Global Head Clinical Development, Biocon Biologics

Elena Wolff-Holz, MD

Elena Wolff-Holz, MD.

Elena Wolff-Holz, MD, global head of clinical development at Biocon Biologics, supports automatic substitution of biosimilars at the pharmacy, citing that Europe often grants this immediately with marketing authorization. She highlights interchangeability in the US specifically refers to automatic substitution, and 

Wolff-Holz emphasizes the importance of patient education at the pharmacy, especially if a biosimilar involves a different administration device compared with the originator drug. She explains how pharmacists would be responsible for explaining these differences and stakeholders would highlight any distinctions and provide necessary educational materials.

This transcript was lightly edited for clarity; captions were auto-generated.

How do you feel about automatic substitution of biosimilars at the pharmacy level, and what safeguards do you believe are necessary?

I think automatic substitution at the pharmacy level is an option, it’s possible, it should be possible. I think this whole discussion on interchangeability that are granted in Europe immediately with the granting of the marketing authorization, and then at a national level, the automatic substitution can also be decided. Several countries, I think most recently, France, has accepted that, but other countries, also in Europe and in the United States, have a slightly different definition of interchangeability, in the United States compared with Europe. In the US, interchangeability really speaks to automatic substitution and if you can solidly justify that, and it is justified for Yesintek, so we've been granted the interchangeability status, then I think it's absolutely possible to do it. It's a clear, clear option.


I think what may have to happen is patient education also at the pharmacy level. If there were different devices, different ways that the drug would be applied, for example, also by the patient himself or herself, then it is important that the pharmacist takes on also the responsibility of educating the patient that there are maybe slightly different features in the apparatus, but it's not the drug, it's how you apply the drug. I think this is absolutely possible. I think we as a company, if there were differences to the originator, would then need to highlight this and bring out the materials, or make sure the pharmacist is aware of that. This could be an aspect, but so far, I don't think it is a problem.

What are the biggest misconceptions the general public has about biosimilars, and how can your research help to correct those misconceptions?

I think there could be an unfounded fear that something that is cheaper is less good, and that's why I don't like the word 

, because it's about affordability. These are more affordable; these are not cheaper products, but more affordable products. They are highest quality, they have to go through a very rigid regulatory process, and at the end of the day, they have been applied to human subjects. 

Our research has proven that. We've done all the analytics. We've done more than 100 orthogonal assays to look that really all the characteristics are the same. We've done a PK [pharmacokinetic] trial, where the dose curves are absolutely superimposable. Plus, we also did the phase 3 efficacy trials. Not only have we confirmed the analytical data with the PK trial, but also, all of those data with a phase 3 trial. There's absolutely no need to be fearful.


The other aspect is, I think, in the clever clinical trial design that we have, we've integrated the switch for those patients. Half the patients that were originally on Stelara, at week 16, they were rerandomized in a 1:1 split. Either they stayed on the Stelara or they then took the BMAb-1200 and we carefully monitored whether there would be a change in the effect or in safety or immunogenicity. We saw that there was no difference. Preswitch and post switch was not impacted, and all these are very solid data that really should ascertain and give the confidence to the patient, to the physician, and ultimately the payer, that these are high quality drugs.

Videos

Elena Wolff-Holz, MD, discussed the rationale and safety surrounding the automatic substitution of biosimilars at the pharmacy level, as well as common misconceptions about these medications.

Automatic Biosimilar Substitution and Patient Education Advocated by Elena Wolff-Holz, MD

Elena Wolff-Holz, MD, global head of clinical development at Biocon Biologics, discussed the approval of 

, for psoriasis treatment, a biosimilar referencing Stelara (ustekinumab). She highlighted the comparable efficacy and safety with reference Stelara, including positive switching data.


Wolff-Holz believes biosimilars will increase patient access through reduced costs and suggests that reference product manufacturers should focus on innovative drug development. She noted that Yesintek has shown to be less immunogenic than the reference product, potentially offering an additional benefit to patients.

With the recent launch of three ustekinumab biosimilars in the US market, how do you see BMAb-1200 fitting into this rapidly evolving landscape?

I think the real comparison is really the biosimilars vs the reference medicine product, Stelara. Coming back to what biosimilars are, these are absolutely high quality products, highly regulated products, and the primary analysis really are at the quality level.


Comparative analytical studies are required, many more than you would have for new drug application and you have to look for physical chemical analysis, for biological functional comparability on very, very solid ground and then you go on with the PK study or with another trial. Actually, the onus, really, of the proof is in this initial quality comparison that really, truly, this is the same biologic drug, and this rigidity with which you have to prove the amino acid sequence is the same, the higher order structures are the same, the glycosylation pattern must be within very strict comparability model. All of this must be done by all biosimilar contestants, and you can only get approved if you have these if you have proven that this comparability exists.

One biosimilar vs another, I think here the features would be how the drug is given, so whether you have it in a PFS or other devices, things like that. Otherwise, it's really the same, and it's rather the question, do you still need the reference medicinal product on the market? That's really the question. I mean, they've been around for 10 years or even more, through patent prolongation. I really think their job should be to think of new drugs, innovative drugs. That is their primary capability, that should be their challenge.


I think they should leave the biosimilars alone. Once they're on the market, I think, from my point of view, the reference medicinal product is superfluous.

What are your thoughts on the impact that these biosimilars will have on patient access and the overall cost of psoriasis treatment?

I think BMAb-1200 or Yesintek on the market is just a wonderful addition to ustekinumab antibodies. I think the good news is it is less immunogenic than the reference medicine product. That is something that you observe, typically, not so much because of the product as such, that is the substance, the actual drug substance, but rather the fluid, the excipients that constitute the other part that makes up the medicinal product. This is something I would say that is quite, quite beneficial.


I think obviously the biggest advantage is reduced price, affordability is a big thing. Bringing down the costs considerably, and by doing that, increases the access patient access, it’s something that we've seen with many biosimilars.


 has nicely studied this, that this does happen, and it's really important, because ultimately, it improves health care. This would serve both sides and free up the space for more expensive, innovative drugs, but on the other hand, you would have then less expensive biosimilar products. This is something where I would think, Yesintek is a fantastic candidate.

Elena Wolff-Holz, MD, discussed the approval and benefits of the ustekinumab biosimilar, Yesintek, emphasizing its comparable efficacy and safety to Stelara, and potential for increased patient access due to lower costs, and a possible lower immunogenicity profile.

Yesintek Biosimilar Shows Comparable Efficacy, Lower Immunogenicity Than Stelara, Says Elena Wolff-Holz, MD

Elena Wolff-Holz, MD, global head of clinical development at Biocon Biologics, discussed the recent approval of 

 as a biosimilar to reference ustekinumab (Stelara) to treat psoriasis.


Wolff-Holz emphasized the comparable efficacy and safety results observed, including pre- and postswitch data, while acknowledging challenges in patient recruitment and navigating diverse global regulatory requirements.

What specific clinical end points or patient-reported outcomes did you find most compelling in support of the study comparing BMAb-1200 with reference ustekinumab?

Well, maybe just a few introductory statements, so BMAb-1200 is now an approved drug. It just got recently approved and is called Yesintek [ustekinumab-kfce] here in the United States and will also be launched in Europe and Japan in the next few weeks.


The clinical basis, the clinical study, the phase 3 trial that was conducted in support of the marketing authorization application, was a clinical trial that lasted 52 weeks. It was a double-blind randomized trial in 384 patients, and they were rerandomized; those patients that received the originator drug Stelara were rerandomized at week 16 to either continue on the Stelara or get the BMAb-1200, and then all patients were followed in a blind fashion until week 52.


In terms of end points, the primary end point, and I think that was the most compelling, was at week 12. That's important because it's sort of in the steep part of the dose-response curve, and you can really, if there was a difference, you would detect it at that time point. Actually there was, in terms of change of the PASI [Psoriasis Area and Severity Index] score from baseline, there was absolutely no difference.


The FDA and also EMA, they have certain requirements on how they define confidence intervals. The 2 drugs must be within this confidence interval, and [for] FDA plus/minus 10% is allowed. We had a difference of 0.68%, so that's very compelling primary end point results. Above and beyond, we've also looked at week 4, 8, 16, and 20-week data, and that was also highly similar. We looked at preswitch and postswitch data, and again, the switching would not have any impact with regard to the PASI score or safety or immunogenicity.


These are all very important findings, and I would think, in summary, those are the most important ones, but there's also the PsA [psoriatic arthritis], actually, and they were also comparable. All of this gives a very comprehensive story.

What were the most significant challenges encountered during the study, and how were they addressed? What lessons were learned that could benefit future biosimilar development?

This was a global study at 41 centers, 5 countries, and 384 patients, so recruiting these patients on time. We had a global development that would satisfy all the legislations, including PMDA [Pharmaceuticals and Medical Devices Agency], that is Japan's regulatory body. At that time, we were asked to have at least 15% Japanese patients, and that was a challenge to include. Luckily, the Japanese regulators now have changed this demand. It's no longer required. It also introduced heterogeneity. That's something we would change, and we would be allowed to change.

Otherwise, I think anything that enhances inspection readiness would be of advantage. I think we've implemented checkpoints already in the trial, but this is something also in terms of monitoring continuity from the CRO [contract research organization] site to the sites. I think that's something I would take more care even to have this continuity so one particular CRA [clinical research associate] or CRM [clinical research management] [is] really being available for the entire study and beyond to carry through, also the inspections.

Elena Wolff-Holz, MD, global head of clinical development at Biocon Biologics, discussed the approval of BMAb-1200, a biosimilar to reference ustekinumab for psoriasis, highlighting comparable efficacy and safety data while noting challenges in global patient recruitment and regulatory navigation.

Elena Wolff-Holz, MD

Automatic Biosimilar Substitution and Patient Education Advocated by Elena Wolff-Holz, MD

Yesintek Biosimilar Shows Comparable Efficacy, Lower Immunogenicity Than Stelara, Says Elena Wolff-Holz, MD

The Global Biosimilar Development and Approval of Yesintek With Elena Wolff-Holz, MD