So good afternoon, everyone, and welcome to Xbrane's webcast by reason of the FDA review and the press release as we published yesterday. My name is Anette Lindqvist, and I'm the CFO of Xbrane since 2001, 2021, sorry. With us today, we have two members of the board. We have Anders Tullgren, our Chairman of the Board since 2018, and we've also Kirsti Gjellan, who joined the board in 2022 and contributes first and foremost with her vast manufacturing and quality experience. I also would like to present three colleagues of mine, David Vikström, our Chief Technology Officer and also Head of R&D, and Anders Wallström, our Head of Manufacturing and Supply Chain, last but not least, our CEO, Martin Åmark. Following a brief presentation, there will be a Q&A for which you can ask questions in writing throughout the presentation.
By that, I would like to give the word to Martin. Please, Martin, go ahead.
Thank you, Anette. So I first wanted to go through the history of our Biologics License Application, also called BLA, for our ranibizumab biosimilar candidate under the development name Xlucane. It was submitted in April last year, and the FDA took a so-called filing decision in June 2023, and the review process of the BLA was then started. And a BsUFA date, that is to say a goal date or a decision date, was set to April 21st, 2024. So that is the date when FDA, according to the dictated process, needs to take action, a decision either to approve the application or to postpone the BsUFA date or issue a so-called Complete Response Letter.
We had, during the review process, as is dictated by the process, both mid-cycle and late-cycle review meetings with the FDA in October and January 2024, respectively, where no major issues were at that point in time identified. As is part of review processes for approval in the U.S., you typically conduct so-called pre-approval inspections at the manufacturing sites involved and proposed to produce the product for commercial supply to the U.S. That took place even for this review process in January and February this year, respectively. In those inspections, there were observations from FDA, which you then typically have a three-week response time on, and the respective sites responded to the FDA within that time frame. We also received, of course, numerous different information requests from the FDA on the application itself throughout the whole review process, which were responded to in time.
So Friday evening U.S. time, that is to say 19th of April, we received a so-called Complete Response Letter from the FDA. It contained two main deficiencies in relation to the application, which, according to FDA, needed to be resolved in order for them to be able to approve the application. The first one was related to the so-called Reference Standard to be used for release of the product to the U.S. market, and I'm here going to hand over to David to elaborate a little bit further on this specific deficiency identified or stated by the FDA.
Yes, thank you very much, Martin. So this is David Vikström speaking, CTO with Xbrane. And as Martin mentioned, we have a Reference Standard in the Xlucane program. And this Reference Standard, it's qualified with several different analytical methods. And the Reference Standard is used to compare a newly produced batch to be certain that it can be released to the market. And during the FDA review process, FDA requested a new tighter specification on one of the methods used in the qualification of the Reference Standard. And to solve this issue, we have created a task force, and this task force is made up by very experienced team members, both from Xbrane but also external expertise. We are certain to solve this issue.
We basically started looking into this immediately, and I would say already now we have identified a good way forward and is working on creating the plans exactly how to solve this. We will also ask FDA for a meeting to be certain then that FDA agrees with our solution to this issue. Handing back to Martin.
Thank you. As David said, this is an issue we are confident in being able to resolve and provide a satisfactory response to FDA on. The other deficiency stated by the FDA was related to the inspections on our contract manufacturers' production sites. On this topic, I would like to hand over to our Head of Manufacturing and Supply Chain, Anders, to elaborate a little bit further.
Thank you, Martin. Yeah, so these pre-approval inspections, as Martin mentioned earlier this year, we have prepared for them since a long time back together with the different manufacturers. We have included external support, expert support. We have used what's called mock inspections with former FDA inspectors in order to ensure that quality systems and processes are in place to a standard which can be accepted by FDA. We have worked through those improvements identified earlier on to make sure that we would be able to make this. The pre-approval inspections were conducted by FDA beginning of this year. They were completed as planned by FDA, and there were observations mentioned by FDA at both sites. The observation is nothing out of the ordinary. It's, according to my experience, very normal and expected to receive observations as an outcome of a pre-approval inspection.
So what happens next is that the sites prepare responses to any observation, and this was done by both sites, and they were submitted on time. These responses, they include comprehensive action plans to improve on those areas where FDA have highlighted the concerns or deficiencies. So we are, of course, already since the inspection working on completing these actions together with the manufacturers. What can be mentioned here is that the pre-approval inspections were conducted very late in the FDA review procedure. We're talking January and February. So the responses were submitted three weeks after inspection, and that's not so long ago. So now, with the Complete Response Letter, it is in itself not specific on which of the actions proposed by the manufacturers are not sufficient, according to FDA, to close out observations.
So we are in contact with our manufacturers, and we will work together with them, continue to work together with them, including requesting meetings with FDA here to clarify if there is something missing in this action or if any additional actions are required by FDA. We have an experienced team both here at Xbrane with our board but also with our partner STADA to support the manufacturers, and we will do that together with the manufacturers to close out all observations. I would like to hand over to Kirsti Gjellan here to comment maybe based on your experience as well in this area.
Thank you, Anders. So, as Anette Lindqvist already mentioned, I joined the board of Xbrane, May 2022, in a time where the pre-approval inspection preparations were already accelerated in close collaboration with the manufacturing contractors and building on the work with tech transfers, scale-up, and validating commercial processes. As you all know, and based on my own experience as Head of Quality and Head of Internal and External Manufacturing in different companies, working with FDA is an extensive journey of compiling data, content, and evidence to support the regulatory requirements of safety, efficacy, and security for the patients. FDA inspections not having 483 observations are rare, and the team has worked diligently to respond to the FDA observations, delivering on time to the FDA through the whole process of providing content to the BLA and where we are today.
Given the fact that we now, unfortunately, have received a Complete Response Letter, we are obviously, as one organization, including the board, working with FDA, leveraging our strong relations with our contract manufacturers and relevant supporting expertise to close the CRL. I think all of you also have noticed that Complete Response Letters are seen in the pharmaceutical industry, both in small and larger companies. FDA has a process in place to continue to work with the applicants to work through the CRL, a process that Xbrane and STADA is starting to close the remaining gaps in collaboration with the manufacturers and other relevant competencies. And this will be done as soon as possible, starting with requesting meetings with the FDA on the different areas, according to what our CEO, Martin Åmark, just mentioned. So please, Martin, do you want to continue?
Yes, and handing over maybe to our Chairman, Anders Tullgren, who also is online to elaborate a little bit on elements where FDA actually did not request additional information.
Thank you very much, Martin. Anders Tullgren here, Chairman of the Board since 2018, and have formerly worked many years globally with more than 15 different launches of new products around the world. I would say in most of them, we had always some issues with FDA or had to work with FDA. This is very much of what is quite common when you work with FDA. There are different things. Let us put also this in perspective because with this response, we actually got some clarity. We got some clarity on where the FDA did not have any questions. They have accepted our clinical trial. As you remember, for biosimilars, we need to compare ourselves with the original product, and we did a clinical trial with more than 600 patients for over three years.
And there has been no request on that, and that has been accepted by FDA. So I think that's very important. We also have done studies on demonstrated biosimilars, and also there, there were no questions from it. So I think when we look at the whole FDA package, it's a huge package, but now we have clarity on the parts of the package which have been accepted by the FDA. And to date, we have also not received any request for reinspection. So, of course, we are disappointed that we got this Complete Response Letter. But as the team has said, we're working together on this, and we need to get more information back from FDA on this and then working on a time plan and action after that.
We also have to remember that there are big parts of this file which have also been accepted by FDA. With that, I leave it back to you, Martin.
Thank you. So with regards then to the path forward from here towards resubmission of the BLA and eventual approval, we are going then, as we have talked about in this call, request for meetings with the FDA to clarify further these deficiencies stated and make sure that we are responding to them in an adequate way when we resubmit the BLA. According to guidelines, FDA is required to grant such meetings within 30 days from request. And we really need to have these meetings before we can get back with a planned date for resubmission. And we will, as soon as we've been able to have these meetings, and as soon as we've been able to decide on a new submission date, we will get back in communication with the market to clarify that. So that was the formal presentation, and we are then going to go into Q&A.
So over to you, Anette.
Well, thank you, Martin. Yes, I can see there are already quite a few questions. One of the key messages is obviously around the timelines and how much delay we can expect. If you can elaborate a bit on that because there are several questions regarding this, and also how confident you are in terms of receiving final approval from the FDA.
Yeah. So with regards to the timing, as I just said, we are not going to be able to comment on that as of now. We really need to have these clarifying meetings with the FDA first before we decide on timing of resubmission. So we ask for being able to get back to the market on that point when we have decided. I think, though, as Anders alluded to, there were things which were not mentioned as issues in our application. And I think in that also, we can conclude actually that the probability of final approval has increased, although we are evidently facing a delay.
Thank you. So regarding the next question is, who's responsible within the company for the application of the FDA? And I was thinking then that we have worked with external consultants for this as well, Martin.
Yeah, I can do. Yeah, of course, I am, as the CEO of the company, ultimately responsible for the application of this program to the FDA and an eventual approval. Then organizationally, we are working with different functional heads representing R&D, as David joined in this call, Anders on the supply side joined in this call, but also functional heads within regulatory and so on. And therefore, in these functions, there are subject matter experts responsible for different parts of the application. But of course, needless to say, I am the overall responsible for making this a success.
The next theme among the questions is the partner for the U.S. and potential launch in the U.S. So could you elaborate a bit on this?
Yes, we have, as everybody knows, and we've talked about, been in a process of tying up a commercialization partner for the U.S. market. That is a process which is far gone with the final stage of contract negotiation. However, needless to say, and I think that everybody on this call understands this, we now, since we received this Complete Response Letter over the weekend, we need to review this with this potential counterpart or commercialization partner and see what potential implications that might have for this potential upcoming deal or collaboration. So this is also a question we really hope that we're going to be able to get back to you all around in the near-term future with positive news, but we really need to keep it at that and have those discussions during the coming weeks.
Yeah. Is there any news around this FDA news that this is a Class 1 or Class 2 resubmission?
Yes, so I think we had this question before coming in over emails as well. I think that this Class 1 and Class 2 categorization is related to medical devices. What this is going to be classified is as a resubmitted BLA for which there is a formal guideline and process within the FDA.
Can you say anything around how long that could take normally after the resubmission?
Our understanding is that according to the guideline, it's a six-month review process by the FDA of a resubmitted BLA. However, we've also seen approvals coming through or conclusions coming through out of such a process within a shorter time frame. But according to the guideline, six-month review process.
Okay, moving on to our financial targets. A question around our earlier communicated view of becoming cash flow positive Q1 2025.
Yeah, so maybe here I hand over to Anders Tullgren to elaborate a bit on this question.
Thanks, Martin, and perhaps you can come back later. I think the way what we need to do as well is to put this in perspective. Of course, we are not the one product, one country company, but we actually have, I would say, five different legs or five different opportunities, all of them with a lot of long-term value. The first one is, of course, Xlucane and the FDA, and we have now got some clarity on that, and we need to work very fast to resolve those issues and launch on the US markets. And as Martin said, we will come back with information about that after the meeting with the FDA. The second leg we have or the second opportunity we have is actually that we are on the market in Europe.
We are selling our product in 15 countries in Europe, and we will continue to do that with our partner STADA. We see a growth here, and we see the sales uptake. We are in a commercial phase with our company, and we see the sales picking up there through our commercial partner STADA. The third thing is on our product, and this is our biosimilar of Cimzia. That project is ongoing and according to plan, and we hope to go into a clinical phase next year together with our partner Biogen. That's progressing very nicely. Cimzia is a product with a fantastic potential. It is actually a very difficult-to-produce product. Thanks to our patented technology, we are still, what we know and what we have seen, the only biosimilar company that's been able to do a biosimilar of this product.
And this is a product with original sales is about $2 billion. So it's a big product. So that's a product with a very big potential and a long-term value and has also created a lot of interest because that we have been able to develop this Cimzia biosimilar. The fourth one is a biosimilar of Opdivo, a product I know very well since I was part of the launch of that product around the world when I worked for Bristol Myers. And here, this is also progressing as planned internally. We are looking for finding the right partner, commercial partner for that product, and that work is ongoing and accelerated. And of course, here, it's a huge opportunity. It's already now a very high sales of the immuno-oncology products, and we foresee them to be even bigger when the patent expires. So that's a huge opportunity.
That's the fourth opportunity we have with a lot of long-term value. The fifth opportunity we have is actually our platform technology, our patent. We have several patents around a unique platform and also the portfolio where we have the capacity of doing one new biosimilar per year. And that is also a lot of value in that patented technology. So I think we are disappointed with the recent setback with FDA, but I think we need to remember as well that we have five different opportunities. And we, of course, also from a financing point of view, are looking at how to work with all of these five opportunities to secure our financing going forward. And with that, perhaps, Martin, you can take a little bit more about the financing.
Yeah, exactly. We are going to continue to work intensively to capitalize on our different programs and opportunities, as Anders laid them out. On the one hand, under established partnerships which we have with STADA and Biogen for Ximluci and our Cimzia biosimilar candidate. Respectively. We are also going to work intensively to establish new partnerships, as we already talked about, for Ximluci, our ranibizumab biosimilar candidate in the U.S., but also to tie up development and commercialization partner for Xdivane, our Opdivo biosimilar candidate. So we're going to work intensively on all these fronts. And then also, as we've talked about throughout this call, we need to get clarification about the extent of the delay we are facing with regards to the first leg, if you will, FDA approval and eventually U.S. market launch of Xlucane.
So all this will dictate financing needs and time of getting to positive cash flow, and also these questions. Given all we've talked about, we need to get back on.
There is one question related to this around the current sales. So how are we doing in Europe with Ximluci?
Well, we are going to release the Q1 report later in May. This is a question we need to defer to that point in time and the related webcast for the Q1 report.
Yep. Yep. Thank you. So just glancing through the questions here. Can you elaborate a bit around how are these issues raised by the FDA different to what happened when we withdraw our first application in 2022? How is this different?
Well, when you submit a BLA to the FDA, the first thing that happens is that FDA goes through a so-called validation process where they essentially shake the application for completeness. Is everything in there that needs to be in there for us to conduct a review process? That is what they're trying to sort out during the first two months. That is what happened first time we submitted a BLA, that there were a few information gaps which, according to FDA, made it not possible for them to conduct the review and hence they couldn't take a filing decision. And we needed to withdraw the file and complete the application with these information gaps stated. But none of these information gaps which were later filled are now subject to the recently received Complete Response Letter.
There's one quick question from Filip Einarsson. Do you consider the timeline for Alvotech CRL for its Humira biosimilar relevant for investors to consider when evaluating the expected timeline for the Ximluci process?
I don't think we should get into speculation with regards to our specific situation and our CRL recently received and similar processes that other companies have gone through. I think we shall stick to what we already have mentioned in this call, that we need to have these initial meetings with the FDA to get clarification and alignment around our response strategies for these different questions and then get back with first timing of resubmission and also envisioned review timeline.
Does this CRL have any impact on the Biogen cooperation?
Short answer is no.
Yeah. And are the deviations stated in the CRL by any means connected to the prefilled syringe presentation?
No, they're not.
Yeah. Could it be a scenario where Xbrane finalized the Xlucane licensing partnership without a formal FDA approval?
Of course. As those of you who have followed us for some time remember, we signed a license deal with Bausch + Lomb for intended commercialization of this same biosimilar candidate long before we even submitted the BLA. Such license arrangements typically take place far before approval. That's nothing uncommon at all.
Yes. A bit around the cost base throughout 2024, will there be any the expected cost base, as we have communicated earlier, that will shift somewhat in 2024? Are there any implications from yesterday's news on this, how the cost base will change and how that could be expected?
I think maybe this question is related to the cost reduction program we launched and communicated around in November last year. You can comment also afterwards, Anette, that is being implemented according to plan, and we envision to realize these savings as previously communicated.
Yes, and I could just chip in on this that that is something that we have been following closely. It has been now fully executed, and we will communicate the first what we can see out of those when we communicate the Q1 report end of May or mid-May. So a bit around what's, so Anders, maybe if you would like to comment, there's a question around what do you see the how is Xbrane different from its competitors, and how do you see the prospect for the company?
Yeah, I mean, we are the only biosimilar global developer in the Nordic countries, so we are quite unique by that. And I think going forward, we know that the biosimilar market will be the fastest market segment in the pharma industry, the fastest growing market segment in that industry. So we are, in that case, quite a unique company. There is, of course, other biosimilar developers globally, but for the Nordic countries, we are unique. And I think what we make us unique as well is our patented technology. We have a very good team of scientists that has developed this technology, and we have been able to patent that. So I think that is where it stands out. I mean, you need to be unique in something. And I think our core competence in drug development of biologic products is actually our biggest core competence.
Perhaps, David, perhaps you can just briefly talk a little bit about what you are doing from a research point of view and also a little bit on the things we have been able to patent that I think differentiate us from a lot of other biosimilar or biologic companies. Perhaps, David, can I ask you to say something briefly about that?
Absolutely. So I think one thing that is really important is to have the expertise in-house. Quite a number of small companies, they rely heavily only on service providers when it comes to development and expertise. We have a great team here in Solna of about 70 people. We have really unique expertise and competencies. I would say it's really a great team to work with where everybody really makes each other better. When it comes also to equipment, we have almost 2,000 square meters of lab space, which means that we can really develop and problem-solve very complex problems. And this is also one of the reasons why we have managed with such a difficult substance such as Cimzia and managed to take that from basically nothing all the way up to scale-up stage. It's a very, very complicated molecule, and that's why we are alone with that biosimilar.
When it comes to more expertise that we're working both with bacteria but also with mammalian cells. We are working with making the cells better, both from a quality perspective but also from a yield perspective. So we're working with the cells, and we're working with the blueprint that the cells are using to produce our biosimilar of interest. When we talk to our collaboration partners, but also when we discuss with our competitors, which happens every now and then, we can really see that we have a technology edge when it comes to this. We can solve problems that others have a lot of difficulties with, and we can also really produce new things that others cannot. Again, this comes back to that we are able to get patents on our technology.
Because if our technology was not new and inventive and can really be used, we would not get these patents. So we currently have 15 patents and 50 patent applications. So I can talk forever, so please stop.
I don't think we have time for that, David, but I think it was important to put the perspective because I think sometimes we are actually not communicating the very strong scientific basis that this company is built on. And that is really what is unique also if we compare ourselves with all global competitors that's also in the biosimilar biologic space. So thank you, Anette, with that, I hand it back to you.
Yep. So no, thanks, Anders and David. I think though there's a question, an interesting question, David, that you might want to elaborate a bit further on, linked to this. Xbrane, in the future, how do you see the opportunity to collaborate with other and be partners with other developers of biosimilars and actually make their production much more efficient using our technology? Is that something that we are looking into?
Well, yes, I would like to say yes. We have discussions. I mean, I can't go in in depth, of course, but during conferences, etc., during different interactions with other companies, we are always investigating these opportunities on how we can use our platforms to make other companies, both big and small companies, their platform, their technology, or their process more efficient using our platform and our technologies. So I would say absolutely, there is an opportunity there.
Thank you, David. There are quite a few questions coming in still around the financing position and also if the FDA requirements force Xbrane to take in more capital. And so, Martin, do you want to say anything further? There's also one question around our target to become cash flow positive in Q1.
I think we answered to that question before, and I think what we also stated very clearly in the prospectus of the recently conducted rights issue and the communication around that, that the proceeds from that rights issue would take us to Q1 2025 provided that we met a couple of very important milestones throughout the year, out of which one was the FDA approval of Xlucane, our ranibizumab biosimilar candidate. In the light of this recently received Complete Response Letter, we need to look back and understand what this means overall for our financing position and timing of reaching positive cash flow. As I said earlier as well, we are working very actively to capitalize on all of our programs, and this is not the only source of income for us during the course of the year.
How far have your next biosimilar reached in the development phase, and when could we expect that to be launched for market?
The next one after Xlucane is BIIB801, the Cimzia biosimilar candidate, which is currently going through the scale-up process and production of clinical material, which then under the collaboration with Biogen is then going to be their responsibility to take the product further into clinic.
Is there anything we know about the inquiries related to your manufacturing partner and again clarity on the timeline for this process?
I think we need again to have these clarifying meetings with the FDA as the Complete Response Letter in this respect was rather generic due to the confidentiality undertakings between actually FDA and our contract manufacturers. We need to have these meetings with the FDA and with our contract manufacturers to understand more in detail which observations and related proposed actions and improvements by the sites are subject to FDA making an assessment that this application was not approvable at this time. Only after we've had those interactions, we can get back with further clarity.
Yeah. I was quite impressed that there were only two findings by the FDA and that all clinical data were considered as sufficient. Do you consider the FDA response basically as quite positive for the long-term development of the company?
As I said, if I may comment, I think probability of approval increased, but we are facing a delay. Of course, if there would have been a Complete Response Letter stating that additional clinical trials would have been required, that would have been a challenge for us, both, of course, from a financial implication perspective, but also from a timing perspective.
Do we know if there's going to be a new BsUFA date this year or not?
As we alluded to and talked about in this call, this is a question we need to get back to.
Yeah. Can you say anything about the response from big investors or big stakeholders?
No comments, except that we are, as we always do, trying to have as good a dialogue as possible with larger shareholders and with all shareholders. We're doing that in webcasts as the one we're currently holding.
Yeah. And then I think where do you see Xbrane in a year? Anyone?
Yeah, I can start on that one. Well, in a year's time, my absolute ambition is that we would have if we stick to the subject of this particular webcast, that we have resolved these outstanding issues and we have Xlucane, our ranibizumab biosimilar candidate, approved in the U.S. and also, of course, have a commercialization partner tied up and either have launched or just are about to launch the product in the U.S. That is my ambition and hope, yes.
Going back to Ximluci's sales in Europe, there's a question around monitoring the sales on a more monthly basis and report that on a continuous basis to the market. Do you want to say anything about our collaboration with STADA and how those reports work?
So we are having, I think, rather close collaboration with STADA and getting, I think, appropriate information with regards to sales process. But we have no intentions of reporting to the market on sales in Europe other than in our quarterly reports on a quarterly basis.
Yeah. And I think with that, we have covered the themes in the questions as far as I can tell. So is there anyone who wants to pose some last questions? So please do. Okay. There are no further questions. So Martin, any final words? Anders?
Yeah, no, I can just say, as we've talked about in this call, we're disappointed, of course, of having received this Complete Response Letter, but we're now committed to work together with the FDA and with our contract manufacturers to resolve these issues as swiftly as possible and get towards resubmission and eventual approval of the product in the U.S.
Yeah.
Yeah, and also from my side, Anders here, I can just say that we're working very hard on this issue. We're working with the FDA, but we also have to remember that we have four other big opportunities, which we are also working with in parallel, and that we are working very closely together from the board with the management and also with our partners to resolve these issues and also working on the future of Xbrane. We welcome all the feedback and all the interests and all the questions. We also continuously moving forward, we'd like to have very close contacts. And as we have more information coming available, we'll, of course, also keep you informed, all of you. So thank you for participating today, and thanks for all the questions that you posed. So I think with that, Anette, I think we can close today's call.
Yes. So thank you very much, everybody listening in. And as always, in case you have any further questions, then please don't hesitate to come back to us through mail to Martin or myself. So thank you very much.