BioNTech SE
Q2 2020 Earnings Call Transcript

Published: 12 Aug 2020

[Operator:]

Thank you for standing by, and welcome to the BioNTech second quarter 2020 operational progress and financial results call. [Operator Instructions] I must advise you this call is being recorded today, the 11th of August 2020. And I would now like to hand the call over to the vice president, investor relations and business strategy, Sylke Maas. Please go ahead.

[Sylke Maas:]

Thank you for joining us today for BioNTech's second-quarter 2020 update call. Before we start, we encourage you to view the slides for the webcast, as well as operational and financial results press release issued this morning, both of which are accessible on our website in the Investors section. As shown on Slide 2, during today's presentation, we will be making several forward-looking statements. These forward-looking statements include, but are not limited to, the timing of enrollment, initiation, completion, and reporting of data from our clinical trials; the potential registrational nature of certain clinical trials; the impact of the COVID pandemic on our business and financial outlook; the timing for any potential emergency use authorizations or approval for BNT162; the potential safety and efficacy of BNT162; and the ability of BioNTech to supply the quantities of BNT162 to support clinical development, and if approved, market demand, including our production estimates for 2020 and 2021. Actual results could differ from those we currently anticipate. You are therefore cautioned not to place undue reliance on any forward-looking statements, which speak only as of the date of this conference call and webcast. Speaking and available for questions today will be Ugur Sahin, Chief Executive Officer; Ozlem Tureci, Chief Medical Officer; Sean Marett, Chief Business and Commercial Officer; Sierk Poetting, Chief Financial and Operating Officer; and Ryan Richardson, Chief Strategy Officer. I now hand the call over to Ugur Sahin, BioNTech's CEO.

[Ugur Sahin:]

Thank you, Sylke. It's a pleasure to welcome you to our second-quarter 2020 conference call. The last few months have been a game-changing time for BioNTech. The groundbreaking potential of our technologies, as well as our ability to quickly respond to new challenges and execute fast, has been on full display. One key highlight is the initiation of the pivotal Phase 2b/3 trial of our lead BNT162 COVID-19 vaccine candidate within six months of starting the vaccine discovery, preclinical, and clinical research program. In parallel to the COVID-19 program, we have continued to advance our oncology pipeline and broadened our base of strategic collaborations. I'm happy about the accomplishments we have made in the second quarter and would like to thank our entire team and also our partners for their tireless efforts and outstanding commitment. Slide 5 summarizes some of our key highlights since our last quarterly update. We reached a number of important milestones over the past few months. We continue to advance our clinical-stage pipeline. We now have 12 immunotherapies in clinical testing across three drug classes that includes eight messenger RNA therapeutic programs, three antibody programs, and one small molecule immunomodulatory program. In July, we and Pfizer selected BNT162b2 as our lead COVID-19 vaccine candidate and initiated a pivotal Stage 2b/3 trial. We have made progress in granting up our manufacturing capacities to support global supply. We have signed commercial supply agreement with multiple countries around the world for more than 250 million doses in 2020 and 2021. This also includes an option to purchase up to 500 million additional doses. All this is subject to regulatory approval. In parallel to our effort to bring COVID-19 vaccine to the market as quickly as possible, we also continued to advance our oncology pipeline. Öztem will provide the key updates made on the call, including for our iNeST program, BNT122; or our BNT111 FixVac melanoma program. Here, we announced a new cooperation with Regeneron to combine BNT111 with Libtayo, an anti-PD-1, in a randomized Phase 2 trial, which we believe could have a registrational potential. Moreover, we significantly strengthened our balance sheet, bringing in commitments of approximately $1.1 billion in gross proceeds from non-dilutive upfront cash payments and equity and debt-financing commitments. These accomplishments have strengthened our ability to advance our pipeline on multiple fronts and deliver on our longer-term vision to bring novel immunotherapies to patients across a range of diseases. Moving to Slide 6. I would like to touch on the importance of our strategic collaboration. This is important because these collaborations continue to play a crucial role in how we are building our business. Our partnerships extend our execution capabilities and global reach, and in some cases, provide us the access to external technologies such as Genmab's DuoBody technology, which are highly complementary to our own. The first half of 2020, we expanded our existing partnership with Pfizer to jointly develop our COVID-19 vaccine program. In addition, we have established a new collaboration with Regeneron in the oncology field. The important aspect here is that we have retained significant economics on our programs through these collaborations. Sean will provide some further details on the Pfizer collaboration later in our prepared remarks. In the case of Regeneron deal, it is important to note that each party keeps 100% of the rights to its own product. That means that BioNTech has kept full product commercialization rights for BNT111 melanoma FixVac. On Slide 7, you'll see an updated version of our multi-platform immuno-oncology strategy. The cornerstone of this strategy is to leverage our immunotherapy expertise with new therapeutic approaches to target cancer and modulate immune responsive simultaneously. We believe the approach can produce multiple blockbuster product opportunities but also will enable the development of powerful combination treatment approaches which combine complementary mechanisms of actions. Despite the challenges associated with the COVID-19 pandemic, we have continued to execute our immuno-oncology strategy on multiple fronts. We are on track to initiate multiple late-stage trials for FixVac and iNeST product candidates. We are anticipating the first data update for our next-generation checkpoint immunomodulator, BNT311, a bispecific antibody targeting anti-PD-L1 and 4-1BB late this year. Furthermore, since our last earnings call, we have initiated a Phase 1/2 trial for our TLR7 agonist small molecule immunomodulatory program and expect to initiate first-in-human trials for two novel cell therapy approaches in the coming months, including BNT211, a first CAR-T cell therapy; and for BNT221, our neoantigen T cell therapy. As we have done in the past, we will continue to be data-driven in how we assess each product opportunity we take into clinical testing. I will now turn it over to Ozlem to provide an update on our programs.

[Ozlem Tureci:]

Thank you, Ugur. In the interest of time, I'm going to focus my remarks to the four programs highlighted on Slide 9. These include BNT111, our FixVac melanoma; BNT122, our iNeST program; BNT311, our anti-PD-L1/anti-4-1BB antibody; and BNT411, our TLR7 agonist. For further details on the status of other programs, please refer to our full quarterly update which was released this morning. So let's start on Slide 10 with BNT111, our melanoma FixVac program. As a reminder, BNT111 is composed of four non-mutated melanoma antigens

[Sean Marett:]

Thank you, Ugur. I will start by recapping our commercial arrangements with BNT162 with Pfizer and Fosun, depicted on Slide 22. Our collaboration with Pfizer involves co-development of a portfolio of COVID-19 vaccine candidates on a worldwide basis, excluding China. Upon approval, we will jointly commercialize the vaccine with Pfizer. As part of our preparation for commercialization, BioNTech is taking steps to establish a limited commercial infrastructure in a selected set of countries while leveraging Pfizer's commercial infrastructure and capabilities in the rest of the world, excluding China, as I just noted. In terms of financials, our collaboration with Pfizer is based on a 50-50 partnership. Both companies share development expenses and gross profits worldwide on a 50-50 basis regardless of which company distributes the vaccine in a given country. Furthermore, capital expenditures are funded by each party independently. In addition to the combined upfront payment and equity investment of USD 185 million, which BioNTech received in April, BioNTech is eligible to receive further development in sales milestones of up to USD 563 million. If reached, these milestones will come in addition to BioNTech's 50% share of gross profits generated. Our Fosun collaboration in China is also a co-development agreement. However, Fosun funds the majority of development expenses incurred in China and would take on commercialization responsibilities if the vaccine is approved. In addition to the combined upfront payment and the equity investment totaling USD 51 million, which was received in April, BioNTech is eligible to receive further development and sales milestones up to USD 84 million. BioNTech would also share gross profits on the sale of the vaccine in China. I will now turn to Slide 23 to provide an overview of our recently announced commercial supply agreements. From the beginning, we have been very clear about our intention to make our vaccines available for global supply to address the pandemic, and we are investing at risk to scale up our manufacturing to enable us to do so. BioNTech and Pfizer have a target to manufacture up to 100 million doses by the end of 2020 and approximately 1.3 billion doses by the end of 2021. This estimate presumes a continued ramp-up in production at our Idar-Oberstein and Mainz facilities in Germany which are currently producing vaccine for clinical supply. We're also working with Pfizer to activate and ramp up vaccine production at several Pfizer sites in the United States and one in Europe. While it is still early, we have announced commercial supply agreements with the governments of multiple countries for more than 250 million doses with an option for an additional 500 million doses. Furthermore, we are currently in a number of discussions with governments around the world in relation to further commercial supply. All agreements are subject to clinical success and regulatory approval of the vaccine. I will now hand over to Sierk to provide an update on our financials.

[Sierk Poetting:]

Thank you, Sean. Now, I would like to summarize our financial results for the quarter that are shown on Slide 25. Our total revenue, which primarily consists of revenue from our collaboration agreements, was EUR 41.8 million for the second-quarter 2020, compared to EUR 25.8 million for the second-quarter 2019. For the period of six months ended June 30, 2020, our total revenue was EUR 69.4 million, compared to EUR 51.9 million for the comparative prior-year period. The revenue from collaboration agreements overall increased due to the recognition of revenue from our new collaboration agreement signed with Pfizer and Fosun Pharma as part of our BNT162 vaccine program against COVID-19. The revenues from other sales transactions increased due to increased orders and include sales of diagnostic product, peptides, retroviral vectors for clinical supply and development, and manufacturing services sold to third-party customers. Research and development expenses were EUR 95.2 million for the second-quarter 2020, compared to EUR 53.4 million for the second-quarter 2019. For the six months ended June 30, 2020, total research and development expenses were EUR 160.3 million, compared to EUR 110.6 million for the comparative prior-year period. The increase was mainly due to an increase in headcount, leading to higher wages, benefits, and social security expenses, as well as an increase in expenses for purchased research and development services, especially with respect to our BNT162 program. In addition, from the date of acquisition, our new U.S.-based subsidiary, BioNTech US Inc, contributed EUR 5.3 million to our research and development expenses. General and administrative expenses were EUR 18.8 million for the second-quarter 2020, compared to EUR 14.6 million for the second-quarter 2019. For the six months ended June 30, 2020, total general and administrative expenses were EUR 34.6 million, compared to EUR 23.9 million for the comparative prior-year period. This increase was mainly influenced by higher expenses for purchase management, consulting, and legal services, as well as an increase in headcount leading to higher wages, benefits, and total security expenses. In addition, from the date of acquisition, our new U.S.-based subsidiary, BioNTech US Inc., contributed EUR 1.6 million to our general and administrative expenses. Net loss was EUR 88.3 million for the second-quarter 2020, compared to EUR 50.1 million for the second-quarter 2019. For the six months ended June 30, 2020, total net loss was EUR 141.7 million, compared to EUR 90.8 million for the comparative prior-year period. Turning to the balance sheet on Slide 26. BioNTech ended the second-quarter 2020 with cash and cash equivalents of EUR 573 million or $641.6 million. Additionally, we raised EUR 680.7 million or $762.2 million in gross proceeds from a private equity placement and our follow-on underwritten offering after the end of the second quarter. Considering these gross proceeds, the expected pro forma cash and cash equivalents balance at June 30, 2020, amounts to EUR 1.25 billion or $1.4 billion. Further, we announced a debt financing of up to EUR 100 million or $112 million from the European Investment Bank in June 2020. All financing transactions are subject to closing conditions that were not fulfilled before June 30, 2020, and did not have an accounting impact within the second-quarter 2020. As a result of increased spending related to BNT162, we now expect net cash used in operating activities and for purchases of property and equipment to be between EUR 450 million and EUR 600 million for the full-year 2020. We anticipate that existing cash and cash equivalents, the net proceeds from the recent underwritten offering and the expected net proceeds from the private investment announced in June 2020, will enable us to fund our operating expenses and capital requirements through at least the next 24 months. With that, I will return the call back to Ryan for concluding remarks.

[Ryan Richardson:]

Thank you, Sierk. Slide 27 outlines the key milestones we're focused on delivering as we look to the remainder of 2020. The first relates to our COVID-19 vaccine program, where the next major milestone is the Phase 2b/3 trial we are conducting with Pfizer. As Özlem mentioned, we expect to be in a position to seek regulatory review as early as October 2020. In the meantime, we expect to publish Phase 1 safety and immunogenicity data for BNT162b2 in the next few weeks. We also intend to publish preclinical data over the same time period. In addition, we anticipate three first-in-human data updates for our oncology programs over the course of the year, including for BNT114; BNT131; and our DuoBody program, BNT311. Data from our BNT114 FixVac Phase 1 study in triple-negative breast cancer has been accepted for an oral presentation at ESMO in mid-September. The Phase 1 study is a three-arm trial as a monotherapy and in combination with iNeST evaluating safety and immunogenicity. The data to be presented will include a preliminary analysis of immune responses in TNBC patients treated with iNeST. For BNT131, our mRNA intratumoral immunotherapy program partnered with Sanofi, we expect the data update for our Phase 1/2 trial in solid tumors in the second half of 2020. The study is a first-in-human multicenter open-label Phase 1 dose-escalation and expansion trial to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of BNT131 both as a monotherapy and in combination with cemiplimab in patients with certain advanced solid tumors. The data to be presented will include safety, tolerability, and pharmacodynamic biomarker data. While updates for these programs will focus on safety and immunogenicity, we expect that our preliminary update for BNT311, our bispecific antibody, will also include top-line response data from our ongoing Phase 1/2 trial. And finally, we plan to initiate up to six additional studies from our oncology pipeline over the remainder of 2020. These include randomized Phase 2 trials for FixVac in melanoma and HPV16+ head and neck cancers; and for iNeST in adjuvant NSCLC and adjuvant CRC cancers. We also anticipate initiating first-in-human trials for our cell therapy programs, starting with our Claudin 6 CAR-T cell therapy, the first program to incorporate our CAR-T amplifying mRNA vaccine or CARVac approach. And with that, I'll hand it back over to Ugur for concluding remarks.

[Ugur Sahin:]

Thank you, Ryan. I'm proud of what we have accomplished over the first half of 2020 and believe a tremendous opportunity lies before us. We thank our shareholders and partners for their trust and support. Let us open up the call for questions now.

[Operator:]

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. [Operator Instructions] Your first question comes from the line of Tazeen Ahmad from Bank of America. Please ask your question.

[Bill Maughan:]

Hi. Good morning. This is Bill Maughan on for Tazeen. So two from me. First of all, how do you think about distributing the initial doses that are going to be manufactured later this year of the potential COVID vaccine, assuming approval? So the initial doses manufactured later this year and early next year given that the first manufacturing batches won't immediately cover all supply agreements. And then secondly, when you have to repay the Pfizer upfront investment out of profit sharing, can you help quantify what Pfizer has already put up in terms of operating investment? And what the pace of paying that back would be out of profit share and milestones? Thank you.

[Ryan Richardson:]

Yes. I'll start with the first question, this is Ryan, on the distribution side and then turn it over to Sierk to comment on the second. So I think we're in the fortunate position to have considerable demand or interest in the vaccine as you can see from the supply deals that we announced so far. Some of those deals do call for doses to be supplied in 2020, others in 2021. I think we've indicated that by end of 2020, we expect to have up to 100 million doses and then expect to be able to increase our capacity pretty significantly as we head into 2021. So I think we can't get into specifics at this point, but I think it's safe to say that we will -- already with the distribution agreements that we've announced, we feel confident that the doses that we can produce, we'll be able to distribute across the countries that are included in those agreements. I don't know, Sierk. Do you want to comment on the second question?

[Sierk Poetting:]

Yes. Happy to. Now, actually, in Q2, this was the first reconciliation that we did with Pfizer. And this quarter, we reconciled $20 million as the total net cost on the BioNTech side. Actually, this was the 50% of cost share for BioNTech in this quarter. So compared with the total program, still a small amount because it was ramping up in April and May and June so far. So $20 million was recognized as cost so far as our share.

[Bill Maughan:]

OK. And I guess how do you get to that $20 million with the large numbers that Pfizer has kind of put out in terms of what they're investing in their manufacturing?

[Sierk Poetting:]

Yeah. So there's only a certain type of cost there, so not everything is shared 50-50. So investments into capacity is everybody's own cost. And what's shared is basically the development cost and scale up. So this is shared, and the $20 million is our part of the share. And so far, it's covered from our upfront that we received when signing the contract.

[Operator:]

And your next question comes from the line of Cory Kasimov from JP Morgan. Please ask your question.

[Matthew Holt:]

Hey, guys. Thanks for taking my question. This is Matthew on for Cory. So I guess just wondering, for BNT162, if you can talk a little bit about how you maintain the integrity of a Phase 3 blinded trial if a large proportion of the BNT162 patients are expected to get fevers and other systemic AEs and what your view is on whether this could impact the ultimate outcome of the trial.

[Ozlem Tureci:]

Yeah. So thanks for the question. First of all, as the as we indicated in the press release when we announced a selection of BNT162b2, we indicated that b2 is significantly better tolerated than the b1, yes? So actually, only a little fraction of vaccinated individuals had fever. And with regard to the other symptoms, you might have seen that even placebo-vaccinated subjects have a number of background symptoms. So we believe that we have a very good overall situation to avoid any type of bias, mediated bias, by the understanding of the participant that he might, or she might, get the vaccine and not the placebo.

[Matthew Holt:]

Great. And then just wondering if you can walk us through your assumptions, or essentially what needs to happen for the Phase 3 program to get data and a potential regulatory filing in October. I guess maybe if you can help quantify how dependent this is on either enrollment or infection rates or what might be the key factor in the timelines.

[Ozlem Tureci:]

Yeah. So this is the efficacy trial. That means at the end of the day, we are comparing the number of infected infections in the placebo whereas in the treatment group. We are online evaluating the blinded session, the safety data. The trial is proceeding very well. It's even recruiting faster than anticipated. And the overall concept is to wait until we have a given predefined number of infections events and then do a first evaluation if there is significant difference between vaccine and placebo group. Yes. The event number, so we will have several options, yes, to evaluate different event numbers, yes. And based on that, based on the lower event numbers, you might be able to file already in October, yes. If the lower event numbers do not support a filing, we will have the opportunity to file four or six weeks later, based, of course, on the assumption that the trial is positive.

[Operator:]

Your next question comes from the line of Arlinda Lee from Canaccord. Please ask your question.

[Arlinda Lee:]

Congrats on all the progress. I had a couple of questions on 162. One, can you provide an update on the enrollment of the pivotal trial? And two, I heard that some of the net cost for the trials have already -- you've given guidance that that was earlier in the development front. I'm wondering what you think the cost might be for the remainder of the year. And then also on your oncology pipeline. I mean, just more broadly, I guess the rapidity and efficiency with which you guys have taken 162 into the clinic, I think, highlights your platform. And I'm wondering what your appetite might be for additional collaborations. And if you've been getting inbound interest.

[Ugur Sahin:]

So maybe we start with the first question. I had difficulties to acoustically understand the second and the third question. So the recruitment, so my understanding is that the first question was related, how fast the recruitment happens for the pivotal trial. So we anticipate to recruit up to 30,000 subjects until mid of October. And at the moment, I can't tell you exact numbers, but the trial is recruiting better than what was modeled. Yeah? Yeah. So we are on track and even ahead. The second question. Can you repeat the second question just a little bit louder?

[Arlinda Lee:]

Yeah. I'm just trying to, I guess, figure out, on the cost-sharing, how much you might accrue by year-end.

[Ugur Sahin:]

This is a question for Sierk.

[Sierk Poetting:]

Yeah. I can take this one. Yes. So as I mentioned before, so the net cost -- the net share in this quarter for BioNTech was $20 million. And this was majorly driven by clinical cost, but also some preclinical research that was shared. Sort of call it about 1/2 or something was clinical cost. But remember, May and June was only the Phase 1 trial. So basically, patients were probably more expensive -- or sorry, subjects were more expensive but also not as many. So I think you can do the math and upgrade it to like it would be a lot more expensive in Q3. And with the Q3 numbers, we'll also host like a better update. But it will be, yes, triple-digit million-dollar amounts, I think.

[Ryan Richardson:]

I mean, maybe just to add to that, one point, which is we had previously guided, Arlinda, to EUR 300 million of spend for the year. And I think it's safe to say that we were tracking on that, ex the Neon acquisition and the impact of COVID. So we've guided to EUR 450 million to EUR 600 million of net cash spend by the end of this year. So that delta there also gives you a sense for what the incremental amount could be.

[Arlinda Lee:]

Great. Thank you. And then I guess the third question was, basically, given you guys want to find the platform, I'm kind of curious about whether you've gotten inbound interest and what your appetite might be for additional strategic collaborations.

[Ugur Sahin:]

Maybe I can take the question. Yes, of course. This project, of course, validates our ability to respond quickly to challenges and opportunities. It validates our technology. It validates the safety of our approach. And of course, it creates a lot of interest in future projects, and we are in discussion with our partners for additional opportunities coming up in 2021.

[Operator:]

Our next question comes from the line of Shanshan Xu from Berenberg. Please ask your question.

[Shanshan Xu:]

Hi. Thank you. Good morning, everyone. Congrats on the progress. So a few questions here on 162. I'd like to understand a little bit more on the old adults, the signals that you've seen in Phase 1 and 2. And maybe qualitatively describe whether that's consistent with what people think the immune response there in this population is a lot lower than younger adults and then whether the results from b2 would -- in old adults will be included in the manuscript that you alluded will be available in a few weeks.

[Ugur Sahin:]

Yeah. So the first part of the question is older adult vaccine responses. So the size, I know there are no publications yet on any group about vaccine responses in elderly adults. But as you, as everyone, can guess, immune response in elderly adults is weaker, yes, and was likely for any vaccine platform, weaker. The reasons. The reasons for that are twofold. It's is the weaker innate immune response in elderly people. And the second is the reduced number of naive T cells and naive B cells in elderly. What we have observed is that a dose which is fully effective to induce a strong antibody and T cell response in younger population is too low in the elderly population. That's the reason why we increased the dose, yes, for our candidate b2. And with increase of the dose, we are well in the range of a fully effective immune response or what is expected to be a fully effective immune response. And of course, yes, the data will be published with the next upcoming manuscript.

[Shanshan Xu:]

And then do you have a plan to publish any results from other areas in c2?

[Ugur Sahin:]

From other candidates?

[Shanshan Xu:]

Yes. Other variants that were on Phase 1/2 study.

[Ugur Sahin:]

Yes, yes, yes. The other variants are in continued clinical evaluation with somehow lower priorities. We expect to have a first publication related to another variant in October, yes. And, yes, we will continue to share insights from this development program, which was not only just about selecting the first candidate but selecting the best candidate and also generating insight into the future generation of vaccines, which may come with lower doses. So where lower doses might result in the same type of immune response.

[Shanshan Xu:]

Great. That's helpful. And then finally, just quickly touching on the oncology program, BNT111. I remember there is an adjuvant cohort in the Phase 1 study. The results haven't been communicated. Is there anything that you have seen in that adjuvant melanoma cohort?

[Ozlem Tureci:]

Thank you for that question. We are evaluating the adjuvant cohort as well and later this year, we'll be able to report on that cohort as well.

[Operator:]

Thank you. Your next question comes from the line of Daina Graybosch from SVB. Please ask your question.

[Daina Graybosch:]

Thank you very much. And maybe I'll start with two on BNT162 and then, after that, come back for one on iNeST. So on BNT162, two questions. One, there's been a lot made over differences in CD8 immunogenicity response between different companies and vaccines. And I wonder if you could comment on -- if there's anything in the BNT162 mRNA construct or lipid nanoparticle that could be driving your relatively higher CD8 response versus some of the others. And then the second question is we've seen some of the CD8 and CD4 T cell response data for patients who have COVID-19. And then a lot of those publications, there's a lot of response, I guess, on nucleocapsid, especially for patients with certain HLA types. And I wonder what you think about your vaccines and others, not including antigens for the nucleocapsid, and whether that will be necessary in life cycle management for full protection for old people.

[Ugur Sahin:]

So thanks, Daina, for the questions. So first of all, yes. Yes, as you know, our focus in messenger RNA vaccine development is optimizing not only antibody responses but particularly CD4, as well as CD8 responses. If you see the track record of the publications that we made in the last 10 years, we have included a number of independent optimizations to increase the translation of our messenger RNA in human dendritic cells, which includes UTR regions, cap analogs, and as well as the delivery of the vaccine. This CD8 response requires a direct expression of the antigen in dendritic cells. So if you express the protein outside of dendritic cells, the classical pathway for antigen presentation is uptake of the antigen by the exogenous presentation machinery of dendritic cells and presenting on Class 2, which produced nice CD40 cell response. That's the reason why the spike on protein vaccines and with vaccines which don't go into dendritic cells get CD40 cell responses, but the only way to get powerful CD8 responses is expression, strong expression with human dendritic cells, which we have proven for our platform and for the COVID-19 vaccine in retail. And I think this is the key differentiator for observing a stronger CD8 T cell response. And the second part of the question was related -- what was the second question?

[Daina Graybosch:]

The nucleocapsid, and whether there's some efficiency by not including that?

[Ugur Sahin:]

Yeah. I think if you ask the question, what is the immunodominant antigen in an infection, this is not the same question with what antigen is particularly suitable to have a protective T cell response. Yes, nucleoprotein is an immunodominant antigen, yes, but we know that the virus entry is mediated, of course, by the full virus and the spike protein is one of the key proteins in this virus. And therefore, having a protein, and particularly with the supposed spike protein, which is more than 1,200 amino acids and a large protein with 1,200 amino acids gives you multiple base of presentation of Class 2 and Class 1 epitopes on multiple MHC haplotypes. So we believe that this spike protein is the near-perfect antigen. We wanted clearly to avoid to add additional antigens into our vaccine because every additional antigen comes with an independent price and independent costs for potential diversification of the autoantibody repertoire. And therefore, having a simple vaccine, which is able to induce CD4 and CD8 T cells in a broad population of people is sufficient, and we believe with the large spike protein, we have an ideal candidate.

[Daina Graybosch:]

That's very helpful. And then on iNeST, looking back at the data that was presented at AACR, one or two questions. I wonder if we should read anything to the biomarkers that there were few TCM cells versus TEM cells and also whether the number of sort of immunogenic neoantigens at around 2.6 is high enough. And sort of with both of those biomarkers, if you're worried about them and if you're doing anything to optimize them as you go forward.

[Ugur Sahin:]

Yes. So the most important learnings from this bucket card is the feasibility of approach for really multiple different indications, the safety of the approach in different indications, in combination also with atezo and the broad immunogenecity. The shortcomings of the part, of course, this is a bucket uncontrolled trial in patients with heavily pretreated, and most of these patients had a progression-free survival time less than three months. So this is not an ideal population for vaccine. And therefore, it's difficult to draw any conclusion with regard to potential clinical activity from this cohort. And this was the reason why we have already started in 2019 our randomized trial in melanoma, yes, in certain melanoma, which gives us with the PFS in the range of above nine months, gives us sufficient time to have fully induced T cells response, succeeded in the T cell response. And here, the key question is if iNeST, in combination with checkpoint locate in our first line a highly mutated tumor type, could induce an added benefit. So this trial would help us to get other indications with a similar type of profile. And the second learning, not only from this iNeST type but also from the melanoma trial that we had published in 2017 and followed up with updated data in 2020 is that tumors with a lower tumor load might be the ideal setting for iNeST. And that's the reason why we are going to start two clinical trials in ctDNA positive tumors. One is the non-small cell lung cancer program and the second one is the colorectal cancer trial. And this is also based on a learning from the basket trial because in the colorectal cancer patient population that we have vaccinated, even though these were advanced patients, we observed really strong T cell response. So that the number of mutation seems not limiting for application of iNeST in this population. And that was encouraging enough to define it to two additional indications. So the next 12 months will be extremely informative for the iNeST project with data coming from the melanoma trial and with the randomized trials in lung cancer and colorectal cancer being active.

[Operator:]

Your next question comes from the line of Navin Jacob from UBS. Please ask your question.

[Navin Jacob:]

Hi. Yes. Thank you for taking my question. Can you hear me OK?

[Ugur Sahin:]

Yes.

[Navin Jacob:]

Perfect. Thanks. And I've had quite a few, if I may start with BNT162. Firstly, congrats on all the progress. Maybe I can just -- on the trial design, I just was hoping for some clarity on some of the statistical powering assumptions. What is the trial powered for, for what size -- for what effect size? And if you could provide any clarity on the number of events at the first interim look versus the second interim look, please. And then I have some follow-up questions.

[Ugur Sahin:]

So these are maybe important questions, but at the moment, we are not able to share this information. But what you can -- yes. So what you can assume is that we have different interim readouts. And these interim readouts, of course, come with different powers and with different assumptions about the efficacy. So that's how the trial in general structure, but I can't share the actual number.

[Navin Jacob:]

And then maybe on regulatory requirement, either based on an interim look and depending on the number of events, what is the -- are there different requirements associated with, say, an interim look with 150 events versus 100 events? And attached to that, what is the regulatory requirement from a safety standpoint, a minimum follow-up of at least six months? If you were to file in October, for example, based on an interim, would you have enough follow-up data as far as duration of the safety that would allow for emergency use authorization?

[Ugur Sahin:]

Yeah. So the safety effect is addressed by two parameters. The one is the number of vaccinated subjects. Though, usually, 3,000 subjects are sufficient to support a pandemic vaccine approval. The second is the follow-up time. And we are all aware that we have, on the one side, the need to get a vaccine approved as fast as possible and make it available. For example, we are an emergency use authorization pathway. And on the other side, to continue to collect the safety data. And that is exactly what is happening. So the subjects in this trial will be followed up for safety parameters and we will get three months, say, to six months safety and we'll continue also to monitor immune responses and the stability of immune response in the subject to understand also the durability of immune response.

[Navin Jacob:]

And what exactly does emergency use authorization mean in the context of a vaccine? Does that mean can be used, if you have the doses, could that be used in a broad population? Or will it be only used in high-risk populations such as patients in the frontline, healthcare workers, so on, and so forth? And then two quick other questions. So you mentioned long-term immunity. Wondering what gives you confidence or what are you seeing that should allow us to have some confidence in long-term immunity or memory function. And then on the Fosun partnership, it looks like you're moving forward with 16b1, if I'm correct, with Fosun and not 16b2. Maybe that is just earlier in where you're developing it in China. So maybe that's one. But if you could just clarify that, that'd be appreciated.

[Ugur Sahin:]

OK. So start with the first question, who could benefit from the emergency use authorization. And of course, this is an issue of the governmental interest. So this is something where the U.S. government or the FDA had to decide for whom such vaccine would be applicable. That's the same as in Europe. It's a decision of every government to make the vaccine available and to be found to which population it should be made available. The second question -- or the third question was about durability. Yes, so we are collecting data with regard to durability of antibody response, as well as evaluation of the durability of T cell responses. So far, we have published data up to 43 days, and we will collect it for three months, six months, nine months, 12 months. We, of course, expect that the antibody titers will drop over time. That is what happens to antibody titers, which is vaccine in tandem. We have to see how fast this drop is and what is the baseline level where the drop stops, yes. And what kind of antibody-based protection still happens at this baseline level. So this is something which we will learn in the upcoming 6sixmonths and continue to collect data. I'm confident that having a vaccine, which comes with a combined immune response, CD4, CD8, as well as antibody response, based on the collaboration of this immune system arms, will require a lower amount of each component since we will have a simplistic activity. But actually, the whole scientific community and the industry has to learn what happens in the next two years, how stable are these immune responses, what is required to protect from the infection. If this is an issue, if the drop of the immune response is an issue, I believe there's a messenger RNA vaccine, we are in a good place to implement a booster immunization because this is one of the key strengths of messenger RNA vaccines. You can really use it several times for boosting the immune response. It is not limited by any type of vector backbone immune response, which limits the activity of inducing and boosting antibody and T cell response.

[Navin Jacob:]

Thank you so much. And just maybe two very quick questions on FixVac. The T cell data in the nature publication certainly look interesting, but it is a plasma data. Wondering what it looks like in the two microenvironment, which, as you know, literature suggests there's better correlation with antitumor activity with T cells in the tumor. And then wondering also when we're going to see the next data set with a later cutoff point from this Phase 1.

[Ugur Sahin:]

Yes. First of all, we have done in other studies, we analyzed tumor tissue and presence of T cell receptors, of vaccine-induced T cell receptors, for example, in the iNeST trial but also for the FixVac. And yes, we confirm that T cells that have been observed in the peripheral blood indeed infiltrate in the tumor and are detectable in the tumor. So this was not required to receive that in this special publication, which was more about the relationship between the strength and duration of the immune responses and the function of the immune response to cytotoxic assumption. The next publication from the study will be sometime in 2021. I assume it's the second half of 2021 with regard to the population in this trial, which is evaluated for relapse-free survival. So we had a patient population, who did not have tumors, metastatic tumor lesions but had surgery and afterwards received the therapy, and we will have relapse-free survival data here. And actually, the next upcoming publication would be the publication describing the Phase 2 data. And so we are -- as you know, we are going to start a randomized Phase 2 study in melanoma FixVac end of this year. And it will be a relatively small study, which we'll record within the next 18 to 24 months. And I hope that this will be pivotal data required for registration of FixVac in second line plus melanoma.

[Navin Jacob:]

Got it. I'm sorry. The question on Fosun, are you moving forward with 162b1 with them or 16b2?

[Ugur Sahin:]

Özlem, could you please...

[Ozlem Tureci:]

Yes, sure. We are moving further with b2 globally, also in China and with Fosun. The reason why the b1 part of our testing in China has started basically at the same time when we make the b2 decision is that we think that it has value to also compare in the Chinese population, meaning in other populations, these two candidates of mod-RNA platform, and we are now preparing the b2 entry in China. So the regulatory processes are the difference there. It's the more sequential approach, not the umbrella trial approach, which works in that regulatory region. We think that generating class-intrinsic data for mod-RNA as such and also benchmarking these two, b1 and b2 mod-RNAs, against each other in the Chinese population is of value for the entire program.

[Navin Jacob:]

That's very clear. Thank you very much for this call. Very helpful details and congrats on the progress.

[Ozlem Tureci:]

Thank you.

[Operator:]

[Operator Instructions] Your next question comes from the line of Suzanne van Voorthuizen from Kempen. Please ask your question.

[Suzanne van Voorthuizen:]

Hi. Good afternoon. I have a question on the COVID-19 vaccine. Looking back at the four different candidates that you went into Phase 1 with originally, I was just wondering, for b1 and b2, these are mod-RNAs. It is our understanding that this format is more often used by BioNTech to de-immunize mRNA to make it especially useful for immune-silent applications. So can you elaborate a bit, are b1 and b2 also uridine modified? Or how are they modified to be more immunogenic?

[Ugur Sahin:]

Yeah. So the rationale for starting with four different vaccine was, on the one hand, to evaluate our three different vaccine platforms. This is that modified messenger RNA platform, which were now used for the candidate b1 and b2. And here, b1 and b2 were selected based on the experience of the field in the past with MERS and the SARS, where both antigens had been evaluated but never benchmarked side by side. Yes, with the RBD and the spike. And our study shows that both candidates are viable candidates, with b2 having some advantage in this case. For the second platform, the uridine-based platform, which comes with the potential advantage of a higher reactogenicity and thereby stronger activity at low doses, we started to evaluate the RBD variant and generated some data, and the data shows that we have immunogenicity but the immunogenicity that not matched the immunogenicity that we have observed with the nucleus-modified mRNA. And the second was the first candidate was saRNA-based candidate. And here, we have in the preclinical models evaluated RBD, as well as full spike, and determined that the full spike for the self-amplifying mRNA is significantly better. So only the full spike is the currently evaluated. And here, we expect immunogenicity data since this is really dose-escalation study started with extremely low doses. We expect the first relevant immunogenicity data in the time frame end of September, and we'll share that with the community. So the third amplified messenger RNA comes with the potential promise of having a potent vaccine candidate, which comes with doses in the low microgram range.

[Suzanne van Voorthuizen:]

Got it. Got it. And then maybe on the Phase 2/3 trial. In terms of the primary endpoint, can you remind us of the bar that you have to achieve? Was that a 50% reduction in infection rates? Do you need to hit both co-primary endpoints or one of the two to claim success?

[Ugur Sahin:]

Yeah. It's very simple. We stick to the guidance of the FDA, and that's the lowest one.

[Suzanne van Voorthuizen:]

And are the co-primary endpoints, are they either/or, or are they and that you need to achieve to claim success?

[Ozlem Tureci:]

These are either/or.

[Suzanne van Voorthuizen:]

OK. And maybe just one follow-up in this regard. Just to clarify for the filing, is the primary endpoint data the hard requirement? Or maybe for an emergency use authorization, will there be immunogenicity data analyzed with the interim analysis? Could it be that you can file on that if your primary endpoint data is trending in the right direction, for example? Or is it a hard requirement?

[Ugur Sahin:]

So this is an ongoing discussion with the FDA, but I think the FDA was crystal clear when it announced in July the requirements for authorization. And if this is still the case, then we would expect that use of the vaccine is only allowed when there are efficacy data around.

[Operator:]

Your final question comes from the line of Olga Smolentseva from Bryan, Garnier. Please ask your question.

[Olga Smolentseva:]

Good afternoon everyone and thank you for taking my questions. Firstly, on BNT162, considering that recent publication suggested that different mutations since spike protein could provide deeper immunogenicity, could you maybe give us a little bit more color on the sort of optimization of the full spark antigen in b2, what kind of mutations in spike protein it includes?

[Ugur Sahin:]

Yeah. So this is publicly used b2 prefusion-stabilized mutation of the spike protein, which has been described to use a stronger antibody response as compared to the virus-type protein.

[Olga Smolentseva:]

OK. That's great. And maybe just a little bit on BNT221. So how should we think about target population here in terms of differentiation with the planned potential pivotal BNT111 program?

[Ozlem Tureci:]

Sorry, I didn't get that. Is this BNT111?

[Olga Smolentseva:]

Sorry, it's on BNT221. Yes, the Neon program.

[Ozlem Tureci:]

OK, OK. The Neon program. Do you mean the adoptive T cell therapy program, which is about to start?

[Olga Smolentseva:]

Yes, yes. I'm just interested in the target population here because it seems to overlap with BNT111. And I'm just thinking how you -- yeah, sorry.

[Ugur Sahin:]

Yeah. So the time which is going to start, Europe will be in relapsing metastatic melanoma patients, and this is more or less a proof-of-concept study because the approach is really an agent. It is an approach of creating new antigen-specific T cells directly from blood. Yes, so this is in principal a universal approach applicable to any type of tumor and the colleagues from BioNTech U.S. have generated data also for other type of solid cancers. But melanoma is, of course, an excellent tumor type for first proof-of-concept study.

[Olga Smolentseva:]

Great. Thank you. And many great observations on all the progress.

[Ugur Sahin:]

Thank you.

[Operator:]

Thank you. I would now like to hand the conference back to Sylke Maas for closing remarks.

[Sylke Maas:]

Thank you for joining today's call. We look forward to speaking to you in the future particularly. Bye-bye.

[Operator:]

That does conclude our conference for today, thank you for participating. You may all disconnect.