Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast Narrator - ? 00:11 is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 56 I'm your co host, Dr. Kane, and Dr. Khyati Patel 00:35 I'm Dr. Patel, and today, actually, we're going to talk about a very interesting topic of biosimilars. We're going to call it entering the era of biosimilars. Dr. Sean Kane 00:45 So before we get into biosimilars, I think we really have to talk about, you know, what are some of the definitions that surround the topic of a biosimilar? So biologics is probably the first thing that we have to talk Dr. Khyati Patel 00:55 about, right? And those were the agents that came out in the market first. And biosimilars, as the name sounds, they're similar to these biologic agents. So, yes, I totally agree. We need to understand what the biologics are. And these biologic drugs or agents are basically, as the name suggests, are created biologically. They're very complex molecules, and so per batch, there could be variation in the molecule size or shape in itself. Dr. Sean Kane 01:22 When you describe it as biologically produced or created, we're talking like bacteria with recombinant DNA technology, where the bacteria themselves, or some organism, is producing these complex, typically protein oriented molecules. So it's not like some kind of test tube is creating a chemical reaction. It's literally a DNA molecule that's given to a bacteria to make the thing that we're we're wanting, which we call a biologic Dr. Khyati Patel 01:47 absolutely and like you said, some of the examples are large amino acid like more than 40 amino acids are considered large proteins, considered biologic. Some other examples are vaccines, cellular therapies or gene therapies. Dr. Sean Kane 02:01 So are these biologics approved in the same way that, let's say, simvastatin would be approved? Or is it a different process? Dr. Khyati Patel 02:08 It's a different process — it goes under the 351(a) application for a new biologic product (BLA 351(a)), and it's different in a way where the approval will also be based on the production process to minimize per-batch variability in shape and size of the molecule. Dr. Sean Kane 02:34 And if you think about this, the drug itself, you look at some of the statin, you can draw what a simvastatin molecule looks like. It's a fairly simple molecule that you could even describe all of the different atoms in it and make sure that every time a manufacturer makes simvastatin, you have the same chemical structure. When we're moving to this, we're getting really complicated in terms of, as you mentioned, maybe more than 40 amino acids. We potentially could have glycosylation, where we have sugar molecules attached to the protein molecules. At some point. It's really beyond the simple structure that it's easy to say, yes, these are identical, and things like you mentioned, in terms of the manufacturing process, could play a big role in the efficacy of that drug molecule. It's not just the structure anymore, right? Dr. Khyati Patel 03:22 Absolutely, and you know, if you think about the 3d structures of these amino acids, you know, a little tweak in the processing or making of the product can completely change the way these amino acids are attached to each other, and then also change the efficacy or safety outcomes. Dr. Sean Kane 03:39 So that, given that these are so different, probably even from a kinetic standpoint, how is it that the FDA is evaluating these biosimilars, which some people think of as kind of a generic version of the biologic drugs? But how are they evaluating these to say, Yes, this is similar enough, even though, chemically, there may be one or two carbons here and there that aren't exactly identical. How do they evaluate that? Dr. Khyati Patel 04:01 So first thing to make it clear is that Biosimilars are not generics of biologic agents. They are produced very similarly. And what I mean by that similarity is that they have to be approved based on the evidence of being highly similar to the FDA approved parent biologic agent. We call this parent biologic agent as a reference product too. So again, as we talked about earlier, this reference product already has been approved through that biologic, new biologic product pathway by FDA. And again, so it's not generic biologics. The process of making this biosimilar again, will be different because of the complexity of the molecule. And then the second thing that they look at is there's no clinically meaningful difference in terms of the molecule's safety, its purity, its potency and all in all, its efficacy. These phrases are very important, and we are. Emphasizing it, because that's the whole approval process of biosimilar that's based on these two important phrases. Dr. Sean Kane 05:07 So then at some point, I'm sure we're going to have a lot of these biosimilars on the market, and some of them are going to be biosimilars of each other, where one's the reference item and then there's a similar one or something else. Are these interchangeable products, or is there a different process for that to say that, you know, one direct molecule is similar to another one, therefore interchangeable? Dr. Khyati Patel 05:28 And it's a very good question, because we there's many different terminologies existing right now. We have biologics, we have biosimilars, and then there is something called interchangeable biological product. So what interchangeable biological product is, but it's a biosimilar item or biosimilar agent to the reference product, but it has to meet certain requirements for the interchangeability, and those requirements for interchangeability is that they should produce the same clinical results if the same product is given to any given patient and the interchange to the reference product or vice versa. So changing it from the reference product to the interchangeable biosimilar, or changing it from interchangeable biosimilar to back to the biologic product, should not produce any alterations in safety or efficacy. We know a lot of these agents are the antibody types agents, and we've heard that sometimes they're neutralizing antibodies produced and they will render the drug ineffective in some patients after a period of time and use so changing between the reference product to biosimilar product should not produce any differences in how the drug reacts in the patient as far as the safety or efficacy goes. Dr. Sean Kane 06:49 I'm sure then, because we have this more strict criteria for interchangeable biologic products, I would presume that there's a reason for having this more strict criteria in terms of being able to switch from one to the other, Dr. Khyati Patel 07:01 then that is correct. So if FDA approves a biosimilar product as an interchangeable biologic product, then a pharmacist can go ahead and change it to the biosimilar interchangeable product from the reference product without contacting the provider. We're going to talk a little bit more about various laws that are revolving around this interchange, and those laws could be state specific. So it will depend on whether your state has already approved a bill revolving around this area, or they're still waiting to see more biosimilars coming out in the market. Dr. Sean Kane 07:36 So Dr. Patel, I know that you said that with biosimilars, we're supposed to see no clinically meaningful difference in safety and efficacy and purity and things like that. But then you just mentioned that interchangeable biologic products that we should really see the same efficacy and safety profiles as well. So I understand that interchangeable biologic products have a higher bar. Could you just clarify what is the kind of difference between the two in terms of that higher bar that the interchangeable biologic products are having to achieve. Dr. Khyati Patel 08:04 Yeah, so it will make a little bit more sense as we talk about the approval process and what kind of data FDA requires for the approval of the biosimilar products. But one change from that biosimilar approval to interchangeable biological approval is that here for interchangeable biologic approval, they're looking at both safety and efficacy outcomes of the parent molecule or the reference product molecule, as well as the biosimilar molecule, and then kind of crossing that over in the same patients to make sure the patients are still producing the same outcomes. So what Dr. Sean Kane 08:41 you're saying is that the interchangeable biologic product has to be similar in the same patient, whether they're on Product A or product B, whereas with the biosimilars, it's more do we see globally, in a big group of people, that they have similar efficacy and safety between product A and B. That is correct. Got it? Okay. So where did all of this come from? It seems this is very new topic to me. Where did this come from? And you know, how has this kind of evolved over time? Dr. Khyati Patel 09:06 So we all know that Affordable Care Act was signed by former President Obama in 2010 but in 2009 biologics, price competition and Innovation Act was approved under the Public Health Service Act, and basically, under this competition and innovation act as the name states, it created abbreviated licensure pathways for Biologics that are demonstrated to be either biosimilar or interchangeable with their reference products, to make sure that we can Make somewhat affordable biosimilar options available to our patients, and that these pathways are abbreviated in the sense that these molecules are reviewed by FDA a little bit faster. Dr. Sean Kane 09:51 So really, you're saying that the whole purpose of this was to get cheaper biologic drugs in the form of having similar products that would come out. Subsequent to the parent compounds that were initially approved Absolutely. Dr. Khyati Patel 10:04 And this has to do with how much money that is involved in a development of a true biologic product versus how much it would be for a biosimilar. Dr. Sean Kane 10:13 And as I understand it, when these biosimilars and interchangeable products are approved, they they kind of have an idea associated with their generic name. Is that? Is that correct? Yeah. Dr. Khyati Patel 10:22 So in naming a biosimilar product, usually it starts with a nonproprietary name. For example, Amjevita is a biosimilar to the brand name Humira (adalimumab). Adalimumab is the nonproprietary name, followed by a four-letter suffix approved by FDA that distinguishes each product. Dr. Sean Kane 11:01 So in the case of Amjevita, that last four letters is atto, correct. So then if someone — and I imagine this has already come up — it's not like the drug's name is adalimumab-atto; it's adalimumab with a four-letter suffix that distinguishes the Amjevita product. If another adalimumab biosimilar comes out, its suffix will be different. Dr. Khyati Patel 11:41 absolutely That's correct. So if I'm seeing a prescription for adalimumab, I know adalimumab is a generic name, and there is no generic or adalimumab available, so I'm going to be able to fill that prescription as HUMIRA. But if I'm getting a prescription for adalimumab, hyphen at, T, T, O, I know the prescriber is meaning for me to dispense Amy Javita, which is the biosimilar. Dr. Sean Kane 12:06 If we go back to kind of the small drug molecules, when a provider writes for Zocor, for example, and they don't check that I cannot substitute, I can provide Zocor, or I can provide generic simvastatin, because they're AB-rated by the Orange Book. It seems like we're probably going to have different rules and different way to look things up with these biosimilars and interchangeables and things like that, absolutely. Dr. Khyati Patel 12:28 And we're going to talk about some of the practice related issues of how to substitute, whether to substitute or not. But one way to look into this kind of biologic versus biosimilar products is purple book. So we know that we have orange book for a B rated generic. So those are the regular chemical drugs. But for these biologics, FDA came up with something called purple book, and it includes all the licensed biologic products, including any interchangeable biologics or biosimilars. Dr. Sean Kane 12:58 So then if I wanted to know if adalimumab atto is interchangeable with humira's version of adalimumab, I would use the purple Dr. Khyati Patel 13:07 book that is correct. Or alternatively, you can also access this database through Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research, Dr. Sean Kane 13:18 both of which house under the FDA right. That is correct. So Dr. Patel in looking up HUMIRA or adalimumab, and the purple book, I noticed that you'll see adalimumab, HUMIRA is the brand name, and then adalimumab-atto, which is the Amjevita biosimilar. One thing I noticed in the Purple Book is that they have a column for 'biosimilar' and 'interchangeable'—in the case of HUMIRA (adalimumab), the Amjevita listing is 'biosimilar' but not 'interchangeable.' Dr. Khyati Patel 13:52 And that is a very correct observation, because so far, we have four biosimilars approved in the market, none of which have been approved as interchangeable biologics yet. So they are simply biosimilar Dr. Sean Kane 14:05 to their reference products. So what you're saying is that if I get a prescription for Humira, I cannot give Amjevita because it's a biosimilar and not an interchangeable biologic. That is correct. As you mentioned, we just have a handful of these biosimilars on the market now. What is the process to become Amjevita — the biosimilar — in the eyes of the FDA? Dr. Khyati Patel 14:26 So there is an application process under the 351(k) application, under the Public Health Service Act, and it can only be evaluated against one reference product. So let's say I want to make a biosimilar to HUMIRA (adalimumab). I can only reference one reference product, which is HUMIRA. Now, within that one reference product, as we know, HUMIRA has nine different indications for treatment as a biosimilar. Other manufacturers, I do not have to have that biosimilar marketed towards all nine indications that HUMIRA has. I can just pick and say I'm going to market for Crohn's and another manufacturer can come and make another biosimilar, adalimumab, but their approval indication is in patients who have rheumatoid arthritis. So it could be for multiple indications. It could be for one indication, but it could only reference one of the biologic product. Dr. Sean Kane 15:32 So again, from the prescriber point of view, we're only talking biosimilar. So these are not interchangeable biologics. So for example, if I'm a prescriber and I want to use adalimumab, and I have the option of using either HUMIRA or Amjevita. If I was to use Amjevita, I could certainly use it off-label for something it hasn't been approved for. For example, uveitis is a HUMIRA-only indication that Amjevita did not pursue. The danger in doing that, though, is that there's no guarantee from the FDA side that it would actually be efficacious because they didn't study it for that specific indication as a biosimilar. Absolutely, that is correct. So then I understand that they're going to select one reference biologic product. They're going to typically at least start with one indication, but pursue multiple indications if they want to. What are some of the actual things that are evaluated during the 351(k) application for being a biosimilar? Dr. Khyati Patel 16:25 So obviously, they're looking biosimilarity to the reference product, which we will talk about in just a moment, how that is proven. But they're also looking at same mechanism of action, conditions for use, route of administration, dosage form, strength as the reference product, as we mentioned earlier, about some of the conditions or indications for use could be different depending on what you're putting in the applications for in addition to all this, the manufacturing, packaging, storage requirements should also meet the standards and talking about the product being biosimilar to the reference product. The biosimilarity is proven by various different studies. So the first study that they're looking at are analytical studies. They these are the main studies will be proven, will be proving similarity. And here they're looking at really the structural and functional characteristic of the molecule. Molecules functions, critical quality attributes. So if you're looking at more of the physiochemical structures and qualities and qualities and features of the drug product, the molecule itself, and then they're looking at animal studies, where most of the toxicity or the safety data or outcomes are derived from, and as far as the clinical studies in human subjects, we are looking to get data for pharmacokinetic and pharmacodynamic parameters and immunogenicity to demonstrate safety, purity and potency in human conditions. Dr. Sean Kane 17:56 As you mentioned, that immunogenicity is actually a really big deal, because with many biologics, patients can actually develop antibodies to the drug molecule on therapy, and if that happens, typically, the drug molecule doesn't work anymore. Again, we're still far beyond the idea of the simple chemical molecules, and now we're going into this very complex interaction with the body, and how the drug interacts in the body, and what the body does in response to that drug that we give. So really, we're in a different field at this point, absolutely. Dr. Khyati Patel 18:24 And so these are the kinds of data FDA is looking for under the 351(k) application for a biosimilar. Dr. Sean Kane 18:31 You know earlier you mentioned that the whole point of this in 2009 was to make some of these biologic drugs cheaper. So how good have we done with that in terms of improving the cost of some of these biologic molecules. Dr. Khyati Patel 18:44 So if you look at from R and D perspective, we're talking about three figures of million dollar involvement, or money involved in developing a reference biologic, like a brand new biologic product. If we compare that R and D money to what's involved in a biosimilar product, that's single digit million dollars. So if you if you look at that, that is a huge difference of how much R and D money is involved. But when it comes to patient side, because really, why are we doing this? R and D is to make products a little bit cheaper for our patient, you know, end users, we're seeing maybe 15 to 30% difference, and when we compare it to the actual biologic drug So Dr. Sean Kane 19:26 you're telling me that we're seeing up to maybe a 100x difference in development cost between hundreds of millions to single digit millions. But unfortunately, on the consumer side, we're seeing somewhere between a 15 and a 30% difference in prescription drug cost for the patient. Dr. Khyati Patel 19:43 That is true, and this is for cash paying patients. But if I am a PBM who is processing, you know, drug claims, I'm going to jump over the bio, similar product as soon as it comes available in the market, because on the drug warehouse prices, it's going to be a little. Bit cheaper for a PBM to afford it. So actually, I've seen one of the agents that we will talk about in just the short future. We've seen formulary change already, and patients are coming to me and approaching and saying, Hey, this is going to be generic, our first preferred drug in my formulary, starting this April. So we're going to make that substitution coming soon. Dr. Sean Kane 20:20 So you know, we've we've alluded to a lot of differences between the idea of a biosimilar, interchangeable biosimilars, and how it's really different than a simple chemical, molecule, generic product. So what are some of the practice related issues that are coming up? As you said, as we're seeing PBM starting to jump on the bandwagon of a biosimilar product and things like that. Dr. Khyati Patel 20:40 So writing prescriptions to distinguish all three different names we just mentioned will be very important. And so if a physician or prescriber truly means to write a product for biosimilar, they should write the non proprietary name, hyphen and the last four distinguish suffix letters. Writing just the non proprietary name doesn't mean that it is a biosimilar product. And here is that caveat between whether we can change it from the reference product to its biosimilar item or not. And you looked up the purple book and you mentioned that none of them are approved to have that I that I stands for interchangeable. So as of right now, none of the pharmacists are going to be just able to change it to a biosimilar without prescribers approval. Like I said, the laws are different per state. And so for example, I can give the Illinois law Senate Bill 455 was signed into law in 2015 and they're saying that the interchange to a biosimilar product is allowed if the product is approved as interchangeable biosimilar, which we established, none of them are yet a prescriber did not designate that the substitution is not allowed. So they did not check that DAW sign, or they did not write on the prescription that do not substitute, and that the patient was informed of the substitution. So all of these three conditions has to be met before we can actually change it from a parent product to a biosimilar product. Dr. Sean Kane 22:14 So just to clarify: if my prescriber writes 'adalimumab' (not a brand), and they don't specify HUMIRA or Amjevita (adalimumab-atto), then the prescription by nonproprietary name defaults to HUMIRA unless the prescriber explicitly writes the biosimilar suffix. Dr. Khyati Patel 22:35 give me? Ideally, that means the prescription is for HUMIRA, not Amjevita — unless the prescriber specifically wrote Amjevita (adalimumab-atto) or included the four-letter suffix. Dr. Sean Kane 22:54 So that's actually really interesting. So we're so far removed from the idea of a generic product at this point, even if they don't check dispenses written the DAW code, even if they don't do that, it's really difficult for the pharmacist at this point to really do that, 15 to 30% reduction in cash cost substitution, until we see some of these interchangeable biosimilars. And again, we don't have any of them yet, correct? Dr. Khyati Patel 23:19 So that's what the pharmacist can do and cannot do based on this interchangeability. But a physician and a patient can definitely discuss some of the available option and decide that, hey, we're going to go about a similar pathway because there is a cost saving for my patient. Dr. Sean Kane 23:36 And of course, on the retail side there's nothing prohibiting a pharmacist from calling the prescriber and getting a verbal yes to prescribe Amjevita instead of HUMIRA, even if the prescription was written as adalimumab. Got it? Are there a lot of these biosimilars on the market? I feel like I haven't seen a lot of them yet. But again, it's a fairly new law that even came up with the designation of a biosimilar, which was in 2009 Dr. Khyati Patel 24:06 that's a very good question. So when I was taking some of the students to the hill and talk about biosimilars as the one of the legislations and stuff, students always ask me, well, has there been a biosimilar product approved in the market yet? Well, at that time, there wasn't. But now we are looking at about 50 different biosimilar products in the pipeline, four of which have already been approved. Some of the examples we mentioned were Amjevita (adalimumab-atto) — that was a recent approval. One of the first one approved were Zarxio, which is the biosimilar for filgrastim. It's developed by Sandoz. Dr. Sean Kane 24:40 So just to shift gears a little bit, you know, when we were planning this podcast episode, I actually thought that Basaglar (insulin glargine) was thought by some to be a biosimilar of Lantus. But it sounds like that's actually not the case in terms of from the FDA point of view, in terms of what is a biologic and a biosimilar and things like that, Dr. Khyati Patel 24:58 that is true. So. So that was a misnomer, but actually Basaglar was approved through the small-molecule pathway. And what these small molecule drugs are, they are chemically synthesized. They're simple structures. There is some consistency from batch to batch when you're looking at the molecule size and shape. And so some of the examples that are approved through the small-molecule drug pathway are insulins (including Basaglar) and some GLP‑1 agonists. Now within those GLP one agonists, we're looking at, albiglutide and dulaglutide. And those are very large molecules, and so because of the large molecule they're approved through biologic process rather than the small molecule process. Dr. Sean Kane 25:42 So given that you're saying that you know some of these protein based injectables, it may be approved on the small molecule pathway, and it may be approved on the biologic pathway. And in the case of incidler Gene, it was approved on the small molecule pathway, Dr. Khyati Patel 25:55 That is correct — the FDA created a new category and called Basaglar a follow-on product, which is similar to basal insulin glargine. This was approved in 2014 but, due to patent issues with Lantus and Toujeo, it was introduced to the U.S. market later. Dr. Sean Kane 26:17 So interestingly, it seems like even to confuse matters more, for insulin, large gene, because it was approved on that small molecule pathway, we in the US cannot have a biosimilar because it was never approved as a biologic product, right? Dr. Khyati Patel 26:32 And that's that's where the whole confusion whether Bassler was a biologic or biosimilar came from, because in EU, vascular is approved as a biosimilar agent, and the brand name for which is a basketlr. Dr. Sean Kane 26:46 So they came up with vascular it's not a biosimilar, but it's this follow on a product approved through the small molecule pathway at the FDA, right? Dr. Khyati Patel 26:55 And they had to do it because FDA said: the parent/reference product (insulin glargine — Lantus or Toujeo) has not been approved through the biologic pathway, so you can't compare a small-molecule parent drug and call Basaglar a biosimilar. Dr. Sean Kane 27:15 And yet, even though insulin glargine is a small-molecule entity, we still cannot call Basaglar a generic product. Dr. Khyati Patel 27:23 That is correct, and that's why they came up with this new category — Basaglar is a follow-on product highly similar to insulin glargine (Lantus). Dr. Sean Kane 27:32 So I'd assume then, because Basaglar is not a generic product, it's a follow-on product, they probably had to have some clinical data to support its use for FDA approval. Dr. Khyati Patel 27:43 process, right? So it was, again, somewhat of an abbreviated approval process, and they looked at clinical data from two different trials. The one trial that was done in type one patient included about 500 patient and one trial in type two patient included about 700 patients. And if you look at efficacy, efficacy was pretty similar, and side effects were also very similar, where they noticed, as usual, hypoglycemia, some allergic reaction, injection site reaction, itching, rash edema and weight gain, as we see with all insulins. Dr. Sean Kane 28:18 So then, basically, if you think about Basaglar, we have a cheaper basal insulin that is going to be competing with Lantus and Toujeo in the insulin glargine market. What has been the insurance or PBM response in terms of tiering these products? At this point we have three insulin glargine products available on the market. Dr. Khyati Patel 28:46 Yeah, it's very interesting. You know, patent is always a very nice game that the pharmaceutical companies play. But I was surprised to see patients say their formularies would change in April 2017 — that they would have to switch from Lantus to Basaglar because Lantus would move to a higher tier or no longer be covered. So it's kind of interesting that the PBMs already had evaluated this data and already decided that as soon as the market launch happens, which happened in December 2016 we're going to change it. So then, Dr. Sean Kane 29:27 Dr. Patel, when you have patients on either Lantus or Toujeo, let's say 100 units of either one, how are you converting them over to Basaglar? Dr. Khyati Patel 29:36 so the 100 unit to 100 unit conversion is actually one to one conversion. But if you have a patient on NPH who's dosing it twice a day, NPH dosing, you want to convert them to vascular, then it will be 80% reduction on the total NPH dose. So to Dr. Sean Kane 29:51 kind of wrap things up, I think that this is obviously a very complex topic that's going to be evolving over time. It seems like the biosimilar pathway. 350, 1k, this is where these Biosimilars are being approved based on PK, PD, immunogenicity and also efficacy and safety for the products, right? Dr. Khyati Patel 30:10 And the biosimilarity, again, means that they are highly similar to the available reference biologic product, and there is no clinical meaningful difference between the two. Dr. Sean Kane 30:19 And yet we still don't have any interchangeable products that would be treated where you can as a pharmacist with no prescriber intervention change between two different biosimilar products Dr. Khyati Patel 30:27 that is correct. And more and more states are getting in line with this new approvals and writing laws specific to those states. So make sure you follow your state specific requirements Dr. Sean Kane 30:37 In terms of Basaglar: this is not a biosimilar because Lantus, the original reference product, was approved under the small-molecule pathway. Basaglar is a follow-on insulin product and is slightly cheaper, but it is not interchangeable with Lantus or Toujeo. Dr. Khyati Patel 30:55 That is correct. And we do get to see some some cost difference, but not whole lot. It's about 15 to Dr. Sean Kane 31:00 20% so with that, please visit us at HelixTalk.com we're also on Twitter at HelixTalk. We love five star reviews and iTunes. And with that, I'll sign off. I'm Dr. Kane. I'm Dr Dr. Khyati Patel 31:10 Patel, and as usual, study hard. Narrator - Dr. Abel 31:13 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there Narrator - ? 31:24 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.