David J. Kerr, CBE, MD, DSc, FRCP, FMedSci; Håkan S.T. Mellstedt, MD, PhD


September 02, 2016

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David J. Kerr, CBE, MD, DSc, FRCP, FMedSci: Hi. I'm David Kerr, professor of cancer medicine at the University of Oxford. I would like to welcome you to this edition of Medscape Oncology Insights, coming to you from the "Windy City," Chicago, and the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO).

Biosimilars. It's a word that keeps cropping up at this year's meeting and more and more in our practice of oncology. I chaired a session the other day looking at sustainable healthcare and how we could get better value out of it. Could biosimilars contribute to this? How good are they? Will they make a significant impact on the clinical practice that we deliver to our patients?

To help sort out these problems, I'm delighted to say that we've invited one of the world's great experts, my friend and colleague, Professor Håkan Mellstedt. Håkan is a professor of oncology at the Karolinska Institute and professor of oncologic biotherapy at Cancer Center Karolinska in Stockholm, Sweden. As our American colleagues would say, this is a twofer, because Håkan and I are both former presidents of the European Society for Medical Oncology. Welcome, Håkan. It's a great delight to bring you to this meeting.

So, are biosimilars just cheap versions of drugs? Is it just a generic play to get drugs from India onto the streets of the United States?

What Is a Biosimilar Drug?

Håkan S.T. Mellstedt, MD, PhD: First of all, David, thank you very much for inviting me to have this discussion. Coming back to biosimilars, I think that these new drugs will play an important role, especially in oncology, because most of these drugs that we talk about are blockbusters. If we could save money on these drugs, it would be important for cancer care.

So, what is a biosimilar? There is much confusion about biosimilars. Biosimilars were introduced in 2006 in Europe when the first patent of erythropoietin ran out. Then came G-CSF [granulocyte colony stimulating factor]. Now we will see a lot of biosimilars—monoclonal antibodies—that are much more complex drugs than the simple hematopoietic growth factors. And here comes the problem.

Dr Kerr: More complex in what way, Håkan?

Dr Mellstedt: Erythropoietin and G-CSF are small molecules compared with monoclonal antibodies, which are large molecules. And hematopoietic growth factors, of them that are in use, are nonglycosylated.

Monoclonal antibodies are complex in their three-dimensional structure and have a lot of posttranslational modifications that are extremely important for the function of the protein. So it was easy, in a way, to produce these first biosimilars. But now we have these monoclonal antibodies. The question is: Are these so-called variants of the original drug the same? These are produced by mammalian cells, mainly, and they cannot be exactly the same. We are used to talking about small chemical molecules for generic drugs and for which we accept that [the original and variant] as exactly the same. You only have to do some bioavailability studies, no clinical studies. But when we come to these complex biosimilars, monoclonal antibodies, do they have the same efficacy and safety profiles as the original drug?

Dr Kerr: So, we cannot take a simple genetic blueprint? We know the sequence of the monoclonal antibodies.

Dr Mellstedt: We know the sequence, yes.

Dr Kerr: We cannot just print these antibodies from a genetic sequence, put them into a cell line, and—abracadabra—out pops a fully formed protein?

Dr Mellstedt: No. What is exactly the same is the protein backbone structure, but the folding and the posttranslational modifications are not exactly the same. However, with improvements in technology, the differences are smaller and smaller. It's these small differences, if there are any differences of clinical significance—that's what the question is about.

Dr Kerr: Gotcha. But if there are differences at the molecular level—folding, glycosylation, and so on—could that mean that they have different pharmacokinetics, different pharmacodynamics, and receptor binding, and all of that could be potentially impacted upon?

Dr Mellstedt: That is exactly the case. If we go back 10 years, the tools that we had to analyze protein drugs were not the same as the ones we have today. There have been tremendous advancements in technology for analyzing proteins. The differences today can be much more easily detected. If there are differences in folding, receptor binding, pharmacokinetics, apoptosis, or complement lysis, if there are differences [in the biosimilars] as detected in what we call the comparative exercise, they will probably not be approved.

Of course, you can accept minor differences, but the regulatory authority and the company decide from the beginning what kinds of margins you can accept. We have a much more robust characterization of the protein drugs today than we had 10 years ago because of the advancement in technology.

Dr Kerr: The specifications are tighter, so that would give you and me greater confidence to use these as clinical tools.

Dr Mellstedt: Exactly.

Regulation of Biosimilar Development

Dr Kerr: Are the regulators supporting the advancement of biosimilars or are they putting hurdles in the way? Is it a comparatively easy pathway for product development or are there hurdles and increased complexity? Are the companies working together in some way?

Dr Mellstedt: Why do we introduce biosimilars? There is only one reason: to produce a cheaper drug. It's not to produce a better drug, because then it's not biosimilar anymore. The regulatory authorities really support the introduction of biosimilars. The company and the regulatory authorities negotiate what types of information they want to have, and the dossier of the biosimilar in regard to its preclinical characteristics is very extensive. If the regulatory organization is not satisfied, they go back to the company and they have to improve it or show the similarities.

Dr Kerr: Tight, tight, tight, tight, tight.

Dr Mellstedt: Yes. And then, of course, there are still some uncertainties, so clinical studies will be required. However, those studies are not to prove the efficacy, because efficacy has already been proven by the original. It should only prove that there is no difference in regard to clinical efficacy and safety.

Dr Kerr: This is a really critical point. You and I have both been involved in trials looking at lack of inferiority. Those are big trials—thousands of patients, millions of dollars, and years spent. For these, we're talking about trials of hundreds of patients rather than thousands.

Dr Mellstedt: Exactly. It's an equivalence study. We are talking about hundreds of patients. If you are going to do a trial of thousands of patients, then the biosimilar drug will be much more expensive because you have to do all of these clinical trials.

Dr Kerr: To be biosimilar and econosimilar as well.

Dr Mellstedt: Exactly.

Dr Kerr: It's a horribly made-up word, but I see your point. So, how long do you think it takes to complete the regulatory dossier—the preclinical stuff, the detailed science, the protein mass spectrometry—and move into clinical studies? Is it 10 years or is it accelerated to 2-3 years?

Dr Mellstedt: Well, the total time for developing a biosimilar is still long. If you have a small chemical drug compound that is a generic, it usually takes about 2-3 years to develop it. To develop a biosimilar drug, however, it takes about 7-8 years. You have to establish a production facility, you have to know that there is consistency in production, and you have to do all of the preclinical tests, both structural and functional. That takes a long time. On top of that, you have to do a phase 3 clinical trial including hundreds of patients. It's still a long commitment.

Dr Kerr: It's still significant.

Dr Mellstedt: Yes, it is.

Dr Kerr: So, we're confident in the science, we're confident in the tools, and we're confident in the clinical pathway.

Dr Mellstedt: Absolutely.

Dr Kerr: Do you feel that by following this scientific and regulatory route, the biosimilars are drugs that you and I should feel confident using in the clinic?

Dr Mellstedt: Absolutely. I have now been involved in the first discussion when we had consultation for erythropoietin in 2003, so I have followed the area very well. I will admit that, in the beginning, I was a little bit skeptical.

Dr Kerr: I remember that very well. You were very skeptical, actually.

Dr Mellstedt: I was very skeptical, but that was because, at that time, we didn't have all of the tools to characterize [the biosimilars]. Also, there were some severe cases of pure red cell aplasia with erythropoietin, so there were some concerns. But I feel much more confident now.

Pricing of Biosimilar Drugs

Dr Kerr: Fantastic. Final question. This has been an absolutely fascinating walk through the past 10 years. So, we want better-value healthcare. You're in charge of a biosimilar company. Where do you price the biosimilar? There's something about the cost of goods and return on investment, and it's a significant investment with the trials and preclinical dossier. Where do you price it?

Dr Mellstedt: There is often discussion about what the price reduction will be. It's estimated that for monoclonal antibodies, the reduction will be around 25%-30%. And that's not bad, because most of these drugs are blockbusters. When they introduced infliximab biosimilars for rheumatologic diseases in Norway, the price reduction compared with the original drugs was 72%, but it has been shown that this is not realistic. But I think that about 30% would be realistic. What will happen is that by the time we are starting to produce more biosimilars, the technology will improve, so the cost of goods will decrease. Maybe 3 years from now, they will refer to Håkan and David's sitting discussion about 30% as rubbish, because it will be 50%.

Dr Kerr: Yeah, let's hope. Håkan, it has been a delight chatting with you, as always. Thank you very, very much for taking us through what has been a fascinating exposition on biosimilars.

Dr Mellstedt: Thank you so much.

Dr Kerr: And let me thank our watchers and our listeners. It has been a terribly interesting morning for me. Here we have biosimilars, something that is set to stay and something that will be impactful in all of our clinical practices. Medscapers, thanks for watching. Over and out.


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