BioNTech SE

NASDAQ:BNTX

Earnings Call Transcript 2020-Q3

[Operator]

Thank you for standing by, and welcome to the BioNTech Third Quarter 2020 Update Call. [Operator Instructions] I must advise you this call is being recorded today, Tuesday, the 10th of November 2020.

And I would now like to hand the call over to Vice President, Investor Relations, Ms. Sylke Maas. Please go ahead.

[Sylke Maas, executive]

Good morning, and good afternoon. Thank you for joining us today to review BioNTech's third quarter 2020 operational progress and financial results. Before we start, we encourage you to view the slides for this webcast as well as the 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: BioNTech's efforts to combat COVID-19; the potential safety and efficacy of BNT162; the timing for submission of data for, or receipt of, or potential approval or Emergency Use Authorization with respect to our BNT162 program; the ability of BioNTech to supply BNT162; the planned next steps in BioNTech's pipeline programs; the timing for enrollment initiation, completion and reporting of data from our clinical trials; and BioNTech's anticipated cash usage for fiscal year 2020 and beyond.

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.

On the call with BioNTech management today will be Ugur Sahin, our Chief Executive Officer and Co-Founder; Özlem Türeci, our Chief Medical Officer and Co-Founder; Sean Marett, our Chief Business and Commercial Officer; Sierk Poetting, our Chief Financial and Operating Officer; and Ryan Richardson, our Chief Strategy Officer.

The agenda for today's call is shown on Slide 3. Ugur will start with Q3 highlights and an update on our COVID-19 program before handing over to Sean to provide an update on our commercial distribution plan for BNT162. Özlem  will then update on our oncology pipeline. She will walk through some of the data we are highlighting this week at SITC for BNT311, our PD-L1x4-1BB checkpoint immunomodulator. Sierk will then provide a recap of our financial results for the third quarter and our financial outlook for the rest of 2020 before handing back to Ugur for concluding remarks. We will then open the call for Q&A.

I now hand the call over to Ugur Sahin, BioNTech's CEO.

[Ugur Sahin, executive]

Thank you, Sylke. Good morning, and thank you to everyone joining the call today. Let's start with Slide 4. I am incredibly happy about the accomplishments we can report to you today. We announced yesterday that our COVID-19 vaccine program demonstrated evidence of efficacy against COVID-19 based on the first interim analysis.

Just to remind you, so far, we have continued to see evidence from mild-to-moderate tolerability profile in our Phase III trial, which is consistent with what we have observed in the earlier studies. We believe the news from yesterday represents a watershed milestone for our company, and one that we believe will constitute an important step for the world after more than 8 months into the worst pandemic in modern century.

When we made this decision to initiate a COVID-19 vaccine program in January, we did that against a backdrop of considerable uncertainty. For example, it was not known at that time point if a vaccine would work at all. But when that decision was made, we went all in, with the hope of considerable resources, both in terms of time and attention, human resources and also capital towards addressing this challenge. We did so without knowing how the pandemic would play out. We did so because we felt a duty to try and to do something because we believe our technology has the potential to make a difference. And with the news this week, I believe, now more than ever that we are in the position to make that difference. And we will still have a lot of work to do, and we'll continue to focus on the goal every single day.

We, along with our collaboration partner, Pfizer, have already initiated the regulatory submission process to the EMA, to the MHRA in the U.K. and to Health Canada. We believe we are on track to submit an Emergency Use Authorization to the FDA as early as the third week of November.

Further, we have initiated clinical trials in Japan, in China as part of what we expect will be a registrational pathway in each country. Finally, we recently acquired a GMP manufacturing facility in Marburg, Germany, intended to increase our capacity to produce COVID-19 vaccines in 2021. And we continue to plan for what would be our first commercial launch with our partner, Pfizer, and Fosun Pharma if we are granted an approval.

We had some slowdowns in our oncology pipe. But despite that, the new phase starts to -- but anyway, we are pleased to present early Phase I data for our next-generation checkpoint immunomodulator, BNT311 at the SITC meeting this week. This molecule is jointly owned by BioNTech and Genmab in a 50-50 cost and profit split collaboration. BNT311 has demonstrated promising data across multiple tumors, and Özlem will cover in some detail the findings from the ongoing Phase I/II study.

In addition, in the third quarter, we provided multiple Phase I data updates for several other programs, including BNT131 for intratumoral messenger RNA partnered with Sanofi at SITC and 1 arm from our exploratory Phase I for BNT114 at ESMO.

Finally, in the third quarter, we received IND approvals for our randomized Phase II trial of INS BNT122 in adjuvant colorectal cancer and recorded the first patient dose in our Phase I/II trial of BNT411, our small molecule TLR7 agonist in multiple solid tumors, including small cell lung cancer.

And finally, we strengthened our financial position in the third quarter to a mix of equity, debt financing, grant commitments of approximately $1.2 billion cumulative gross proceeds. Hence, we are in a strong position to capitalize on our opportunities that lies ahead of us.

Slide 6. Slide 6 highlights the development time line since initiating of our BNT162 program in January after the SARS-CoV-2 sequence was first published. The accelerated development path depicted here reflects the intense focus that we and our partners have bought into this program from day 1, all without cutting corners.

We started the first of multiple Phase I trial in late April, which means that our update yesterday demonstrated 90% of efficacy as of our interim efficacy analysis, and our pivotal Phase III trial comes approximately 6.5 months after initiating the Phase I trial.

Again, this accomplishment speaks to the incredible dedication and hard work of our team and of our collaborator, Pfizer. We and Pfizer published our protocol, so all the endpoints are clear for the world to see. We defined our primary efficacy endpoint in this trial as the efficacy of our BNT162b2 vaccine against confirmed COVID-19 in participants without evidence of infection before vaccination.

We expect test sufficient safety data to support our Emergency Use Authorization submission to the FDA as early as the third week of November. This safety data set is needed to be in position to request Emergency Use Authorization in the U.S. We kept the stage of testing that we have gone through with our BNT162b2 vaccine, which has so far resulted in 3 peer-review publications in journals of the New England Journal of Medicine and Nature.

The important point here is that we have done extensive testing over the past 9 months in many different contexts. And overall, I would say we have seen a consistent picture of the vaccine's pharmacodynamic effects. We conducted preclinical testing, starting with more than 20 vaccine candidates. This preclinical testing was conducted in multiple animal models and included a full GLP toxicology testing. In preclinical testing, we observed a dose-dependent immune response against virus, coronavirus, including antibody titers as well as strong CD4 and CD8 T cell responses.

And in non-human primate study, our vaccine prevented lung infection in 100% of SARS-CoV-2-challenged rhesus macaques. Further, no viral RNA was detected in the nose 3 days post challenge.

Following successful preclinical studies, we conducted multiple distinct Phase I trials, and we observed for the first time that our vaccine candidate resulted in mild-to-moderate side effects with no serious adverse events. Now over in Phase I trial, we observed strong neutralizing antibody titers at or above the level of convalescent sera from patients who have recovered from SARS-CoV-2. We also have observed high magnitude CD4 as well as CD8 T cells in vaccinated subjects.

So on Slide #7. The key question what we had to address in the Phase III trial is whether the vaccine can prevent COVID-19 in humans while having a good safety profile? Based on our announcement yesterday, we now have early evidence that it can prevent COVID-19 infection with high efficacy. The vaccine candidate was found to be more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection in the first interim efficacy analysis.

So the first analysis evaluated 94 confirmed cases of COVID-19 in prior participants. The case split between the vaccinated individuals and those who received the placebo indicate the vaccine efficacy rate above 90% as measured 7 days after the second dose. This means that protection was achieved 28 days after the initiation of vaccination, which consists of a 2-dose schedule. As of yesterday, the study enrolled more than 40,000 -- 43,000 participants, with 42% having diverse background.

It is important to mention that no serious safety concerns have been observed to date. We plan to collect further data on the other endpoints in the trial and we'll continue to collect longer-term safety data. We would like to remind you that the clinical trial is continuing to the final analysis at 164 confirmed cases in order to collect further data and characterize the vaccine candidate performance against other study endpoints.

On Slide 8. Slide 8 illustrates the current status of the BNT162 program globally. There are ongoing clinical trials in the countries shown in green. This includes the Phase III trial in the U.S. and Germany as well as ongoing tires in Brazil, Argentina, Turkey, South Africa, China and Japan.

The Phase I/II trial in Japan initiated in October will evaluate safety, tolerability and immunogenicity of 2 doses of BNT162b2, again, separated by 21 days and a single dose of BNT162b2 in healthy adults to 20 to 85 years of age.

The Phase I study in China remains ongoing. With our partner, Fosun, we expect to initiate the Phase II clinical trial with our BNT162b2 candidate by the end of 2020. Once we gain regulatory IND approval from the Chinese regulator authority and the NMPA, we will start the clinical trial.

There are ongoing regulatory submissions in the countries in blue, including EMA, the U.K. and Health Canada. We plan to work with EMA Committee for Medicinal Products for Human Use to complete the rolling review process to facilitate the final marketing authorization application.

The rolling submission in Canada was accepted under the Minister of Health Interim order allowing companies to submit safety and efficacy data and information as it becomes available. In the U.S. we expect to be in the position to request an Emergency Use Authorization potentially as early as the end of November.

I am now going to ask Sean to provide a brief update on our commercial supply and distribution model. Sean?

[Sean Marett, executive]

Yes. Thanks, Ugur. So just turning to Slide 9. Here, we're providing a snapshot of where we are on the commercial side. Demand is strong around the world. We currently have entered into commitments with purchases to supply more than 570 million doses by the end of 2021 with options in the United States and Europe for an additional 600 million doses.

We continue to work diligently with Pfizer to complete additional commercial supply agreements and are in negotiation with a number of governments around the world and other bodies like COVAX. All agreements, of course, are subject to clinical success and regulatory approval of the vaccine.

Just moving on to Slide 10. Here, we're highlighting the distribution model that we expect for the vaccine in the pandemic phase. We have a co-commercialization arrangement in place with Pfizer, as many of you know, and are really working very, very closely with them and with the governments for global distribution. Pfizer has developed a thermal shipper unit, which has GPS tracking, specifically for this vaccine, which is designed to keep the product at low temperatures for up to 10 days if stored at 15 to 25 degree Celsius without opening the shipper.

And if we do open it, then upon re-icing several times we can extend to 15 days on reopening. Further, we have the ability for 5 days storage in a refrigerator at 2 to 8 degrees centigrade. So that gives us really some flexibility with respect to storage and distribution. And the distribution model will, of course, depend on the region. But in general, we are engaging specialized supply chain providers, which we've indicated in the picture here, for air and ground shipping to and from our manufacturing sites in Europe and the United States to distribution hubs all around the world. And from those distribution hubs, we expect to distribute the vaccine to step -- specialized points of care.

In some markets, we expect there to be a focus on a more centralized network of points of care with high-volume distribution, whereas in other regions there will be a higher number of these points of care. In most regions of the world, we will leverage Pfizer's distribution capabilities through, though in some markets, for example, here in Germany, BioNTech plans to distribute. However, it's important to note that our agreement with Pfizer is 50-50 profit sharing worldwide, excluding China. So the economics to BioNTech are the same regardless of who distributes the vaccine.

Okay. So going further, it is important to note that at the point of care, we will have multiple short-term storage options available, as we mentioned earlier. And in addition to the thermal shipper, which I described earlier, sites, of course, can use ultra low-temperature freezers. These freezers are commercially available and provide the ability to store the product as a frozen liquid at minus 70 degrees for long-term storage. For shorter period, the product can be stored up to 5 days at 2 to 8 degrees centigrade as I said earlier. It's important to note that if there is a freezer available, ultra low-temperature freezer available, the vaccine can be stores for up to 6 months in these freezers.

I'll now turn over to Özlem to provide an update on the oncology pipeline.

[Özlem Türeci, executive]

Yes. Thank you, Sean. We are changing gears now. And on Slide 12, you can see our clinical oncology pipeline. In the interest of time, I am going to provide updates on selected programs only. And for BNT311 detail the data released yesterday at the SITC conference. For further details on the status of other programs, please refer to our quarterly update, which we released this morning. I want to note that we have seen some continued impact from the ongoing COVID-19 pandemic on our clinical operations.

Specifically, there has been a slowdown in the enrollment of some of our ongoing studies and impairments of clinical site initiation of our planned studies. This is causing us to delay time lines for some of our programs.

Now starting with BNT111, our melanoma FixVac program on an RNA vaccine, which is composed of 4 non-mutated melanoma antigens. Recently, we published an exploratory data analysis in Nature from our ongoing Phase I trial. The publication highlighted the favorable safety profile of BNT111 in stage 3 B-C and stage IV melanoma patients who were pretreated with several lines of therapy, including PD-1 inhibitors. Our publication also noted BNT111's ability to mediate durable objective responses, both as a single agent and also in combination with approved anti-PD-1 antibodies, nivolumab and pembrolizumab.

During the first quarter, we entered into a strategic collaboration to pursue a development program with our colleagues from Regeneron. We plan to investigate the combination of BNT111 and Regeneron's PD-1 blocker, Libtayo, also known as cemiplimab, in patients with unresectable stage III or IV melanoma, who have progressed under or after treatment with PD-1 blockade. The Phase I -- the Phase II randomized and open-label trial is expected to include 120 participants who will receive either BNT111 and cemiplimab in combination or either of these compounds alone. The primary outcome measure for the trial is the objective response rate for the combination.

Moving to BNT113, our RNA vaccine encoding E6 and E7 proteins of human papillomavirus 16. Our randomized open-label trial is expected to enroll 285 patients in the first-line setting with unresectable recurrent or metastatic squamous cell carcinoma of the head and neck that are positive for HPV16.

The trial will include a safety run-in to confirm safety and tolerability in combination with pembrolizumab. Upon completion of the safety run-in, the trial is designed to evaluate BNT113 in combination with pembro versus pembro alone. Both BNT111 and 113 are currently under review by the FDA. We are targeting commencement of these 2 Phase II trials in the first half of 2021, subject to allowance of the IND by the FDA.

Now moving to our individualized neoantigen-specific immune therapy or iNeST platform, which is partnered with Roche, Genentech.

For BNT122 in first-line melanoma, the enrollment rate has been slower than originally expected due to the impact of the COVID-19 pandemic. Along with our partner, Genentech, we are currently evaluating the timing for conducting an interim analysis for this trial, and we'll provide an update once finalized.

Two trials are planned to investigate BNT122 in the adjuvant setting. The first adjuvant trial will include patients with early and adjuvant stage non-small cell lung cancer; the second is in patients with colon cancer, surgically resected stage 2 high-risk with circulating tumor, ctDNA, in stage 3 patients. First dosing is expected in the first half of 2021. The U.S. IND application for this trial was approved in July.

At ESMO in September, we presented data from the ongoing TNBC-MERIT trial in patients with triple-negative breast cancer, who had undergone neoadjuvant/adjuvant treatment. Patients in one arm of this trial were vaccinated with our individualized neoantigen immunotherapy. The data presented at ESMO provided a preliminary analysis of initial T cell responses in 14 of these patients. The analysis demonstrated that the neoantigen vaccine is highly efficient in inducing strong poly-epitopic T cell responses in the post neoadjuvant/adjuvant setting in TNBC. In all 14 patients, vaccine induced T cell responses against up to 10 neoantigens were detected, with the majority of which were de novo, indicating that this tumor type may be a candidate for neoantigen-specific immunotherapy as well.

Interim results from our ongoing first-in-human Phase I trial of BNT131 in patients with advanced solid tumor have been released for the SITC conference and will be presented there. BNT131, partnered with Sanofi, is a nucleotide modified RNA that encodes cytokines, namely IL-12, IL-15, GM-CSF and interferon alfa for intratumoral administration. The study is a dose escalation and expansion trial evaluating safety, PK and PD as well as antitumor activity.

As of July, 17 patients had received BNT131 monotherapy and 6 patients received BNT131 in combination with Regeneron's PD-1 blocker, cemiplimab. BNT131 was generally well tolerated. No patient experienced dose-limiting toxicity and no grade-free or greater treatment-related adverse events were reported to date.

Downstream effector cytokine signals and T cell infiltration in the monotherapy arm suggests an immunomodulatory effect. We are pleased with these preliminary results and look forward to continued development of this program with our partner, Sanofi.

For our preclinical pipeline, on Slide 13, I would just like to point out that while we had constraints of the COVID-19 pandemic to overcome, we expect the first half of 2021 to be very active in terms of our new modalities entering the clinic. We have shown 5 programs here that we expect to start Phase I trials for, including our cell therapy programs, BNT211, which is our CARVac approach, and BNT221, the personalized adoptive transfer approach of autologous T cells by our U.S. team. We also expect to initiate first-in-human trials for our and RiboMabs and RiboCytokines platforms.

Now moving to Slide 14 and BNT311, also called GEN1046. The first of 2 next-generation bispecific antibody programs, we have partnered with our esteemed colleagues from Genmab. To date -- 2 datasets featuring BNT311 were released at the SITC conference, which include, on the one hand, preclinical mode of action data and dose escalation and preliminary expansion data from our first-in-human Phase I/II trial. We are delighted that the clinical data presentation was selected by SITC to be featured by Ignacio Melero, one of our investigators at the press briefing of a conference yesterday.

The BNT311 is the first-in-class next-generation checkpoint immunotherapy being investigated for the treatment of advanced solid tumors, despite specific antibody simultaneously blocks the PD-L1 access and activate T cells through conditional 4-1BB costimulation. Conditional activation of 4-1BB is crucial as clinical development of 4-1BB agonist has been hampered by severe liver toxicity. The preclinical studies presented at SITC demonstrate that this dual targeting conditional mechanism of action induces a stronger and improved immune response in mice compared to PD-L1 alone in both the tumor-draining lymph nodes and tumor microenvironment of the mice. An increased CD8 to Treg ratio was observed, which led to potent and antitumor activity in the animals.

Slide 15 now shows the Phase I dose escalation part of this open-label single-arm trial expected to enroll up to 192 patients on the left side. Patients enrolled in the trial are adults with metastatic or unresectable solid tumors, who are not candidates for standard therapy. In the dose escalation part, 61 patients received flat doses of BNT311 at dose levels ranging from 25 milligrams to 1,200 milligrams every 3 weeks until disease progression or unacceptable toxicity to determine the recommended Phase II dose. The expansion part of the study will include cohorts of patients with non-small cell lung cancer, urothelial cancer, endometrial, triple-negative breast cancer, squamous cell carcinoma of head and neck and cervical cancer.

As shown on Slide 16, most frequent indications treated in the dose escalation part were colorectal, ovarian, pancreatic and lung cancer. Patients enrolled were heavily pretreated, and nearly 40% had received prior PD-1, PD-L1 treatment. As of the data cutoff date, treatment is ongoing in 10 patients and the maximal tolerated dose has not been reached.

On Slide 17, we show initial safety observations from the Phase I dose escalation part of the trial. Overall, BNT311 was generally well tolerated. The most common treatment-related adverse events were transaminase elevations, hypothyroidism and fatigue. Treatment-related transaminase elevations occurred in about 26% of patients. 9.8% of patients had grade 3 transaminase elevations, which improved with corticosteroid treatment. There were no patients with great for transaminase elevations or treatment-related bilirubin increases. Dose-limiting toxicities occurred in 6 patients and resolved without sequelae.

On Slide 18, you can see pharmacodynamic activity, which we observed over a broad range with maximal induction 8 to 15 days following treatment. These included interferon gamma and IP-10 increase, increased frequencies of proliferating CD8 T cells and proliferating CD8 effector memory T cells, altogether providing evidence of biological activity.

On Slide 19 now, we show antitumor activity observed with BNT311 during the dose-escalation phase. While this is early data, only 3 months median follow up, clinical benefit was observed across different dose levels. We were quite pleased to see disease control in 66% of the 61 patients, including 4 partial responses, 1 in a triple-negative breast cancer patient, 1 in an ovarian cancer patient and 2 in immune checkpoint inhibitor pretreated non-small cell lung cancer patients.

Finally, on Slide 20, we see 12 non-small cell lung cancer patients from the dose expansion cohort, who could be objectively assessed. These patients have progressed on or after immune checkpoint blockade prior to BNT311 treatment. We observed 2 confirmed partial responses, 1 unconfirmed partial response and 4 patients with stable disease. Our Genmab colleagues and we are considering these results as encouraging. We are actively enrolling additional patients in the dose expansion cohorts I previously mentioned. We look forward to presenting additional data for this potentially powerful new checkpoint immunomodulator in the future.

With this, I will now hand the call over to Sierk to provide an update on our financials.

[Sierk Pötting, executive]

Thank you, Özlem. I would like to summarize our financial results for the quarter that are shown on Slide 22. So our total revenue, which primarily consists of revenue from our collaboration agreements, was EUR 67.5 million for the third quarter 2020 compared to EUR 28.7 million for the third quarter 2019. So for the period of 9 months ended September 30, 2020, our total revenue was EUR 136.9 million compared to EUR 80.6 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 the company's BNT162 vaccine program against COVID-19. These revenues from upfront payments are recognized based on the underlying costs incurred and increase with increasing costs. The revenues from other sales transactions increased due to increased orders and include sales of diagnostic products, peptides, retroviral vectors for clinical supply and development and manufacturing services sold to third-party customers.

Research and development expenses were EUR 227.7 million for the third quarter 2020 compared to EUR 50.4 million for the third quarter 2019. For the 9 months ended September 30, 2020, total research and development expenses were EUR 388 million compared to EUR 161 million for the comparative prior year period. This increase was mainly due to an increase in the development expenses from our BNT162 program. In addition, from the date of acquisition of our new U.S.-based subsidiary, BioNTech US Inc. contributed to our research and development expenses.

General and administrative expenses were EUR 23.3 million for the third quarter 2020 compared to EUR 10.6 million for the third quarter 2019. For the 9 months ended September 30, 2020, total general and administrative expenses were EUR 58 million compared to EUR 34.5 million for the comparative prior year period. This increase was mainly influenced by higher expenses for purchased management consulting and legal services as well as an increase in headcount, leading to higher wages, benefits and social security expenses. In addition, from the date of acquisition, our new U.S.-based subsidiary BioNTech US Inc. contributed to our general and administrative expenses as well.

The net loss was EUR 210 million for the third quarter 2020 compared to EUR 30.1 million for the third quarter 2019. And for the 9 months ended September 30, 2020, total net loss was EUR 351.7 million compared to EUR 120.9 million for the comparative prior year period.

So now turning to Slide 23, which is turning to the balance sheet. BioNTech ended the third quarter 2020 with cash and cash equivalents of EUR 990.5 million or $1,159.7 million, so that is $1.2 billion. This includes EUR 658.9 million or $776.7 million in gross proceeds from our follow-on underwritten offering, a private equity placement at an investment in a 4-year mandatory convertible note completed in the quarter.

Mainly influenced by the spending related to our BNT162 program, we still expect net cash used in operating activities and for investments into property, plant and equipment to be between EUR 450 million and EUR 600 million for the full year 2020 likely to hit the upper end of the range due to our acquisition of the manufacturing facility in Marburg.

And with that, I will return the call to Ugur for concluding remarks.

[Ugur Sahin, executive]

Thank you, Sierk. So turning to Slide 24. As we enter the final weeks of 2020, we are focused on executing our ongoing Phase III trial, COVID-19 vaccine and planned submissions along with our partners. We are preparing for commercial launch and with our partners, Pfizer and Fosun, and continue to scale up our manufacturing effort to ensure a support for global supply.

We have generated promising data for BNT311 and are continuing to advance the rest of our oncology pipeline towards multiple late-stage trials in 2021, and we expect to initiate our first-in-human trials for 2 cell therapies. This includes BNT211, our CARVac program targeting claudin 6 with claudin 6 specific CAR-T cell therapy in refractory advanced solid cancers; and BNT211, our personalized neoantigen targeted T cell therapy in patients, who are refractory or unresponsive to checkpoint inhibitor treatment.

We are also very capitalized to deliver on our commercial, operational and pipeline milestones. Our vision has always been to bring novel therapies to patients most in need. The development of a vaccine to prevent COVID-19 would be a remarkable accomplishment of our vision. We truly believe that if we are successful, we will have an extraordinary opportunity not only to impact this pandemic on a global scale, but have also the opportunity to accelerate our long-term vision to build the next-generation immunotherapy pharmaceutical company.

We thank our shareholders and partners for their trust and support, and we'll now open up the floor for questions. Operator?

[Operator]

[Operator Instructions] Your first question comes from the line of Tazeen Ahmad from Bank of America.

[Tazeen Ahmad, analyst]

As it relates to a couple of data follow-ups for COVID, I wanted to get a little bit more color. So for pediatric patients, I know that you had opened up your study to younger patients. I think that occurred maybe in October. I am just wondering if any pediatric patients have been enrolled and are being studied with the vaccine at the moment? And what would be the longer-term needs in order to get a label that would be inclusive of pediatric patients?

And then my second question is as it relates to durability of response, based on what you know now about the profile of the vaccine, do you think booster shots will be needed? I think for modeling purposes, most of us are assuming that after the 2-dose regimen, folks won't have to be revaccinated, but we'd like to know if that isn't a proper assumption to be making or is it too early to know?

[Özlem Türeci, executive]

Yes. Thank you for the question. So the first question was about pediatric patients. In the global -- in the ongoing global study, we have included smaller cohorts of pediatric patients, cohort of 16- to 17-year-old adolescents and a smaller cohort of a 12- to 15-year-old subjects.

And so these are, as I said, smaller cohorts. We are currently discussing with regulators, with the FDA and EMA, our pediatric plan, including which types of studies, in which sequence, in which age strata of pediatric populations are required. At this point, we cannot make any comments, but we will be able to do so soon once these agreements have been accomplished.

The second question was durability. Ugur, do you want to take this one or...

[Ugur Sahin, executive]

Yes, I can take this. So we do not yet have robust data for predicting the durability of immune responses based on our observations that we have up to now -- for up to 3 months after second dose. We believe that the durability of neutralizing antibody responses would reach at least 1 year. And we already know from prior studies that messenger RNA vaccines are suitable for prime boost approaches. So that means we will generate data in the upcoming 6 to 9 months to also evaluate such protocols and identify an appropriate schedule for optimal boost protocols.

[Tazeen Ahmad, analyst]

Okay. And if I could just ask one last question. How important do you think it is to be able to come up with a formulation where it's just 1 shot for patients as opposed to the current 2 because there are patients that are not -- it might be a small number, but there are patients that are not coming back for the second dose. And do you think that, that could be something that in the commercial setting could be somewhat rate-limiting?

[Ugur Sahin, executive]

Yes. So the 1 dose vaccine is quick-fire to key information. First of all, we do not have at the moment the biomarker correlate for protection in humans. It is well established at high neutralizing antibody titers required for preventing infection. And T cells are required for preventing disease. And it is also now established that given the high affinity of the SARS-CoV-2 spike protein to the human receptor that very high antibody concentrations are required to translate this into strong neutralizing antibody titers.

And so at the moment, we have to assume that 2 injections -- 2 doses of vaccine are needed to have an effective prevention from infection. We will learn in the next 6 to 12 months whether also lower titers, neutralizing antibody titers might be sufficient to come up or to continue with a schedule, which have just a single injection.

[Operator]

Your next question comes from the line of Cory Kasimov of JPMorgan.

[Cory Kasimov, analyst]

First off, big congrats, and a thank you for that matter for all the intense efforts and the great result with your COVID vaccine. So my first question is on manufacturing? And how we should think about the scale-up process of going from roughly producing 50 million doses by the end of this year to about 1.3 billion by the end of next year. Is it best to assume something of a linear trajectory here? Or is it a process that's likely to be a little bit more back-end loaded? And then I have a follow-up.

[Ugur Sahin, executive]

Sierk, would you like to take the question?

[Sierk Pötting, executive]

Yes. I'm happy to take it, yes. Thank you, Cory. I think this is more like a step-wise approach actually. So you have like Pfizer ramping up their network, and we are ramping up our network, so the European BioNTech network. And I think it will come in tranches. So basically with Puurs coming up, the facility of Pfizer in Belgium, with finishing drug product and then adding our facility, it will be rather like step changes. So I don't think that you would expect lower volumes that go higher, evenly. I think you would have like bigger chunks in Q1 coming up and then another chunk in Q2 coming up actually.

So then you have -- I mean, the bottlenecks will be moving all the time. So when you have like a drug substance, which will come up and then you will debottleneck a drug product, and then you have like various finish capacities. And I think eventually, if Marburg is really up and running and stable, potentially, yes, upside for collaboration in the end.

So -- but yes, step wise, the biggest step ups that come away from the 50 million would probably be in Q1.

[Cory Kasimov, analyst]

Okay. Perfect. And then on the logistics front, do you expect that in time, it will be possible to improve upon the current cold chain storage that's required for BNT162? Could you just talk about the work that's going on there?

[Ugur Sahin, executive]

Sean, would you like to take the question?

[Sean Marett, executive]

Yes, sure. Cory, of course, we're not stopping the development of the vaccine, and we're looking at formulations that are more or less, say, ordinary course of the business use. We have programs running to do that. And if we're successful in generating the data in those programs, we will, of course, be launching line extensions that are more, as I said, ordinary course of business and primary care physicians can stick them in the fridge for a longer period of time.

[Operator]

Your next question comes from the line of Daina Graybosch from SVB.

[Daina Graybosch, analyst]

Thank you for all the work that you're doing, and congratulations. I can't say that enough. I have many, many questions, but I'll focus perhaps on 2. The first is, do you believe the efficacy you've seen greater than 90% prevention of BNT162 suggests that all vaccines against the spike protein will be effective? Or do you believe there's some unique elements to your platform that potentially could be differentiating short-term and long-term?

And then second question is, when do you think we'll learn about the potential protection against infection and transmission? We've seen in the protocol that you're looking at exploratory serology at 1 and 6 months. Will we be able to see anything at 1 month already at the EUA filing? Or do you think we'll need to wait for 6 months to understand that?

And then I guess, finally, on that, do you believe that this vaccine will protect against infection as well?

[Ugur Sahin, executive]

Thank you, Daina. So I will start with the easier question, which is first one. So first of all, I think the good message for mankind is that we now understand that infection, COVID-19 infection can be indeed prevented by a vaccine. And of course, we believe that that our vaccine will not be the only vaccine, which accomplishes that. There are a number of vaccine trials, Phase III vaccine trials ongoing.

With regard to the efficacy, we have to understand, and this will come in the next 6 to 12 months, what caused the prevention rate? Is it the neutralizing antibody titer? Is it the T cell response? Is it the combination of both?

So we expect that other vaccines will also be effective, but we, of course, don't know how effective these vaccine trials will be. And maybe depending on the efficacy of this different vaccine trials, we can learn more about the mode of action of prevention of COVID-19. Currently, a number of different publications hint that neutralizing antibody titers are required, of course, to prevent entry of the virus into cells. But it is also well established that people with preexisting T cell responses have a much better prognosis, clinical prognosis than infected with COVID-19. So we have to see and how this immune responses correlate with prevention.

With regard to in addition of infection, this is difficult to assess. This is -- this would require a completely different approach for clinical testing, meaning that we would also need to test subjects without having any symptoms. This is currently not doable based on the complexity of such trials, but we might get information in an indirect fashion from our ongoing trial. I expect this type of information will not be solid before the time frame of 6 to 12 months.

[Operator]

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

[Navin Jacob, analyst]

Congrats to the whole BioNTech team for the very hard work and amazing results. Two, if I may, on 162b2, or the COVID program, and two, if I may, on GEN1046. On the COVID program, wondering if you could share with us how many cases -- severe cases of COVID-19 were seen in the placebo arm, I am presuming at least 5 because that was, I believe, the requirement per the guidelines? And then secondly, wondering if you could provide an update on your self-amplifying program and how that technology contrasts with the Arcturus' self-amplifying vaccine?

And then if I could follow-up on GEN1046 after.

[Ugur Sahin, executive]

Yes, the first part of the question with regard to further specific information. So we can't provide at the moment on this type of information because the extent of information that we got from the data monitoring committee is extremely limited to ensure the integrity of the primary endpoint, which is expected in about 2 to 3 weeks from now. And so we expect that in 3 weeks, we will be able to answer this question and many other questions, for example, also the question, how is the protection rate in the elderly as compared to the younger population.

With regard to the -- to our self-amplifying vaccine approach, we did prioritize this vaccine trial. The -- our self-amplifying messenger RNA trial is still in the dose escalation. We reached a dose of 30 micrograms at the moment and further dose escalation is ongoing. We will be able to report immunogenicity data. Initially, we expected to report initial immunogenicity data end of October. This will become now more beginning next year.

[Navin Jacob, analyst]

And then on GEN1046, if I may, but wondering if -- and I know you touched upon this slightly, but the mechanistic rationale for seeing lower liver tox with 1046 versus perhaps other 4-1BB molecules? And also, I am sorry if I missed this, but what dose was selected for dose expansion for 1046 or 311 in non-small cell, please?

[Özlem Türeci, executive]

So the first question, the reason for reduced liver toxicity is the conditional binding mechanism to 4-1BB, which means that the antibody has to be bound to PD-L1 in order to be able to bind to 4-1BB by a confirmational change. The second question was what our recommended Phase II dose is, this will be 100 milligrams.

[Operator]

Your next question comes from the line of Akash Tewari from Wolfe Research.

[Akash Tewari, analyst]

And thanks again for all of your hard work on the vaccine front. A few, if I may. I just wanted to confirm, I think on the call, you mentioned that titer levels were similar to natural infection. Was that similar or were they multiple folds higher, like you've seen in your previous data? And did you see any level of titer corresponding to efficacy based on the 94 patients you've looked at so far?

And I guess I'll ask this a little bluntly. What's the split of U.S. and ex U.S. dose allocation? And if someone were to say Pfizer, BioNTech could sell the remaining 700 million dose allocation at $20 a dose, that could be a reasonable target for 2021, how would you respond to that assertion?

And then lastly, in your updated protocol for the COVID vaccine, we saw that you introduced a new manufacturing process in order to scale up. What are the differences between your old manufacturing process and the new one? And what are the kind of the FDA and European requirements in terms of demonstrating equivalents using those 2 manufacturing processes?

[Ugur Sahin, executive]

This is multiple questions. Let me try to address most of them except for the commercial aspect. Maybe Ryan can start with the question related to the supply of vaccine. Ryan?

[Ryan Richardson, executive]

Yes, sure. So Akash, the U.S. versus ex U.S. and so the U.S., it's a 100 million order with an option for an additional 500 million. And so it's about 1/5 of -- or 1/6, actually, of over 570 million dose commitment that we mentioned. Of course, the option would take it much higher than that to as much -- as high as 600 million doses. So you can see the bookings there, 1/6 to about half.

In terms of your average price question, at this point, we can't provide an average price. What we can say is that we've indicated that the price for the U.S. for the first 100 million doses was $19.50 per dose for the first 100 million doses. And you can think about that as a benchmark for how we would price the vaccine to the developed world for similar volumes.

So we do expect prices to differ by country, by region. But for the developed world, I think that's the key benchmark. And you can see from the dose numbers that we've indicated here in the presentation today that most of those, at least committed orders, are in the developed world, but we are, as mentioned, also looking to supply the developing world. So it's going to be an average across those.

[Ugur Sahin, executive]

So I can continue with the questions related to the vaccine. So the neutralizing antibody titers, indeed, are at least two to threefold higher than the titers that we have observed in the convalescent sera. I think the note that level of titers are in the same level is only true for subproportion, proportion of sera from hospitalized patients.

The second question related to the manufacturing process. So the manufacturing process has been scaled up during the development, including changes in the way how the messenger RNA is purified to ensure that we can increase the batch side. These manufacturing changes did not result in any change of the release criteria. So the product remains in the specification of the original product.

And so far, the comparability data that have been generated show that both processes are comparable. We have submitted this data to FDA, to EMA, and are currently in discussion with both authorities to ensure that this manufacturing change is accepted and discuss potential additional studies to be performed.

With regard to the split, we can't provide any information because the information that we obtained from the data monitoring committee is extremely limited. And essentially, each piece of information is already in the press release. So additional information will come up with the final readout in about 3 weeks.

[Operator]

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

[Arlinda Lee, analyst]

Congratulations on the impressive efficacy, and thank you for the tremendous effort to get here so quickly. I had a few questions about 162 and then also 311. I guess I'm curious on the dose guidance. The 1.3 billion doses from -- for next year, does -- that guidance doesn't seem to have changed. So I'm wondering if the Marburg facility is included in that?

And then on the logistics of delivery, there's some debate in the U.S. about allocations. And I'm curious when you deliver the 100 million doses to the U.S., are you delivering to the sites per -- based on where they tell you to go or how does that work?

And then on 4-1BB with the conditional activity, I am wondering, one, how did you decide on the expansion cohorts? And if that conditional activity is something that you're planning to work into some of your other programs as well?

[Ryan Richardson, executive]

Ugur, do you want to take the 4-1BB part, and then I'll take the guidance.

[Ugur Sahin, executive]

Okay. So the Phase I trial that we are currently executing had different patient populations and with different indications. And based on the observations that we made in this patient population and based on the mode of action of the compound, we decided to select indications, second-line indications that mean checkpoint responsive indications with patients who failed prior checkpoints blockade. That was one rationale because our expectation is that the dual body will have -- might test significant activity even in patients who did not respond or failed checkpoint blockade treatment or progressed upon successful checkpoint blockade treatment.

The second group of patient groups or clinical indications of first-line patients and where particularly clinical indications in which checkpoint blockade is already approved, but effect size is still limited like non-small cell lung cancer and triple negative breast cancer are currently discussed as expansion cohort. And this expansion cohort intended to guide us in a past session to control randomized Phase II, Phase III trials.

[Ryan Richardson, executive]

And on the first part of your question, the 1.3 billion, I think it's important to remember that that's a supply capacity number, cumulative supply by the end of 2021. And you're correct that we haven't updated the guidance since the acquisition of Marburg, the Marburg site. As Sierk mentioned, the Marburg site will really accelerate our production ramp-up over the course of 2021, starting in the first half of the year. And the extra volumes will support both the Pfizer alliance and also the Fosun alliance. And it's important to remember there, too, that the 1.3 billion guidance number for supply was a Pfizer-BioNTech number, and we have not yet guided specifically to China market opportunity. So that would be on top of the 1.3 billion number.

[Arlinda Lee, analyst]

Okay. Thank you. And then on the logistics of delivery, I'm just curious about how you're going to deliver it to the U.S.? And whether you're going to give it to the sites, in particular, as U.S. direct, or how does that work?

[Ryan Richardson, executive]

Yes. So the logistics plan for the U.S. is to -- we're going to have a number of centralized depots, followed by the more diffuse distribution points that we alluded to in the presentation. So centralized depots and then spread out throughout the country, distribution sites, including high volume and also lower volume sites. So it's -- and it will be -- distribution in the United States will be executed by Pfizer.

[Operator]

Your next question comes from the line of Zhiqiang Shu, Berenberg.

[Zhiqiang Shu, analyst]

And I want to add my congrats as well to the team. It's definitely a critical moment for mRNA and for BioNTech.

A few questions on the COVID-19 vaccine. So the first one is I'd like to know what was the initial rationale for the protocol change from 32 cases to 62 cases for the first interim analysis? And then secondly, I assume that once you reach the final efficacy analysis, you would unblind the trial. I wonder how would you reassure fair assessment of long-term protection and safety once you unblind the trial?

And then also, I'd like to understand the -- for booking sales, I remember -- I recall, there are a few countries that you would take the sales -- book the sales for a few European countries. Would you disclose those countries at this time?

And then finally, for the oncology, I have a quick question on BNT111 plus PD-1 study that -- you mentioned in your press release that you would conduct additional trials for registration. Can you provide more color on that? Why do you think that will be the case? And then for -- can you remind us the -- to randomize the arms for the -- for that trial, BNT111 plus PD-1?

[Ugur Sahin, executive]

Okay. So let's start with the first question to the rationale for the protocol change. So when we decided the protocol, this was sometime in July, it was not clear how the pandemic situation, the continuity evolves. And one scenario was that the number of infections, the infection rate could drop, providing a difficulty to collect sufficient cases in 2020. Therefore, we have included an early interim analysis arm with 32 cases.

But what happened is contrary, instead of dropping of the infection rate, the infection rate went up, as we have seen in the last week dramatically. And therefore, we realized that the time points between 32 cases and 62 cases are so close to each other that it does not make sense to do the readout with 32 cases. We went back to the FDA and requested if we can drop the 32 cases, the FDA after evaluating the protocol change accepted that.

The whole process took about 1 week. And when we started evaluation of the number of cases, we have passed 62 cases and came up with 94 cases. So that's the background for the protocol change.

The second question is related to BNT111. So we plan to submit our randomized Phase II protocol with -- resubmit our randomized Phase II protocol for BNT111 with 3 arms, with 1 arm combining entire PD-1 with BNT111, one arm of anti-PD-1 alone and another calibrator arm vaccine alone. And the -- and with the feedback from the FDA, FDA was -- the feedback from the FDA was additional request that the clinical trial protocol for registrational trial would require a potency assay. And we got additional questions to that. The questions are addressed, and we submitted now the modified protocol, including the information for the potency assay. And expect feedback from the FDA in the coming 30 days?

[Ryan Richardson, executive]

Yes. And on the booking sales question, we intend to book sales in Germany. We're still assessing the overall accounting treatment, but you can assume Germany where we're going to commercialize. And also, we'll expect our profit share from our partners, Pfizer and Fosun, also to flow through the P&L, of course. And remember, that's a gross profit share.

I don't know, Sierk, if you want to add to that?

[Sierk Pötting, executive]

Yes, that's correct. I think we -- what we are evaluating right now is because we have to line on the accounting with Pfizer because they're under U.S. GAAP, and we are IFRS. Although similar, especially on this revenue recognition, there are a couple of subtle differences, which we are working out right now. And once we know what piece flows through which line item actually on the P&L, we will give you guidance actually that you can actually model this out a little bit more subtly.

[Zhiqiang Shu, analyst]

Great. And then one question. I asked about the assessment of long-term protection if the trial is unblinded. Can you comment on that as well?

[Ugur Sahin, executive]

Yes. So the key reason for potential unblinding, of course, is that with this efficacy, of course, at a certain time point, we have to offer also for the placebo group the vaccine. And we will continue to monitor the new infections in the vaccine arm and this might give us indirect evidence based also by comparison of epidemiological data how this long-term protection would evolve. And so we are confident that the 2 years follow-up, including a follow-up of neutralizing antibody titers, in this -- in a subgroup of subjects would allow us to give an estimate for long-term protection.

[Operator]

We have 2 more questions. And your next one comes from the line of Daniel Wendorff from Commerzbank.

[Daniel Wendorff, analyst]

Also a big congratulations from my side on this achievement. Two questions on BNT162, if I may. The first one, on the interim analysis. Can you talk about the phasing of the observed COVID-19 cases in the vaccine arm? Did that occur rather at the beginning of the trial or more towards the end, if you have this data at all already?

And my second question would be on the gross profit per dose, basically. So assuming what you said on potential pricing assumptions for modeling purposes, how should we think about the gross profit per dose? Is there any kind of guidance you can give us, in general, putting aside how you book eventually then the gross profit share from Pfizer potentially?

[Özlem Türeci, executive]

Yes. Thank you for the questions. I can quickly answer the first one. As Ugur has pointed out, the interim analysis was a very lean one. It was really about assessing the primary endpoint. And in particular, we, as the blinded ones have not any further information. We have to wait a couple of weeks so that the final analysis and all the prespecified assessments, including also better understanding of the kinetics of when cases evolved, is available for us.

For the second, I guess I have to defer to Ryan or Sierk.

[Ryan Richardson, executive]

Yes, sure. I can take it. Unfortunately, Daniel, we can't provide an updated gross margin guidance at this point. It's going to depend on, of course, mix ultimately in sales, but we will plan to provide a further update as we get closer to commercialization.

[Operator]

And your final question today comes from the line of Olga Smolentseva from Bryan Garnier.

[Olga Smolentseva, analyst]

Many congratulations and many, many thanks on all the hard work. I have a few questions, one on COVID vaccine. Thinking about potential upcoming EUA submission, would you consider to file right after sufficient safety data with efficacy with basically efficacy data available at that point? Or would you wait for the full readout with 164 events?

[Özlem Türeci, executive]

Thank you for the question. So this is really very agency-specific. And we have been in close interaction with all agencies, including FDA and EMA and MHRA and others, from the very beginning and have the respective specifications, which type of data they want to see. With regard to EMA, for example, you may know that we are -- we have started actually a rolling submission some time ago and are complementing that in subsequent roles for the FDA, for EUA approval, whereas, for example, key safety endpoints that FDA wants to see. And we are adhering to those requests of respective agencies with regard to when and what exactly to file.

[Olga Smolentseva, analyst]

Okay. And maybe when might we expect additional stability data? And maybe could you speculate what do you expect to see, like potential stability at minus 20 or a longer stability at refrigerated temperatures, et cetera?

[Ugur Sahin, executive]

Yes. So a number of stability studies are ongoing. We have stability studies, including minus 20, minus 40 degrees as well as stability studies to support extended storage at 2 to 8 degrees. So it is -- we will have continuous updates on the stability studies, expecting the next update sometime in mid-December.

[Olga Smolentseva, analyst]

Great. And just a quick one on BNT311, PD-L1x4-1BB specific. For the responded patients, do you have any visibility on the PD-L1 status? And for those that received prior checkpoint inhibitors, if they were considered sort of nonresponders or rather developed quiet resistance?

[Ugur Sahin, executive]

So we had several cases where patients did respond at all to initial checkpoint blockade treatment and progressed under treatment. We so far do not have a correlation between the objective responses that we have observed and PD-L1 status of the original tumor.

[Operator]

Thank you. That was your final question.

[Sylke Maas, executive]

Thank you for joining the call today. We look forward to speaking to you in future. Thank you, and have a nice day. Bye-bye.

[Özlem Türeci, executive]

Thank you.

[Ugur Sahin, executive]

Thank you.

[Operator]

Thank you. Ladies and gentlemen, that does conclude your call for today. Thank you all for participating, and you may now disconnect.