Biosimilars and Their Use in Cancer Treatment

00:00:00:00 - 00:00:29:23
Unknown
Hello everyone. Welcome to today's webinars. Biosimilars and their use in cancer treatment. I'm Kate Pfitzer, the Metastatic Breast Cancer Program Director at SHARE. And I'm Joan Mancuso, a breast cancer advocate. Before the presentation begins, I'd like to tell you a little bit about SHARE. We're a national nonprofit that supports, educates and empowers anyone diagnosed with breast or gynecological cancers.

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Unknown
We provide outreach to the general public about signs and symptoms because no one should have to face breast, ovarian, uterine, cervical or metastatic breast cancer alone. For more information about upcoming webinars, support groups, podcasts, and our help lines, please visit our website at Share Cancer Support dot org.

00:00:50:24 - 00:00:55:19
Unknown
Now I'd like to hand it over to Dr. Gralow to introduce herself.

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Unknown
The screen is yours.

00:00:58:21 - 00:01:37:09
Unknown
Thank you very much. My name is Julie Gralow. I'm a breast medical oncologist, and about three years ago, I joined the American Society of Clinical Oncology as the chief medical officer. I also have had extensive experience in clinical trials with the U.S. Sunshine's SWOG Clinical Trials Network, and I was the executive officer for breast and lung cancer. Prior to joining ASCO about 30 years ago.

00:01:37:09 - 00:02:23:03
Unknown
Now, as I was just starting off on faculty, I was the co-founder of a group in the Seattle area called Team Survivor Northwest, which is a nonprofit aimed at helping female cancer survivors improve their health, their physical and their emotional health through fitness and exercise. And then I was also a professor of global health, and in that role formed the Women's Empowerment Cancer Advocacy Network, or Weekend, where I helped promote women cancer patient advocates starting in Eastern Europe, Central Asia, mostly the former Soviet Union in the beginning, and then in East and Southern Africa.

00:02:23:05 - 00:02:41:10
Unknown
So that's my background. And I am going to talk to you today about biosimilars. And do you want me to share my screen or. Yes, Doctor. There we go.

00:02:41:12 - 00:03:12:22
Unknown
Okay. I'm going to get rid of some of these floating things. Okay. And I hope this is sharing. Okay. Can you confirm it's perfect? Okay, great. So, thanks to Share and the team for inviting me to speak to you today on biosimilars and their use in cancer treatment.

00:03:12:24 - 00:03:48:17
Unknown
So let's start with what are biosimilars? It's kind of a funny name and it's a little bit complicated. So biosimilar drugs are what we call biological products or biologics. So there are actually a lot of biologics in cancer treatment and beyond out there. And they're different from kind of a classic medicine in that they're generally very large molecules and they're made from living sources.

00:03:48:19 - 00:04:23:04
Unknown
So they're grown up in bacteria, yeast or animal cells. This is how you produce them. And monoclonal antibodies. There are a lot of antibodies now in cancer treatments. They are they're produced in cells that are grown in big vats, if you will, and then you purify out the protein, these monoclonal antibodies. And so that's what makes it different from a classic molecule where you can just kind of make it in in the lab and it's not grown and big that you don't have to purify it out.

00:04:23:06 - 00:04:59:01
Unknown
So vaccines are biologics. These monoclonal antibodies that I'll talk more about are biologics. They're very important in cancer, insulin is a biologic and then gene therapy. So biologics are used to treat a lot of diseases, including cancer. And I told you that they're usually big and complex and all. But insulin is considered a very simple biologic protein, whereas monoclonal antibodies are much more complex.

00:04:59:03 - 00:05:26:08
Unknown
And so where does this name biosimilar come from? Well, even within a brand name biologic medicine, every time you make a big batch of it, you grow it up. You know, the antibodies are made in these cells, you purify it out. The composition of that batch can vary a tiny bit in terms of the kinds of sugars you put on the protein, etc..

00:05:26:10 - 00:06:00:08
Unknown
So we we say the composition of biologics can only be defined by a certain extent. Now we have very narrow windows and it's always tested. Each batch is tested to how much does it compare to the reference batch that was made early on. But there's a little bit of minor variability that happens, whether you're making the reference biologic, meaning the brand name approved drug or whether you're making a biosimilar, which is a version of that biologic.

00:06:00:09 - 00:06:28:19
Unknown
And so we as we make biologic, as we make biosimilars to those biologics, we have to be very carefully tracking the the range of minor variability to make sure we're consistent in terms of safety and efficacious. So again, I told you a little bit about this. Here is how you make a monoclonal antibody. You know, they are made from living organisms.

00:06:28:21 - 00:07:00:19
Unknown
And so you've got the cell line here and you've got it's it's grown, you know, in an incubator, and then you've got this upstream processing, you've got a big that, then you purify it, you separate it, you characterize that, and then you put it in a vial. So again, I haven't stress this enough. They're more complicated to to purify, process and manufacture than standard drugs.

00:07:00:21 - 00:07:36:16
Unknown
So biosimilars are biologics, and they have to be, by definition, highly similar to biologic that's already FDA approved. So the originator drug, the one that we're copying is called the originator or the reference product. I'm going to talk a bit about trastuzumab, a monoclonal antibody, the first one approved in breast cancer and the first one with the biosimilar and the originator or reference product would be called Herceptin.

00:07:36:18 - 00:08:09:06
Unknown
Now when I give talks, I'm actually not supposed to use brand names of drugs. That's how we're all taught. We're supposed to use the generic name. But but in this case, it's really important to point out that the originator, the reference would be Herceptin, the one that was originally approved in order to be approved as a biosimilar. The biosimilar can't have any meaningful difference from the reference or the originator product in terms of safety, purity or potency.

00:08:09:08 - 00:08:42:11
Unknown
And by definition, biosimilars have to have the same route of administration. So if it's intravenous, it has to be given intravenously the strength and the dosage form and the potential side effects as the originator. So biosimilars are very similar but not identical to the original biologic medication. And the FDA requires that there be no differences in the safety or effectiveness between biosimilars and the original biologic.

00:08:42:13 - 00:09:22:08
Unknown
They're made from the same sources, they give the same benefits when treating diseases, response rates, etc. again giving it the same strength and dosage. And they're not expected to cause new or worsening side effects. Now, biosimilars have been developed with a couple of key goals. One is that they're more affordable. So just like you know much about generics, you know, generics come on the market after a drug goes off patent and now you have competition and that usually drives down the price.

00:09:22:10 - 00:10:09:18
Unknown
But it's not just about the cost to insurance to our government, to the patient with copays, etc., but it's also biologic biosimilars were developed for equity purposes. So that more patients could get access to these drugs because they're more affordable. And that's true within the United States that lower cost drugs generally are more available. And it's also very true globally that a lot of biologics are not put on the World Health Organization's Essential medicines list or covered as part of the National Cancer Control Plan solely because of the costs, not because of the effectiveness.

00:10:09:20 - 00:10:40:17
Unknown
So biosimilars can provide patients with more treatment options, increase access to the medications and potentially lower health care costs through competition. And I've mentioned generics a little bit, but are biosimilars the same as generics? Why don't we just call them generics? I think I've given you that ammunition. You know, they are very similar, but they're not identical. And a generic is basically identical.

00:10:40:19 - 00:11:07:03
Unknown
So biosimilars and generic drugs are versions of a brand name drug. And the differences, the active ingredients of generics are smaller, simpler. They can be copied. Biologics can't be copied exactly, because they contain a mix of many slight variations. And again, just to bring home the point, the generic is a term we use to describe a non biologic copy.

00:11:07:08 - 00:11:44:01
Unknown
So they're smaller, less complex. They're they really are identical to the reference or originator product. Biosimilars, larger, more complex come from living organisms. Highly similar, but never actually exactly the same. So here's the timelines in Europe on the left and in the US on the right of oncology biosimilar development. So biologics are kind of a relatively new category of drugs, certainly in oncology.

00:11:44:03 - 00:12:15:12
Unknown
And as the originator biologic patents approached exploration, which meant that you could bring in competition, we had to develop what we call regulatory approval framework. So the FDA, the EMA, the European Medical Association, had to figure out how we're going to assess and approve biosimilars. In Europe, they started before us in part because their patents generally were off before ours.

00:12:15:14 - 00:12:51:14
Unknown
So Europe was ahead of us in terms of establishing a framework for how biosimilars would be evaluated at the regulatory level. They in Europe, they approved the first oncology supportive care, biosimilar, epoetin, erythropoietin. It's a red blood cell growth factor to keep your your red blood cells up. And they approved their first therapeutic oncology biosimilars, trastuzumab, which is Herceptin and bevacizumab, which is Avastin in 2017.

00:12:51:16 - 00:13:20:03
Unknown
In the U.S., the FDA took longer to figure out our regulatory framework essentially. And in 2010 we had something that came along as part of the Affordable Care Act called the U.S. Biologics Price Competition and Innovation Act. In 2015, we approved our first oncology supportive care biosimilar, which was still Grasim or G6, for a new position that keeps your white cells up.

00:13:20:04 - 00:14:02:07
Unknown
Many of you may have been on that drug and in 2017, the FDA approved our first oncology treatment biosimilars, again, the same ones that they approved in Europe in 2017, trastuzumab and bevacizumab. So they haven't even really the treatment biosimilars in cancer have not even been around for for ten years yet. But it's really speeding up. As of August, as of this month, there are 59 FDA approved biosimilars, but they're only for 15 different reference biologics.

00:14:02:07 - 00:14:34:20
Unknown
And this goes across all disease types, not just cancer. 26 of them are oncology. But again, 59 sounds like a lot. But most of them, you know, the originator has 3 to 5 copies. So right now, for the cancer treatments or the cancer therapeutics in the U.S., we have three biosimilars. Bevacizumab, there are five different bevacizumab, two biosimilars, trastuzumab or Herceptin.

00:14:34:20 - 00:15:04:19
Unknown
We have six different biosimilars approved. And for Rituximab or Rituxan, which is used to treat lymphoma mostly we have three biosimilars for cancer supportive care drugs. We have for reference or originator products. I told you Epoetin Alfa, that was the first one that was approved in Europe. There's only one biosimilar version of that eelgrass stem CSF new pigeon.

00:15:04:20 - 00:15:38:18
Unknown
There are four versions of biosimilars peg. So Grassington, which is new last year, that's a long acting CSF. There are six biosimilars and just earlier this year denosumab got approved as a biosimilar. I think it's it hasn't come on the market or it's just coming on the market and that would be excessive, which we used for patients with bone metastases to try to quiet down the bone metastases and prevent development of more.

00:15:38:20 - 00:15:51:06
Unknown
Also, in a different dosage and strength, we can use denosumab to prevent or treat osteoporosis.

00:15:51:08 - 00:16:25:07
Unknown
So I know you don't need to know or want to know probably all the details of how we develop these drugs. But for a brand new biologic, say we have a new antibody that looks like it targets something on ovarian cancer. The FDA has a clear pathway for the development of that biologic and the bulk of the data you start with a little bit of analysis and nonclinical work that might be in animals and then you do a lot of analysis.

00:16:25:07 - 00:16:56:13
Unknown
But to get approved you need big, huge clinical trials comparing the biologic to the standard of care to show that it's safe and effective. So the original biologic lays all the groundwork for targeting. Maybe that receptor on ovarian cancer actually works and it's not harmful. So there's an emphasis on safety, purity, potency when it comes time to develop the biosimilar from that biologic.

00:16:56:15 - 00:17:35:10
Unknown
You've already proven that it's safe to have an antibody that binds to that target, for example, and that it doesn't cause excess toxicity. Everything causes some toxicity but doesn't cause excess toxicity compared to the bio biologic. And then the clinical trials that have been mandated are much smaller because you're really trying to show that within a given window that they look like they're giving the same side effect and the same response rates and benefits as the originator.

00:17:35:12 - 00:18:11:06
Unknown
So biosimilar development, you don't need the huge, huge trials showing that hitting that target with this antibody works. You need to show that it's similar to the reference product. And I know what concerns a lot of physicians and lots of patients is how do we know that biosimilars are the same quality as the reference product? And the FDA outlines, you know, how they're helping ensure us, the prescribers and the patients getting the drugs, that biosimilars are good quality.

00:18:11:08 - 00:18:52:09
Unknown
So they mandate a lot of research by the manufacturer to demonstrate high similarity. And then they do studies to show that there are no meaningful differences in safety, purity or potency. And then they review all of that data. The FDA goes in and inspects the manufacturing facilities and importantly, even after the biosimilar is approved, just like with any other drug they do post-market meaning after approval, drug safety surveillance that's required to be reported to the FDA and the manufacturers have to track it as well.

00:18:52:11 - 00:19:23:07
Unknown
So biosimilar naming is is kind of funny and it's very confusing. So I told you already that, for example, for trastuzumab, we have five or six different biosimilars that are approved and yet they all start with trastuzumab. That's the name of the antibody. And we need to be able to distinguish the biosimilars from the reference product, but the biosimilars from each other as well.

00:19:23:12 - 00:19:52:03
Unknown
So that if there were a problem that we would know which one was causing the problem. Right? So what the FDA decided to do was you take the the name of the core drug, which we're talking about just to be trastuzumab and they give four lowercase letters that are like randomly generated and put it after that. Now, the companies can come up with their own trade names and they do.

00:19:52:05 - 00:20:30:06
Unknown
But this is the generic nomenclature for the six different trastuzumab biosimilars that are out there and approved right now. So let's delve a little bit more deep into trastuzumab. If it targets HER2, the human epidermal growth factor receptor two protein, which is found on maybe 20% of breast cancer. It is a monoclonal antibody. It's you know, we make our own antibodies all the time, but with our immune system to fight infection and things.

00:20:30:08 - 00:21:10:14
Unknown
And it was created in the lab and when it's made, it's produced in Chinese hamster ovary cells, the reference biologic Herceptin, that was the first biologic approved in breast cancer, it was approved in 1998 in metastatic breast cancer and then 2006 in early stage breast cancer. And then the first trastuzumab biosimilar was FDA approved in 2017 and it didn't launch and we didn't actually have anybody receiving these trastuzumab biosimilars until 2019.

00:21:10:14 - 00:21:51:06
Unknown
So it's only been about five years. And the delay between FDA approval and the U.S. launch was due to patents, expiring settlement agreements between the manufacturers. There's lots of stuff that goes on where, you know, the company that's been making the drug Herceptin for so long is looking to keep its patent life as long as possible. And and yet, because of all this difference in the way that the U.S. grants patent prolongation and protections actually trastuzumab went off patent in India and the trastuzumab biosimilar was available in India in 2014.

00:21:51:08 - 00:22:26:07
Unknown
So in India we've got more than ten years of experience using trastuzumab, biosimilars. This is a paper that came out around the time that the trastuzumab biosimilars were being considered, and this is just showing the global need for a biosimilar because patients were not getting access to this really important HER2 targeted antibody. And so this paper looks over a 15 year period between 2000 when trastuzumab was first approved.

00:22:26:07 - 00:23:01:15
Unknown
I think I told you in 1998 for metastatic breast cancer. So this looks between 2020 15 at the percentage of patients who had HER2 positive metastatic breast cancer, who didn't get trastuzumab or any HER2 targeted agent in the U.S., it was 12%, which means 88% were, but still 12% in the US did not have access to it for whatever reason in Europe, the number who didn't have access to her two antibodies was higher ranged by country 27 to 54%.

00:23:01:17 - 00:23:37:19
Unknown
In China, it was about 27 up to 50%. And then trastuzumab was approved in early stage breast cancer later. So this period looked at 2005 to 2015 when trastuzumab was approved and early stage HER2 positive breast cancer and people who still weren't getting it in that time frame with early stage breast cancer ranged from about 20 to 60% as you looked across the higher income countries North America, Europe, Australia, New Zealand, China.

00:23:37:21 - 00:24:17:21
Unknown
But there was less than 10% availability of anti HER2 therapies during this time periods in low and middle income countries, the real 90% plus of patients in rest of world in low and middle income countries were not able to get her two targeted antibodies, primarily because of the cost. So I've gone over what the general FDA strategy is for biosimilar the trastuzumab biosimilars they had to show that the antibodies that they made were highly similar in structure and function and binding to her too.

00:24:17:23 - 00:24:49:18
Unknown
They then did clinical pharmacology. G where you actually give these drugs. It could even be to healthy humans, but to humans in general. And they show that the way the drug is distributed and metabolize is then excreted and the biologic response is the same as the originator. And then especially with antibodies, we need to make sure that we we don't get what we call immunogenicity, that the antibodies are causing us to react to these for antibodies.

00:24:49:20 - 00:25:33:09
Unknown
So we've got clinical trials that were done that showed that the biosimilars were similar to the originator. And then we've got very active ongoing post-approval activities to make sure that they're safe and they're effective. And this is I just show you data from one trial. This was the heritage trial that showed that one of the biosimilars to trastuzumab was compared to the originator Herceptin, and they were given with attacks, tax and drug and a relatively small study, about 500 patients.

00:25:33:09 - 00:26:04:00
Unknown
They showed that the response rate was similar, not statistically different. If anything, numerically, it might have been even a little better for the biosimilar, but it was statistically the same, about the same response rate and the number of patients with one or more serious side effects was statistically the same. Now, I told you the biosimilars are approved at the same dose and the same route of administration as the originator.

00:26:04:02 - 00:26:54:06
Unknown
So very shortly after the trastuzumab biosimilars came on the market. Now we had approval in the U.S. for giving trastuzumab Herceptin underneath the skin as opposed to intravenously, and this just shows a picture of a subcutaneous injection. And so that means that now we can't give the biosimilar subcutaneously. That was an intentional strategy of the company that made trastuzumab that they now got a new patent for taking trastuzumab and adding something called higher on a dose that helps break down the area so that the trastuzumab can go through the skin and get absorbed into the blood vessels.

00:26:54:08 - 00:27:23:08
Unknown
And they got a new patent on it in 2019. So we're not going to have subcutaneous biosimilars to trastuzumab or other antibodies until those patents expire. The patent for subcutaneous trastuzumab is due to expire in the U.S. in 2030. So there are things that happen, you know, at a market level to try to keep the branded name on the market for as long as possible.

00:27:23:10 - 00:28:00:09
Unknown
And this is one strategy. So right now, pretty much any antibody actually could be given under the skin, but they were developed to be IV infusions. And and so this has been a strategy to prolong the patent. So this is what happens after approval. There's what we call pharmaco vigilance, where we're looking for product quality after approval. We look at long term safety now with biosimilars.

00:28:00:09 - 00:28:34:21
Unknown
And this might be why I've been asked to talk with you about it. As you know, there's both patients, but also physicians, you know, have been slow to accept biosimilars. There's been, we call it maybe a nocebo effect that if, you know, you're getting the non branded biosimilar, you might as the physician report worse symptoms as a patient report or symptoms than if you thought you were getting the branded drug.

00:28:34:21 - 00:29:07:11
Unknown
There's been some concern about that. And then I'm going to go into a little detail about something called biosimilar interchangeability and substitution, because the European Regulatory Group and the U.S. FDA have somewhat different positions. And I'll explain what that means in a little bit. ASCO, the American Society of Clinical Oncology, which is the professional organization I'm the chief medical officer for We've we've really been reviewing this.

00:29:07:11 - 00:29:43:19
Unknown
Our our job is to, you know, help our members understand these new drugs. For example, understand side issues, how we should use them, etc.. So we've issued three different statements over the years on biosimilars and when you can change interchangeability, etc.. And also, you know, we issue clinical practice guidelines and we really use evidence to try to make recommendations for what the best way to treat a given situation is.

00:29:43:21 - 00:30:19:23
Unknown
And so we've looked in our guidelines where we've where we've recommended biologics of any kind across any cancer type. And for the most part, we've said that if we've said you can use trastuzumab or bevacizumab or this antibody drug conjugate, and if there's an approved biosimilar to that drug, as long as it's approved for the indication where we said, you should give it, then we're saying it's okay to substitute.

00:30:20:00 - 00:30:44:22
Unknown
But we also said that the reflective switch between like the brand name reference product and the biosimilar without the knowledge of the prescriber or the patient is not recommended. So if there's a switch done because now all of a sudden your insurance says you can only get this biosimilar and not the reference, or if your pharmacy is only stocking one version of the drug.

00:30:44:24 - 00:31:26:09
Unknown
If that happens, they at least need to tell you about that. The both the prescriber as well. Who then should alert the patient and and so this whole issue of switching between the originator or the reference product and biosimilars has been part of the reason why there's been some slow acceptance, actually. And as I've already indicated, there could be a lot of reasons why treatment could be changed from the reference product to a biosimilar for one biosimilar to another or even back again from a biosimilar back to the originator product.

00:31:26:11 - 00:31:55:09
Unknown
But switching is typically done to decrease costs, make sure it's covered by insurance or because of drug availability. There's you were getting one version of a biosimilar and now it was cheaper to, you know, for your pharmacy to buy a different biosimilar. And so they've switched there is really strong real world evidence that switching from a reference product to a biosimilar doesn't reduce treatment effectiveness or increase risk of adverse events in Europe.

00:31:55:11 - 00:32:27:08
Unknown
They've allowed the switching. They call that interchangeability without even letting anybody know which you're getting. They've been allowing it. So we've got lots of experience. Four in Europe, for example, of switches that go back and forth without any negative effect, observed on patients. And the FDA just did a big what we call a meta analysis of the clinical trials that had a switching and a non switching arm between biosimilars and their reference products.

00:32:27:10 - 00:32:50:15
Unknown
And that big FDA analysis of the long term results of many of these clinical trials of biologics and their biosimilar has not shown a difference in outcomes between the group that did switch and the group that didn't. So this is the study. It's it's kind of published on the FDA website of the FDA review of switching or not.

00:32:50:15 - 00:33:26:07
Unknown
It was just done in 2023. They were looking to see if it was safe to do in terms of toxicity and in terms of effectiveness. They looked at 31 studies that evaluated 21 different biosimilars to eight different originator, a reference products, over 10,000 participants across these studies. And they found there were no differences in the number of deaths, serious adverse events or study discontinuations due to an adverse event between those who were in switching arms of the study and those who weren't.

00:33:26:09 - 00:34:04:10
Unknown
And the results didn't seem to be affected by the product class or the direction of the switch or the number of switches. So that gets to what we call interchangeability. So switching and interchangeability. So in the US we took a different strategy in Europe and we made a regulatory pathway for approval of biosimilars and then we added on top of that you could do some extra tests and get your biosimilar named an interchangeable biosimilar.

00:34:04:12 - 00:34:38:14
Unknown
So you have to do everything for an interchangeable biosimilar, as you do for a standard biosimilar, plus some additional studies which are mainly switching. And the interchangeable designation in the U.S. meant that the products could be substituted at the pharmacy level without the intervention of the prescribing health care provider. So if I wrote for Percept in the pharmacy could switch it with one of these trastuzumab biosimilars.

00:34:38:16 - 00:35:10:12
Unknown
Now we do that all the time with generics. I don't know. I'm sure lots of you have feels that are filled all the time and you get it and you you get the generic name for it. You're not sure which generic version of the drug you're getting. You're probably not getting the brand name much with pills anymore. So that's done all the time with generics, but with biologics, you have to have this interchangeable designation for the pharmacy to be the one who decides to switch.

00:35:10:14 - 00:35:35:12
Unknown
Now, it varies by state, and different states have different laws regarding interchangeable products, regarding the length of time to notify the prescriber. So basically you do need to notify the person who wrote the prescription, but they don't need to rewrite the prescription. And how much time and an advance notice you need to give to the prescriber varies state by state.

00:35:35:12 - 00:36:01:01
Unknown
Whether patients need to be informed varies state by state, and then how long the pharmacist need to retain their records about substitution varies from state to state. In Europe, the EMA considers all biosimilars interchanged label. In the U.S., very few biosimilars went all the way to get this interchangeable designation because it requires more time and money and work.

00:36:01:03 - 00:36:43:08
Unknown
None of the oncology biosimilars that I showed you have an interchangeable designation, but the FDA is revisiting this mainly based on that 2023 data as well as the real world data that comes out of rest of world showing that the switching doesn't seem to be harming patients in terms of disease response or control or side effects. I show you this if you're interested in learning more this the FDA's biosimilars action plan that was developed in 2018 and just in April of this year, 2024, they actually published a summary of all the accomplishments.

00:36:43:14 - 00:37:09:04
Unknown
But the four key areas that the FDA outlined for their action plan back in 2018, where they wanted it to be efficient, not difficult to get biosimilars approved. They wanted it to be clear. They wanted everybody to understand how you get this approval. They wanted to have good communication out to the public, to patients, to insurance companies, to clinicians.

00:37:09:10 - 00:37:34:16
Unknown
On what biosimilar terms were. And they wanted to promote competition. So you can see their summary of what they accomplished over that six year period. If you're interested. And this is something that just got posted in June of 2024 on that interchangeability that the FDA is in the process of updating its guidance to the pharmaceutical industry on interchangeable.

00:37:34:18 - 00:38:13:13
Unknown
And I put here on the slide a quote from Dr. Yim, who's the director of the FDA Office of Therapeutic Biologics and Biosimilars. She says, We've gained valuable experience reviewing both biosimilar and interchangeable biosimilar meds in the past two years. Both of them meet the same high standard of bio similarity for FDA approval. Both are safe and effective as the reference product, and the recommendations in today's draft guidance, when finalized, will provide clarity and transparency about the FDA thinking and align the review and approval process with existing and emerging science.

00:38:13:13 - 00:38:50:22
Unknown
So essentially, if you read between the lines, they're thinking of taking away the need to do these extra studies for interchangeability. Now this is up and posted, it's draft guidance and it's up for responses and comments on it at the present time. And this kind of comes out of their statement. It's a misconception that because an interchangeable biosimilar designation meets additional requirements that it's safer, experience shows that biosimilars and interchangeable biosimilars of the same safety and effectiveness.

00:38:50:24 - 00:39:21:00
Unknown
And the FDA says that because some biosimilars are now interchangeable and others aren't, that it actually creates the illusion that it's easier to switch if you've got this bio similar interchangeability designation when it's not actually the case. And they're basically saying that with all the experience, with all the biosimilars approved to date, there's really no risk between switching.

00:39:21:02 - 00:39:55:17
Unknown
So here's what's happened. Since biosimilars had a pathway for approval in the US, it's estimated that the cost savings to the United States, whether it be to the payer, the government, the patient for using biosimilars between 2015 and 2019 was $19 billion and that the projected cost savings will occur in the past four years. 2020 to 2024 is 104 billion USD.

00:39:55:17 - 00:40:29:09
Unknown
That's only in the US and this comes from a report of the Association for Accessible Medicines if you want to read it. So biosimilar savings just is exponentially increase. It's been increasing, the savings has been increasing by at least 2 billion per year. So each year the savings is $2 billion higher than the year before. And what's leading the charge are the three oncology treatment biosimilars, bevacizumab rituximab, ARB and trustees.

00:40:29:09 - 00:41:03:17
Unknown
SAMAD They are saving the most money. Biosimilars have had a positive impact on health equity. This comes from that same report from the Association for Accessible Medicines. They are delivering on their promise of expanded patient access. Of the 700 million days of therapy that used patients have had with biosimilars in this report up to 2023 344 million days.

00:41:03:22 - 00:41:37:22
Unknown
They estimated to be days that patients got these drugs that they otherwise might not have received because of coverage issues, cost issues, etc. And we really biosimilars are helping improve access to medicines that wouldn't normally have been covered or would have been unaffordable. So biosimilars do face challenges to adoption and sustainability, although it's improving the adoption of the use of biosimilars in the U.S. in particular has been slow.

00:41:37:24 - 00:42:07:15
Unknown
Two of the biosimilars out there have adoption rates of greater than 80%, but others are as low as only 13% of the time. A prescription is written for that drug as a biosimilar use. There still are misconceptions lack of education awareness among physicians and patients, and in industry and in practice and in the payers. We have misaligned incentives that are slowing it down.

00:42:07:17 - 00:42:40:06
Unknown
In some ways, there are incentives that exist in our system that the more a drug costs, the more you get paid or get rebates on or whatever. So we've got some incentive issues that are misaligned with the adoption of biosimilars. We have 106 different biosimilars that are currently in development. I'm sure number is wrong already because there's more on the market that are that are being developed all the time, but there are a lot that are being developed.

00:42:40:06 - 00:43:08:09
Unknown
So 86% of the brand name biologics that would be eligible to create biosimilars don't have a biosimilar under development right now. And the high cost of development and the uncertainty regarding the future of the biosimilar market in the US is a bit of a problem and that's what's causing many potential biosimilar manufacturers to not even develop a biosimilar for a drug.

00:43:08:11 - 00:43:41:08
Unknown
So it'll be ready to go at the time that drug goes off patent. Here's a really good reference for you if you want more information on biosimilars that was just updated in June from the US FDA. Nine Things to Know about biosimilars and Interchangeable Biosimilars. So in conclusion, biosimilars can reduce treatment costs and improve patient access to biologic therapies without evidence that they compromise quality of care.

00:43:41:10 - 00:44:15:19
Unknown
The extent to which biosimilars are being integrated into cancer treatment is depending on the acceptance by those who are prescribing the pharmacist, the regulators and patients. And we absolutely have opportunities that remain for improved awareness, acceptance, educate and knowledge. And for that reason, since we have opportunities that remain in the area, I really think share for inviting me to give this talk on biosimilars and to offer the opportunity for you to ask your questions about them.

00:44:15:21 - 00:44:55:24
Unknown
And I'm going to stop screen sharing. There we go. Thank you for the excellent presentation, Dr. Grillo, on Biosimilars. Now we're going to start with the Q&A. You can still submit questions in the Q&A section at the bottom of your screen. We will try to get through all of the submitted questions by may not be able to do so due to time constraints.

00:44:56:01 - 00:45:36:07
Unknown
So I'm going to start with the first question. Somebody is asking whether any biosimilar is being used to treat ovarian cancer. So one of the three therapeutic biosimilars bevacizumab or Avastin is sometimes used in the of ovarian cancer. We have other biologics being used across the gynecological answers. For example, we have these immune checkpoint inhibitors, immunotherapies. You may have heard about their antibodies as well.

00:45:36:09 - 00:46:02:01
Unknown
They're all still on patent, but you know, they are biologics and they will go off patent. There's a very cool new antibody drug conjugate, so don't even talk about those. We've got those for triple negative breast cancer as well as HER2 positive breast cancer, a lot of other cancer types. But an antibody drug conjugate is taking one of those antibodies and then linking it directly to a drug.

00:46:02:01 - 00:46:36:00
Unknown
So the antibody brings the the the drug inside the cancer cell, the link between the drug and the antibody is cut off and now you've got chemo delivered inside the cancer cell. So there is a new antibody drug conjugate that's been approved in ovarian cancer. Now it's going to have a long patent life. This is a fairly new drug, but it's just an example of another ovarian cancer drug that's a biologic that someday will be available, hopefully in ovarian cancer.

00:46:36:02 - 00:47:18:01
Unknown
We have a live question that we'd like to have answered. Chris Upton has many biosimilars since they must all be different. Yeah, very similar. How do the drug companies maintain the effectiveness while being different from each other and what is the change in that formulation to make them different so another company can can produce it? Yeah. So, so by design, the antibodies, the basic structure of the drug are essentially the same in all the key points, the parts that bind to the HER2 molecule and the cancer cell.

00:47:18:01 - 00:47:55:20
Unknown
The point the part at the end of the antibody that brings in complement and the T cells and everything else. There's just a little minor differences in areas that don't really, if you will matter. There might be minor differences in how the sugars are put. You know, the body puts sugars on it. Now what's very interesting in that question is when trastuzumab came out, one of the first antibodies that were used for cancer, even within the originator perceptron, the company is obligated to look at each batch and make sure it's not drifting.

00:47:55:24 - 00:48:17:19
Unknown
And there was some early evidence that when Herceptin was being made, they saw this drift in terms of the molecule just changing a little bit from batch to batch and they had to go back. I don't know how many times they had to go back, but when they saw the drift, they went back to an original cell line that was frozen down and then kind of brought it up.

00:48:17:19 - 00:48:40:10
Unknown
So even not in biosimilars, even just biologics more broadly, you can get a little bit of drift, but you're monitoring it and you can bring it back and go back to where you started from. So the answer to the question is what's different about the six trastuzumab biosimilars? They really are an antibody to HER2 that at least for the binding parts of it.

00:48:40:10 - 00:49:11:18
Unknown
The key parts of it is identical. You know, there's not much to distinguish any of them. If anything. Thank you. We have a few questions about lobular breast cancer and whether biosimilars are equally effective for treating lobular breast cancer when compared with the ductal carcinoma or ductal breast cancer. Yeah, good question. We're always looking at where can we pull out data on lobular breast cancer?

00:49:11:20 - 00:49:51:16
Unknown
So right now, the, you know, very little lobular breast cancer is HER2 positive. And so the main biosimilar that we have for breast cancer is trastuzumab, which binds to her too. So you're not going to have very many, you know, lobular because lobular generally is positive for estrogen receptor and progesterone receptor negative for her too. Now this is going to become relevant because we have an antibody drug conjugate now to her too.

00:49:51:18 - 00:50:23:13
Unknown
But trastuzumab directs to can that you've seen data that not only is it effective in classic HER2 positive breast cancer meaning three plus or fish positive, but it's also effective in two plus one plus and even some HER2 zero where you just have a faint amount of her two on the cell that's going to bring in the lobular, right?

00:50:23:19 - 00:50:50:18
Unknown
If you can get down to these low levels HER2 that we would have classically considered HER2 negative, then you've got the lobular. So we will be getting data on how are the lobular is doing with this antibody drug conjugate that's basically trastuzumab plus chemo attached to it, but that won't be available as a biosimilar for a long time if that makes sense.

00:50:50:20 - 00:51:25:19
Unknown
So how long after a patent expires that we are seeing the biosimilars being approved and available to patients? Sometimes it's pretty immediate because the companies know when patents are being expired, right? So they're developing them and also because rest of world generally has patterns expire before the U.S. because we are a little bit more lenient and patent prolongation, etc..

00:51:25:21 - 00:51:55:04
Unknown
You know, companies have geared up for rest of world before it goes off U.S. patents. So a highly competitive market trastuzumab, bevacizumab rituximab, the three treatment biosimilars we have in oncology, those are commonly used. You know, there's a big market for that. So there was a lot of interest to have a ready to go and get them out there as soon as the patent expired and all the legal stuff was taken care of.

00:51:55:06 - 00:52:22:24
Unknown
But they're going to be other biologics. And I talked about how many potential biologics aren't being developed as biosimilars, and that's because the market is so much smaller. So it's costly to develop a biosimilar. It's much more expensive to make it a classic generic drug, you know, which is much easier to produce, etc.. So that's why we're not having it developed for biologics where there's not a big market.

00:52:23:01 - 00:53:01:17
Unknown
So it kind of depends on how big the market is. You've had several questions about hormone replacement therapy or HRT and bioidentical hormone therapy or bioidentical hormones, the same as biologic or biosimilar drugs. That's a good question. You'd think from the name bio identical that they would be, but they they really aren't because the biologic or biosimilar, it's how the drug is manufactured.

00:53:01:19 - 00:53:27:04
Unknown
And in this case with kind of the bioidentical use of of estrogens of of hormones, you're just trying to match what's in the body. So that's where the bio part gets in. But they're they're not made. They're more generic, if you will, than they are. So it's all about the way they're made. They're not made in a vat, you know, in living organisms.

00:53:27:09 - 00:54:05:06
Unknown
You're you're just trying to match them to what's in our own body. So they're not. Thank you. So you had mentioned that the efficacy is pretty is the same, right? Because we have studies to show that and you talked about like adverse side effects. But I wonder because you know, in generic in a generic area, a lot of us have taken, you know, aromatase inhibitors and we do notice there's a difference between the different medications and you can have different side effects.

00:54:05:06 - 00:54:53:18
Unknown
And while that might not be an adverse side effect, passive bleh, there is a side effect and there's so many biosimilars for each drug that you had mentioned. Do you are there side effects, differences between all the biosimilars and is it easy for a patient to switch? Is it okay to switch to see if there's a difference? So great question with Hills and when you see differences between you know, generics and the brand name, the difference is usually explained not by the active component of the drug but by the filler.

00:54:53:22 - 00:55:30:01
Unknown
What it is that keeps the active component of the drug in the pill form. So it's actually the extraneous stuff that you're reacting to, not the chemical structure of the drug itself, because that's identical. So it's it's how they package it, basically to keep it all together with with biosimilars. They're virtually, you know, all given intravenous at this point you don't have could you have a little difference in the way they're packaged?

00:55:30:03 - 00:55:57:24
Unknown
You could I'm not aware that they're adding other things, though to keep them in solution, you know, or different preservatives. But I suppose in theory there could be maybe a slightly different preservative or something, but that would be what's accounting for it. It's not the drug itself. And then you said, can you ask if you think you're having a different reaction or something you know of?

00:55:58:01 - 00:56:50:19
Unknown
Of course you can ask. It's your body. Sure. But whether or not the, you know, insurance will approve it unless you kind of got some good evidence. You know, the is is unclear. You know, so it's it's it's making the case to the person who's paying for it. And that's where the barrier comes into play. I mean, but if you have you know, you collect your symptoms and you've got some good evidence, it's absolutely appropriate to to ask, of course, of this, wondering how do you address concerns from patients who might be hesitant to switch from biologic to a biosimilar?

00:56:50:21 - 00:57:30:11
Unknown
I'd say if that were the case, Yeah. Well, that's why our uptake has not been as fast as in some other parts of the world. And I think we just we have to have open communication, but we have to, you know, try to show the evidence and, you know, hopefully reassure. You know, this is it's complicated. But what's interesting to me is, I mean, especially if you're doing really well and you're on a drug and you just don't want any disruption.

00:57:30:11 - 00:58:05:19
Unknown
Right. You know, I can absolutely understand where there might be concern, even if the FDA is saying, hey, look, we see no difference. You know, if you switch or not. So I think it takes a while to get comfortable with something like this. And I think you know, I have real concerns about if we as it seems, we are kind of giving this interchangeability to all drugs, that you wouldn't be at least mandated to tell the person writing the prescription and the patient who's going to get the drug that is being switched.

00:58:05:19 - 00:58:25:18
Unknown
I mean, that's of a concern. And right now, there are some states, if you have an interchangeable where you don't necessarily have to do that. So that's ASCO stance is the prescriber should know. So not only do they have it in their records and they know, but they can notify the patient and the patient can be aware as well.

00:58:25:20 - 00:58:55:01
Unknown
It's a it's a you know, it's a real conversation. You know, I would say the majority of my patients, if I show them the data and the safety and what the FDA has done and how many more years other parts of the world have been using these drugs with long term data, you know, it's very reassuring, but sometimes you get very comfortable with it when trastuzumab had the subcutaneous version came out, I thought a lot of my patients would want to switch.

00:58:55:01 - 00:59:08:19
Unknown
It's easier to just get a shot underneath the skin than to get your I.V. hooked up. But I had a, you know, a good group of patients who said, I am just so comfortable with the way things are right now. I don't want to rock the boat at all. And that was okay.

00:59:08:19 - 00:59:16:15
Unknown
Thank you. Very interesting. Thank you so much, Dr. Grillo, for your thoughtful and thorough answers to our many, many questions.

00:59:16:15 - 00:59:27:21
Unknown
Also, please make sure to check Sherry's website for upcoming educational programs, podcast episodes and support groups. And don't forget to follow us on social media as well.

00:59:27:21 - 00:59:38:08
Unknown
This concludes the webinar. Thank you again, Dr. Grillo, and I hope that everyone has a pleasant evening. Thank you. Thank you.