Allan Gibofsky, MD: What are the physical differences between a biosimilar and a generic?
Gary R. Lichtenstein, MD: To start, there are different ways that they’re made. Biosimilars are made in host cell lines, whereas the generics are small molecules.
Peter L. Salgo, MD: OK. So one is alive, one isn’t?
Gary R. Lichtenstein, MD: Correct.
Peter L. Salgo, MD: That’s a huge difference, right?
Gary R. Lichtenstein, MD: Exactly.
Peter L. Salgo, MD: It’s not “I know where this carbon goes and where this oxygen should be,” it’s “I’m going to grow this, and it should work the same.” Right?
Allan Gibofsky, MD: Well, yes and no. I’m sure what will develop in a few minutes is that the primary structure, the sequencing of the amino acids, has to be the same for a biosimilar and for a bio-originator.
Peter L. Salgo, MD: That’s important.
Allan Gibofsky, MD: Yes.
Peter L. Salgo, MD: That’s good.
Gary R. Lichtenstein, MD: It’s the tertiary structure, the afucosylation, and all different variations which may occur. It’s a different chemical overall tertiary structure that makes a difference.
Peter L. Salgo, MD: And I think you said that they were grown, not manufactured?
Vibeke Strand, MD: That’s where a lot of the variability can occur. So, during the manufacturing process (when the cells are making the product), we get changes to the secondary, tertiary, and even the quaternary structure. Now, those changes have to be very, very small, so that, in fact, the biosimilar will behave exactly like or highly similar to the reference product. We’ve learned a lot about this because we’ve learned so much about manufacturing biologics over the last 30 years. And thus, we can control for these things. But, more importantly, we can actually test for the variability to assess that any of the variability that occurs doesn’t change how the product actually behaves.
Peter L. Salgo, MD: I have this image based on what you said: that when the cells don’t listen to what you tell them, they’re going to do what they want to do.
Vibeke Strand, MD: That’s true.
Peter L. Salgo, MD: And the trick is to make the cells do enough to make this behave well. Is that fair?
Vibeke Strand, MD: That’s fair. And the other process is that manufacturing these products has improved so much in the last 20 to 30 years with much better scale at much more efficiency of production. All that technology has now allowed us to reverse engineer these products.
Peter L. Salgo, MD: We’ve also got the issue of stability.
Vibeke Strand, MD: Right.
Peter L. Salgo, MD: These are biologicals. These are not pills that you put, I hesitate to say, in the medicine cabinet in your bathroom (because you shouldn’t put pills there). They’re different. They’re not as stable, are they?
Allan Gibofsky, MD: No, they’re not. They can be or they might not be, depending upon the molecule.
Peter L. Salgo, MD: Well, there’s a definitive statement there.
Allan Gibofsky, MD: Well, yes. It depends on the molecule that we’re talking about. But the working definition is that there can be differences in the molecule between a biosimilar and a bio-originator (the reference molecule), but they can’t be clinically meaningful. They can’t affect the safety. They can’t affect the efficacy. They can’t affect the purity or the potency of the molecule that we’re dealing with.
Peter L. Salgo, MD: So, we’re focusing on end effect, as opposed to absolute mirrored structure.
Vibeke Strand, MD: Right.
Allan Gibofsky, MD: Right.
Vibeke Strand, MD: Exactly.
Peter L. Salgo, MD: What are we dealing with in terms of immunogenicity potential?
Vibeke Strand, MD: Essentially, chemical products really have very little, if any, immunogenicity, but all biologics are immunogenic, and they’re different in different people. What’s been interesting about the biosimilar process is that we’ve actually learned a lot more about immunogenicity of both the biosimilar and the reference product because the assays that we’re using now to detect immunogenicity are much more sensitive. They’re much more modern.
Peter L. Salgo, MD: So, the bar is actually higher?
Vibeke Strand, MD: Yes, it is.
Peter L. Salgo, MD: We can examine things in more detail.