Biosimilars

2020 ◽  
pp. 411-424
Author(s):  
Vibeke Strand ◽  
Jeffrey Kaine ◽  
John Isaacs
Keyword(s):  
Quaternary Structure ◽  
Reference Product ◽  
Clinical Indication ◽  
Open Label ◽  
Observational Series ◽  
Equivalent Efficacy ◽  
Primary Amino ◽  
Multiple Switching ◽  
Biologic Function

Biologic therapy for treatment of rheumatoid arthritis (RA) has evolved considerably over the past 20 years. Biosimilar development continues to accelerate at a frenetic pace worldwide. Initial regulatory efforts were developed within the EU and subsequent guidelines have now evolved in over 20 countries. Biosimilars by definition are highly similar, with ‘comparable quality, safety, and efficacy’ (EMA) and ‘no clinically meaningful differences in safety, purity, and potency’ (FDA) to the reference product. Development and manufacturing are based on reverse engineering of the reference product as only the primary amino acid sequence is known. Testing of primary, secondary, tertiary, and quaternary structure, binding pharmacokinetics, and stability is required. Characterization of post-translational modifications and biologic function, pharmacokinetics, evaluation of immunogenicity, and at least one comparative efficacy clinical trial are major requirements for regulatory approval. Clinical trials to assess biosimilarity are required in only one clinical indication and may be extrapolated to other indications for which the reference product is approved. Both single and multiple switching trials (between biosimilar and reference product) have yielded consistent results across numerous patient populations and diseases, with no evidence of detrimental outcomes. Two prospective large observational series (Danbio and Nor-Switch) have similarly assessed non-medical switching. Several open-label switching studies have revealed equivalent efficacy, safety, and discontinuation rates but real-world studies have raised concerns about potential nocebo responses.

Characterization of Tamm-Horsfall Urinary Glycoprotein

1973 ◽  
Vol 31 ◽  
pp. 420-421
Author(s):  
John P. Robinson ◽  
J. David Puett
Keyword(s):  
Electron Microscopy ◽  
Circular Dichroism ◽  
Secondary Structure ◽  
Quaternary Structure ◽  
Normal Adult ◽  
Morphological Properties ◽  
Adult Males ◽  
Circular Dichroïsm ◽  
Urinary Glycoprotein

Much work has been reported on the chemical, physical and morphological properties of urinary Tamm-Horsfall glycoprotein (THG). Although it was once reported that cystic fibrotic (CF) individuals had a defective THG, more recent data indicate that THG and CF-THG are similar if not identical.No studies on the conformational aspects have been reported on this glycoprotein using circular dichroism (CD). We examined the secondary structure of THG and derivatives under various conditions and have correlated these results with quaternary structure using electron microscopy.THG was prepared from normal adult males and CF-THG from a 16-year old CF female by the method of Tamm and Horsfall. CF female by the method of Tamm and Horsfall.

scholarly journals Genomic Organization and Characterization of the white Locus of the Mediterranean Fruitfly, Ceratitis capitata

Genetics ◽  
2001 ◽  
Vol 157 (3) ◽  
pp. 1245-1255 ◽  
Author(s):  
L M Gomulski ◽  
R J Pitts ◽  
S Costa ◽  
G Saccone ◽  
C Torti ◽  
...  
Keyword(s):  
Ceratitis Capitata ◽  
Dna Encoding ◽  
Cloning And Sequencing ◽  
Deletion Event ◽  
Exon 2 ◽  
Independent Events ◽  
White Locus ◽  
Primary Amino ◽  
Organizational Patterns

Abstract An ∼14-kb region of genomic DNA encoding the wild-type white eye (w+) color gene from the medfly, Ceratitis capitata has been cloned and characterized at the molecular level. Comparison of the intron-exon organization of this locus among several dipteran insects reveals distinct organizational patterns that are consistent with the phylogenetic relationships of these flies and the dendrogram of the predicted primary amino acid sequence of the white loci. An examination of w+ expression during medfly development has been carried out, displaying overall similarity to corresponding studies for white gene homologues in Drosophila melanogaster and other insects. Interestingly, we have detected two phenotypically neutral allelic forms of the locus that have arisen as the result of an apparently novel insertion or deletion event located in the large first intron of the medfly white locus. Cloning and sequencing of two mutant white alleles, w1 and w2, from the we,wp and M245 strains, respectively, indicate that the mutant conditions in these strains are the result of independent events—a frameshift mutation in exon 6 for w1 and a deletion including a large part of exon 2 in the case of w2.

scholarly journals Single-operator cholangioscopy for diagnosis of cholangioadenoma (bile duct adenoma) and its potential impact on surgical management

2018 ◽  
Vol 06 (11) ◽  
pp. E1312-E1316 ◽  
Author(s):  
John Eccles ◽  
Aducio Thiesen ◽  
Gurpal Sandha
Keyword(s):  
Bile Duct ◽  
Surgical Management ◽  
Liver Enzymes ◽  
Clinical Indication ◽  
Targeted Biopsy ◽  
Patient Demographics ◽  
Single Operator ◽  
Potential Impact ◽  
Per Oral

Abstract Background and study aims Cholangioadenoma is not recognized commonly and is often only diagnosed on surgical specimens. Direct per oral single-operator cholangioscopy (SOC) allows characterization of common bile duct (CBD) lesions through direct visualization and directed forceps biopsies with potential for impacting surgical management decisions. This is a retrospective review of all SOC cases diagnosed with cholangioadenoma. Patient demographics and outcomes were recorded. Three patients (all male), average age 68 years (range 62 – 76 years), were identified to have a cholangioadenoma. The clinical indication for SOC was deranged liver enzymes with a dilated CBD and a CBD abnormality identified on biliary imaging. The site of cholangioadenoma was proximal, mid and distal CBD, respectively. All patients had a successful SOC with targeted biopsy-proven diagnosis. One patient had a synchronous cholangiocarcinoma and underwent palliative stenting whereas the other two patients underwent appropriate curative resection based on cholangioadenoma location. We conclude that SOC is safe and effective for diagnosis of cholangioadenoma and has potential impact on decisions for surgical management.

scholarly journals Analytical characterization of recombinant hCG and comparative studies with reference product

2018 ◽  
Vol Volume 12 ◽  
pp. 23-35 ◽  
Author(s):  
Rajamannar Thennati ◽  
Sanjay Singh ◽  
Nitin Nage ◽  
Yena Patel ◽  
Sandip Bose ◽  
...  
Keyword(s):  
Comparative Studies ◽  
Reference Product ◽  
Analytical Characterization

scholarly journals Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

2020 ◽  
pp. 1009-1016
Author(s):  
Manjunath Nookala Krishnamurthy ◽  
Gaurav Narula ◽  
Khushboo Gandhi ◽  
Ankita Awase ◽  
Ruta Pandit ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Reference Product ◽  
Lymphoblastic Leukemia ◽  
High Price ◽  
Maximum Plasma ◽  
Open Label ◽  
Middle Income ◽  
Middle Income Countries ◽  
Parallel Group ◽  
Low And Middle Income

PURPOSE Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar). PATIENTS AND METHODS This study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m2) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC0-t) geometric mean test-to-reference ratio was within 75% to 133%. RESULTS Twenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC0-t for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups. CONCLUSION Generic and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries.

A study of rovalpituzumab tesirine in frontline treatment of patients with DLL3 expressing extensive small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2598-TPS2598 ◽  
Author(s):  
Christine L. Hann ◽  
Daniel Morgensztern ◽  
Afshin Dowlati ◽  
Timothy Francis Burns ◽  
Robert M. Jotte ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Initial Therapy ◽  
Primary Objective ◽  
Notch Receptor ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Frontline Treatment ◽  
Novel Target

TPS2598 Background: Treatment and survival of SCLC patients (pts) has remained mostly unchanged over past decades with high response rates to initial therapy (cisplatin/carboplatin + etoposide), but relapse is near universal with median survival < 1 year in extensive disease. Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family identified as a novel target in high-grade neuroendocrine tumors, and is highly expressed in SCLC but not in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3. A Phase I study of Rova-T monotherapy in 2nd and 3rd line SCLC pts demonstrated encouraging antitumor activity with an ORR of 18% in all pts, and an ORR of 38% in DLL3-high pts (Rudin et al., Lancet Oncol, 2016.). Methods: This is a Phase I, open-label, multicenter study (NCT02819999; no pts enrolled as of 7 February 2017).In Phase Ia (escalation), 15-34 previously untreated DLL3-high pts will be enrolled and randomized to 1 of 4 cohorts. The primary objective of the Phase Ia portion is assessment of safety and dose-limiting toxicities (DLTs). Phase Ib (expansion) will enroll up to 2 cohorts of 30 pts each, and its primary objective is to characterize antitumor activity of the selected cohort(s). Secondary objectives (Phase Ia/b) include assessment of pharmacokinetics and anti-therapeutic antibodies against Rova-T, and characterization of antitumor activity (Phase Ia). Eligible pts: adults with histologically or cytologically confirmed extensive DLL3-high SCLC based on immunohistochemistry; ECOG 0-1; and life expectancy ≥ 12 weeks. Clinical trial information: NCT02819999. [Table: see text]

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