Good morning, and welcome to the Moderna Corporate Update and 2018 Financial Review Conference Call. At this time, all participants are in a listen only mode. Following the formal remarks, we will open up the call for your questions. Please be advised that the call is being recorded. At this time, I would like to turn the call over to Laura Schneck, Investor Relations at Moderna.
Please proceed.
Thank you, operator. Good morning and welcome to the Moderna corporate update and 2018 financial review conference call. This morning, we issued a press release that outlines the topics that we plan to discuss today. You can access the press release as well as the slides that we'll be reviewing by going to the Investors section of our website atmadernapx.com. Today, call, we have Stephane Vonsal, our Chief Executive Officer Tal Zaks, our Chief Medical Officer and Laurence Kim, our Chief Financial Officer.
Stephen Hote, our President will also join us when we open up for Q and A at the end. Before we begin, I would like to remind everyone that this conference call will include forward looking statements. Slide 2 of the accompanying presentation and our SEC filings have important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward looking statements. We undertake no obligation to update or revise the information provided on this call as a result of new information or future results or developments. I will now pass the call over to Stephane.
Thank you, Laura, and good morning, everyone. Welcome to Moderna's first quarterly conference call as a public company. As you know, we believe that Moderna, the mRNA, has a potential to become a new class of medicines. And since Moderna's inceptions, we have worked hard to build a company that could become the leader in the field. What has energized us is a potential to make new medicines for untreated diseases, medicines which cannot technologically be made using small or large molecules.
We believe that over time, this can go beyond our current therapeutic areas of infectious disease, oncology, rare genetic diseases and cardiovascular diseases. Because mRNA is an information containing molecule, we believe that this new class of medicines and the company we have built around it may have many advantages. First, we are able to use similar technology components across programs. As a result and over time, as we derisk the use of those components, successive mRNA medicines should have a higher probability of technical success than traditional medicines. 2nd, by investing in automation, robotics and IT, we should be able to move very quickly.
Unlike small molecular large molecule technologies, every time we make a product at every scale, we intend to use similar manufacturing processes, accelerating timelines for both the discovery of new development candidates as well as a scale up for clinical trials. And finally, because we make mRNA in a liquid phase, self resolution, we believe that over time, our cost of goods will be similar to small molecule injectable commercial products. With the possibility to build a new class of medicines, we're helping many patients and creating value for shareholders along the way. We focus on managing 4 different type of risk: technology risk, biology risk, execution risk, financing risk. As you can see on Slide 4, it has always been our goal to derisk each of our modalities by beginning with a development candidate that could allow us to systematically and separately address the biology risk and the technology risk.
Early on, we did the mind that vaccines presented the least technology risk and therefore decided to pursue this first. From a biology risk perspective, we started with influenza vaccine to see if we could safely demonstrate in a Phase 1 trial, a defined level of antibodies in healthy volunteers not previously exposed to the virus. At the time of our IPO, we had advanced programs across 3 of our modalities in the clinic: cancer vaccines, intratumoral immuno oncology and localized regenerative therapeutics. Already in 2019, we have initiated human dosing in our 5th modality, systemic secreted therapeutics with mRNA-nineteen forty four and mRNA encoding an antibody against the chikungunya virus. This program uses the same delivery technology as our 4 rare genetic disease programs, MMA, PA, PKU and Fabry as well as our relaxing cardiology program.
On Slide 5, you can see our 2019 2020 priorities. As we build the company, our top priority is to advance our development pipeline to get these important innovative medicines to patients. We also focus on growth and therefore have a subset of our team focus on creating new development candidates within our existing 6 modalities. Given that these new development candidates use the same technology component that was already in the clinic, we're able to significantly reduce technology risk and move swiftly from a drug concept to development candidate. Our further focus is on the long term, meaning inventing new modalities, which can deliver mRNA to new tissues and or cell types.
On Slide 6, outlined in red, you can see our pipeline of advance in the 90 days since our IPO. Let me spend a minute on this from right to left. We are planning a Phase II study for PCV and the Phase II cohort of XOTI ligand in ovarian cancer. We reported positive interim Phase I hMPV plus PIV3 vaccine data, supporting the move into a Phase Ib age de escalation study in children. We have begun dosing in Phase 1 studies for mRNA encoding an antibody against chikungunya virus and for the immuno oncology triplet.
INDs are now open for MMA and IL-twelve. On Slide 7, let me give you a quick update about the manufacturing site in Norwood, Massachusetts. We have 3 distinct activities on the slide. First, we manufacture clinical material. Since the site opening, we have successfully manufactured clinical grade mRNA and then move to formulation and then to filling and finally labeling of our virus.
We are now actively working toward vertical integration of critical raw materials like DNA plasmid used as templates to our mRNA buffers and overall materials. We have also successfully transferred the 2nd capability to Norwood for personalized cancer vaccine or PCV. We started our PCV clinical trial in 2017 by making the PCV vaccines as a contract manufacturer in the U. S. Using Moderna manufacturing process and the robotics we invented to be able to make one lot personalized for one patient.
I am pleased to report that we are now capable of making all our PCVs in Norwood for patients in the remainder of Phase 1 as well for Phase 2. The first capability transfer to Norwood, which will enable us to reduce cost is our preclinical robotics that makes all of our research grade mRNA and formulations. Let me close my introduction by saying that I'm very proud of the progress our team made in 2018 and in the 19 days since our IPO. Momentum and growth are very important to Moderna's success and it is exciting to see significant progress across the business. I would like now to turn to Tal.
Thank you, Stephane. Let me now review our progress by modality. If you go ahead to Slide 9 and 10, I'll start with the prophylactic vaccines. A few weeks ago, we reported the Phase 1 data for our combination vaccine against 2 respiratory viruses, human metapneumovirus and parainfluenza virus 3 or hMPV and PIV3. These are two important causes of respiratory tract infections in children and can lead to viral pneumonia and hospitalization, particularly in children under 2 years old.
There are currently no approved vaccines against either hMPV or PIV3. On Slide 11, as we had disclosed, the top line interim data from this study showed that a single vaccination with mRNA-sixteen fifty three boosted the titers of neutralizing antibodies against both hMPV and PIV3 and that the magnitude of the boost was similar at all dose levels tested. As you would expect, all study participants had some level of baseline neutralizing antibodies against both viruses. Yet 1 month after a single mRNA-sixteen 53 vaccination neutralizing titers against hMPV rose to approximately 6 fold baseline and those against PIV3 rose to approximately 3 fold baseline. A second vaccination 1 month later did not further boost antibody titers suggesting that a single vaccination is already achieving a plateau in the generation of neutralizing antibodies in this pre exposed population.
MRNA-sixteen fifty three was found to be generally well tolerated. No serious adverse events, adverse events of special interest or adverse events leading to withdrawal were reported. Injection site pain was the most commonly reported adverse event and the most common Grade 3 adverse event. The magnitude of responses that we observed is sufficient for us to advance mRNA-sixteen fifty three to a Phase 1b trial in toddlers, a trial that we are currently designing. I look forward to further discussion of this point in other aspects of our clinical data at a future medical meeting.
Let me move to our congenital CMV vaccine on Slide 12. This is a vaccine against cytomegalovirus, which is the most common congenital viral infection impacting close to 40,000 infants annually in the United States. Congenital CMV infection can severely affect infant brain development and is an important cause of childhood hearing loss. There's currently no approved vaccine to prevent CMV. Our vaccine mRNA-sixteen forty seven has enrolled the initial three dose levels in the Phase 1 trial.
While we have not yet seen any immunogenicity data, the safety and tolerability data both in this trial and across our other infectious disease vaccines suggest that we should be able to dose escalate above 180 microgram. So we are expanding the trial to enroll 2 additional dose levels at higher doses in the range of 300 micrograms. As a reminder, 300 microgram was the top dose that we tested in the hMPV PIV3 study. Reviewing our overall progress on Slide 13, we have to date dosed approximately 950 healthy volunteers enrolled across 7 Phase 1 trials at doses up to 300 microgram. The emerging safety and tolerability profile has been consistent with that of marketed adjuvanted vaccines and with a positive readout for hMPV PIV3, we have now shown promising data from 5 Phase 1 programs within our prophylactic vaccines modalities and we continue to make progress.
I spoke about our plans for hMPV, PIV3 and CMV. On Zika, we previously disclosed data for mRNA-eighteen ninety three, which has the potential to be a much more potent follow on to mRNA-thirteen twenty five. We're in the process of writing the IND for it and so we'll not be further developing mRNA-thirteen twenty five. Overall, our development of a vaccine against Zika continues to be funded by BARDA under the grant award of approximately $125,000,000 Lastly, our partners at Merck are preparing to initiate a Phase 2a trial of mRNA-seventeen seventy seven, our RSV vaccine. Let me now talk about our cancer vaccine programs.
And if you advance to Slide 15, you can clearly see the immunogenicity data from a patient in the Phase 1 trial of our personalized cancer vaccine. As we previously disclosed, at the 2nd dose level of 0.13 milligram, we were able to show that we elicited new antigen specific T cell responses. To date, we have dosed over 30 patients. At the top dose of 1 milligram, we have not seen any dose limiting toxicities either for the vaccine alone or in combination with KEYTRUDA. And so we have selected this as the dose to move forward into Phase 2.
On Slide 16, you can see the design of this Phase 2 study. It is designed to assess whether post operative adjuvant therapy with mRNA-four thousand one hundred and fifty seven and KEYTRUDA can improve the recurrence free survival for melanoma patients when compared to KEYTRUDA alone. We will be testing this in patients who remain at high risk of recurrence despite having had their tumors resected. So the primary endpoint for this study will be recurrence free survival and we're planning to have the primary analysis done 12 months after the last subject is enrolled. This protocol has been submitted to FDA.
As an aside, I would note that we are increasing the neoantigen count in our personalized cancer vaccines from 20 to 34 neoantigens, all still encoded on a single mRNA chain and we intend to apply this advance to the Phase 2 study. Let me now turn to our intratumoral immuno oncology programs, which you can see on Slide 18. We continue to advance the Phase 1 study of mRNA-two thousand four hundred and sixteen, which encodes for the OX40 ligand membrane protein and have dosed over 30 patients on this study, some for as many as 10 cycles at doses of up to 8 milligram. We have not seen any dose limiting toxicities. We have shown that OX40 ligand protein expression in certain injected lesions and have observed regression of injected lesions in 2 patients with advanced ovarian cancer, although these regressions did not meet resist criteria.
These observations have motivated us to trigger the Phase 2 cohort in patients with ovarian cancer. The top dose tested in the Phase 1 trial, 8 milligram currently in the dose confirmation stage and this is the dose we intend for the Phase 2 cohort in ovarian cancer. Let me talk about mRNA-two thousand seven hundred and fifty two, which encodes the triplet combination of OX40 ligand, interleukin-twenty three and interleukin-thirty six gamma. In January, we published new pre clinical data in science translational medicine showing that local delivery of the triplet induced a broad immune response and caused tumor regressions in both injected and distant un injected lesions in murine models. Additionally, when combined with checkpoint inhibitors, this triplet was able to induce responses in tumor models that are otherwise unresponsive to checkpoint inhibitors.
So these data provide the scientific basis for the Phase 1 study of mRNA-two thousand seven hundred and fifty two. We initiated dosing late last year and we have not seen any dose limiting toxicities in the first dose level and are now begun to treat patients at the second dose level. Finally, there's always there's also been progress with MEDI1191 and mRNA encoding interleukin 12. IL-twelve is a potent immune modulator whose preclinical profile has generated much interest as a potential anti cancer agent. In the past, the clinical development of systemically administered recombinant IL-twelve has been hampered by systemic toxicity.
We have demonstrated pre clinically that intratumoral doses of mRNA encoding IL-twelve can be delivered safely and induce the complete response in multiple murine models, providing the scientific foundation for our partners at AstraZeneca to advance MEDI1191 into the clinic. So indeed, I'm happy to report that AstraZeneca filed the IND for MEDI1191 and this IND is now open. This trial is designed to evaluate safety and efficacy in patients with solid tumors in combination with a checkpoint inhibitor. On Slide 19, I want to briefly mention the modality of localized regenerative therapeutics. AstraZeneca continues to enroll patients in the randomized Phase 2a trial of AZD8601, which is an mRNA encoding for VEGF A.
As a reminder, the Phase 1 showed that AZD8601 was well tolerated and led to the translational of functional VEGF A protein, which caused the dose dependent increase in blood flow where it was injected. These data were recently published in Nature Communications. Moving next to our systemic secreted therapeutics, let me provide some context on our first program in this modality. On Slide 21, you can see that as we were assessing the biology risk for our systemic secreted therapies, we began the development efforts by encoding a monoclonal antibody with a goal of inducing transient passive immunity in the recipient. An antibody would represent a complex protein as it requires the co translation of 2 separate mRNAs and the correct intracellular folding and eventual secretion to the blood of a formed antibody.
From a safety perspective, we would expect an antiviral monoclonal antibody to be safe and we should be able to measure its blood levels. This would then allow us to quantify the PKPD relationship. In other words, how much mRNA is required to produce how much protein in a relatively straightforward manner. And this relationship would be of obvious relevance to our pipeline of mRNA medicines for rare diseases, particularly because the lipid nanoparticle delivery system is shared with our rare disease programs as well as with relaxant. And so we chose an antibody against the chikungunya virus encoded as mRNA-nineteen 44.
On Slide 22, you can see the Phase 1 design for this study. We're conducting it in healthy volunteers. So it should give us a read on the safety and tolerability of the formulation. The pharmacological goal is to determine how much antibody we can produce as a result of systemically administered mRNA and whether one day we may be able to offer people passive immunity against infection by this virus, which today has neither vaccine nor specific therapies available. On Slide 22, you can see our progress overall in systemic secreted therapeutics.
We recently completed dosing of all 8 subjects in the first cohort of healthy volunteers in this Phase 1 study. And I look forward to sharing more about this study once we have a complete picture of the data. In addition, we're continuing to move our Fabry and relaxant programs forward into clinical trials. Finally, let me turn to our systemic intracellular therapeutics. On Slide 25, I'm happy to share today that FDA has given us fast track designation for our methylmalonic acidemia program and has allowed us to open the IND for mRNA-three thousand seven hundred and four, which encodes the mute enzyme missing in children with this disease.
We're now preparing to begin the Phase onetwo study and I'll come back to this in just a moment. In addition to mRNA-three thousand seven hundred and four, we continue to progress the preclinical development for both propionic acidemia and phenylketonuria programs with the goal of bringing them into the clinic. On Slide 26, let me describe the design of the MMA study. The primary objective is to evaluate the safety, pharmacodynamics and pharmacokinetics of mRNA-three thousand seven hundred and four in patients with methylmalonic acidemia. We intend to enroll pediatric patients with elevated plasma MMA levels and the first dose level will begin with adolescents aged 12 to 18.
Once we assess the safety and tolerability of this age group, we then intend to enroll patients who are between the ages of 1 18 years old. Following dose escalation, we anticipate this study will move into a dose expansion phase. As a reminder, we have an ongoing natural history study underway for both methylmalonic acidemia and propionic acidemia, which we call the MAP study. As of the end of February, we have 32 patients enrolled in this study, 20 with MMA and 12 with PA. Let me close on Slide 27 with our pipeline, which illustrates the breadth of our development programs.
We're proud of our ability to advance multiple programs in parallel across many different treatment modalities and for different diseases. I look forward to updating you further as we continue to progress our programs. With that, I will now turn the call over to Laurence to walk through the financials.
Thank you, Tom. Let me turn to Slide 28. In today's press release, we reported our Q4 and full year 2018 financial results. Please note these results are unaudited. We ended 2018 with cash, cash equivalents and investments of $1,700,000,000 This compares to $902,000,000 at the end of 2017.
This increase was due primarily to the financing proceeds, approximately $563,000,000 in net proceeds from our initial public offering in December 2018, approximately $661,000,000 in net proceeds from preferred stock issuances earlier in 2018 and a $13,000,000 premium associated with the 2018 amended and restated PCB agreement with Merck. All of this was offset partially by the cash used in 2018 to fund operations and for purchases of property and equipment. In further discussing our financial results, let me then focus on 2 cash flow metrics, which provide a better view on cash used given the quantity of deferred revenues, stock based compensation and depreciation embedded in our operating income. Net cash used in operations was approximately $331,000,000 for the full year 2018, which was comparable to 2017. Secondly, cash used for purchases of property and equipment was $106,000,000 for the full year 2018 compared to $58,000,000 for the full year 2017.
Of that cash used specifically related to our Norwood manufacturing facility was $95,000,000 in 2018 compared to $41,000,000 in 2017. Revenue for the full year 2018 was $135,000,000 as compared to $206,000,000 for 2017. The decrease was mainly to the termination of the Alexion strategic alliance arrangement in October 2017, which caused an accelerated recognition of deferred revenue in 2017. Also there was a decrease in grant revenue from the BARDA contract, primarily due to revisions in the Zika program, leading to a focus on preclinical studies of mRNA-eighteen ninety three, our follow on to mRNA-thirteen twenty five. The decreases were partially offset by increases in collaboration revenue from AstraZeneca and Merck.
R and D expenses for full year 2018 were approximately $454,000,000 compared to $410,000,000 for 2017. The increase was primarily due to an increase in personnel related costs, including stock based compensation, mainly driven by an increase in the number of employees supporting our R and D programs, an increase in consulting and outside services and an increase in facility and equipment related costs. G and A expenses for full year 2018 were approximately $94,000,000 compared to $65,000,000 in 2017. This increase was mainly attributable to increases in personnel related costs, including stock based compensation, driven by an increase in the number of employees and consulting and outside services, all of which were in support of our public company readiness. I'll finish the slide with our expectations for our cash use in 2019.
Currently, we expect that we will finish the year with between $1,150,000,000 $1,200,000,000 in cash, cash equivalents and investments. Our use of cash is rising from 2018 driven by our advancing
Two last points before I hand the call back over to Stephane. As noted in our press release,
we expect to continue to be Two last points before I hand the call back over to Stephane. As noted in our press release, we're pleased that we are to be added to the Russell 1,000 and Russell 3,000 indices effective March 18. And lastly, I am very excited to welcome Lavina Talakdar to our team as Head of Investor Relations effective April 1. Lavina joined us from Adia and a long career on the buy side. Now let me turn it over to Stefan.
Thank you, Laurence. Moving to Slide 29. To close our remarks, I would like to reiterate that the company is very focused on execution. I hope our recent progress gives you a sense for that focus, which is central to both our culture and our mission. 3 priorities: number 1, advancing the development pipeline and get into clinical readouts as fast as we can with high quality.
Number 2, investing new development candidates in the 6 existing modalities and moving them to our development pipeline. Number 3, investing new modalities. If you can turn to Slide 30, which shows our anticipated clinical next steps. 2019 2020 are going to be important for Moderna. We expect additional Phase 1 readouts and multiple Phase 2 starts and readouts.
Turning to Slide 31. We would like to announce 2 important investor events for Moderna this year that we hope you can join. We will host the Science Day in Cambridge on May 7, led by Doctor. Stephen Hogg, and we'll host an R and D Day in New York City on September 12, led by Doctor. Talzak.
On Slide 32, you have an update of Moderna. I believe that Moderna is operating from a place of tremendous strength. Enabled by mRNA platform, our large development pipeline continues to progress based on the data we are generating. We have now 4 programs in or planning for Phase 2, 6 positive Phase 1 readouts, 5 ongoing Phase 1 trials, 3 open INDs. If you look at the pipeline by prophylactic area, I'm very proud that we now have 5 immuno oncology programs, OX40 ovarian and PCV preparing for Phase 2.
The triplet is continuing dose escalation in Phase 1 and 2 open INDs, KRAS with Merck and IL-twelve with AstraZeneca. 4 rare disease programs, MMA, PA, PKU and Fabry, 3 vaccines for large unmet medical needs, RSV, CMV and the combo hMPV PIV3. More than 750 talented employees, we are committed to leading mRNA sites. A 200,000 square foot manufacturing site in Norwood, which is a strategic asset for Moderna. This capability will enable us to scale and provide an important competitive advantage to Moderna to keep executing and accelerating.
The strong balance sheet with $1,700,000,000 of cash, this provides multi years of financing for operations and investments in our future. On Slide 33, our mission. We know that we have a special opportunity and we are committed to delivering on the promise of our science and bringing forward a new class of medicines for patients in need. I'd like to add our remarks by thanking the many people who participate in our clinical studies, including patients, healthy volunteers and physicians. With that, we'll now be happy to take any questions.
And our first question comes from the line of Matthew Harrison of Morgan Stanley. Your line is open.
Great. Good morning. Thanks for taking the question. I guess 2 for me. Can you talk about first for PCV, why you chose that specific indication?
And just because maybe I'm not familiar with what's typical recurrence free survival for patients that you're enrolling here? And maybe you could just talk about how the study is powered or what you're hoping to achieve, with the PCV combination versus that? And then the second question, just given the fact that you've pushed OX40 ligand into a Phase 2 study on it. So how should we think about that program versus the triple and is there a point at which you have to pick 1? Thanks.
Thank you. This is Tal. Let me answer them in sequence. So let's start with the adjuvant trial for PCV. The reason to pick this indication is because I think it's generally true across anti cancer drugs that when a drug is effective, the magnitude of effect tends to be higher and lower in earlier lines of treatment and even more so in the adjuvant setting.
And you would expect this to be true for melanoma and for immunotherapy specifically because you need some time and a healthy immune system for the patient to be able to react. It is also notable, I think that most if not all of the data to date and similar approaches has been developed in adjuvant melanoma. So it's a place where I think overall the likelihood of success is highest. In terms of this patient population, the in recent studies, I think the recurrence free survival of patients with advanced melanoma that has been resected has been around 33% to 40% if you look at recent studies. Our underlying assumptions, since we're taking a slightly higher risk patient population was that the baseline rate should be about 45%.
The trial is powered at about 85% power with a one-sided alpha of 0.1 as is typical for Phase 2 POC studies to show a hazard ratio of about 0.5. So, I think typical stats more or less for a proof of concept study. I would note that the study has randomization of 2 to 1. And the reason that we're enrolling more patients on the treatment arm with the vaccine is because there's a good body of recent evidence on how patients perform in terms of just KEYTRUDA alone. And our partners Merck have all that experience at hand from their recent Phase III trials in this setting, which led to the approval of KEYTRUDA in this setting.
So we should be able to leverage not just the control arm on this study, but a wider body of data as a comparator for the study, helping us overall with the sense of power here. So that's on PCV. For the OX40 ligand, it's a good question and one that obviously we wrestle with as well. Like any cancer doc, when you see a signal of activity, you feel compelled to go and see if there's real benefit there for patients. Ultimately, OX40 Ligand is ahead of the triplet in terms of the clinical trials.
Time will tell what is the magnitude of activity that we see in this trial and what type of activity we can see with the triplets. So I think it's too early to predict how this will play out. I think for now we are following the clinical signals
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And Tal, can I just ask a follow-up on the triplet? I mean, I assume the dosing strategy there is to go a little bit slower given some of the cytokines you have involved as well. I mean, will that one maybe even take longer to potentially catch up or have similar data to OX40 Ligand alone?
Not necessarily. So I think, yes, we are starting it at a somewhat lower dose than we started with OX40 ligand alone because OX40 ligand is a membrane bound protein, you'd expect less risk. And of course, when you've got locally secreted cytokines, you want to dose them at a dose that has the local activity without spillover to systemic toxicity. So there's probably a couple more dose cohorts in that study, but I don't think it's going to be a significant delay relative to our experience with OX40 ligand.
Great. Thanks very much.
Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your line is open.
Good morning. Two questions for me as well. With regard to the PCV program, you mentioned that you've increased the neoantigen count of the cassette from 20 to 34. Just wanted to get your thoughts around that and whether you think that's a broad enough sample set. And then secondly, on the systemic therapeutic modalities, can you help us understand with regard to the chikungunya program, you're looking at a single dose right now, but at one point you look to multiple doses.
How should we think about the safety profile in the context of derisking this program based on the re dosing aspect? And then the second that will the second systemic therapeutic question is when could we see MMA data? Thank you.
Thank you for those. Let me start in the sequence
that you asked, the
neoantigen number. So look, what we know from immuno oncology is that it really only takes one antigen if you have a sufficiently potent immune response to lead to cancer aggression. The question is, how do you increase the probability of getting the right one? If you look at the average number of mutations that occur within coding sequences and then get expressed in proteins, Depending on the tumor type, you can have up to typically in the order of a couple of 100 is sort of the number at the median range. So increasing the number, I think overall should increase the probability of success.
Now you have to do it within the context of what you think is feasible for the technology. One of the benefits of having it all encoded in mRNA is that going from 20 to 34 in this case doesn't materially affect our complexity of either process or cost of goods. It just took us some optimization of the mRNA and what we're doing. So I think it's a step in the right direction in terms of how one thinks about eliciting the most potent immune response possible. It will be obviously difficult to nail down what is the right number.
We're trying to give this vaccine the best possible opportunity to succeed for patients here. In terms of how to think about a single dose versus multiple doses in the safety, it's a good question. The place for us to start is at a place where we can have the clearest understanding of what a safety profile would be. And so that's why we started with a single ascending dose in healthy people for approaching that should be innocuous in and of itself. And that's why I think the chikungunya, we view it as a very informative first step.
It's a good question on the safety of single versus repeated doses. If I look at the totality of our preclinical models, I don't think we have a sense that giving multiple doses should give you a different safety profile than giving a single dose. And if you look at typical adverse event profiles for injected medicines, whether they be antibodies or lipid nanoparticles, the sort of acute reactogenicity or hypersensitivity reactions, should you see them, don't necessarily increase over time. In some cases, they decrease over time. In some cases, it just happens sporadically.
So, I'm not sure that I expect a different safety profile on repeat dose versus single dose. And that's how we think about the relevance of this first program to the rest of our rare disease repeat dose programs. Your last question on when can we expect data from MMA, look, we're not forward guiding. Obviously, this is a very rare patient population. We have to start in a place that balances the age of the patients and the age of where actually disease is prevalent, which is what led us to this adolescent group.
What we are committed to is being terms of enrollment until you'll see us give you regular updates on our progress.
All right. Thank you.
Thank you. Our next question comes from the line of Cory Kasimov of JPMorgan. Your line is open.
Hey, guys. Thanks for taking my questions. And this is Matthew on for Cory. Just to follow-up on the PCC program. Curious if you can help us better understand what informs your decision from an efficacy perspective to move ahead to the Phase II trial specifically at the 1 mg dose cohort?
Yes. It's a great question. We are talking about cancer vaccines, which obviously are a tough place to predict efficacy historically. I think it's a combination of 2 things. Our sense of the totality of the immunogenicity data that we've seen to date in our program.
We've disclosed for 1 patient, the rest we'll disclose when there's a body of evidence that's sufficient to really had a scientific discourse at a medical meeting. But the totality of our data combined with our sense of the tolerability and safety profile at the 1 milligram dose, I think has given us and our partners Merck the confidence that we are ready to go to Phase 2. In terms of what it takes to plan your Phase 2. We've always been committed to ensuring that we test this personalized cancer vaccine in a way that is as definitive as possible, which is why you see us launch relatively early a randomized Phase 2 study. We will be continuing to expand the Phase 1 experiment with additional cohorts to further characterize both the immunogenicity and the potential for benefit in the single arm sense.
But if you want a definitive result, you run a randomized Phase 2 and that's what we're doing here.
Great. Thanks. And then just quickly on the CMV vaccine program, does the opening of the 300 microgram dose cohort effect timelines for when we should expect to see initial immunogenicity and safety data?
Yes. I think that's a fair question and I would anticipate it will delay somewhat the timeline. We have made great progress to date. We've completed enrollment in the first three cohorts. It is a healthy volunteer study.
So our ability to recruit patients on time and analyze the data has been exactly where we'd want it. But I think the nature of these studies is that you first get a sense of tolerability and only later immunogenicity. So I'd hate to come to the end of this study and figure that I'd under dosed, which is why we've decided to take a little bit longer and make sure we're exploring the full range of doses that we think is appropriate.
Great. Thanks for taking my question.
Thank you. Our next question comes from the line of Ying Huang of Bank of America Merrill Lynch. Your line is open.
Hi, good morning. Thanks for taking my questions. The first one is on the PCV program. Tau, can you comment whether you observed any epitope spreading in the Phase 1 portion? And also can you comment on the manufacturing needle to needle timeline now that everything is brought in house?
And then I have a second question on the OX40 ligand program. So do you believe that you need to go to a higher dose for OX40 ligand? Or do you think maybe ultimately you need a combination, the triplet to achieve meaningful clinical activity here? Thanks.
Thank you for those. Let's start with antigen spreading. I think that's a tough one. We are not to be fair, the majority of the thrust for our translational experiments has been to ascertain whether we can actually elicit the immunogenicity against the new epitopes for which we encode. So, the magnitude, I think overall of data here is not going to be as scientifically, I think, rewarding as you might want in terms of answering such a multitude of questions in this first Phase 1, really the goal of the Phase 1 was to establish a dose where we believe there is immunogenicity against that which we encode.
Some of those questions we will answer I think later in the program and you'll see some of the data as we get a sufficient body of evidence to be able to share it with the broader scientific community. The turnaround time, we are currently at around 50 days, I'd say needle to needle. We're continuously looking at ways to improve it. As you would expect, bringing it to Norwood should enable us to tighten the timelines. But this will be a continuous evolution over time as we look, every day matters here and we look at hours and days as a metric to continuously improve there.
In terms of the dose for OX40 ligand, I think that to date we've seen protein expression in the injected lesions. So, it's hard to determine what is the optimal dose. I think the fact that we've been able to show some local pharmacology when you actually look at the stained tissue, gives us a sense that we are activating the pathway in the way that we hope to. And to your point, I think that or from a scientific perspective, you would expect that you would need additional signals, whether they are additional local signals like in the triplet or potentially even the additional of a systemic checkpoint inhibitor to see the maximal activity of this type of therapy. And I think that's been borne out for other approaches in this space as well.
Thank you.
Thank you. And our next question comes from the line of Geoff Meacham of Barclays. Your line is open.
Hey, guys. Good morning and thanks for the question and congrats on your first public call. Just have a couple. The first one is an active comparator study in PCV obviously is a high bar, but it really is the best way to achieve proof of concept. The question is philosophically, should this be the template that we should expect going forward in oncology or really wherever you're targeting indications where there is an existing standard of care?
And the second question is on manufacturing. I know the Nord facility is obviously built for scale up, but just given the breadth of the pipeline, is there ample capacity, for example, to get to pivotal or large scale studies in all your disclosed programs? Or do you think ultimately you need to expand even more down the road? Thank you.
Thank you. Let me take the first question in terms of active comparative study. Clinical development remains artisanal. The truth is that it depends on the situation. I think in oncology, in large indications, there are instances where the signal is unquestionable there and you go on a single arm and everybody agrees that yes, you're bringing benefit to patients.
Traditionally, one expects at some point a randomized trial. I think to make sort of broad statements of what's always applicable is hard, certainly for a company that's so early in this stage. And I would further note that if you look across our pipeline, some of the indications we're targeting are extremely rare indications in which it's impossible to conduct a full randomized study as you would for more prevalent indication. So I don't think I can really give you a more satisfactory answer than that. In terms of our manufacturing capacity, let me ask Stephane to take that one.
Yes. Thanks, Tal. So regarding manufacturing, the thing that is very clear is that the vision and the mission of Norwood is to be a development site long term. Having said that, as you know, managing risk is really important to the team. And so what we have done as we designed and built Norwood from a utility standpoint, it can accommodate Phase 3 and launches.
It is not launched ready today for commercial, but we have roadmaps and timelines that have been developed by the team so that if we were to decide to get ready for Norwood for launches, we could do that. We have also, of course, a second plan that gives us full optionality, which is we have enabled a commercial contract manufacturing organization in the U. S, which is doing commercial product as we speak. They are acted as a backup for Norwood. And so as we get closer to launch and to running pivotal, we could decide to either rapidly enable Norwood for our 1st few launches or use the contract manufacturer.
In the long term, our goal will be to build a commercial plant, but for obvious reason of managing risk, we do not want to do that until we have our first product approved. And so we have a good path forward of how we manage the next phase of our growth dealing with pivotal and commercial.
Okay. Thanks.
Thank you. Our next question comes from the line of Ted Tenthoff of Piper Jaffray. Your line is open.
Great. Thank you very much for taking my questions. And congratulations on all the progress. My question has to do with hMPV PIV3 and congrats on that good Phase 1 data, really clean safety profile. What are some of the special considerations or how should we be thinking about this TOPLER study?
Obviously, safety is going to be paramount, but are there anything else we should be considering like when you dose or things like that, that maybe you learned sort of from the immunogenicity curves from the healthy? Thanks.
Thank you for that question. I think there are several relevant considerations here. The first is to note that the first exposure in the pediatric population will still be in seropositive. We have to make sure that because of the history, primarily of inactivated RSV back in the day, there is a theoretical concern of disease exacerbation. And so one always starts by evaluating safety in seropositive toddlers.
I think the nice thing for the Phase 1 or for the data is because we reached a plateau so soon, we have a wide margin of doses that we could test that should give us a read on safety and tolerability of this seropositive toddlers. I can't comment further because we're still in the design phases of this study. And obviously, we would have to sit down with the regulatory authority as well before we can commit to what that is.
Great. Excellent. Thank you very much.
Thank you. Our next question comes from the line of Hartaj Singh of Oppenheimer and Company. Your line is open.
Great. Thank you. Thanks for the questions. I just have a couple of questions, one general and one specific. The general question is, you've been having a lot of regulatory interactions now as you're having your programs going to Phase I and II.
You've got a lot of different, I'd call them orthogonal approaches ongoing interacting with different groups with the FDA. What do you get a sense that with different groups that there's a potential to accelerate some of the programs, oncology, for example, versus vaccines, etcetera? Do you get a sense that some groups are more amenable to an accelerated approach versus others? And what would those be? And then the more specific question is, just on the PCV, what percent of the patients with their resected melanoma with a high risk of recurrence actually get KEYTRUDA?
And then will you be selecting for patients that have sort of a better immune system status if that's possible? Thank you.
Thank you for those. I'm just jotting a note, so I don't forget the questions.
The let me
start with your general question on FDA. It is true that we are interacting across 3 very different disease areas. We've got healthy volunteers in the vaccines division. We've got oncology applications and obviously rare disease applications. We primarily interact with 2 groups at FDA.
It's either the division of vaccines or OTET under which falls both the cancer and rare disease indications. On the vaccine side, I think we're in a very fortunate position. Wellington Sun was the Director of that division for the past decade and is over and Strategy for and Strategy for Vaccines. So I think under his leadership, we have a good sense of what is the best way forward to balance the regulatory risk and the development risk, if you will. In terms of OTET and are some groups different than others at FDA.
I think to give FDA credit, their framework of understanding benefit risk is pretty systemically applied across. I think the hard reality is that we're talking about very different indications and very different assessments of safety and risk versus potential benefit. So of course, when you go into healthy kids with a vaccine, it's a very different bar of how you development versus going after rare diseases with huge unmet needs and no standard of care or oncology, which we're all familiar with. I think the totality of our indication of our interactions with FDA today, I think has been very positive, numerous pre IND meetings, discussions on changes in clinical design, patient population, CMC. I think we found a very active partner that has really helped us.
We're starting our first steps Europe. We've been to Europe both us and our partners in several countries, but I give FDA a lot of credit as providing really deep insight and help as we move forward. In terms of PCV and KEYTRUDA, I'm not sure what the actual commercial numbers are for KEYTRUDA, suffice to say that it's a recognized standard of care. They have a label in this indication. And I think it's hard to argue that KEYTRUDA is if not the best, one of the best checkpoint inhibitors in the space.
And so I think we're on very solid footing. Certainly, the investigators that I talked to out there who are treating these patients are all very familiar and very comfortable with using KEYTRUDA in this indication. Selecting for patients who are more immunocompetent, I wish I had a way to do that. I'm open to any ideas. I think it's hard to we as a scientific community have not really yet found a way that can parse out who is likely to respond and who isn't.
I think by going early or in the life of a patient with cancer, if you will, before they've been extensively treated after basically getting a surgical resection, I think gives us the best opportunity to immunize a patient whose immune system is as robust as it can be.
Great. Thank you so much for those really granular responses. Really appreciate it. Thank
you. Our next question comes from the line of Alan Carr of Needham. Your line is open.
Hi, thanks for taking my questions. You've obviously got a pretty sizable pipeline as it is, but you have talked about your ability to expand beyond that. I wonder if you can give us a sense of to what extent you expect it to grow this year and how you might disclose new programs as they move forward? And then also in terms of spend for 2019, you said the CapEx would go down. I'm wondering if you can give us a sense, is this something that's going to be substantially lower than 2017 levels even?
Thanks.
Thank you, Stefan. So I'll take the first question and obviously, Laurence will take the finance question. As we've said in the past, we don't disclose the important work that's happening in research as we go and as we build the business. What we will do is have a full quarterly calls or full different model events. We will share any new development candidate.
The team is working on all of our modalities to advance new development candidates. And when they'll be ready, we will communicate those to investors and analysts. Laurent?
Thanks, Alan. On our 2019 and the CapEx question, yes, we're not specifically guiding on CapEx, but what I can say is that when you look at what's driving CapEx down for this year, it's the fact that Norwood is complete and the investment in Norwood, which was substantial and well worth it was really bridges between 2017 2018. And so if you look at the total cash used to purchase property equipment in 2017, that was $58,000,000 And again, a big chunk of that $40 plus 1,000,000 was Norwood. So, I think that gives you a sense for where we're heading without the specificity of guidance here.
Great. Thanks for taking my questions. Okay.
Thank you. I'm showing no further questions at this time. I'd like to turn the conference back over to Stephane for any closing remarks.
Well, thank you very much everybody for joining us today and for your questions. We look forward to catching up with many of you in the coming weeks. At the latest, I hope to see you on our May 7 Science Day in Boston. Have a nice day. Thank you.
Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone have a great day.