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 investor section. As shown on slide two, 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 received of or potential approval for emergency use authorization with respect to our BNT162 program, the ability of BioNTech to supply BNT162 to 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 three. 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 update on our oncology pipeline.
She will walk through some of the data we are highlighting this week at SITC for BNT311, our PD-L1/4-1BB checkpoint immunomodulator. Sierk will 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.
Thank you, Sylke. Good morning. Thank you to everyone joining the call today. Let's start with slide four. I'm 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 of a 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 eight months into the worst pandemic in more than a 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. When that decision was made, we went all in. We devoted 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 had the potential to make a difference. 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 and China as part of what we expect will be a registration 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. We continue to plan for what would be our first commercial launch with our partners, Pfizer and Fosun Pharma, if we are granted an approval.
We had some slowdowns in our oncology trials, despite that, anyway, we are pleased to present early phase I data for our next generation checkpoint immune modulator, 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. 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 intra-tumor messenger RNA, partnered with Sanofi at SITC. One arm from our exploratory phase I trial, BNT114 at ESMO.
Finally, in the third quarter, we received IND approval for our randomized phase II trial of iNeST, 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. Finally, we strengthened our financial position in the third quarter to a mix of equity, debt financing, grant commitments of approximately EUR 1.2 million cumulative gross proceeds. We are in a strong position to capitalize on our opportunity that lies ahead of us. Slide six. Slide six highlights the development timeline 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 brought into this program from day one, all without cutting corners.
We started the first of multiple phase I trials in late April, which means that our update yesterday demonstrating 90% of efficacy as of our interim efficacy analysis in a pivotal phase III trial comes approximately six and a half 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 publish our protocol. 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 to have 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 recap the stage of testing that we have gone through with our BNT162b2 vaccine, which has so far resulted in three peer review publications in journals at the New England Journal of Medicine and Nature. The important point here is that we have done extensive testing over the past nine months in many different contexts. 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 were observed a dose-dependent immune response against virus and coronavirus, including antibody titers, as well as strong CD4 and CD8 T cell responses.
In a 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 three 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. Moreover, in phase I trials, 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. On slide number seven. 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. The first analysis evaluated 94 confirmed cases of COVID-19 in the trial participants. The case split between the vaccinated individuals and those who received the placebo indicates the vaccine efficacy rate above 90%, as measured seven days after the second dose. This means the protection was achieved 28 days after the initiation of vaccination, which consists of a two-dose schedule. As of yesterday, the study enrolled more than 43,000 participants, with 42% having diverse backgrounds. 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 eight. Slide eight 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 trials 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 two doses of BNT162b2, again separated by 21 days, and a single dose of BNT162b2 in healthy adults 20- 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 regulatory authority and the NMPA, we will start the clinical trial. There are ongoing rolling regulatory submissions in the countries in blue, including EMA, the U.K., and Health Canada. We plan to work with EMA's 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's 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'm now going to ask Sean to provide a brief update on our commercial supply and distribution model. Sean?
Yeah, thanks, Ugur. Just turning to slide nine. Here, we're providing a snapshot of where we are on the commercial side. Demand is strong around the world. We have currently entered into commitments with purchasers to supply more than 570 million doses by the end of 2021, with options in the U.S. 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 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- 25 degrees Celsius without opening the shipper. 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 five days storage in a refrigerator at two to eight degrees centigrade. That gives us really some flexibility with respect to storage and distribution. The distribution model will, of course, depend on the region.
In general, we're 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 U.S. to distribution hubs all around the world. From those distribution hubs, we expect to distribute the vaccine to 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. It's important to note that our agreement with Pfizer is a 50/50 profit sharing worldwide, excluding China.
The economics to BioNTech are the same regardless of who distributes the vaccine. Okay. Going further, it is important to note that at the points of care, we will have multiple short-term storage options available, as we mentioned earlier. 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 - 70 degrees for long-term storage. For shorter periods, the product can be stored up to five days at two to eight, as I said earlier. It's important to note that if there is a freezer available, an ultra-low temperature freezer available, the vaccine can be stored for up to six months in these freezers. I'll now turn over to Özlem to provide an update on the oncology pipeline.
Yes. Thank you, Sean. We are changing gears now. On slide 12, you can see our clinical oncology pipeline. In the interest of time, I'm going to provide updates on selected programs only. For BNT111, detail the data released yesterday at the SITC conference. For further details on the status of other programs, please refer to our full 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 timelines for some of our programs. Starting with BNT111, our melanoma FixVac program on an RNA vaccine, which is composed of four non-mutated melanoma antigens.
Recently, we published an exploratory data analysis in "Nature" from our ongoing phase I trials. The publication highlighted the favorable safety profile of BNT111 in stage III-B/C and stage IV melanoma patients who were pre-treated 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 third quarter, we entered into a strategic collaboration to pursue a development program with our team 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 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 two 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 Immunotherapy, our 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 will 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 II high risk with circulating tumor ctDNA and stage III 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 neo-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 polyepitopic T cell responses in the post neo-adjuvant setting in TNBC. In all 14 patients, vaccine-induced T cell responses against up to 10 neoantigens were detected, 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 colon tumors have been released for the SITC conference, and will be presented there. BNT131, partnered with Sanofi, is a nucleoside modified RNA that encodes cytokines, namely IL-12, IL-15, GM-CSF, and interferon alpha 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 six patients received BNT131 in combination with Regeneron's PD-1 blocker cemiplimab. BNT131 was generally well-tolerated. No patient experienced a dose-limiting toxicity and no grade three or greater treatment-related adverse events were reported to date. Downstream receptor 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 five programs here that we expect to start phase I trials for, including our cell therapy programs, BNT211, which is our CAR-T 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 RiboMab and RiboCytokine platforms. Moving to slide 14 and BNT311, also called GEN1046. The first of two next generation bispecific antibody programs we have partnered with our esteemed colleagues from Genmab.
Two 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 Professor Melero, one of our investigators at the press briefing of the conference yesterday. BNT311 is a first-in-class next generation checkpoint immune therapy being investigated for the treatment of advanced solid tumors. This bispecific antibody simultaneously blocks the PD-L1 axis and activates T cells through conditional 4-1BB co-stimulation. Conditional activation of 4-1BB is crucial, as clinical development of 4-1BB agonists 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 anti-tumor 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 25-1,200 milligrams every three 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 the 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 cut-off date, treatment is ongoing in 10 patients, and the maximum 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 three transaminase elevations, which improved with corticosteroid treatment.
There were no patients with grade four transaminase elevations or treatment-related bilirubin increases. Dose-limiting toxicities occurred in six patients and resolved without sequelae. On slide 18, you can see pharmacodynamic activity, which we observed over a broad range with maximal induction 8- 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 anti-tumor activity observed with BNT311 during the dose escalation phase. While this is early data, only three months medium 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 four partial responses, one in a triple-negative breast cancer patient, one in an ovarian cancer patient, and two 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 had progressed on or after immune checkpoint blockade prior to BNT311 treatment. We observed two confirmed partial responses, one unconfirmed partial response, and four 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 cohort I previously mentioned. We look forward to presenting additional data for this potentially powerful new checkpoint immune modulator in the future. With this, I will now hand the call over to Sierk to provide an update on our financials.
Thank you, Özlem. I would like to summarize our financial results for the quarter that are shown on slide 22. 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. For the period of nine 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 nine 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, 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 nine months ended September 30th, 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 high 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.
For the nine 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. 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. 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, and an investment in a four-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. With that, I will return the call to Ugur for concluding remarks.
Thank you, Sierk. 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 plan the submissions along with our partners. We are preparing for commercial launch 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. We expect to initiate our first in human trials for two cell therapies. This includes BNT211, our CARVac program targeting claudin 6, with a claudin 6 specific CAR-T cell therapy in refractory advanced solid cancers, and BNT221, our personalized neoantigen targeted T cell therapy in patients who are refractory or unresponsive to checkpoint inhibitor treatment.
We are also well-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 will now open up the floor for questions. Operator?
Thank you. As a reminder, ladies and gentlemen, if you wish to ask a question, please press the star and one on your telephone keypad and wait for your name to be announced. Your first question comes from the line of Tazeen Ahmad from Bank of America.
Hi, good morning and good afternoon. Thanks so much for taking my questions. As it relates to a couple of data follow-ups for COVID-19, I wanted to get a little bit more color. For pediatric patients, I know that you had opened up your study to younger patients, I think that occurred maybe in October. I'm just wondering if any pediatric patients have been enrolled and are being studied with the vaccine at the moment. What would be the longer-term needs in order to get a label that would be inclusive of pediatric patients?
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 two-dose regimen, folks won't have to be revaccinated. We'd like to know if that is a proper assumption to be making, or is it too early to know? Thanks.
Yes, thank you for the question. The first question was about pediatric patients. In the ongoing global study, we have included smaller cohorts of pediatric patients, a cohort of 16- 17-year-old adolescents, and a smaller cohort of 12 - 15-year-old subjects. 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 this one [crosstalk]
Yes, I can take this. 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 three months after second dose. We believe that the durability of neutralizing antibody responses would reach at least one year. We already know from prior studies that messenger RNA vaccines are suitable for prime boost approaches. That means we will generate data in the upcoming six - nine months to also evaluate such protocols and identify an appropriate schedule for optimal boost protocols.
Okay. 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 one shot for patients as opposed to the current two? 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. Do you think that that could be something that in a commercial setting could be somewhat rate limiting? Thank you.
Yeah. The one-dose vaccine requires two key informations. First of all, we do not have at the moment the biomarker correlate for protection in humans. It is well established that high neutralizing antibody titers are required for preventing infection, and T cells are required for preventing disease. It is also now established that given the high affinity of the SARS-CoV-2 spike protein to the human receptor, and that very high antibody concentrations are required to translate this into strong neutralizing antibody titers. At the moment, we have to assume that two injections, two doses of vaccine, are needed to have an effective prevention from infection. We will learn in the next 6- 12 months that also lower neutralizing antibody titers might be sufficient to come up or to continue with a schedule which have just a single injection.
Okay. Thank you.
Thank you. Your next question comes from the line of Cory Kasimov from JP Morgan.
Good morning, everyone. First off, a big congrats and a thank you for that matter for all the intense efforts and the great result with your COVID vaccines. 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? Then I have a follow-up.
Sierk, would you like to take the question?
Yeah, I'm happy to take it. Yes. Thank you, Cory. I think this is more like a stepwise approach, actually. You have Pfizer ramping up their network, and we are ramping up our network, so the European BioNTech network, I think it will come in tranches. Basically with course coming up, the facility of Pfizer in Belgium with fill and finish and drug product, then adding our facility, it will be rather like step changes. I don't think that you would expect lower volumes that go higher evenly. I think you would have bigger chunks in Q1 coming up then another chunk in Q2 coming up, actually.
The bottlenecks will be moving all the time. Basically you have drug substance, which will come up, then you will bottleneck on drug product, then you have various fill and finish capacities. I think, eventually, if Marburg is really up and running and stable, potentially, yeah, upside collaboration in the end. Stepwise, the biggest step-ups that come away from EUR 50 would probably be in Q1.
Okay, perfect. Then on the logistics front, do you expect that in time it'll 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?
Sean, would you like to take the question?
Yeah, sure. Cory, of course, we're not stopping the development of the vaccine, and we're looking at formulations that are more, let's say, ordinary course of business use. We have programs running to do that. If we're successful in generating the data in those programs, we will of course be launching line extensions that are more, as I say, ordinary course of business and primary care physicians can stick them in the fridge for a longer period of time.
Okay. Very helpful. Thank you guys very much.
Thank you. Your next question comes from the line of Daina Graybosch from SVB.
Thank you for the question. Thank you for all the work that you're doing, and congratulations. Can't say that enough. I have many questions. I'll focus perhaps on two. 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? Do you believe there's some unique elements to your platform that potentially could be differentiating short term and long term?
A 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 one in six months. Will we be able to see anything at one month already at the EUA filing, or do you think we'll need to wait to six months to understand that? I guess finally on that, do you believe that this vaccine will protect against infection as well?
Thank you, Daina. I will start with the easier question, which is the first one. Yeah. First of all, I think the good message for mankind is that we now understand that COVID-19 infection can be indeed prevented by a vaccine. Yeah. Of course, we believe 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- 12 months, what drives the prevention rate? Is it the neutralizing antibody titer? Is it the T cell response? Is it a combination of both?
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 these 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. It is also well established that people with preexisting T cell responses have a much better prognosis, clinical prognosis, when infected with COVID-19. We have to see how these immune responses correlate with prevention.
With regard to inhibition of infection, this is difficult to assess. 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. 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- 12 months.
Very helpful. Thank you again.
Yeah. You're welcome.
Thank you. Your next question comes from the line of Navin Jacob from UBS.
Hello. Thank you so much for taking the question and congrats to the whole BioNTech team for the very hard work and amazing results. Two, if I may, on BNT162b2 or the COVID program, and two, if I may, on GEN1046. On the COVID program, wondering if you could share with us how many severe cases of COVID-19 were seen in the placebo arm. I'm presuming at least five, because that was, I believe, the requirement per the guidelines. Secondly, wondering if you could provide an update on your self-amplifying program and how that technology contrasts with the Arcturus self-amplifying vaccine. Thank you so much. If I can follow up on GEN1046 after.
Yeah. The first part of the question with regard to further specific information. 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 two to three weeks from now. We expect that in three 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 our self-amplifying vaccine approach, we did prioritize this vaccine trial. Our self-amplifying messenger RNA trial is still in the dose escalation. We reached a dose of three microgram at the moment, and further dose escalation is ongoing. We will be able to report immunogenicity data. Initially, we expected to report immunogenicity data end of October. This will become now more beginning next year.
Thank you. Then on GEN1046, if I may, and thank you for taking the questions. 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. Then also, I'm sorry if I missed this, but what dose was selected for dose expansion for 1046 or 311 in non-small cell, please?
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 conformational change. The second question was what our recommended phase II dose is. This will be 100 milligrams.
Thank you very much.
Thank you. Your next question comes from the line of Akash Tewari from Wolfe Research.
Hey, thanks so much for taking my questions, 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? Did you see any level of titer corresponding to efficacy based on the 94 patients you've looked at so far? I guess I'll ask this a little bluntly. What's the split of U.S. and ex-U.S. dose allocation? If someone were to say Pfizer-BioNTech could sell the remaining 700 million dose allocation at EUR 20 a dose, that that could be a reasonable target for 2021, how would you respond to that assertion?
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? What are the FDA and European requirements in terms of demonstrating equivalence using those two manufacturing processes? Thank you.
Thank you. This one is a multiple question. 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 vaccines. Ryan?
Yeah, sure. Akash, you asked U.S. versus ex-U.S., the U.S. is 100 million order with an option for an additional 500 million. It's about a fifth, or a sixth, actually, of the over 570 million dose commitment that we mentioned. Of course, the option would take it much higher than that, to as high as 600 million doses. You can see the bookends there, 1/6 to about a 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. That you can think about that as a benchmark for how we would price the vaccine for the developed world for similar volumes.
We do expect prices to differ by country and by region. For the developed world, I think that's the key benchmark. 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. We are, as mentioned, also looking to supply the developing world. It's going to be an average across those.
I can continue with the questions related to the vaccine. The neutralizing antibody titers indeed are at least two to threefold higher than the titers that we observed in the convalescent sera. I think that the note that level of titers are in the same level is only true for sub proportion of sera from hospitalized patients. The second question related to the manufacturing process. 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 size. These manufacturing changes did not result in any change of the release criteria. The product remains in the specification of the original product. 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 obtain 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 three weeks.
Thanks so much.
Thank you. Your next question comes from the line of Arlinda Lee from Canaccord.
Hi, guys. 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 for next year, that guidance doesn't seem to have changed, and so I'm wondering if the Marburg facility is included in that.
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 based on where they tell you to go, or how does that work? On 4-1BB, with the conditional activity of that, I'm 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? Thank you.
Özlem, do you want to take the 4-1BB part, and then I'll take the guidance?
Okay.
Background noise .
Okay, [inaudible] phase I trial that we are currently executing had different patient populations and with different indications. Based on the observations that we made in these patient populations, and based on the mode of action of the compound, we decided to select second-line indications. That means checkpoint responsive indications with patients who failed prior checkpoint blockade. That is one rationale, because our expectation is that the DuoBody might have 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 are first-line patients, and here particularly clinical indications in which checkpoint blockade is already approved, but the effect size is still limited, like non-small cell lung cancer and triple-negative breast cancer are currently discussed as expansion cohorts. These expansion cohorts are intended to guide us, in a past session, to a controlled randomized phase II/III trial.
Thank you.
Yeah. 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 for cumulative supply by the end of 2021. 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. The extra volumes will support both the Pfizer alliance and also the Fosun alliance. 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. That would be on top of the 1.3 billion number.
Okay. Thank you. 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 a U.S. direct, or how does that work?
Yeah. The logistics plan for the U.S. is we're going to have a number of centralized depots, followed by the more diffuse distribution points that we alluded to in the presentation. Centralized depots and then spread out throughout the country, distribution sites, including high volume, and also lower volume sites. Distribution in the United States will be executed by Pfizer.
Thank you.
Thank you. The next question comes from the line of Zhiqiang Shu , Berenberg.
Hi, good morning. Thanks for getting to my questions. I want to add my congrats as well to the team. It is definitely a critical moment for mRNA and for BioNTech. A few questions on the COVID-19 vaccine. The first one is, I would like to know what was the initial rationale for the protocol change from 32 cases - 62 cases for the first interim analysis. Secondly, I assume that once you reach the final efficacy analysis, you would unblind the trial. I wonder how would you ensure fair assessment of long-term protection safety once you unblind the trial?
Also, I like to understand for booking the sales, I recall there are a few countries that you would book the sales for a few European countries. Would you disclose those countries at this time? Finally, for the oncology, I have a quick question. 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 would be the case? Can you remind us the two randomized arms for that trial, BNT111 plus PD-1? Thanks very much.
Okay. Let's start with the first question to the rationale for the protocol change. When we designed the protocol, this was sometime in July, it was not clear how the pandemic situation will continue to evolve, and one scenario was that the number of infections, the infection rates, could drop, providing a difficulty to collect sufficient cases in 2020. Therefore, we have included an early interim analysis arm with 32 cases. What happened is, the contrary, instead of dropping the infection rate, the infection rate went up, as we have seen in the last week dramatically. Therefore, we realized that the time point between 32 cases and 62 cases are so close to each other, that it does not make sense to do that read out 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 one week, and when we restarted evaluation of the number of cases, we have passed the 62 cases and came up with 94 cases. That's the background for the protocol change. The second question is related to BNT111. Yes. We plan to resubmit our randomized phase II protocol for BNT111 with three arms, with one arm combining anti-PD-1 with BNT111, one arm anti-PD-1 alone, and another calibrator arm vaccine alone. With the protocol, the feedback from the FDA was an additional request that the clinical trial protocol for registration trial would require a potency assay. 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.
On the booking sales question, we intend to book sales in Germany. We're still assessing the overall accounting treatment. You can assume Germany, where we're going to commercialize. Also, we'll expect our profit share from our partners, Pfizer and Fosun also to flow through the P&L, of course. Remember, that's a gross profit share. I don't know, Sierk, if you want to add to that.
Yeah, that's correct. I think what we are evaluating right now is because we have to align on the accounting with Pfizer because they're under US GAAP and we are under IFRS. Although similar, especially on this revenue recognition, there are a couple of subtle differences which we are working out right now. Once we know what piece flows through which line item actually on the P&L, we'll give you guidance, actually, that you can actually model this out a little bit more subtly.
Great. For the question I asked about the assessment of long-term protection if the trial is unblinded, can you comment on that as well? Thank you.
Yeah. 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. We will continue to monitor the new infections in the vaccine arm. This might give us indirect evidence based also by comparison of epidemiological data, how this long-term protection would evolve. We are confident that the two-year follow-up, including a follow-up of neutralizing antibody titers in a subgroup of subjects, would allow us to give an estimate for long-term protection.
This is very helpful. Thank you.
You're welcome.
Thank you. We have two more questions, and your next one comes from the line of Daniel Wendorff from Commerzbank.
Good afternoon, thanks for taking my questions. 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 they occur rather at the beginning of the trial or more towards the end, if you have this data at all already? My second question would be on the gross profit per dose, basically. 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 it actually, then the gross profit share from Pfizer, potentially? Thank you.
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. 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 pre-specified assessments, including also a 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.
Yeah, 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 and sales. We will plan to provide a further update as we get closer to commercialization.
Fair enough. Thank you.
Thank you. Your final question today comes from the line of Olga Smolentseva from Bryan, Garnier & Co.
Good afternoon, and many congratulations and 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 basically efficacy data available at that point? Or would you wait for the full readout, with 164 events?
Thank you for the question. 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 have started actually a rolling submission some time ago and are complementing that in subsequent roles. For the FDA, for EUA approval, there are, for example, key safety endpoints the FDA wants to see, and we are adhering to those requests of respective agencies with regard to when and what exactly to file.
Okay, thank you. When might we expect additional stability data? Could you speculate what you expect to see, like potential stability at - 20 or longer stability at refrigerated temperatures, et cetera?
A number of stability studies are ongoing. We have stability studies including - 20, - 40 degrees, as well as stability studies to support extended storage at 2- 8 degrees. We will have continuous updates on the stability studies, expecting the next update sometime in mid-December.
Great. Thank you. Just a quick one on BNT311, PD-L1 4-1BB bispecific . For the responded patients, do you have any visibility on the PD-L1 status? For those that received prior checkpoint inhibitors, if they were considered sort of non-responders or rather developed acquired resistance?
We had several cases where patients did not 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 the PD-L1 status of the original tumor.
That's clear. Thank you.
Thank you.
Thank you. That was your final question.
Yeah. 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.