Biotech Values

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DD has suggested that Teva is not the source of the generic Lovenox that they filed with the FDA. Some suggest it makes no difference. Does it? I think it does lower the inference of quality we associate with Teva. But IF we find that the tL is already being marketed in South America or elsewhere then we may be able to compare relevant factors under the FDA guidelines.

What other “enoxiparins” are marketed? How do these compare to Lovenox? Are they the “same”? Would they meet the FDA criteria for approval as a substitutable for Lovenox?

Molecular weight and Molecular Profiling differ from L:
http://www.fasebj.org/cgi/content/meeting_abstract/22/1_MeetingAbstracts/1118.6

Molecular Profiling of Generic Versions of the Low Molecular Weight Heparin Enoxaparin and Their Digestion by Heparinase-I.
Melanie Clark, He Zhu, Debra Hoppensteadt and Jawed Fareed
Pathology, Loyola University Medical Center, Maywood, IL
ABSTRACT
Generic versions of the low molecular weight heparin (LMWH) enoxaparin (Lovenox, Sanofi-Aventis, Bridgewater NY) are available in Southeast Asia and South America. The purpose of this study was to compare Lovenox with two generic versions, Lupenox (co.name) and Loparin (co. name). The molecular weight (MW) profile of these agents and unfractionated heparin (UFH) was determined using HPLC prior to and after heparinase-I digestion. The MW of the generic versions of LMWH ranged from 3.9 to 4.7 kDa. Lupenox exhibited the lowest mean MW (3.9 kDa), whereas Loparin was 4.7 kDa. UFH had a MW of 17.1 kDa. Heparinase-I digestion resulted in marked decrease in the MW of all agents studied. UFH was the most susceptible to the actions of heparinase-I digestion (> 50% reduction in MW) whereas the LMWHs exhibited a 20–30% reduction. Loparin was more susceptible to heparinase-I digestion (30%) compared to Lovenox and Lupenox. The molecularcomponents with a MW > 7.5 kDa ranged from 3–10% for the LMWHs and >90% for UFH. The molecular components with a MW < 7.5 kDa ranged from 90 to 97% for LMWHs and 9% for UFH. These results suggest that the generic versions of LMWHsexhibit differences in their molecular profile and digestion by heparinase-I. Moreover the studies indicate that relative to UFH, both generic and branded enoxaparins are less susceptible to heparinase-I digestion.

>>>>Compare L at 4,500 da.


Differentiating Low-Molecular-Weight Heparins Based on Chemical, Biological, and Pharmacologic Properties: Implications for the Development of Generic Versions of Low-Molecular-Weight Heparins

Walter P. Jeske1, Jeanine M. Walenga1, Debra A. Hoppensteadt2,Curtis Vandenberg1, Aleah Brubaker1, Cafer Adiguzel2,Mamdouh Bakhos1, Jawed Fareed2

1 Cardiovascular Institute, Loyola University Medical Center, Maywood, Illinois
2 Department of Pathology, Loyola University Medical Center, Maywood, Illinois
ABSTRACT
Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

http://www.fasebj.org/cgi/content/meeting_abstract/22/1_MeetingAbstracts/1118.4?maxtoshow=&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT

Differential Interaction of Anti-heparin Platelet Factor 4 Antibodies with Branded and Generic Versions of Low Molecular Weight Heparins. Pathophysiologic and Bioequivalence Implications.
Jawed Fareed, Debra Hoppensteadt, Omer Iqbal, Cafer Adiguzel, Harry Messmoreand Jenaine Walenga
Pathology, Loyola University Medical Center, Maywood, IL
ABSTRACT
Low molecular weight heparins (LMWHs) such as enoxaparin (E) and dalteparin (D) are now widely used for the management of thrombotic and cardiovascular complications. Several generic versions of these drugs have recently become available. Due to the compositional differences in the branded agents, such as E and D, their interactions with platelet factor 4 (PF4) differ and potentially have impact on immunogenic responses.Similarly, because of the apparent differences in the source material and oligosaccharide composition, obvious differences in PF4 titration have been noted. To compare the potential interactions of D and one of it’s generic versions daltehep (DH) and E and two of its generic versions, namely, lupenox (LU) and loparan (LO), each of these agents were tested in an in vitro heparin induced platelet aggregation (HIPA) system, where pooled serum from clinically diagnosed heparin induced thrombocytopenia (HIT) patients was used as an antibody source. Significant differences in the aggregation responses were noted between D and E. Therewas no difference in D and DH (30.8 ± 7.8% vs. 34.7 ± 8.1%). However, significant differences between E (18.2 ± 4.2%), LO (38.1 ± 9.0%) and LU (68.1 ± 9.1%) were noted. These results underscore the observation that HIT antibodies interact differentially between the branded and generic LMWHs, owing to their oligosaccharide composition.


http://www.fasebj.org/cgi/content/meeting_abstract/24/1_MeetingAbstracts/951.6?maxtoshow=&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT

Differential Immunogenic Responses of Branded and Generic Versions of Low Molecular Weight Heparins
Eduardo Ramaciotti1, Marisa Gomez1, Jeanine M. Walenga2, Debra Hoppensteadt2,Gundu Rao3, Helena Nader4, Walter Jeske2 and Jawed Fareed2
1 Univ. of Michigan, Ann Arbor, MI
2 Loyola University Medical Center, Maywood, IL
3 Lillehei Heart Institute, Minneapolis, MN
4 Universidade Federal de Sao Paulo, Sao Paulo, Brazil
ABSTRACT
Low molecular weight heparins (LMWHs) are complex mixtures of oligosaccharides. Compositional and structural features impact their biological effects including their interaction with endogenous proteins such as platelet factor 4 (PF4). Purified PF4 was titrated with the branded LMWHs dalteparin (Fragmin), enoxaparin (Lovenox), and reviparin (Clivarin) and two generic versions of enoxaparin (Cutenox and Lupenox). The prevalence of anti-heparin/PF4 antibodies (HIT antibodies) in patients treated with approved regimens of branded products and Cutenox were investigated in plasma samples obtained 7–10 days after the administration of these drugs. Marked differences in the PF4 titration among branded products were noted in the aPTT, Heptest, TT, and amidolytic anti-Xa, anti-IIa assays. HIT antibody prevalence and the antibody sub-typing profile was significantly different among the branded products (18–32 %). While there were pharmacodynamic differences between Lovenox and Cutenox, there was no significant difference in the global (IgG, IgA, IgM) titers of HIT antibodies. Sub-typing of the antibodies demonstrated a greater prevalence of IgG type antibodies (those implicated in mediating the pathologic responses in HIT) in the plasma from patients treated with the generic LMWH. These studies suggest that the compositional differences in LMWHs may result in differential immunogenic responses.

Other links:
http://natfonline.org/jan_2008/LMWH_009.pdf
(Fine graphics)

http://ourpharmacology.blogspot.com/2008_04_05_archive.html

http://scholar.google.com/scholar?hl=en&lr=&cites=8421845392665849039&um=1&ie=UTF-8&ei=dpDDTKCYNsT_lge8-5AD&sa=X&oi=science_links&ct=sl-citedby&resnum=1&ved=0CBYQzgIwAA