TNR Grand Rounds - Update On Biosimilars Save

Hi, everyone. Welcome to Tuesday night rheumatology. This is the last in our two month installment of a grand round series, and we're gonna end up with the best, doctor John Kay from the University of Massachusetts. Hey, John, how are you?

Great, Jack. It's great to see you.

It's great to have both a friend and such an expert on our weekly broadcast. This has been, you know, you were one of the people who immediately stepped up when I said, hey, let's do some education during the shutdown and you didn't hesitate. So I really thank you for doing that. We've had a lot of good series and we're gonna end with a good one. Tonight, Doctor.

K is going to give us an update in biosimilars, something he's been following now for, gee, almost, is it five years that you've been working on this?

It's actually a decade now.

Wow. Amazing. So you were almost stealth then in the first few years, or I wasn't following you on. I just remember your first one being at Targeted Therapies somewhere in Europe, and that was like a mind blowing exercise where you went over the Obamacare and the legal stuff and whatnot. But anyway, he's gonna get into that.

We're gonna hear what we need to know and where we're going with biosimilars. John, I wanted to start with a few things. This week, there was a second drug that became FDA approved for non radiographic axial spondyloarthritis. The first drug being cerdulizumab, and now we have ixekizumab, an IL-17A inhibitor. I like that, but at the same time, what's your take on non radiographic axial spot?

Is it a reality or is it just another ASAS invented diagnosis that we don't see much of? Is it really helped the marketplace or does it help patients and the doctors taking care of? What's your take on that?

Well, non radiographic axial spondyloarthritis is a real condition. I have a number of patients with that condition. Patients who have inflammatory back pain but have no changes on plain radiographs, you get an MRI and it shows osteitis. So those patients have true non radiographic axial spondyloarthritis, and they're in need of therapy. Therapy.

They can take a non steroidal anti inflammatory drug, but oftentimes don't respond adequately. Having cerdulizumab pegol as a therapeutic option has been helpful, but as you know, the IL-17A inhibitors are very effective in treating axial spondyloarthritis and should be for this condition as well.

You know, the interesting thing about non radiographic axial SpA is when the FDA had its hearing and that was a prelude to a submission by both AbbVie and UCB for the indication and it fizzled out and that was a number of years ago. I remember spending almost like two weekends in a row and going through the hearing and kept thinking to myself, I don't know, I just don't. And I was trying to recruit for a trial for it and I just couldn't recruit anyone. Anyway, went through the FDA hearing and I still wasn't too sure. That next Monday, I saw two patients back to back perfect cases of non rego exo SpA.

So I think for anybody in doubt, it's a matter of waiting. They do exist and your life got easier with two new drugs being indicated. You have to do creative coding or find other ways to get them treated. I wanted to see how you were handling the change in practice and give me your best and worst story about telemedicine and virtual exams.

Well, my worst story is probably the no show. A patient who had an appointment for a telemedicine visit, and I called him and he didn't answer. And I called him several times and he just didn't answer. So I guess that's either a blessing in disguise or a worst case scenario. We've been doing a lot of telemedicine at first.

Our clinic closed March 15, the week before targeted therapies was supposed to take place, and I hadn't been into the clinic until a couple of weeks ago, but we've been doing telemedicine visits. Follow-up patients are very happy. A number of patients who have to travel a fair distance to get to clinic have been very pleased that they could be seen from the comfort of their living room without having to drive or park. It's been very helpful to be able to look at their joints, and your guide to the virtual joint exam is very helpful. And you can have the patient fold their hands up like that, and you can see the knuckles, you can see the loss of the space in between metacarpophalangeal joints.

A lot of times we go through the motions in an in person visit to feel all the joints, but you can oftentimes tell almost as much by listening to the patient in a virtual visit and having them show you their joints on the camera.

Yeah. It's it's certainly been an interesting exercise and something it seems like one week we knew nothing about it. And within, you know, one or two weeks, we're we're we're in the game, you know, and and we're learning day by day how to make it a little better. By now we're almost pros at it. It's pretty interesting.

But the technology is still a challenge for some of our patients and for some of our colleagues. I think the documentation part's an important part. Patient satisfaction seems to be good, but I think there is going to be always a 20% people that are not gonna like this, and really do need the physical connection. So it'll be interesting to see how it changes rheumatology going forward. And it's going to change rheumatology going forward.

Speaking of changes, I think that the big one, another big one happens tomorrow and that's the onset of EULAR twenty twenty, a meeting that was, you and I would normally have been drinking a stein of something in Frankfurt, Germany getting ready for tomorrow morning's meeting, but instead we're here in The States and about ready to go through a virtual meeting. What's your expectation on how that's gonna work or can it work?

I think it'll work. I really miss the social aspect of the meeting, running into you and other good friends and exchanging ideas. It's really one of the two major opportunities to exchange ideas and thoughts with other rheumatologists from around the world. It's still not the same seeing Ian McGinnis and Tom Heisinger and others on camera, Joseph Smolin, Daniel Alataha. It's nice to be able to sleep a little bit later.

And with EULAR starting in the afternoon tomorrow, that'll be early morning here on the East Coast. But the next couple of days, I'll be getting up probably at about two or three in the morning to be able to attend EULAR.

I know our clocks are about to get disrupted. Well, John's always been one of the great guys. No matter when I see him in EULAR, ACI, grab him and say, hey, let's shoot a video on that presentation you just did. He's like, all right, I got three minutes, let's get it done. So thank you so much for doing that.

I'm gonna go off and let John take over. This is update in biosimilars given by an expert, Doctor. John Kay. Take over, John.

Great. Thanks, Jack. Am I screen sharing? Because not folks disabled me.

Did I do that? Oh, let me just see if Yep. Share screen. Oh, wait, here we go. Now you can do it.

Okay.

Here it is. Can you see my title slide?

Yes, we can. Go Your All Fantastic. To

Thank you so much for this opportunity to talk about a topic that's near and dear to my heart. I'm going to give an update on biosimilars over the next twenty five minutes or so. My disclosures are on this slide. We have a couple of clinical trials that are going on at UMass and I've consulted to a number of companies, many of which make biosimilars or reference products. I'm going to talk first by defining biosimilarity and then I'll talk about the marketplace and biosimilars for inflammatory diseases, and then I'm gonna talk a bit about manufacture of biopharmaceuticals and the variability, drift, and evolution that occurs during that process and the implications that that has for biosimilars as well as the implications that biosimilar clinical trial design has on reference biopharmaceuticals.

I'm going to then switch over to a topic that really is the crux of the issue that supports the existence of biosimilars, namely economic aspects. The regulatory definition of biosimilarity was put forth in the Affordable Care Act of 2010, the so called Biologics Price Competition and Innovation Act of 2009 that was passed by the United States Congress. In this, the United States Congress defined a biosimilar or defined biosimilarity as being that the biologic product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and that there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity, and potency of the product. The European definition by the European Medicines Agency is very close to this, not identical but truly biosimilar to The United States definition. My definition of a biosimilar based on reading not only United States and European Union regulations but regulations from agencies around the world is that a biosimilar is a legitimate copy, a legal copy, of a biopharmaceutical that no longer is protected by patent, which has met two criteria.

First, it has undergone rigorous analytical and clinical assessment in comparison to its reference product, and it has been approved by a regulatory agency in a highly regulated area according to a specific pathway for biosimilar evaluation. If the biopharmaceutical has not met both of these criteria, the rigorous analytical and clinical assessment compared to the reference product and the approval by a regulatory agency according to a specific pathway for biosimilar valuation. It is not a biosimilar. We call those biomimics which are the illegitimate copies, essentially the Gucci bag that you would buy from an African vendor on the banks of the SEN which falls apart two days later. So the goals of standalone biopharmaceutical development and biosimilar development are different.

Standalone new novel biopharmaceuticals are developed according to section 351A of the Public Health Service Act and the goal is to establish the safety and efficacy of a new product. The product is developed and then there are analytical studies that are performed to characterize the product both chemically and functionally. And then there's a non clinical animal toxicology program that occurs to make sure that the molecule is safe for trial in humans. This then undergoes clinical pharmacology, pharmacokinetic studies, typically in healthy human subjects. And then it undergoes clinical safety and efficacy, phases one, two, and three.

Phase one is typically the first in human study, dose escalation studies looking primarily at safety. Phase two are the dose finding studies in diseases for which the drug is intended. And then phase three consists of two large placebo controlled trials in each indication for which approval is sought. So the phase one, two, and three clinical safety and efficacy development forms the major part of a standalone development program. A biosimilar on the other hand is developed to copy an existing biopharmaceutical.

As such, the major part of the development is the analytical process whereby the biosimilar candidate and the reference biopharmaceutical are compared in over 100 different analytical assays and functional assays to demonstrate high similarity between the two. Once the analytical process has been completed, a non clinical program, some animal toxicology, is conducted but that has been increasingly rare given the better understanding that we have of biosimilars. Finally clinical pharmacology is conducted also typically in healthy volunteers where pharmacokinetic equivalents between the reference product and the biosimilar candidate are established and then at least one clinical study performed in an indication that is highly likely to detect differences between the, or most likely to detect differences between the biosimilar candidate and the reference product conducted in one indication and then extrapolated to other indications based upon indications for which the reference product has already been approved. So the development of the biosimilar candidate occurs according to the three fifty one ks pathway, section three fifty one ks of the Public Health Service Act, and it follows pyramidal process compared to this more robust and expensive clinical development for a new biopharmaceutical. The FDA uses a risk based totality of the evidence approach to evaluate all available data and information submitted in support of the biosimilarity of the proposed product.

What that means is that they don't consider just the analytical studies or just the clinical studies or just the pharmacokinetic studies. They look at immunogenicity throughout the program and they consider everything together, not just one item by itself. This complex slide shows the current state of the biosimilars market worldwide. On the left you can see different classes: hematopoietic agents, erythropoiesis stimulating agents, granulocyte colony stimulating factor, human growth hormone, follicle stimulating hormone, endocrine proteins that are now available as biosimilars in some countries. Then we have the TNF inhibitors and the anti CD20 monoclonal antibody drugs that are used to treat inflammatory diseases, insulins, anticoagulants, and drugs that are used in oncology, as well as an enzyme that's used to replace patients with enzyme deficiency.

The biosimilar pathway in the European Union was initiated in 2006 with the approval of Somatropin Biosimilar, Omnitrope, which was the first biosimilar approved in the world in the European Union. There are now 58 biosimilars that are approved by the European Medicines Agency and available on the market in the European Union. The United States came later to the biosimilar world. As I pointed out, the Affordable Care Act passed in 2010 established the pathway for biosimilar evaluation and approval in The United States and the first biosimilar was approved in The United States in 2016, ten years after the first biosimilar in the European Union. There are 19 biosimilars currently approved in Canada, 28 in Australia, 21 in Japan, and then 13 in South Korea, a country that hosts two of the major biosimilar manufacturers, Celltrion and Samson Bioepis.

I've got an asterisk here next to The United States number 26 because only 15 of the 26 FDA approved biosimilars are currently marketed in The United States. Let's take a look at the current biosimilars market in The United States. As of yesterday, there were two filgrastim biosimilars approved and marketed, three pegfilgrastim biosimilars approved and marketed, and one epoetin alfa biosimilar approved and marketed. So these are the hematologic drugs. Filgrastim SNDZ was the first biosimilar approved in The United States in 2016.

It's a small protein, about 100 amino acids without glycosylation, so it's very similar to its reference product, very little chance for variation because it's not glycosylated, and there's a biomarker, the neutrophil count, which is used to assess it in comparison to its reference product. So there's very good evidence suggesting that filgrastim SNDZ differs hardly at all from filgrastim reference product. The drugs that we use to treat rheumatologic diseases, the monoclonal antibodies infliximab, atalimumab, and rituximab and the fusion protein atanercept are large proteins, molecular weight of about 150,000 for an antibody highly glycosylated. So these are highly similar to the reference product but not identical. However, the biosimilar evaluation and approval process has demonstrated that there are no clinically meaningful differences between any of the approved biosimilars and the reference products for these drugs.

There are four approved infliximab biosimilars, of which three are on the market. Pfizer's biosimilar infliximab, Exifi is the brand name, infliximab QBTX has not been marketed since Pfizer purchased Hospira which markets infliximab DYYB. So infliximab DYYB is Pfizer's biosimilar infliximab, brand name Inflectra, and their own infliximab QBTX which they developed, Ixifi, has been approved but is not marketed. There are five approved alimumab biosimilars in The United States, none of which are marketed and will not be marketed until 2023. I'll discuss that later on in my presentation.

There are two approved etanercept biosimilars in The United States, neither of which is marketed because the patent for etanercept is valid until 2028. There are two approved rituximab biosimilars in The United States, both of which are currently marketed. Then there are two drugs that are used to treat cancer, trastuzumab and bevacizumab. There are five approved trastuzumab biosimilars of which two are on the market and the two approved bevacizumab biosimilars are both marketed in The United States. So there are 26 approved biosimilars but only 15 are marketed because three of the trastuzumab biosimilars, both of the etanercept biosimilars, all of the adalimumab biosimilars, and one of the infliximab biosimilars are not currently on the market.

This timeline shows the approval of biosimilars for inflammatory diseases by the European Medicines Agency and the United States Food and Drug Administration. The infliximab biosimilar CTP-thirteen developed by Celltrion in South Korea and marketed by Celltrion as REMSMA and also by Hospira as Inflectra was reviewed by the European Medicines Agency and recommended for approval and granted approval in September 2013 by the European Commission. It was not until 2016 that two more biosimilars were approved in Europe for treatment of inflammatory disease, an etanercept biosimilar Benepali and an infliximab biosimilar Flixabi. In The United States, the first biosimilar approved was Celtreon and Hospira's biosimilar infliximab called Inflectra approved in April 2016. Then Sandoz's etanercept biosimilar Rrelzi was approved in August 2016.

Finally the following month in September Amjavida Amgen's italimumab biosimilar was approved. So as of 2016 there were three approved biosimilars, one each of infliximab or well two each of two of infliximab in the European Union, one in The United States, one each of etanercept in the European Union and The United States, and then in The United States an approved atalumab biosimilar. 2017 brought six new biosimilar approvals in the European Union, three more in The United States. The European Union saw its first adalimumab biosimilars and its first rituximab biosimilars in The United States. Two more infliximab and one more adalimumab were approved.

2018 we saw another adalimumab approved in The United States, two more in the European Union. The first rituximab biosimilar approved in The United States and another infliximab biosimilar in the European Union. 2019 was a banner year for the United States Food and Drug Administration with the approval of five more biosimilars and in the European Union one more biosimilar was approved for treatment of inflammatory disease. And then this year, 2020, so far a rituximab biosimilar and an alimab biosimilar were approved by the European Medicines Agency. So you can see here that there have been an increasing number of biosimilars approved and available for treatment of inflammatory diseases both in the European Union and The United States.

I'd like to turn now to a discussion of manufacture. During the manufacture of biopharmaceuticals, which are produced by human cells these are proteins that are grown in cell culture there's normal batch to batch variability because these are proteins manufactured by living cells. There are proven acceptable ranges of variation, goalposts established during the development of the product. These are for different categories, different properties, general properties, higher order structure, impurities, both process and product related functional aspects, primary structure, product related substances such as glycosylation, particles and aggregates, and then stability. So for each of these different attributes, a proven acceptable range of variation is established by the manufacturer in consultation with the regulatory agency.

And as long as the product falls within these proven acceptable ranges of variation during manufacture, it is deemed to not pose a safety or an efficacy risk to patients, and those batches are released for market. Drift can occur during the manufacture over the lifetime of a biopharmaceutical. This is due to unintended alterations in the manufacturing process resulting in deviation of product attributes over time. In this graph on the right, the top graph, you see a gradual trend of a property that is increasing but within the proven acceptable range of variation. So although at the later time point the property has a higher value than earlier on, this falls within the proven acceptable range and the product is released for market.

Here in the lower graph you can see a sudden shift due to some unintended alteration in manufacturing that then remains stable, but since all of these values fall within the proven acceptable range, this product is released for market. Now there's also evolution and evolution occurs when deliberate process changes are made by the manufacturer. These include implementation of state of the art technology over time. Processes improve. A manufacturer may upgrade the manufacturing equipment.

They may scale up production, perhaps opening a new plant. And these changes are known to both the manufacturer and the regulators with whom the manufacturer must file notifications of these process changes. In this lower histogram, this is taken from Christian Schneider's editorial in Annals of Rheumatic Diseases from 2013 in the issue where the first two studies of CTP-thirteen, the infliximab biosimilar, were published, the PLANETAS study in ankylosing spondylitis and the PLANETRA study in rheumatoid arthritis. At that time, as of 2013, the European Medicines Agency had been informed of 37 process changes made by the manufacturer in the production of Remicade reference infliximab. There were 21 process changes reported for Enbrel reference etanercept and 18 for Humira reference adlimimab, six for MabThera reference rituximab.

So you can see here that a significant number of changes occur during the manufacturing life of a product which are known to the manufacturer and regulators but which are not disclosed to patients or providers. So we go from lot to lot to lot of a reference product where there may be slight subtle differences between the earlier lot and the current lot but the patient uses the drug, oftentimes notices no clinical significance but occasionally patient loses the efficacy of a biopharmaceutical. We don't know whether it's due to a change in manufacturers perhaps switching lots or whether it's due to the patient's disease becoming more active, we've not paid a lot of attention to lot numbers on the boxes of the biopharmaceuticals that patients use. So as I've suggested, commercial lots of bio originators of reference products are not identical. Small modifications in manufacturing processes may result in gradual changes.

This is an important paper that was published by Martin Shistel, the Chief Scientific Officer of Sandoz, a division of Novartis manufactures their biosimilars, and Martin Schistel and his lab analyzed different lots, commercially available lots of etanercept, rituximab, and darbepoetin that were produced between 02/2011 and they published their findings in Nature Biotechnology. And they found in this study here looking at etanercept, here is cation exchange chromatography before change in manufacture and afterwards. And you can see there are more basic variants here, C terminal lysine content changes, and in the glycan mapping chromatogram you can see that after the change there's more G0 glycan and less G2 phucosylation. So there are changes in C terminal lysine content in glycosylation, but despite these differences, since the product fell within the pre specified proven acceptable ranges of variation, it was marketed with no change in label. Now these proven acceptable ranges are known to the manufacturer and to the regulators but not to competitors or to patients or healthcare professionals, we have to trust that the drug fell within the proven acceptable range of variation since it was released for market.

Now most of these changes have no functional consequence but changes in the manufacturing process of a bio originator may result in differences compared to the initially approved product. Here in Martin Schiesl's paper they compared pre and post change batches of rituximab. Looking at G0 glycan content, here are the pre change range of G0 glycan in batches from 2007 to 2010, Then in batches with expiration dates between May 2010 and September 2011, there's a threefold increase in G0 glycan content. When they looked at antibody dependent cell mediated cytotoxicity, a functional assay, they found that this increase in G0 glycan was associated with an increase in antibody dependent cell mediated cytotoxicity. So the non fucosylated G0 glycan change resulted in more potent antibody dependent cell mediated cytotoxicity which could have functional consequences.

Now when a biosimilar manufacturer develops a biosimilar, they purchase all commercially available lots of the reference product over time and subject them to extensive analytical study so that they can reverse engineer the product and recapitulate the product in their biosimilar manufacturing process. Thus they establish proven acceptable ranges of variation based upon their analysis of the reference product. So here you've got an initial reference product quality range before a change in manufacture, and after the change in manufacture you've got the current reference product quality range. Assuming that the only commercially available batches are those that are falling within the current reference product quality range and not those earlier batches which fell within the initial reference product quality range, the biosimilar manufacturer develops a range for control of the biosimilar product that is comparable to the current reference product quality range. However, this range for control of the biosimilar product is narrower than the reference product quality range over time.

So theoretically a biosimilar answers to a higher authority just like Huber National Francs and the range for control of the biosimilar product is actually tighter than that for the reference product over time. But what clinical consequence does this have? I'd like to share with you some data that have been published about phase three double blind randomized controlled trial that compared a trastuzumab biosimilar SB3 Sampson Bioethesis product to bio originator trastuzumab Herceptin in patients with HER2 positive early breast cancer. In this study patients with HER2 positive early breast cancer were randomly assigned to treatment either with SB3, the biosimilar trastuzumab, or reference trastuzumab for eight cycles. They got four cycles of Doxataxil and then four cycles of Fluorouracil, Epirovosim, and Cyclophosphamide in conjunction with the Trastuzumab in both groups.

This was considered the neoadjuvant treatment period at the end of which patients underwent surgery. And the pathological clinical remission rate was assessed as a measure of success of this neoadjuvant therapy. The subjects then underwent 10 additional cycles of trastuzumab either with the biosimilar or the reference product during the adjuvant treatment period, and the end of the study was after those 10 cycles. So here you see the randomized double blinded period, and then following the end of study there was a long term extension study of sixty months, five years, during which cardiac safety and survival follow-up was conducted. Well, the primary endpoint is shown here and this is the proportion of subjects who achieved a pathological complete response in the breast.

Fifty two percent with the SB3 treated subjects, forty two percent of those treated with the reference product Herceptin, and the predefined equivalence margin for the adjusted ratio was 0.785 to 1.546. This equivalence margin is derived based upon placebo controlled trials of the reference product looking at the difference in the response between active drug and placebo, and then a fraction of that is taken, typically fifty percent. And so the 95% confidence intervals of the adjusted ratio have to fall within this predefined equivalence margin and it did. The 95% confidence intervals were 1.085 to 1.46 which fell nicely within this predefined equivalence margin. So this was successful trial that demonstrated biosimilarity and this SB3 was approved as a biosimilar to bio originator trastuzumab.

Now looking at the adjusted difference between the two groups, SB3 and bioregenerator trastuzumab, this was 10.7. Fifty one point seven minuteus 42 gives you 10.7. Now the predefined equivalence margin for this endpoint was minus 13% to positive 13% and the 95% confidence intervals for this adjusted difference, the lower bound fell within this predefined equivalence margin, but the upper bound was above this margin. Now since the primary endpoint was met, biosimilarity was demonstrated, but this raised some questions in the minds of the regulators. Is this truly a biosimilar or is it a bio better?

In which case it would not be biosimilar and could not be approved as a biosimilar. So to investigate this, the manufacturer Samson Bioepis subjected all of the lots of the reference product to which the biosimilar was compared to analytical studies. And what they found was that lots with expiry dates between 2015 and mid-twenty eighteen, both European Union sourced Herceptin and United States sourced Herceptin, European Union Herceptin in blue, United States in red, fell within a proven acceptable range of between 813% relative area. However, lots between mid-twenty eighteen and mid-twenty nineteen fell outside of that proven acceptable range or that range of variation. And they actually had lower proportions of A fucosylation and high mannose content.

There was another drift, a second drift between mid-twenty nineteen and 2020 which fell back closer to the original range of phucosylation. Well what significance might this have? When they looked at functional assays they looked at relative FC gamma R3A binding activity and this correlated with the proportion of A fucosylation and high mannose content. There was a decrease in FC gamma R3A binding activity, with that decrease during the first drift and then a slight return to the previous range during the second drift. There was also much lower antibody dependent cell mediated cytotoxicity activity with each of those drifts compared to the earlier lots.

So there's a functional difference in these later lots as well. So when they looked at event free survival by the drifted groups or the in blue you see the event free survival for the SB3 biosimilar. And when you look at the drifted there is much lower survival event free survival. But during up to this time point at about forty months the non drifted trastuzumab, the earlier lots of trastuzumab when the subjects that were treated with the earlier lots in the clinical trial are almost superimposable upon the biosimilar survival curve. So what this shows is that the subjects that were treated with later lots of trastuzumab reference product had lower survival than did those treated with the earlier non drifted lots or the biosimilar candidate.

This is an incredibly significant study because it demonstrates that the reference product, which falls within the proven acceptable ranges of variation and is allowed to market, has become less effective resulting in lower event free survival compared to earlier lots. Now, if there were not this study comparing it to a biosimilar, one would never have learned that there was this difference because one would not have observed that the upper bound of the adjusted difference between the two groups was outside of the pre specified equivalence range and one would never have subjected all of the lots to these analyses demonstrating that the drifted trastuzumab, the more recent lots of trastuzumab, are less effective than the earlier lots or the biosimilar. So a biosimilar comparative effectiveness clinical trial is the design by which one can determine, and really the only way that one can determine, that a reference product has lost efficacy over time. Otherwise more patients would have been dying with breast cancer and just would have been assumed that their disease was not responsive or not as responsive to Herceptin but it turns out that the more recent lots of Herceptin are different from the earlier lots resulting in a lower survival rate than the earlier lots or the biosimilar.

So turning now to a little bit more of a philosophical discussion, What are the potential benefits of biosimilars? Well, first of all, the only benefit of a biosimilar should be that the availability of biosimilars should decrease the cost of treating patients. Biosimilars should be as close to the reference product as would be another batch of the reference product. So there's really no clinical difference between the biosimilar and the reference product. The biosimilar should be less expensive, thereby decreasing the cost of treating patients.

However, lower priced biosimilars introduce market competition, provoking discounts and rebates for bio originators. That's good because it drives the price of the reference product down, and multiple biosimilars of the same reference product will probably drive the price down further. Biosimilars should be more readily available to patients for whom the reference product had been inaccessible because a lower cost might make it more affordable, and greater global access to effective biopharmaceuticals should reduce disability, morbidity, and mortality associated with inflammatory diseases. Well, what are the advantages to different stakeholders of lower cost biosimilars? To payers, greater competition in the market should result in price reductions and direct savings and spending could then be redirected toward expanded patient access either for the same molecule allowing more patients to be treated with that molecule or to other medicines allowing patients access to innovative treatments.

For providers, the availability of lower cost biosimilars should facilitate the choice of the most appropriate treatment for the patient since cost will not be as much of a barrier and has the potential to improve treatment outcomes. For patients, medications for optimal treatment should become more accessible because insurers would be less restrictive presumably for a lower priced medication. However the patient should share in the financial savings. It's not good enough for the insurer to be able to save money but for the patient to reap no benefit, whether it be a benefit in terms of a lower insurance premium or a decrease in the co payment required, the patient should share in the financial savings of a lower cost biosimilar. I'm going to talk about some examples of how biosimilars have reduced cost of medications.

In Norway, a Scandinavian country where there's a very progressive health care system, the national government has an annual tender process for hospital administered medications. The government agency charged with this invites bids from the manufacturers, all of the manufacturers of each of the products, and then in consultation with the physicians and other health care providers who use those medications chooses the lowest acceptable bid and that bid then that company gets the contract for that product for the subsequent year. So in 2014 the National Hospital Tender for Biologicals, infliximab, there were three bids, Janssen for Remicade, Hospira for Inflectra, and Celtreon for REMSMA, noting that Inflectra and REMSMA are the same drug, CTP-thirteen just marketed by different companies. The cost for REMSMA was 39% lower than that for Remicade. The cost for Inflectra 32% lower and 39% reduction in price was the winning bid.

And for 2014, REMSMA was the infliximab that was available in Norway and nearly 40% cost savings. In 2015, the tender resulted in a 69% price reduction for REMSMA compared to Remicade and subsequent years the reduction in price has not been made public but the price dropped even further. In this graph provided by Tory Kreen, you can see that the use of the biosimilar Rhamsima crossed the curve for that of Remicade, the reference product, in March 2015. So before that there was more use of the reference product but after March 2015 the use of the biosimilar SORD and the use of the reference product dropped because it was more expensive. In 2019 Paul Emory was quoted as saying that the cost of biosimilar avelumab in the coming year will be less than $3,000 annually in The United Kingdom healthcare system.

In the New York Times on 01/06/2018, an article pointed out that the price of Humira has risen from about $19,000 a year in 2012 to more than $38,000 in 2018 per patient after rebates. And another article in Forbes Magazine in July 2016 pointed out that at that time Humira can cost consumers, insurers, employers, or taxpayers $50,000 or more a year per patient. Now based upon the $3,000 a year cost of a year of adalimumab biosimilar in The United Kingdom, one hundred patients can be treated with biosimilar adalimumab in The United Kingdom for what it costs to treat six to eight patients with Humira The United States. That's striking. 12 to 15 times as many patients can be treated in The United Kingdom for the same cost of treating six to eight patients with Humira in The United States.

So in a national health system like that in The United Kingdom, the availability of biosimilars has greatly increased access to biopharmaceuticals. Now competition from biosimilars doesn't always result in a lower price for the biosimilar. In Sweden it actually drove down the price of the reference product. Over here on the left you see the European product forecast for AMGEVITA, Amgen's biosimilar ailimumab and the European sales in millions of euros was projected by 2022 to hit €140,000,000 for Amjavida. Now in late October twenty eighteen Sweden has a tender process just like Norway and AbbVie bid at a price reduction of 80% compared to its previous price for Humira which actually won the tender process.

So AbbVie came in with a price for Humira that was lower than any of the prices for the adalimumab biosimilars in that tender. So adalimumab biosimilars had been available in Nordic countries at 10 to 80% discounts but AbbVie undercut the price of the biosimilar adalimumabs in the Swedish national tender in October 2018 becoming the only aylemumab available for the year of 2019 in Sweden. However, Nordic markets are relatively small and constitute only about four to 5% of AbbVie's international business. Now AbbVie has a significant portion of its sales are in The United States. The sales of Humira in 2017 were about $18,000,000,000 of which 12,000,000,000 were in The United States and 6,000,000,000 were outside of The United States.

So it's important to AbbVie to maintain sales in The United States to maintain its revenue. As a result, AbbVie, because of patent issues, reached agreements with multiple developers of biosimilar to Limbat to forestall U. S. Market entry until 2023. AMGEVITA will be allowed to enter The U.

S. Market on 01/31/2023 in late June and early July. Samson Bioethis and Behringer Inglheim's ailimumab biosimilars will be able to launch Mylan's biosimilar ailimumab 07/31/2023 and September 30 Sandoz and Fresenius Kabi's BiosimilarAIDLIMMAPs, finally Momenta's BiosimilarAIDLIMMAP 11/20/2023. So this is in contrast to October 1638 which was the date by which most European Union countries were allowed to launch their ailimumab biosimilars were allowed to be launched in most European Union countries because the patent in those countries expired at that time. So small molecule generics.

Biosimilars are not generics. Small molecule generics are chemicals and the active ingredient is an exact copy of that in the reference product. Small molecules are much less expensive to develop and synthesize compared to, biopharmaceuticals. So the generic drug is typically launched at a 40% or higher price discount compared to its reference product and early on takes on about a threefour of the market share. On the other hand filgrastim SNDZ, the first biosimilar launched in The United States, the price discount was 15% lower than that of the reference product and as of January 2019 it has about a 30 market share.

The infliximab biosimilars however, the first one launched at a 15% price discount, the second at a 35% price discount, occupy only a 3% and a 0.4% market share as of January 2019. Why? Well, the regulatory process in The United States has been relatively slow. Early on only a couple of biosimilars were approved. In 2016 there were only four biosimilars that were available.

The filgrastim biosimilar was approved in 2015. 2016 saw one infliximab, one etanercept, one aylimimab biosimilar approved. In The United States, the patent filing is much more extensive than in Europe, and there are many more patents on a given drug, which makes it much harder for a biosimilar manufacturer to be able to contest these patents. So preemptive competition such as that by Advi limiting the release of biosimilars has also delayed release of biosimilars and lowered the uptake of biosimilars in The United States. Pharmacy benefit managers have oftentimes given bio originators preferred formulary status because of higher discounts and rebates which, go to the pharmacy benefit management company.

There's been no systematic effort to educate physicians and patients in The United States who are concerned about biosimilar safety and efficacy. And finally, there's no economic incentive in the current Medicare reimbursement system to healthcare providers to prescribe a lower cost biosimilar. Despite the United States Congress putting forth a biosimilar approval pathway and the Food and Drug Administration being proactive in approving biosimilars, the Center for Medicare and Medicaid Services has not developed an economic incentive aligned with that goal. Medicare Part B, which reimburses hospital administered medications, reimburses medications based on the average sales price. And this average sales price takes into account discounts, rebates, volume discounts.

And the Medicare Part B drugs such as infliximab are reimbursed at 106% of the average sales price. So you get back what you pay for the drug, the average sales price, and you get a 6% markup which is essentially the incentive to administer the medication. On 04/05/2016, shortly after its approval, HC PCS code Q5102 was introduced for biosimilar infliximab DYYB which reimbursed the drug at the average sales price of the biosimilar plus 6% of the average sales price of the reference product. So if the biosimilar is more expensive, you get back what you're paying for it, but you only get a 6%, the same 6% that you would get if you infuse the reference product. If the biosimilar was less expensive, you wouldn't get a lower incentive but you wouldn't get a different incentive compared to that for the reference product.

So following this, in the introduction of this code all biosimilar infliximab products were grouped under this code. As of 04/01/2018 Medicare coding was changed to allow each infliximab product to have its own average sales price, and code. So these two codes were introduced to, code for the two different infliximab biosimilars and this created price competition among biosimilars. However, it did not incentivize use of biosimilars by providers because as I've mentioned, the biosimilars reimbursed at its average sales price plus 6% of the average sales price of the bio originator. So regardless of whether you're infusing reference infliximab, infliximab DYYB biosimilar infliximab, infliximab ABDA biosimilar infliximab, you're getting the same 6% of the reference infliximab average sales price as your incentive.

So when the first biosimilar infliximab, Inflectro, infliximab DYYB was launched, the average sales price was actually $180 more per one hundred milligram vial than that for reference maveramicate and this held through the first two quarters during which there was hardly any uptake of the biosimilar. As of the 2017 the price of the average selling price of the biosimilar was now $55 lower per one hundred milligram vial than that of Remicade and this continued to drop and widen the gap so that by the 2018 there was about $130 difference between the biosimilar being less expensive than reference infliximab. At that point the second biosimilar infliximab was introduced, Renflexis, and the price was only about $7 different per one hundred milligram vial. And the price for both has decreased and again it differs only by about $20 between the two biosimilars and those are about $60 or $80 less than reference infliximab. What you can see here is that over time there's been a gradual decrease in the average sales price of reference infliximab and that largely started to happen when the second biosimilar infliximab was introduced.

The price of the biosimilar infliximab has decreased in parallel with that of the reference product. But as I showed in an earlier slide, the market share of the infliximab DYYB is only about 3% and the market share of RENT FLEXIS is 0.4. So there has not been tremendous uptake. And is that because of this lack of incentive, lack of financial incentive to prescribe the biosimilar perhaps? To look at what physicians were doing and whether there was any role that an institutional incentivization might play in increasing biosimilar use, Josh Baker at the Hospital University of Pennsylvania and colleagues looked, and I was involved in this study which was just published in Arthritis and Rheumatology, we looked patients or we looked at the use of biosimilar infliximab at the Philadelphia Veterans Administration Medical Center and at the Hospital University of Pennsylvania and affiliated hospitals, the academic medical center.

The Hospital University of Pennsylvania is located about four blocks away from the Veterans Administration Medical Center. However, the VA Medical Center the cost for one hundred milligram vial of infliximab is over $500 less than that of the reference product, an 81% savings per one hundred milligram vial. As a result, the VA Medical Center incentivizes and suggests that unless there's a good reason not to, that providers should prescribe the biosimilar infliximab. And at the VA Medical Center sixty two percent of infliximab orders were for the reference product, 38% were for the biosimilar compared to 99% of infliximab orders at UPenn Health System being for the reference product and only 1% for the biosimilar. So an institution incentivizing or encouraging, strongly encouraging prescribers to use the biosimilar because there's a financial incentive for the institution to use the biosimilar is more successful than leaving it up to providers who have no financial or other motivation to prescribe the biosimilar.

So in summary, we've talked about how all biologics are subject to variability with drift and evolution occurring over time. A clinical trial comparing a biosimilar to its reference product is the study design that may reveal loss of efficacy of a bio originator due to drift. And this is quite significant because we didn't know about this previously. The availability of biosimilars introduces market competition that should drive down the cost of biopharmaceuticals but doesn't always do that, and it does this more in a system where there's a tender, a winner takes all bidding process. However, if the actual cost of a biosimilar is not lower than that of its reference product after discounts and rebates, availability of the biosimilar introduces market competition that may result in effective treatment for patients with the reference product at a lower cost as we saw in Sweden.

So regardless, the availability of biosimilars has for the first time brought some market competition into the market for biopharmaceuticals and forced manufacturers, insurers, and providers to be more conscious of cost when treating patients. So with that, I thank you for your attention. I'll stop sharing my slide, my screen and give it back to Jack.

John, that was great. Thank you very much for that. I want to remind the audience that we're we have a few minutes for questions still. So you can hit the Q and A tab on the bottom and ask your question. Phil Moy asked a question, how will all this change in biosimilars get we'll talk about interchangeability is what he wants to know.

I can show of how that applied to

Sure. So I can show slides, but I Interchangeability is a definition that was put in the Affordable Care Act, which allows someone other than the prescribing provider to make a substitution of a biosimilar for the reference product if biosimilar has been approved as being interchangeable. As of now, no biosimilar has yet been approved as being interchangeable, and it was only in May 2019 that the FDA came up with a final document that described its clinical trial design to show that there's no loss of efficacy, no increase in safety risk with repeated switching between a reference product and a biosimilar to allow this designation of interchangeability. The provider can still write no interchange or no substitution to prevent that even if there were to be an interchangeable biosimilar. So people shouldn't worry about it.

What does the designation of interchangeable mean or what will it mean when it is given? It may be like Hebrew National Franks that that biosimilar answers to a higher authority and maybe the only way that a biosimilar can distinguish itself as being a little bit of a better biosimilar.

So, I think that right now what's going on in The United States is that there's a lot of biosimilar substitution for infliximab. Therapy that people are not aware of. So yeah, where do think that stands right now?

Okay, so that's non medical switching. So there's always been non medical switching that occurs. When we have a patient and you want to prescribe golimumab and the insurance company tells you no you can't prescribe golimumab, you have to first use adalimumab, That's not a biosimilar, it's a completely different TNF inhibitor, but your patient is getting the drug that the insurance company is determining is advantageous to the insurance company for financial reasons. So non medical switching in our institution, the cost of the biosimilar infliximab is less to the institution than the reference product, and so patients are encouraged or were encouraged to prescribe the biosimilar unless there's a major reason not to. And in that case, it's not an interchange that's being done because of an interchangeable biosimilar, but it's a non medical switch where the provider ultimately has to write for the biosimilar.

If you write an order saying that you want your patient infused with Remicade, the nurse has to infuse Remicade and the pharmacist has to provide that. However, typically what happens in institutions is that you write prescription for infliximab allowing biosimilar or reference product whichever is chosen by the hospital pharmacy.

In my hospital systems, it's if I write Remicade or infliximab, they're going to use the biosimilar they've got the contract for at a 10% discount. And the problem with that is, not so much with me, I'm a believer in biosimilars, but the problem is when the patient finds out that they're not getting Remicade, that they're getting something called Renflexis or Inflectra, and that really kind of jars them and makes them think, what do you mean? You're giving me, I'm not getting Oreos, I'm getting Hydrox cookies, I should have known. And then, you know, it just creates more work for the doctor as usual. Just the same thing with, you know, prior authorizations for drugs that we didn't, that we don't want to use.

Absolutely. But the biosimilar has been compared more closely closely to the reference product than the current lot of the reference product has been compared to the original version that you prescribed twenty years ago when it first came out. This gets into the whole issue of the nocebo effect, where a patient might not respond as well because they're worried that they're getting something else. But in the end, if the patient were to get a financial benefit, if they were told that they didn't have to pay a 20% copayment compared if they took the biosimilar compared to getting the reference product. The patient might be more willing to accept that.

Problem is that for Medicare Part B, patients have hardly any co payment, and so they don't feel any kind of financial pressure to receive either a more expensive reference product or a less expensive biosimilar.

So speaking of nocebo, there are some studies out there talking about patient perceptions of switching and how those aren't uniformly, wonderful. What do you think of that what's your interpretation of that data? And do you think that the patient attitude reflects the physician's attitude in some way?

Absolutely. If a physician is comfortable with biosimilars and explains that a biosimilar, I don't have to go into the whole explanation because I've talked about biosimilars just now. But if a physician understands the reason for using biosimilars and explains that clearly to a patient, the patient is more likely to accept the biosimilar than if the physician is angry that the insurance company is requiring them to prescribe a biosimilar instead of the reference product that they would have otherwise prescribed. There's a study that was done in Nijmegen in The Netherlands called the BioSwitch Study, in which the nurses and the pharmacists in the rheumatology clinic were trained to teach the patient about why a biosimilar was better for the patient, that it would save money for society, and that it was very similar to the reference product, and that they would do just as well. The patients that were switched to similar after that educational program took place did quite well and persisted on the biosimilar essentially the same as a historical cohort of patients treated with the reference product.

So what it shows is that education is most important in framing the use of the biosimilar, framing the transition of the biosimilar to the patient in a positive way, will be the best way to get the patient or achieve success with that patient.

So I'm not familiar with this, but does 340B pricing help with biosimilar?

Yes, but 340B pricing provides a discount for the reference product as well. Ours is an institution that gets 340B pricing, and we now have a better price for the biosimilar than we did for the reference product. Initially, we didn't. Initially with 340B pricing, the pricing for the reference product was better than that of the biosimilar, but all of that's been worked out now so that biosimilar pricing in the 340B setting is less expensive.

So should we be thinking much about biosimilars since there seems to be have been some negotiated, delay in biosimilars with the five adalimumabs and, and the two etanercepts, that we're not gonna have to use them for another five years or can't use them for another five years. You know, again, it seems like that's a major roadblock to the uptake of biosimilars.

It is a major roadblock to the uptake of biosimilars, but it's not a complete roadblock. There is the possibility that a company might launch a biosimilar at risk, which means that they have a fairly good sense that they may win the patent litigation, in which case they would launch their biosimilar and risk the triple damages that they'd have to pay if they were to lose that litigation. So it all comes down to the probability of winning or losing a lawsuit, and we're at the mercy of the lawyers.

Yeah, so there's two rituximab biosimilars. You know, rheumatology has about half the biosimilar market right now between TNF inhibitors and then the two rituximab, Ruxients and Truxima both approved for CLL and hematologic indications, but they're both approved for GPA, and one's approved for RA, I guess Truxima. And, do you see those being used right now, in the treatment of rheumatology patients?

Yes, and also it's very interesting, the whole concept of extrapolation of indications. There was a lot of concern on the part of gastroenterologists that the infliximab biosimilars had not been studied initially in their diseases, but were approved with extrapolation indications. GPA is an extrapolated indication. These drugs were studied initially in non Hodgkin's the rituximab biosimilars were studied initially in non Hodgkin's lymphoma. There was a rheumatoid arthritis study done, afterwards, but they've not been studied in GPA, yet certainly they can be used in GPA and should be used, if there's a price advantage.

Lastly, want to talk to the a silly issue, silly if you're European but confusing if you're American, and that's the suffix issue. Infliximab DYYB is the name you would use for Inflectra, the CTP-thirteen biosimilar. It's the FDA's convention for naming. Where does this sit in your mind? Because I don't think they're using this naming scheme in Europe, and if not, what are they using?

Well, in Europe, they're using the brand name, and that would get us in trouble here for CME talks. With biosimilars, really the way you can differentiate between biosimilar and the reference product, until we had approved biosimilars with suffixes, we had to use brand names because otherwise you'd be talking about a clinical trial of infliximab compared to infliximab showing that infliximab was superior to or was equivalent to infliximab. So the suffix is helpful in terms of distinguishing among different biosimilars. It's confusing. The original, the first biosimilar was filgrastim SNDZ.

It was made by Sandoz, and SNDZ was Sandoz. The concern was that if that product was sold to another company and it was ultimately marketed by company XYZ, and it was still filgrastim SNDZ, that that would be confusing. FDA initially proposed that the suffix, the four letter suffix, had to be devoid of meaning. The most recent guidance has taken away that devoid of meaning from the suffix, so I think you may be seeing suffixes that are a little bit easier to remember. There was one devoid of meaning that was etto which is the Italian word for act such as an act in an opera, ato primo, ato doe and so on.

So that has a meaning in Italy but not in The United States. So the other thing to remember about these suffixes is that they're not just for biosimilars. When you see ads on television for new biopharmaceuticals, these are applied to all biopharmaceuticals. They were going to be applied retroactively, and there had been a suffix assigned to infliximab reference product, but that's been taken away. But when you see the ads for the biopharmaceuticals used for atopic eczema and so on, they have four letter suffices as well.

So it's just a matter of getting used to this new system. As long as CME providers don't let us use brand names, we're gonna be stuck with these suffixes.

Yeah. Alright, John. That was great. Thank you for that overview. It's it's timely.

It's something we're gonna need to pay attention to. I wanna encourage everybody to watch for what John's gonna put out at ULAR in his podcast or in his writings or what video he may get him to do for us here at RheumNow. Euler starts tomorrow. We're going to have a heavy week of reporting beginning next Monday. I hope you'll follow that on RheumNow.

And again, John, good night. Thanks for doing Grand Islands.

My pleasure. It's nice seeing everybody. Nice seeing you, Jack. See you in Frankfurt virtually. Exactly.

All right. Take care, everyone. Bye bye.