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Product Development

Moderna moves & Immunocore breaks through: a BioCentury podcast

Dec 1, 2020 | 2:46 AM GMT

After its latest readout positioned the company to seek FDA authorization of its COVID-19 vaccine, Moderna has begun to look ahead to unblinding the Phase III trial of mRNA-1273 so participants who received a placebo can be given the chance to be vaccinated. On the latest edition of the BioCentury This Week podcast, BioCentury’s editors discuss the risks and benefits of unblinding the COVE study as well as which COVID-19 vaccines will read out next and what the results are likely to reveal about the different modalities in development.

Then the editors turn to Immunocore, with Senior Editor Lauren Martz explaining how the company has become the first to solve one of the biggest challenges in immuno-oncology.

Washington Editor Steve Usdin recaps his discussion with Tal Zaks, CMO of Moderna Inc. (NASDAQ:MRNA), regarding the company’s latest data for mRNA-1273, which saw the mRNA vaccine prevent 94.1% of symptomatic and 100% of severe cases of COVID-19.

Usdin explains the real benefits Moderna gained via its participation in Operation Warp Speed, which surprisingly did not include an accelerated timeline for its vaccine.

He also details how the company is balancing what it sees as its ethical obligation to unblind the trial with its responsibility to provide FDA with the data it needs.

Executive Editor Selina Koch predicts Phase III readouts from COVID-19 vaccines will keep coming at a steady pace through early next year. She discusses the challenges of using viral vectors to deliver vaccine antigens and how four upcoming readouts could shed more light on the modality. Phase III findings are also on the way from the more conventional modalities of inactivated viruses and protein-based vaccines, she says. A roundup of approaching readouts can be viewed here.

Turning to cancer, Martz explains how last week’s Phase III data from Immunocore Ltd. marked a big step forward for the company and for the immune-oncology field, addressing the major hurdles of moving bispecifics into solid tumors and treating immunologically cold tumors with an immunotherapy.

The company, which is led by CEO Bahija Jallal, reported on Nov. 23 that its bispecific protein therapy tebentafusp had a survival benefit in uveal melanoma, an indication not well-served by checkpoint inhibitors. Tebentafusp combines an anti-CD3 antibody with a soluble TCR targeting GP100.

TARGETS
GP100 (SILV; PMEL17; PMEL) – Silver homolog

A transcript of the podcast follows.

[00:00:00] Jeff Cranmer: Moderna has once again impressed with Phase III data for its COVID-19 vaccine, and today the company will submit an application to FDA seeking Authorization for Emergency Use. Welcome to BioCentury this Week, I'm Jeff Cranmer, Executive Editor of BioCentury, and I'm joined by

[00:00:25] Lauren Martz: Lauren Martz, I head our Translation and Clinical Development Coverage,

[00:00:28] Selina Koch: Selina Koch, Executive Editor,

[00:00:31] Steve Usdin: Steve Usdin, Washington Editor,

[00:00:33] Jeff Cranmer: First up word of a benefit from our friends at Kendall Square Orchestra who kindly do our intro and outro music. They will be presenting Symphony for Science, an online event with music and words for Next Step supporting people with rare diseases, cancers, and HIV. That will be December 17th, at 8 o'clock Eastern; you can register for this great benefit at www.symphonyforscience.org

[00:01:05] Today, we'll dig into the latest from Moderna, and check in on timelines for other vaccines. We'll also turn to Washington to check in on what HHS Secretary, Azar has been up to. And then Lauren will explain how Immunocore has become the first company to solve one of the biggest challenges in immuno-oncology.

[00:01:27] Steve, you caught up with Moderna's CMO, Tal Zaks to discuss the data. Beyond the data itself, one thing that really caught my eye in your first take story on the news is that Zaks told you that Moderna's COVID-19 vaccine development was much better as a result of the company's collaboration with Operation Warp Speed (OWS), but it was not faster. And that is the opposite of what I thought Operation Warp Speed (OWS) was all about.

[00:02:00] Can you break that down for us?

[00:02:01] Steve Usdin: Yeah, so I spoke with Tal Zaks, Moderna's Chief Medical Officer (CMO) last night. It was 321 days since the company produced the first dose of its mRNA vaccine -- that's amazingly fast. We were discussing the Phase III efficacy data that they're using to apply for Emergency Use Authorization (EUA) in the United States, and for similar kinds of authorizations in Europe, and around the world. When I asked him to discuss how much faster the development of the company's vaccine was as a result of Operation Warp Speed (OWS), he said it didn't speed it up by a single day. And he pointed to Pfizer, which didn't get any assistance from Operation Warp Speed (OWS) on its R&D and it had a similar timeline to Moderna's. Instead he said the Warp Speed made the development program much better, especially by ensuring that the vaccine was tested in a trial that enrolled a population with demographics that matches the U.S. population, and that was enriched for individuals with risk factors for severe COVID. He also said that the financial backing from Operational Warp Speed (OWS) was really important for giving reassurance to Moderna's investors because the development program was obviously quite expensive.

[00:03:15] Jeff Cranmer: Let's turn to the data itself.

[00:03:17] Selina, I know you've been tracking a lot of these vaccines, anything stand out to you in particular, anything that you were looking to see from this latest batch?

[00:03:27] Selina Koch: Well it was just the top-line data, I think Steve already hit on the highlights which is that it was effective in quite a broad population... a diverse population of individuals, including people over age 65, people of minorities, people with co-morbidities. The company as far as I could see it didn't break down the efficacy rates by all of those different measures. But they did say that the findings were consistent across them, so that's encouraging.

[00:03:54] Steve Usdin: The other thing that they report is that a 100% of the severe cases of COVID were in the placebo arm, and that one person died from the placebo arm, which is sobering, it makes this whole thing real. And I think it also goes a long way to explaining another thing that Tal Zaks told me which is that he personally and Moderna as a company feel a commitment to people in the trial to unblind it as soon as they get Emergency Use Authorization. So that those who were in the placebo arm can have the opportunity to get the active vaccine. Sometimes we talk about these things abstract and people say "Oh, you would be better to keep the trial going on in a blinded fashion for the whole, time period, 6 months or, a year" or something like that. But the fact that 30 people have already gotten severe disease who were in the placebo arm and one person has died brings it home. And you think, yeah... if I were in that trial and I'd taken my chances, and I'd gotten the placebo I would feel that the right thing to do would be the offer me the active vaccine.

[00:05:02] Jeff Cranmer: Is FDA and NIH on board with unblinding at that point, or do they want the companies to keep the trials blinded a bit longer?

[00:05:12] Steve Usdin: What Tal Zaks told me is that they're going to coordinate this with FDA, and they're going to ensure that FDA gets the data that it needs. The advisory committee that's considering the vaccines made a point at their last meeting of encouraging the companies to keep the trials blinded as long as possible. There does seem to be a tension between what the advisory committee is asking and what the companies -- because Pfizer's made similar comments feel that they're able to do on an ethical basis.

[00:05:46] Selina Koch: What's the biggest risk with the unblinding, what's to be lost, cause you can still measure safety of the vaccine over time after unblinding?

[00:05:53] Steve Usdin: There's a sense that this data, the safety and the efficacy data won't be as reliable from an unblinded trial. What Tal Zaks told me is that look there's 94.1% efficacy in the arm that received treatment, and that if there's a loss of protection, or if there's what we he called a breakthrough of disease among people who were vaccinated that will be obvious regardless of blinding especially for the severe cases. So his contention is that it'll still be possible to obtain valuable information going forward even after the trial is unblinded.

[00:06:32] Jeff Cranmer: Now next up is the advisory committee that you mentioned is expected to meet to review the application on December 17th. I believe they are reviewing the BioNTech and Pfizer vaccine December 10th.

[00:06:50] Steve Usdin: That's correct.

[00:06:50] Jeff Cranmer: That's incredibly fast, but I've got a wonder given the state of things why aren't they meeting tomorrow, why aren't they meeting this week?

[00:07:00] Steve Usdin: I think that FDA has to review the data. You remember, FDA is different from regulators in other countries, FDA goes through the raw data and analyzes it themselves. In other countries regulators in Europe, and other countries regulators take the summary data that the companies present and they make their regulatory decisions based on that. It's got to take some time for FDA to go through the data and perform their own analysis of it they can't do that overnight.

[00:07:29] Jeff Cranmer: Alright, and this is just one of many vaccines that is starting to read out.

[00:07:34] Selina as I said, you've been tracking this. Which COVID vaccines will we see data from next, and what are the results likely to tell us about the different modalities in development?

[00:07:46] Selina Koch: Yeah, we've had a lot of Phase III data to digest over the last three, four weeks from COVID vaccines. And so I just got curious last week to see, you know, is there going to be a lull now or is it going to keep on rolling with these Phase III results? So we went into BioCentury's COVID-19 Resource Center in the portal where we track these things, and look for all the publicly available information from the vaccines in there about Phase III trials, and basically what we learned was the pace of readouts is probably only going to increase if anything. So what we're going to see through the end of this year, and early next year is going to tell us more about the different technologies in development. So we're going to see more data from viral vectored vaccines, which I think is going to be really important because the first readout from AstraZeneca was not nearly as clear or robust as the results we've seen from Pfizer and Moderna. Johnson & Johnson has a adenovirus based vaccine that's going to read out probably the end of this year, or early next year. And CanSino, a Chinese biotech, also has an adenovirus vectored vaccine that's going to read out likely very soon. We'll see more data from the Russian vaccine, which I'm told is pronounced "Spoot-nik," not Sputnik. And hopefully we'll see some more data from AstraZeneca as well.

[00:09:07] With the viral vector vaccines they're also not a tried and true technology like mRNA. And one of the big questions about them, the risks that people are concerned about, our immunity is immunity against the vectors themselves. So for the ones that are based on human adenoviruses, you have this possibility of pre-existing immunity against the vector, because the person has seen the virus the adenovirus at some point in their life. You have this other problem of the vaccination itself inducing immunity against the vector so that when you go to give a boost shot its not as effective cause the immune system recognizes the vector and attacks it before the antigen has time to do what it needs to do. There's those two issues and we're just going to need to see more data to see what's the best way to use these vectors, and how useful ultimately will they be. So Johnson & Johnson's testing right now -- the data we're going to see first from them was going to be from a single dose of an adenovirus vaccine. With the first read out they're not even trying to get efficacy out of a second dose, they're just giving one. But they have started another trial where they're testing two, and we'll get the data from that a little later next year.

[00:10:24] Steve Usdin: The other things that I would bring up is the subunit protein vaccine from Novavax.

[00:10:30] Selina Koch: Right.

[00:10:30] Steve Usdin: Which is in Phase III trials in the U.K. in Phase II trials in HIV patients in South Africa, and is going to be starting trials in the U.S. in a few weeks.

[00:10:41] Selina Koch: Their U.K. trial is likely to read out sooner, like early next year.

[00:10:46] Steve Usdin: And the question will be whether they'll be able to file in the United States, or the U.K., or elsewhere based on that data. When I spoke with them a few weeks ago, they suggested that was a possibility.

[00:10:58] Selina Koch: And then we're going to see the first data from inactivated virus vaccines, that's one of the oldest, most tested technologies out there. Two Chinese biotechs should have Phase III data at any time really -- Sinovac, and Sinopharm both have inactivated virus vaccines. The big difference there between those and the all the other ones, is all the other ones focus on one protein from the coronavirus, the spike protein, or even a piece of the spike protein. Whereas these you have a full complement of things on the surface of the virus, so in theory you could have a broader immune response but we will see.

[00:11:37] Steve Usdin: The other thing that I came away from my discussion with Tal Zaks last night that was interesting, was his prediction that NIH and FDA will certify correlates of protection for COVID-19 vaccines in the second half of 2021, which is going to be really important for all of these other vaccines that are being developed because it's not going to be possible to do really large placebo controlled trials, after there are multiple vaccines on the market. Correlates of protection will make it possible to continue to develop vaccines in the absence of those large placebo controlled trials.

[00:12:14] Jeff Cranmer: Now one of the key players in the Trump Administration's response to the pandemic has been HHS Secretary Alex Azar; what has he been doing lately in terms of the government's response Steve?

[00:12:30] Steve Usdin: I wrote a couple of stories recently, and I'm working on a bigger story now which we'll be done today, or tomorrow about what I call Azar throwing sand into the gears at FDA, and other public health agencies on his way out the door. There are two particular things that I'm focusing on, one is a rule that he's proposed that would make all HHS regulations automatically sunset 10 years after they went into effect, and create a very onerous process for the agencies that created those regulations to seek to have them renewed. It's something that people at FDA have told me is that would really gum up their operations. And then of course a regulated industry is really opposed to this because it would create a great deal of uncertainty about the durability of regulations. And the second thing, its not an Azar thing its something that's happening from OMB Director [Russell] Vought and others in the White House, which is to create a new portion of the civil service, which will not have the protections against political interference and job protection that is traditionally available to civil servants. Large numbers of people potentially at FDA and CDC could fall into this, what they're calling category F. There's a lot of consternation in government about this, and there's also a great deal of expectation that the Biden administration would reverse it. There's also efforts to have Congress cut off the funding so that it won't even be possible for the Trump Administration to put it into effect in its remaining time in office.

[00:14:11] Jeff Cranmer: So what's the latest word on the mean streets of Washington as to who the Biden administration will select as HHS secretary?

[00:14:21] Steve Usdin: They've been pretty tight-lipped about it, and I'm really hesitant to say anything. It's you know what Lao Tzu said: it's the people who know don't talk, and the people who talk don't know.

[00:14:31] Jeff Cranmer: I know you've got your ear to the ground and once you do have some concrete information you'll be reporting about it in BioCentury.

[00:14:38] Let's move away from the pandemic for once... let's turn to Immunocore, which last week reported positive pivotal data in a subset of melanoma. Lauren, you are following this story what do the data mean for the company and for solid tumor immunotherapy?

[00:14:57] Lauren Martz: I think for anyone who has been following Immunocore's story knows that this is a really big deal. The company has seen a lot of management turnover lately, and has been at this for a long time so it's great to see this positive Phase III data. But I think even more importantly this is one of the biggest challenges that cancer immunotherapy has been facing is turning these T cell therapies and bispecifics that have worked so well in liquid tumors into a solid tumor therapy. The modality that we're looking at here is a bispecific protein, unlike most of the bispecifics that are using an antibody to target a tumor antigen, this is using a soluble T cell receptor. So this is opening up a lot of different possibilities for the types of targets that you can go after which makes it potentially easier to address some solid tumors.

[00:15:54] Selina Koch: Well, it opens up target space, yeah? Because the TCR binds to things on HLA proteins that were intracellular targets, so you're not limited to the world of surface proteins.

[00:16:05] Lauren Martz: Exactly yeah, one of the biggest challenges in translating these to solid tumors is that if you're using an antibody it has to be a cell surface protein, and it's very hard to find cell surface proteins that are very specific for cancer cells. So in something like a B cell malignancy, it's okay if the targets expressed on B cells, because you can knock out all the B cells and they'll come back, but that's not okay for solid tumors -- it's going to cause a problem in a lot of different tissues.

[00:16:35] Selina Koch: So it's a soluble TCR on one part of it and there's another part?

[00:16:40] Lauren Martz: These are T cell engaging peptides, so the other part also engages the CD3 like any other bispecific.

[00:16:46] Selina Koch: So, was it part antibody part TCR?

[00:16:50] Lauren Martz: I believe so.

[00:16:51] Jeff Cranmer: Now one thing that's interesting to note about Immunocore for those who haven't been following it closely, as Lauren said they have had some management shakeup, but they did bring in early last year Bahija Jallal who's the longtime MedImmune and AstraZeneca president, R&D leader. She came on board in January 2019, after about 11 years in the AstraZeneca and MedImmune universe, so they definitely have steady hands at the wheel there. What are you looking for next from this company, Lauren?

[00:17:31] Lauren Martz: I think we're waiting to see what happens with the regulatory filing. These data were really strong in uveal melanoma. And in addition to being a huge win for the company, and for the modality, this is a big deal for those patients. These are incredibly cold tumors, and I don't think there's been a new therapy approved in 40 years or something. So the fact that these are cold tumors is also really impressive for an immunotherapy because that's been another big challenge is trying to find ways to get the immune cells into tumors that have sort of blocked them off. It's a suggestion that these TCR bispecifics could potentially be one modality to address solid tumors, and to address cold tumors. Win for the patients, and win for the company, I think.

[00:18:16] Jeff Cranmer: Thanks for the update there Lauren, and Steve, and Selina of course. That's all we have time for this week.

[00:18:23] I'd just like to remind everyone that BioCentury and BayHelix recently wrapped up the live portion of our 7th China Healthcare Summit. It's the first time we did it virtually which means there's still time to register. All sessions will be available for at least another week and you can register: www.biocenturychinasummit.com.

[00:18:48] All of our podcasts are available on our website, Spotify, Stitcher, Apple, and Google.

[00:18:54] And music for all of our podcasts is provided by Kendall Square Orchestra which connects science and technology professionals and other members of the greater Boston community to collaborate, innovate, and inspire through music while supporting causes related to healthcare and education, such as their upcoming Symphony for Science, on December 17th.

Sponsorship opportunities: Sponsorship and Underwriting packages are available for webinars, podcasts and surveys. For more information, please contact Eric Pierce and Josh Berlin at conferences@biocentury.com.

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