Peter- Thanks for your comments. My thoughts on the five issues are touched upon, and are below your comments:
<(1) equivalence of physicochemical properties, such as molecular weight distribution and overall chemical
composition;>
<presumably an easy-to-meet test for copaxone generics.>
The molecular weight (Mr) distribution will be easy to meet, the only concern is with the Mr issue is whether the overall components within the Mr distribution quantitatively match that of copaxone (ie slopes of the lines from the apex), but if the follow on copolymer 1 is made the same way, the extent of copolymer sizes should be the same. Note that copolymer 1 is a synthetic amino acid copolymer composed of L-alanine, L-lysine, L-glutamic acid and L-tyrosine in a residue molar ratio of 4.2:3.4:1.4:1.0.
<(2) equivalence of heparin source material>
<not applicable>
I agree that this is not applicable.
<(3) equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species>
<the counterpart test here will be the critical factor>
I agree that this will be the critical factor, dealing with the amino acid residues in each copolymeric peptide. For glutamate, this will be perhaps a potential issue since if on the amino terminus in the synthesis, a pyroglutamate could be the residue instead of glutamate as this residue could cyclize during the synthesis. Some naturally occurring peptides (GnRH) have an N-terminal pyroglutamate, and that is generally a good immunogen when on a carrier or within a protein.
<(4) equivalence of in vitro biological and biochemical assay results;>
<don't know how they can find a counterpart except for some simple PK-type stuff>
This is big issue to me as I have had not FDA interaction experience on this type of issue. This is a difficult criteria as there is no easy/quick way to define the mixture in terms of immunogenicity and specific Ab clones generated that contribute to the antisera population that brings about the immunological response. This is a notoriously difficult criteria for immunogens, but relatively easily handled for the peptide portion of Premarin, for example, since one can evaluate in vitro receptor activity. PK on peptides as in a related mixture is notoriously difficult, as carboxypeptidase and aminopeptidases cleave a residue at a time and one cannot simply look at loss of parent in the serum as the number of individual peptides in the copolymer 1 mixture in a 8K to 12K Mr range would be upwards of 40 or so (average of 100 atomic mass units per amino acid. Each copolymer 1 peptide will have a different sequence, yet each peptide's amino acid composition should be similar to the input amino acid mixture.
<(5) equivalence of in vivo pharmacodynamic profile based upon measurements of in vivo anti- Xa and anti-IIa profiles>
<no obvious counterpart. With copaxone you are dealing with the drug's interactions with the immune system which is an altogether different ballpark than the clotting system>
I fully agree with your comments on this one Peter, and I touched upon it in the 4th point above.
Having said all this, to me the difficulty is with the in vitro testing (if relevant) for an immunogen. I don't know if PseudoBiologist still reads these threads, but I am sure both you and I would value his input on the immunogen issue. |
