Challenges With Off-Label Bevacizumab Use in Retinal Diseases

EP: 1.Overview of Biosimilars and the Approval Process in Ophthalmology

EP: 2.Interchangeability of Biosimilars in Ophthalmology

EP: 3.Impact of Biosimilars in Ophthalmology

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EP: 4.Challenges With Off-Label Bevacizumab Use in Retinal Diseases

EP: 5.Rationale for Shorter Endpoints in Biosimilar Clinical Trials

EP: 6.Current Anti-VEGF Biosimilars Approved for Ophthalmologic Conditions

EP: 7.Biosimilars in Ophthalmology: Challenges, Access, and Patient Assistance Programs

EP: 8.Building Confidence in Biosimilars in Ophthalmology

Rishi P. Singh, MD: In the era of off-label bevacizumab,…what is the value of biosimilars and what can they offer over that off-label therapy we’ve been using for years now?

Michael A. Klufas, MD: Off-label bevacizumab is…really interesting. I’m not sure if loophole’s the right term but [it’s] something that’s been going on in retina for…greater than 10 years and for sure is a very cost-effective option. But I think we have to remember how off-label bevacizumab is actually produced and this goes through a compounding pharmacy. Now there are more regulations in 2023 and 2024. I remember when I was in my training, there were outbreaks of compounding medications causing meningitis and then also some infections in the eye, and there [have] been more regulations since these problems have arisen in the past. However,…compounding is not really regulated to the on-label standard in the production process.… I’ve done a study with one of my colleagues in the past, and before the era of requiring a lot of prescriptions specific for off-label bevacizumab, I think we obtained about 20 samples, and some syringes came with no medication in the vial. We did a lot of preclinical studies looking at aggregation of bevacizumab stored in plastic syringes, and we’ve got to remember this is not a powder that’s mixed. These are biologics, proteins that are produced from cells, and when they’re repackaged in things such as a plastic syringe, these bevacizumab monomers can form different aggregates. And then actually the clinical efficacy of these repackaged bevacizumabs may not be as good as what we saw in the past, and a lot of times people will cite the CATT trial where bevacizumab showed near equivalence to monthly ranibizumab. And it did, but they were using glass syringes and repackaging the medicine to a very different degree than what we do today. Another concern has always been silicone oil in the off label of bevacizumab. We have silicone-free syringe preparations. They’re more costly, but potentially better for our patients. And we have to be aware of that side effect as well.

Rishi P. Singh, MD: Great, I agree with you. And in fact, I would add that we have been privy at the clinic to have really well-formulated bevacizumab in our practices. And I think our mindset would have been very different about using more branded drug for those patient populations because we’ve had such a good source of it for so many years. As you said, we’ve already done our own studies as well. And looking at some of the half-lives of the drug is really quite interesting. I think, as you pointed out, obviously there [are] issues of protein aggregation and so on and so forth. But in fact, if it sits out on the shelf for a period of time, it does lose its efficacy. And I think Szilard Kiss, [MD,] and others have done some work on…looking at some of those half-lives of drugs there. In addition, we went from our satellite office to a compounding pharmacy that wasn’t our own. And the syringes are different. You don’t know how much volume you’re giving sometimes. It’s a very difficult process because they’re trying to maximize their cost benefit to the company that’s doing that formulation. So it’s been a challenging area. And this is where I think, again, we needed a better option than off-label bevacizumab with that. And we’ve seen…those compounding issues we’ve heard [about] across the country,

some outbreaks. Even more recently, there’s been an outbreak…in Pine Pharmacies for off-label bevacizumab and they had to actually stop for a while. And that certainly threatened our supply of it all together. And let’s differentiate this. I think there’s a differentiation [that] needs to happen between biosimilar and bevacizumab and the ONS-5010 Outlook [Therapeutics] product. Can you talk a little bit about the difference there? Is ONS-5010 in comparison with what we’re talking about today?

Michael A. Klufas, MD: Yes, great question. As we’ve just been discussing some of the issues with compounding, because bevacizumab compounded is so widely used and generally as safe as some of our branded products and almost as efficacious, especially in age-related macular degeneration, a company that’s developing OSN-5010 actually thought, well, why don’t we make an FDA-approved noncompounded version of bevacizumab to eliminate these potential variabilities we see with compounding pharmacies? Most of us as retina specialists are comfortable with intravitreal bevacizumab, but perhaps not comfortable with the compounding aspect. So this new compound may allow us to have an FDA-approved bevacizumab for intraocular use.

Rishi P. Singh, MD: Yes, and I think that that’s where people…call these products that are being registered as we’re talking. But just like any drug [that] is registered, they call it a biosimilar just because they think it’s the same class, but it truly is not. It has to go through a different approval process altogether and therefore it’s very different. And it’s not considered a generic, as you said as well. So I think it’s also a very important distinction. As you’re aware, we heard recently the results from the Outlook study for the FDA submission. And it turns out that the FDA has required more information in regard to submission, both from an efficacy [standpoint] and from a standpoint of the actual area that’s being used to produce the product. So hopefully we’ll hear back soon enough about some response from the FDA and from the company about a path forward to getting more sustainable with this in our clinical practice.

Transcript is AI-generated and edited for clarity and readability.