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.
4. Food and Drug Administration, FDA. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Guidance for Industry, 2015.
5. Food and Drug Administration, FDA. Draft Guidance: Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations, 2019.

Efficacy

Releuko® was Approved Based on the Totality of Evidence, Including a Comparative PD Study as a Surrogate for Comparative Clinical Efficacy1

The two PK/PD studies provided the comparative PD characteristics that established PD similarity and hence comparative clinical efficacy for Releuko® versus Neupogen®.

References:
1. Releuko® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm

Similar Safety and Immunogenicity to Neupogen® Demonstrated1,2

Over 300 subjects have been exposed to Releuko® along with Neupogen® in the three studies conducted as part of overall biosimilarity assessment. The safety profiles of Releuko® and Neupogen® appear to be safe and equally tolerated in the healthy adult subjects who were exposed to single SC doses (2.5μg/kg or 5μg kg) or multiple SC doses (5μg/kg) in the three completed clinical pharmacology and safety studies.1

Based on the two PK/PD studies and one immunogenicity study:1,2

  • Releuko® demonstrated similar safety and immunogenicity to Neupogen®
  • There were no new or unexpected safety signals for Releuko® compared with Neupogen®
  • No antibody formation against filgrastim was detected
  • No evidence of immunogenicity was noted in the three studies

Multiple subcutaneous administrations of Releuko® and Neupogen® were generally safe and similarly tolerated in the healthy adult subjects.

Adverse reactions in patients with cancer receiving Myelosuppressive Chemotherapy (with ≥ 5% higher incidence in filgrastim compared to placebo.2

System Organ Class Preferred Term Filgrastim (N=294) Placebo (N=157)
Blood & lymphatic system disorders
Thrombocytopenia 38% 29%
Gastrointestinal disorders
Nausea 43% 32%
General disorders & administration site conditions
Pyrexia 48% 29%
Chest pain 13% 6%
Pain 12% 6%
Fatigue 20% 10%
Musculoskeletal & connective tissue disorders
Back pain 15% 8%
Arthralgia 9% 2%
Bone pain 11% 6%
Pain in extremity* 7% 3%
Nervous system disorders
Dizziness 14% 3%
Respiratory, thoracic & mediatinal disorders
Cough 14% 8%
Dyspnea 13% 8%
Skin & subcutaneous tissue disorders
Rash 14% 5%
Investigations
Blood lactate dehydrogenase increased 6% 1%
Blood alkaline phosphatase increased 6% 1%
*Percent difference (Filgrastim – Placebo) was 4%
References:
1. Releuko® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
2. Releuko® Product Quality Approval: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm

Clinical data

PK/PD Data1,2
Releuko® was Approved Based on the Totality of Evidence, Including a Comparative PD Study as a Surrogate for a Comparative Clinical Trial

Two PK/PD studies were carried out in healthy volunteers to investigate and compare the PK profiles of Releuko® and Neupogen® and confirmed bioequivalence between both products.

The PK results for one study are shown below. The peak and overall baseline-corrected blood ANC (as measured by geometric mean Emax and AUEC0-t) were similar following a subcutaneous injection of either Releuko® or Neupogen®, as shown by the less than 10% difference in Emax and AUEC0-t between treatments.

Pharmacokinetics Demonstrate Bioequivalence to Neupogen®

References:
1. Releuko® Summary Basis of Approval – Drug Approval Package https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm
2. Releuko® Product Quality Approval: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/761082Orig1s000TOC.cfm