Study Result

Jul 1, 2020

Ladies and gentlemen, thank you for standing by, and welcome to the BioNTech Conference Call. At this time, all participants are in a listen only mode. There will be a presentation followed by a question and answer session. I must advise you that this call is being recorded today, Wednesday, 07/01/2020. Okay. And I would now like to hand the call over to the vice president, investor relations and Business Strategy, Silke Maas. Please go ahead. Thank you for joining us today for BioNTech's conference call to provide preliminary Phase one results for one candidate from our PNT162 vaccine program against COVID-nineteen. You can access the press release issued this morning as well as the slides that we'll be presenting by going to the Investors section of our website. During today's presentation, we will be making several forward looking statements. These forward looking statements include, but are not limited to the timing for enrollment and completion and reporting of data from our ongoing clinical trials. Actual results could differ from those we currently anticipate. You are therefore cautious not to place undue reliance on any forward looking statements, which speak only as of the date of this conference call and webcast. Speaking today will be Ugur Sahin, Chief Executive Officer Ottlem Toreci, Chief Medical Officer and Ryan Richardson, Chief Strategy Officer, will be available for the Q and A session. I'll now hand the call over to Uger Zahin, BioNTech's CEO. Thank you, Weike. So good morning, everyone, and thank you for joining our call. Today, we released the first data from our BNT162 vaccine program and are pleased to provide our first clinical data for project Lightspeed, our coronavirus vaccine program, which is executed together with our partner Pfizer. I want to note that the data we will be presenting today are interim data. That means the trial is ongoing. The data has been submitted for publication in a peer reviewed journal and is currently available online on a preprint manuscript server net archive. Let us start on slide three. So as a background to you, we initiated Project Lightspeed in late January of this year after we we have seen the news to the coronavirus outbreak in China and after the SARS CoV-two genetic sequence was published on January 12. So we started early on to generate more than 20 messenger RNA vaccine candidates and performed a series of preclinical studies, yeah, to select four candidates which were selected to go into the clinic. So these four candidates together are collectively known as our BNT one hundred sixty two vaccine program. So then in March, we announced a collaboration with Pfizer to develop BNT one hundred sixty two worldwide, excluding China, because for China, we have we have established a separate partnership with Fossein Pharma to develop the program in China. We initiated a first in human clinical trial with this candidate in Germany late April. And we dosed the first subject with a COVID nineteen vaccine in the European Union and initiated a trial along with our partner Pfizer in The US in early May. So that means we have two clinical trials running. The preliminary results we are going to share with you today are one of the four vaccine candidates, which entered first into clinical testing. We refer to this candidate as BNT162b1, and these results results from the ongoing phase one trial in The US only. So this result do not include the German trial participants. So I'm going to quickly review the principles of the virus infection. So slide four, please. So it begins with the exposure to a virus. The virus enters the cell where it utilizes the host to replicate. The virus copies are then released from the host cell and spread to other cells, and the process is repeated. And by this amplification process, the magnitude of the infection can become significant very quickly. As shown on slide five, a vaccine delivers both the virus antigen and the appropriate immune activating stimulant. And this ideally together induces an immune control, which brings two components, one neutralizing antibody and T cells. While outside the host cell, the virus is accessible to this antibody, Inside the host cell, it can be targeted by T cells. So antibodies and T cells cooperate. Antibodies inhibit the spread from cell to cell, but also from individual to individual. An untapped antibody producing B cells can adapt a memory function. Once induced, this memory function can stay active for years. T cells are able to kill infected cells and are able thereby to reduce the overall viral load. CD four T cells, these are also known as helper T cells, serve multiple purposes, including providing a memory function to induce rapidly a T cell response when the immune system is encountering the virus again. So slide six provides an overview of our four vaccines vaccine candidates, which are current in the clinic. Our vaccine program leverages clinical candidates against two distinct targets. The one is the full length spike protein, and the second is a much smaller optimized receptor binding domain, which is also known as RBD, and which is just a part of the spike protein, which is essential for the uptake of the virus into into host cell. So to our knowledge, we are the only company so far in the clinical stage with a vaccine targeting the receptor binding domain alone. So so having having vaccine targeting different domain is relevant relevant since we, at the moment, or the whole field at the moment, does not know which is the optimal antigen, yes, to induce a vaccine response. Our b n t 162 program also includes different messenger RNA forms. Two of our four candidates uses use a nucleoside modified mRNA backbone. One includes a iodine containing messenger RNA, and the fourth vaccine candidate utilizes a step entry time messenger RNA. Today, we will focus only on BNT162b1, which targets the RBD domain and is based on the nucleoside modified mRNA construct. So on slide seven, it is shown that BNT162b1 encodes a natively for the receptor binding domain. So we have included a primerization motif, which enables functional primerization. And and together with our Pfizer colleagues, they have shown that by electronic microscopic analysis of recombinant, it produced protein showing that this receptor binding domain indeed primarized as a primalization. And moreover, we have shown that this final receptor binding domain is able to bind to the ACE2 receptor. That means it comes really with the right folding, which is relevant because we, of course, want to get antibodies which are directed against the correctly folded protein. So on slide eight, you see the design of our phase one study. This phase one two study is is is intended to determine safety and immunogenicity, and we will also we use also different doses to define a dose level for our vaccine candidate and then to select a further dose for phase two, phase three studies. The first subjects immunized in stage one of the study are healthy individuals in the age of 18 to 55 years old. All the adults will be immunized with a given dose level of a vaccine candidate once testing of that candidate and the dose level in younger adults has provided initial evidence of safety and immunogenicity. In the German portion of the trial, the dose escalation portion of the phase onetwo trial include about 200 healthy subjects in the age of 18 to 55 and also target a dose range of one to one microgram minimum and one hundred microgram and the maximal dose. The data to date is from the ongoing US phase one two randomized trial, which is a placebo controlled, observer blinded study, which evaluates the safety, tolerability, immunogenicity of escalating dose levels of BNT162b1. The initial part of the study included 45 healthy subjects in the age of 18 to 45 55 years of age. The preliminary data was evaluated for 24 subjects who who received two injections of ten microgram and thirty microgram, and 12 subjects who received a single injection of one hundred microgram, as well as nine subjects who received two doses of placebo controlled. So in terms of demographics, the mean age range was 35 years old, and, and, the age of the participant was 19 to fifty fifty four years and with an almost equal gender distribution. Some of the safe information for BNT162b1 is outlined on slide nine. The most commonly reported local reaction was injection side pain, which was mild to moderate, except in one subject who received one hundred microgram dose. Systemic reactions, including fever, were more common after the second dose than the first dose. Following dose two, eight percent of the participants who received ten microgram and seventy five percent of participants who received thirty microgram of the vaccine candidate reported fever greater than or equal 38 degrees of, values. Local reaction and systemic, events peaked at day two and both were fully resolved on day seven. No serious adverse events were reported in the subjects. In summary, BNT162b1 was well tolerated at the doses of ten microgram and thirty microgram. So now let's move to slide 10. The participants received two doses of the vaccine, twenty one days apart of placebo, ten microgram or thirty microgram of BNT162b1 and or received a single dose of one hundred microgram of the of the vaccine. So because of a strong vaccine booster effect, the high neutralizing target drops seven days after second dose of ten microgram and thirty microgram on the twenty eighth of the vaccination. The mute neutralizing geometric titers were one hundred sixty eight and two hundred sixty seven for the ten microgram and thirty microgram dose levels, corresponding to about 1.2 to 2.8 times of neutralizing neutralization the neutralization type of observed in thirty eight sera from subjects who had contracted DUS COF2 and recovered. In all twenty four subjects who received two vaccination at ten microgram and thirty microgram dose levels of BNT1 and EC2 to B1, elevation of RBC binding IgG concentrations were observed after the second injection with with geometric mean concentrations in the range of 4,800 or 27,800 units per milliliter at day twenty eight. That means seven days after immunization. These concentrations are eight to 46 times higher than the geometric mean concentrations observed in the convalescent serotine. At day twenty one, after seeing injection, 12 subjects who received one hundred microgram of twenty one hundred sixty two b one had an RBD binding of seventeen seventy eight units and a vascov neutralizing type of 33, which is three times or 0.3 times of the GMCs and GMT of the convalescent serum. So let us move to the open questions on slide 11. So this result are positive, but the study at the moment has several limitations. First of all, we use convalescent sera as a comparator for neutralizing antibodies, and and T cell responses are not yet available. T cell responses are measured in the German studies, which will be published in the next weeks. The level of immunity and the pattern of B and C cell contribution needed to protect from the COVID nineteen are unknown at the at the at the present. That means we have high neutralizing antibody titers, but we don't know if these titers are sufficient to induce a protection. Further, this analysis of the available data did not assess the immune response of safety beyond two weeks after the second dose of the vaccine. So that means we don't know how the process will follow on, yeah, on the on when monitored for the longer period. And this is, of course, important for public public health use of the vaccine because ideally, a vaccine should have high titers over a longer period of time. So we will continue that. Yeah? So follow-up will continue for all participants and include collection, yeah, also of serious adverse events for the next six months, yeah, potential COVID nineteen infection, and we will have multiple additional immunogenicity measurement to up to two years. So another limitation is that this is this population is is just about healthy, yeah, adult of five 55 years or younger. Yeah. And we and, therefore, it does not accurately reflect the population at the highest risk for COVID nineteen. So this will be adult of 65 years of age or older, And this population is being currently enrolled into the studies and will be reported when we have generated sufficient data. So a later phase of the study will also prioritize enrollment of more diverse population, including those with chronic underlying health conditions, and of course, also from racial and ethnic groups adversely affected by COVID nineteen. So I want to end my prepared remarks by highlighting key next steps for the BMP 162 program as shown on slide 12. A manuscript with additional data from The US trial of BNT162b1 has been submitted for publication in peer reviewed journal and is currently available online on the preprint manuscript server med archive. In addition, data from ongoing German trials for BNT162b1 is expected to be released within the next few weeks. The preliminary data will be used together with additional data being generated to select a lead candidate and dose for the initiation of a large Phase IIb trial anticipated to start by late July. Finally, we and Pfizer are working closely together on manufacturing scale up, supply chain and network planning. I will now hand over to the operator to open the line for questions. Operator? Thank you for that. I would like to say, ladies and gentlemen, that if you wish to ask a question, you need to press star one on your telephone and wait for your name to be announced. An operator will take your name if necessary, and we will compile the question and answer. So if you wish to cancel your question, you can press the hash key. And we already have our first question coming from the line of Robert Bearings. Sorry. I am sorry. I have to redefine that. It's Corey Kasimov who asks the first question. Excuse me. Please go ahead, Corey. Great. Thank you, and thanks for taking the questions, and great to see the early progress here. So first question I have for you is in terms of the convalescent sera samples that were used from patients who recovered from COVID-nineteen, can you speak to the severity of their infections and whether this has a meaningful impact on the subsequent antibody levels you were using as a comp in this scenario, or do you not know that information? And then I have a follow-up. Yeah. Probably, this is an important question. We have partial information that at least some of the patients that had more severe infection. We have, of course, also compared the data that we have from this patient to publish data, for example, from a Chinese patient population, were characterized by more or less severe pulmonary infection. So it is well known that patients with a severe disease tend to have higher titers. But we have also seen patients with severe infection with relatively low titers. And we believe that the collection of the sera which we have is a good representation of the disease cause of patients, of COVID-nineteen patients, including those which do not require hospitalization, but could also reflect those which have hospitalization. There are patients who have status above 5,000, but we have also seen a number of patients with status below 30. So this is, I think, the selection reflects a meaningful collection collection of of of, yeah, of the other. Okay. That's helpful. And then my follow-up question is just in light of FDA's guidance that was released yesterday around COVID nineteen vaccines, does that change at all how you think about designing a phase three trial or how you think about potential approval timeline should ongoing development continue to be successful? No. We were prepared, prepared, for this type of of announcement. And and, accordingly, our plan with with Pfizer, foresees to go the path, which is which is, described in the FDA announcement. Okay. Terrific. Thanks for taking the questions, and good luck with continued progress here. Thank you, Corey. Thank you for that. We will now take our next question, and that question comes from the line of Dana Graybosch. Hopefully, you can hear us. Thank you. Yep. Thank you very much for the questions. I have many, so I'll try to prioritize. The first one is if you had a chance to characterize the IgG and the neutralizing antibodies against strains that have some of the more calming mutations in the receptor binding domain. And after that, I'll have a follow-up. Yeah. Hi, Dana. So so so these are ongoing studies, and and we will report report about the findings in the coming weeks. K. I thought. And then the second one is maybe to ask you to to speculate a little bit on the the really strong boost effect on the neutralizing titers. And I wonder if that teaches you anything about the biology of what's needed to generate an immune response. I also saw, you know, comparing to the adenovirus vaccine, you're getting much higher titers. Does that tell anything else about the immune response? Does that inform you at all about the need for long term boosting? Yeah. So so this is an excellent question. So, I think this is one of the key advantage of using a messenger RNA vaccine. So if you have a viable vaccine, regardless which type of virus you use, you you get a a pretty good prime response. Yeah? But since you get also immune response against the virus itself, the boost response is limited by the immune response against the virus and the virus backbone. So that means the viral vaccines, yeah, have the limitation that the boosting is really difficult. Therefore therefore, there is there are these models where heterologous prime boost vaccines are used. So virus one for the prime and boost for the second. The nice thing about messenger RNA vaccine is it has really a very clean backbone, so there is no viral backbone. This is just pure antigen, and the lipid nanoparticle itself is not immunogenic or minimally immunogenic. That means it gives you an excellent chance chance to get this boost response because the second injection provides the antigen in the in the same clean clean form and is not limited by backbone immune response. That's the reason why why we see this, this wonderful boost after after after, the second injection. Very helpful. Thank you. You're welcome. Are there further questions? Yeah. We have more questions. Just a second. We now have a question from the line of Akash Tewari. Hey, guys. Thanks so much. So a few questions. Number one, have you done any analysis on the T cell responses in terms of quantity and quality of viral specific T cells? We're seeing that severe disease is kind of marked with impaired CD four function, lower interferon type one, type three, and kind of lower T cell diversity in general. Is there any concern that the receptor binding domain approach is just too specific to generate a broad enough T cell response? And I have a a follow-up as well. Thanks. Hi, Akash. Yeah. Excellent question. So so the T cell analysis is ongoing in from the from the T cells from the German participants, and we will come up with data in the coming three weeks reporting about details about the strength of T cell responses as well as about the type of immune responses, investigating the key cytokines, for example, Th one cytokines IL-two interferon gamma, as well as IL-four, which could be an indicator for a Th two response. Got it. And just, if I may, on the transient drop of lymphocytes and the great true neutropenia, it seems to be on target. But do you think that, lymphopenia is a result of circulating lymphocytes getting stimulated going to the spleen, or is there something else that may be causing this? And is this like, would we would it be fair to say that this is an on target side effect in order to generate an interferon response? And have you seen this in your other kind of mRNA formulation? Yes. Yes. That's that's exactly the the explanation. So the the lymphopenia is a pseudolymphopenia. That means it is it is just a redistribution of lymphocytes from the blood to the second level lymphoid tissues and the spleen. And we see that also with our other RNA vaccine platforms, and it is an intended mode of action because you want you want you want the lymphocytes going into the lymph nodes where the immunogen is presented to get teached and then go back to the blood, and that's exactly what we observe. It's a temporary lymphopenia, and then this is recovering after three days, and and the the lymphocyte then travel to the to the target tissues. Great. Thanks so much. Thank you, Akai. Thank you for that. We will now take our last question, and that question will be from Naveen Jacob. Please go ahead. Hi. Can you hear me? It's Naveen from UBS. Thanks so much for taking the question. Hi, Naveen. Yes. We we hear you. Perfect. Thank you so much. So just quickly thank you for providing all the details that you did. Very helpful to us. Wondering if you were able to characterize the IgA IgA antibody levels. I appreciate the IgG information. And curious wondering if if you consider IgA to be useful at all information at all in the context of perhaps IgA being important for respiratory infections given potentially better mucosal penetration? That's question number one, and then I have a follow-up. Yeah. So in the in the coming six to eight weeks, there will be a lot of exploratory biomarker analysis, which will be published. We will also come up with a with a preclinical paper in the next next few weeks addressing this question. The general general general observation for this type of vaccines is that they induce immune globulin responses to including IgA responses. But for for this specific vaccine, there will be exploitive studies coming coming in the next few weeks. Very helpful. And then just a practical question, if I may. Can you remind us what the, storage requirements are, for your, eventually as you continue to, enhance formulation? How challenging is is this, from a storage perspective? Do you need extra cold storage? Any kind of color around that would be very helpful. Yeah. So we are working with our colleagues from from Pfizer on on stability data, generating stability data at minus 70, at minus 20, at two to eight degrees. Yeah? The data incoming, and and we started also to to implement and and model supply logistics to ensure that vaccine can be shipped and, can be taught at the at the target places and stored in the respiratory generator until it is it is used. So we will provide more details once we have done once once we have a longer stabile data available. Thank you so much, and congrats on the progress. Yeah. Thank you so much. So with that, we we close the call. Thank you again for joining the call today. We look forward to speaking with you in the future. Thank you. Thank you. That does conclude our conference for today. Thank you all for participating. You may now disconnect.