GenSight Biologics S.A. (SIGHT) Earnings Call Transcript & Summary

Good morning, everyone, in the U.S. and good afternoon for those who are joining us in Europe. Thank you for attending our webcast, which is devoted to our CMC development. Following this development a few weeks ago, I think we really wanted to be as transparent as possible but we had to do such several investigation to make sure that the information we're giving out are accurate and safe. In the meantime, I think we received a vast number of questions. And because of the very nature of this question, I think it was important for us to ask Scott Jeffers, our Chief Technical Officer, who is based in Boston and who is working in partnership with our sub-contractor, Thermo Fisher to give you a little bit more insight into what process, what is the nature of the process. And then, of course, he will come to the root cause of what happened last. And you will see that indeed that again confirm that it is not an issue with the process. It is an operational issue. And he will also give you the remedies that we are putting in place to resolve the situation, avoid that there is any further issue in the future. And we confirm that we will restart the PPQ campaign by mid-May, so that we can confirm the dates that were in the PR with the final decision of the CCMP in Europe in Q1 of 2024. Thank you for taking us through the process and through the issues, Scott. The floor is yours.

Thank you for that introduction, Bernard. Great. Thank you very much. Everyone, thank you for attending. And I'd like to really take you through the process and how the process has been working and what we're doing to -- how we understood what occurred and how we have fixed the issue. But first, I'd like you to take you through the process itself from beginning to end. In this first slide, you can see a person on the left side of the screen who is holding a bottle. That bottle has a bunch -- has HEK293 cells in it. HEK stands for human embryonic kidney cells. Those cells are the factories that produce our AAV viral vector. The cells are put into that box that has the 2 orange caps on top of it, which is just to her right, I assume. You can see that there is that red media inside of it and that red media contains the cells. That is what the cells grow upon. These are adherent cells and they grow in these kind of flasks. So the first 3 weeks of the process is upstream and that is -- and most of that time is spent expanding the cells. So cells are thawed on day 0. Those cells then grow and are expanded into multiple of these, what we call cell stacks. These cell stacks then are grown until the cells are fully confluent and have enough cells there. The cells are then transfected. And you can see on the right-hand side, where we've got transfection harvest, the cells are transfected with those 3 plasmids which make up our AAV vector, a helper plasmid, which gives the components necessary to make AAV, a vector plasmid, which has the rep and cap or the components of AAV itself that make the protein coat and then a gene of interest plasmid, which is the treating agent. So cells are transfected. They're allowed to grow for a few days and then these cells are harvested, they're [indiscernible]. And from that, we get viral vector, which contains the gene of interest. We also get empty capsids, which have no gene of interest and we get impurities, things like host cell protein, host-cell DNA, plasmid DNA, cell debris. All of this comes through after the harvest. In our next slide, we go through the downstream. And this is where we remove the impurities and capture the viral vector for making drug substance and eventually drug product. So the purification starts with the clarification of the viral -- of the bulk harvest. It goes through 2 filters and in one single step. And this basically removes all of this cell debris from the bulk harvest. The next step is our affinity purification and chromatography column. This column is a column with beads that have a ligand on it or a protein on it that specifically binds to the AAV vector. It binds both to empty and full vector particles. As the material -- the bulk harvest, the clarified bull harvest flows over that column, the AAV binds to that ligand on the column and sticks there. We wash it multiple times with various buffers to get rid of the -- to get rid of the impurities, the host cell DNA, host cell protein, et cetera. And then afterwards, we lower the PH or we acidify the column and the AAV vector comes off. When the AAV vector comes off, it comes out of the column and goes into a collection reservoir. In that collection reservoir, we must neutralize the viral vector in order to bring it from the acidic condition that it's into a more neutral condition and this protects the virus from degradation. That neutralization step is where we found that we were losing product in the last GMP run. After that neutralization step, the [ ABL ] is concentrated and diafiltered, meaning the buffer is changed via tangential flow filtration. This step is to put the -- to take it out of the [ ABL ] buffer, the neutralized [ ABL ] buffer and to put it into the BSS buffer. The BSS buffer is the buffer that is our final buffer for drug substance and drug product. After this is completed and diafiltration has been completed, the product is sterile filtered through a 0.22 micron filter and then frozen until we fill the drug substance. After all of this is completed, we have roughly -- we have a high-purity material, roughly 95% pure that is ready for vialing into drug product. And that product -- that drug substance contains both full capsids and empty capsids. On vial fill finish date, we thaw the material. We dilute it to the desired PG concentration, petro genome concentration and then we fill it into vials, those vials that have been frozen and ready for shipment to patients. The 2 pictures on the right are the 2 apparatuses that we use or representations of the 2 apparatuses that we use. The first one is the tangential flow filtration device and the second one is a column. And this is a rather large column but it is a column that is, it is a type of column that is used to hold the resin, which has the ligand for capturing the AAV. In our next slide, in the second quarter -- in the fourth quarter of 2022, we performed 2 engineering runs at our -- in the Process Sciences lab at our CDMO partner. We use manufacturing sciences and technology -- we use manufacturing scientists and technology scientists and technicians. These engineers and scientists have PhD level and master level degrees and they are scientists. Their job is to test, adjust, validate the process and write the work instructions and transfer those into the manufacturing operations team. In the process scientists, there are less stringent rules or stringent guidelines to performing operations, meaning people can go faster and they can do things quicker. In the GMP suite, well, of course, there are much -- many more rules and things are slowed down because of that. When we went into the -- well, so there -- so in the process sciences, we had 8 -- we had 2 very successful runs. Historically, we were -- we had 8 to 10-fold increase in recovery from our previous historical average across all the batches manufactured at our manufacturing partner. From this, we quickly moved the process into the GMP manufacturing operations team under GMP conditions but the GMP run was not successful. We've just completed a thorough investigation in collaboration with our partner, to find the root cause of that failure. And as I alluded to in the previous slide, this was -- it was found that the neutralization step was the root cause of that failure. We didn't realize that, that timing that could be done in the engineering process sciences lab was not the same timing that could be done in the GMP suite and this did cause the failure. Turning to our next slide. What we're doing now? We're currently working with our manufacturing partner to understand -- to train in our manufacturing operations team, to improve the work instructions and the batch records, to place limits on the amount of time for that neutralization step. We also have our manufacturing sciences team and our own GenSight persons in the plant to support the manufacturing suites and provide hyper care to the process. We'll start the PPQ batches in May of 2023 and have data showing success of our manufacturer in July. So you can imagine the process science is run as an orchestra rehearsal. The team of experts are working on the music. They're working to improve their craft and they are really working to be ready to go into the dress rehearsal. Since March and through May, we will be doing that dress rehearsal. We're adjusting and training the process -- adjusting the process and training the teams -- the manufacturing operations team will have extensive training from the MSAT team or manufacturing sciences and technology team. They will have direct supervision from the MSAT team and direct supervision from GenSight team. The instruction -- the work instructions have been extensively redlined and are now being reviewed both in table reads and during specific unit operations to both increase clarity and ease of use. During these manufacturing operations, manufacturing operations unit operations work throughs, we will further red line as we come to issues that operators find and then we will continue to redline those for constructions and batch records to improve that clarity. Together, these 3 mitigations will improve the execution of the process in the GMP manufacturing operations and I believe that this will allow us to succeed. The manufacturing operations team are in May through July, the validation campaign is the orchestral -- it's the show. It is where you paid the money to watch the orchestra do its job. That is the concert with our partners, we'll perform those 3 PPQs that will show the processes are robust and reproducible. GenSight will have our persons in plant as well as the MSAT team with the -- our partner, and they will be on the floor to support those operations. We're confident that these mitigations will solve the issues and that we will be successful in these 3 PPQ runs. And that is all I have. So I'm going to turn the floor over to Thomas for any questions.

Thank you, Scott. So we are now opening the floor for roughly 15 minutes of questions from research analysts.

[Operator Instructions] We'll take our first question from Damien Choplain from ODDO.

Two, if I may. So first, assuming that the next run meets the specifications or can you guarantee that it will be predictable in the future? First question. And will the new time line impact the EMA approval process? And is there a risk that the EMA has to resubmit the -- their product process when the production is validated?

Okay. So I can take the first question. I'll take the first question. So the PPQ runs are the set of runs that show that, that process is robust and reproducible and that it will meet those specifications. And that's exactly what we're working towards, is to have that occur. We believe that the training and improvement of the work instructions will go a long way to allowing that to happen. We know the process works. Process scientists has already shown that. It is the operational issues that will bring us across the line.

And maybe Damien I will take the second question. I think we can confirm the new time line. I think the impact have been disclosed in the last press release. So indeed, as you know, I mean, all the clinical data always has been submitted as per the 180 response that was last -- ahead of March. And so we submitted the clinical question. And the last missing piece is, in fact, the CMC data that relates to the PPQ campaign. So yes, I think, we, of course, have an impact that we have identified and communicated. And we are now indeed waiting for the final CHMP approval by early of next year, Q1 2024.

We'll move on to our next participant, Ingrid Gafanhao from [indiscernible].

If I may ask a bit of a follow-up on the EMA question. Just to clarify how the process is going. So in March you submitted the answer to their questions. And are you currently sort of on a clock stop with the EMA? Do you have to request any extension of the time line until you have the GMP in place? How does that look in terms of the process with the EMA?

Well, at the moment, we, of course, have discussed the CMC issue that we recently faced with the EMA and we don't think that we'll -- there will be any need to ask for a clock stop. I think the EMA is going to review the clinical data. They are aware of our issues with the CMC and they know that we will now bring the full PPQ data by the very end of this year. In fact, we will have the PPQ campaign starting by mid-May. We expect to get the data on the titles sometimes in -- during summer, which is the time that was presented by Scott to manufacture those batches. But then we need to wait for the 3-month stability. It normally does not cause any issue. It's within that 180 days. So there's no issue. And this final data and the certificate of release are going to be available only by end of December or early January. So we'll finally submit this. And the EMA is aware of these time lines.

And if I may have a follow-up. So you do have to produce some GMP batches. Can you later use these batches for commercialization as well? Or everything goes towards the validation process?

It's a good question. So yes, the PPQ campaign can be used for -- as GMP batches for clinical use and for commercialization of course. So with these PPQ batches, we will, of course, store a number and use that number for the controls and for the archives. And then we will use the rest for restarting the early access program that we expect before the end of the year. And then we will also use it for commercial sales.

Once again, ladies and gentlemen. [Operator Instructions] Sushila Hernandez from VLK.