Innovator Filgrastim versus Generic Filgrastim in Hematopoietic Stem Cell Transplantation Mobilization.
作者: Sadik Husian ; Preethi Jeyaraman ; S K Gupta ; Reeta Rai ; Sangeeta Pathak ; Nitin Dayal ; Rahul Naithani
Methods This is a retrospective study. G-CSF was administered in the dose of 10 μg/kg subcutaneous as a single dose for 4 days. On day 5, peripheral blood stem cell (PBSC) apheresis was performed using Haemonetics MCS plus or COBE Spectra apheresis machine through a double-lumen central venous catheter. Primary outcome parameters were the total number of CD34+ HSCs/kg of recipient weight mobilized in peripheral blood and the number of days required for neutrophil and platelets engraftment, respectively. Objective We compared the effectiveness and safety of innovator filgrastim versus generic filgrastim in patients who underwent hematopoietic stem cell transplantation (HSCT). Results A total of 91 stem cell mobilizations was analyzed. There were 58 normal healthy donors for allogeneic HSCT and 33 patients for autologous HSCT. There was no statistically significant difference among groups in terms of total collected CD34+ cells value ( p = 0.609). The mean time to neutrophil engraftment was 13.7 days in the innovator group and 13.2 days in the Grafeel group ( p = 0.518). The mean time to platelet engraftment was 16.2 days in the innovator group and 14.8 days in the generic group ( p = 0.435). The patient who received generic filgrastim had more febrile episodes during the course of transplantation ( p = 0.020). Conclusion Generic filgrastim was found to be comparable to original filgrastim for peripheral blood stem cell mobilization in normal healthy donors for allogeneic HSCT and patients for autologous HSCT.
Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.
1区 · 医学
作者: A Eapen ; M Joing ; P Kwon ; J Tong ; E Maneta ; C De Santo ; F Mussai ; D Lissauer ; D Carter ; RESPONSE study group
Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss?
rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.
WHAT IS KNOWN ALREADY:
The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates.
STUDY DESIGN, SIZE, DURATION:
A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat.
MAIN RESULTS AND THE ROLE OF CHANCE:
A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93).
LIMITATIONS, REASONS FOR CAUTION:
This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s.
WIDER IMPLICATIONS OF THE FINDINGS:
To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy.
STUDY FUNDING/COMPETING INTEREST(S):
This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.
The biosimilar industry is witnessing an unprecedented growth with the newer therapeutics increasing in complexity over time. A key step towards development of a biosimilar is to establish analytical comparability with the innovator product, which would otherwise affect the safety/efficacy profile of the product. Choosing appropriate analytical tools that can fulfil this objective by qualitatively and/or quantitatively assessing the critical quality attributes (CQAs) of the product is highly critical for establishing equivalence. These CQAs cover the primary and higher order structures of the product, product related variants and impurities, as well as process related impurities, and host cell related impurities. In the present work, we use such an analytical platform for assessing comparability of five approved Granulocyte Colony Stimulating Factor (GCSF) biosimilars (Emgrast, Lupifil, Colstim, Neukine and Grafeel) to the innovator product, Neupogen(®). The comparability studies involve assessing structural homogeneity, identity, secondary structure, and product related modifications. Physicochemical analytical tools include peptide mapping with mass determination, circular dichroism (CD) spectroscopy, reverse phase chromatography (RPC) and size exclusion chromatography (SEC) have been used in this exercise. Bioactivity assessment include comparison of relative potency through in vitro cell proliferation assays. The results from extensive analytical examination offer robust evidence of structural and biological similarity of the products under consideration with the pertinent innovator product. For the most part, the biosimilar drugs were found to be comparable to the innovator drug anomaly that was identified was that three of the biosimilars had a typical variant which was reported as an oxidized species in the literature. But, upon further investigation using RPC-FLD and ESI-MS we found that this is likely a conformational variant of the biotherapeutic been studied.
Granulocyte colony stimulating factor is referred as stimulating factor 3, which acts to increase production of stem cells and granulocytes. Filgrastim is a granulocyte colony stimulating factor (G-CSF) prepared by recombinant DNA technology and often used in the treatment of low blood neutrophils. It is also frequently used in conditions where lukapheresis with increased white blood cells is observed. Common adverse effects of Filgrastim include joint pain, chest pain, hair loss, and vomiting. Filgrastim is a recombinant form of naturally occurring G-CSF and functions by stimulating neutrophil production. It was approved in the U.S. in 1991 for the treatment low blood neutrophils. The World Health Organization declared Filgrastim in the List of Essential Medicines as safe and most effective medicine. Filgrastim was first discovered by Amgen, Inc. and sold under the brand name Neupogen. Large number of biosimilar companies are engaged in the manufacture and marketing of Filgrastim across the world. Filgrastim costs around US$ 200 in the U.S, around GBP 50 in the U.K., and US$ 100 in developing countries.
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Filgrastim is prescribed for neutropenia, which is caused due to bone marrow transplantation and chemotherapy. It has been considered a supportive therapy in various types of cancers. In the last decade, there has been significant increase in cancer prophylaxis in developed countries and awareness initiatives taken by governments to educate about early treatment. These factors are expected to fuel the growth of the global Filgrastim market. Approved biosimilars such as Grafeel, Colstim, Neukine, and Filcad, which are much cheaper and readily available in developing countries, are expected to fuel the growth of the global Filgrastim market. Ongoing biosimilars research and strong pipeline drugs are likely to boost the growth of the global market during the forecast period. Increase in the number of cancer patients, particularly in developing countries such as China and India, is one of the key factors likely to propel the global Filgrastim market during the forecast period. However, high cost of branded biologics and stringent regulatory guidelines for the approval of biosimilars in developed countries act as major restraints of the global market.
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The global Filgrastim market can be segmented based on type, distribution channel, and region. In terms of type, the market can be bifurcated into biologics and biosimilars. The biologics segment is expected to be driven by high sales of established brand Neupogen. Availability of Neupogen in developing countries and higher cost restrain the biologics segment. The biosimilars segment is expected to expand at a higher growth rate due to low cost and easy availability in developing countries. Based on distribution channel, the global Filgrastim market can be categorized into hospital pharmacies, retail pharmacies, and online pharmacies. High demand for biologics in hospitals across the globe is projected to propel the hospital pharmacies segment from 2018 to 2026.
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The global Filgrastim market can be segmented into five key regions: Asia Pacific, North America, Europe, Latin America, and Middle East & Africa. North America is expected to account for a major share of the global market owing to developed health care infrastructure and favorable reimbursement policies. Europe was the second largest market for Filgrastim in 2017. India, China, and Japan are the major markets for Filgrastim in Asia Pacific. The global Filgrastim market is fragmented, with presence of large number of companies with global reach. Major players in the global Filgrastim market include Amgen Inc., F. Hoffmann-La Roche Ltd., Dr. Reddy's Laboratories Ltd, Intas Pharmaceuticals, Cadila Pharmaceuticals, Lupin Limited, Emcure Pharmaceuticals Ltd., and Biocon.
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