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Vaccines march forward & CAR Ts move earlier: a BioCentury podcast 

Dec 15, 2020 | 1:40 AM GMT

On the latest edition of the BioCentury this Week podcast, BioCentury editors discuss the latest advances and setbacks among COVID-19 vaccines in the wake of FDA’s emergency use authorization on Friday for Pfizer and BioNTech’s mRNA vaccine, as well as the market access barriers facing CAR T therapies as they continue to move into earlier treatment settings. 

Washington Editor Steve Usdin says FDA’s advisory committee meeting to discuss BNT162b2 from Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) ahead of the EUA was a missed opportunity since committee members were not given a chance to explain their votes. While 17 members voted that the vaccine’s benefits outweighed its risks for individuals 16 years of age and older, four voted against it and one abstained. He expects more active discussion at the Dec. 17 advisory committee meeting on mRNA-1273 from Moderna Inc. (NASDAQ:MRNA).

“It’s going to be hard for them to fill the time up again with canned presentations about the epidemiology of COVID or the distribution plans because they had that last week,” says Usdin. “There’s also I think more data about the Moderna trial to discuss because they did a better job of enrolling a more diverse population, so there’s more to say about the efficacy and safety spread across different groups.” 

Editor-in-Chief C. Simone Fishburn notes that in conversations with industry KOLs, the consensus has been that the rapid advancement of both mRNA vaccine frontrunners “is not luck. This is mRNA and it’s that good.” 

“Obviously there’s always an element of luck in execution and so on, but they really said [it’s] a big vote of confidence in that actual modality,” says Fishburn.

Vaccines coming up behind the Pfizer-BioNTech and Moderna ones use more established modalities, but have also faced more setbacks. Last week, partners Sanofi (Euronext:SAN; NASDAQ:SNY) and GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) said regulatory submissions for its protein-based vaccine would be delayed by about six months after Phase I/II data showed it lacked efficacy in older adults; and mixed Phase III data for the adenovirus-based AZD1222 from AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and the University of Oxford have raised questions about the levels of protection it could provide. 

One much-anticipated readout will deliver Phase III data for the single-dose version of JNJ-78436735 from Johnson & Johnson (NYSE:JNJ). Operation Warp Speed’s scientific adviser Moncef Slaoui has said the trial for the adenovirus vector vaccine could be completed by January and if successful, receive an EUA as early as February

Turning to CAR Ts, Senior Editor Lauren Martz says market access barriers for CAR Ts haven’t stopped companies from pressing on into earlier lines of therapy, with the Kite Pharma Inc. unit of Gilead Sciences Inc. (NASDAQ:GILD) presenting the first clinical evidence of CAR T efficacy in the first-line setting earlier this month. 

While moving from later to earlier settings is standard practice for cancer therapies, CAR T agents come with extra complications, including high costs, complex delivery and manufacturing and safety issues including cytokine release syndrome and neurotoxicity.

Martz says safety may not be as big of an issue in earlier line settings, though the data have yet to bear out. “You may not see the same level of toxicity that you see in the patients who are more sick, because the more cancer cells and the more rapidly they’re dividing, the greater chance that you’re going to have these CAR T cells causing these types of toxicities.” 

To make the case for reimbursement, Martz thinks it will come down to a combination of response rate and how the cost of the CAR T and its associated delivery costs compare with a patient receiving several other therapies first. 

A transcript of the episode follows. 

[00:00:00] Virginia Li: Welcome to BioCentury this Week, I'm Virginia Li, BioCentury Associate Editor, and today I am joined by

[00:00:07] Simone Fishburn: Simone Fishburn, Editor in Chief,

[00:00:09] Steve Usdin: That should be Dr. Fishburn, and it's Steve Usdin, Washington Editor,

[00:00:14] Lauren Martz: Lauren Martz, I head Translation and Clinical Development Coverage,

[00:00:19] Virginia Li: Before we get started I'd like to give a shout out to our friends at Kendall Square Orchestra they will be presenting Symphony for Science and online event with music and words for next step supporting people with rare diseases, cancer, and HIV. The event is this Thursday, December 17th, at 8:00 PM Eastern time, and you can register at symphonyforscience.org. Now today we will be speaking with Lauren about CAR T therapies that are moving into earlier lines of treatment despite the fact that companies and payers are still working out some of the market access barriers for the modality.

[00:00:53] But first I'd like to turn to Steve to discuss last week's advisory committee meeting on Pfizer and BioNtech's COVID vaccine and the FDA's subsequent authorization of that vaccine on Friday. Steve, let's start with the meeting: what questions did the committee address, and what questions are still left open?

[00:01:10] Steve Usdin: To me it isn't really so much an issue of questions, it's an issue that the meeting was just a massive missed opportunity. Sure they voted on the question of whether there's enough evidence to support Emergency Use Authorization (EUA) of the Pfizer-BioNTech vaccine and they voted 17 to 4 with one abstention that it should be. But reporters and members of the public who tuned into this adcomm, haven't watched adcomms in the past misunderstand their purpose they focus on the vote as if it's an election, or a sporting event, or something like that. But really what's important about adcomms is the discussion and that's what didn't happen at this meeting. Most of the meeting was taken up with canned presentations of data that the committee should have read in advance things that were in their briefing books, and things that were available to the public and then when it came time to discussion it was very brief. The key thing is after everyone voted, the normal procedure in advisory committees is for each participant to explain why they voted the way that they did. That's really important they didn't do that at this adcomm they just cut it off then and missed a big opportunity. They missed the opportunity for the people who voted in favor of it to go on the record of saying why they believe that there was a rigorous review, why they believe that this is safe and effective. And they missed an opportunity for the people who voted against it to say why they did. We're left were left guessing... and that really isn't a good situation.

[00:02:42] Simone Fishburn: So Steve, what are you gonna expect this week? Do you think they will have a better run of a meeting this week?

[00:02:49] Steve Usdin: I expect so, I think that they probably heard the criticism hopefully from me, and from others. And it's going to be hard for them to fill the time up again with canned presentations about the epidemiology of COVID, or the distribution plans because they had that last week, so I would hope that there will be more discussion. There's also I think more data about the Moderna trial to discuss because they did a better job of rolling a more diverse population, so there's more to say about the efficacy and safety spread across different groups.

[00:03:25] Virginia Li: Now that the vaccine has been authorized the attention will now shift to Operation Warp Speed's procurement and deployment strategies. How has that process been going and what should we be expecting there?

[00:03:37] Steve Usdin: Oh a huge surprise... there's politics, there's controversy, people don't think that it's being done quite right, this is going to be a point of contention for months until there's a lot of vaccine available. One of the things that I've written about is a dispute which has been mis-characterized to some extent over how they should deploy the Pfizer vaccine. So it's a two dose vaccine and what Operation Warp Speed (OWS) is doing is they're deploying half of the doses actually less than half of the doses, they're keeping someone reserve, less than half of the doses initially with the idea that then they have to have the second dose on hand that they can give in three weeks.

[00:04:22] There's some people who have criticized this. Former FDA commissioner, and Pfizer board member, Scott Gottlieb has criticized it. He's criticized it because he believes that there's very little chance that Pfizer won't have the vaccine on hand to give the second dose. In fact they already have most of it in the production process. So he thinks that what should happen is they should just get as much out there as quickly as possible, especially because there's good data showing that there's protection that happens after the first dose you don't have to wait until the second dose. So he wants to get as much of it out there and start helping people as quickly as possible. Unfortunately this has been misinterpreted by some people, the Governor of Florida DeSantis made statements over the weekend saying that he thinks that people should only get one dose and that you can double the amount that people get by doing that. That's not what what Gottlieb had been advocating and it's not what anybody responsible would advocate based on the data that's out there.

[00:05:22] Simone Fishburn: I think another thing that's really gonna make this probably even worse is that we now know that some of the other vaccines actually aren't on track and so it's going to be even longer. One example is the GSK and Sanofi vaccine which is a I think they were hoping to have data by the middle of next year and that's been put back to the end of next year. So we're going to sort of be relying at least in the foreseeable future for the mRNA vaccines and they need ramping up right in terms of production to get them really distributed broadly. I think, Steve tell me, I think a lot of people think AstraZenneca vaccine is going to get approved but we've also seen problems there.

[00:06:05] Steve Usdin: I think with the AstraZeneca-Oxford vaccine that it's going to be authorized in Europe, in the U.K., widely in developing countries I don't think that it will be authorized quickly in the United States. And it's a real contrast there between really the excellence of the execution on the part of Pfizer and BioNTech, and Moderna. AstraZeneca which has fallen short and it's fallen short on the really the key area I think that the most the second most important thing in drug development, the first one of course is getting drugs or vaccines that are effective, but the second most important thing is proving that science, it's a pursuit of the truth. And they have not done a very good job of demonstrating its safety and effectiveness in a robust way and that's that's really going to be a problem.

[00:06:57] The other thing I'd say is that a lot of people are going to be looking to the Janssen, the Johnson & Johnson, vaccine which is supposed to be a one-shot vaccine data for that could be coming out in January. That's going to be really important, its going to be important for the world, because they're planning on ramping up huge volume and they reserved very, large volumes of it for the developing world. It'll also be important for the United States because it would top off the number of doses that are available. We've got about a hundred million from Pfizer, we might have eventually as many as 200 million from Moderna but that's gonna take some time. If you have the J&J vaccine coming in February that would really accelerate the rate of vaccination in the United States. But I think it also be much more important for the rest of the world, especially since it's a single dose vaccination if it works.

[00:07:49] Simone Fishburn: Yeah, and I just want to make one more point about this because I do think that BioNTech Pfizer study was done very well, and Moderna certainly executed, but we can see that lots of other big companies or several other big companies aren't. So GSK and Sanofi ran into what is effectively a formulation problem, each of the three of these have got different issues. And AstraZeneca's was, well, I guess it was problems in the way the clinical trials were executed, they had some manufacturing issues, and some dosing issues. And now we've also got the University of Queensland in Australia with CSL and their's is really a drug design problem where they used a portion of HIV innocuous portion of that virus to construct -- I think it was to construct the antigen but in all events it's created cross-reactivity with HIV testing, which means I guess they have to go back to the drawing board on that one. It's not simple to make these things but certainly some of the problems could have been avoided. Although I should just say on the other hand I was speaking to a couple of industry leaders last week and asking them like how lucky did we get with the mRNA ones Their answer to me was this is not luck, this is mRNA, it's that good. This is thanks to that modality you know obviously there's always an element of luck in execution and so on, they really said a big vote of confidence in that actual modality.

[00:09:13] Steve Usdin: And we're damn lucky to have it, because none of the tried and true modalities for vaccines have come through with the kind of speed and efficacy that mRNA has. The other one to mention I think is the Novavax vaccine which is a subunit protein vaccine that's adjuvanted, people have a lot of confidence in the vaccine. But they've also run into some manufacturing glitches, and it isn't completely clear that how quickly they're going to be able to overcome that, and how quickly they're going to be able to actually ramp up production if in fact their trials are successful.

[00:09:47] Virginia Li: Well, wait, we will continue to cover all of that data as they come in. I'd like to turn over to Lauren. Now who wrote a story last week on how car T developers are moving into first and second line settings for cancer. Lauren, you mentioned in your story that developing cancer therapies first and late line settings, and then moving them earlier is standard practice given that risk tolerance is higher in patients with fewer therapeutic options. And we're seeing that with CAR Ts now. So what makes that process different and more difficult for car T therapies.

[00:10:19] Lauren Martz: CAR Ts have had safety issues... I mean any cancer drug has safety issues but the cytokine release syndrome, and the neuro toxicity have been big issues with these therapies in the late line settings. And they also come with really high costs, and really complex delivery and manufacturing. I think those are two things that some of the standard modalities don't necessarily face to that extent when you're thinking about moving them forward into earlier line setting. So if you have a patient who hasn't been treated with many therapies before, the fact that you could have these dangerous side effects could be a bigger issue. When I spoke with people about the safety issues for moving earlier the thought is that you may not see the same level of toxicity that you see in the patients who are more sick, because the more cancer cells and the more rapidly they're dividing the greater chance that you're going to have these CAR T cells causing these types of toxicities. We don't necessarily have that data yet showing that safety is not going to be as big of an issue in patients who aren't as sick as it is in the patients who've been treated with 4, or 5... 6 other therapies before this point. What hasn't necessarily been sorted out as well yet either is the access issue. So there has been progress on that but it's different getting a therapy to patients who have no other options getting that paid for than it necessarily is if there are 10 other therapies that a patient could try.

[00:11:49] Steve Usdin: One of the things that strikes me about CAR T therapies that's also different from other therapies. I interviewed Steve Rosenberg at NCI years ago, who was the father of all of this technology and one of the things he pointed out to me that differentiates it is that it seems to be effective regardless of the stage of disease. Even people with cancer that was quite far advanced respond well to CAR T therapies. It's not like other therapies where, what he was saying at that time anyway, where "the sooner that you get to people the better they are" necessarily. Obviously nobody wants to live with cancer a minute longer than they have to, but I thought that was an interesting observation, I don't know if it's held up over the years this was several years ago and he told me that.

[00:12:34] Lauren Martz: Well I think we're just starting to see that because we saw the first data from a first line setting at ASH this year so I don't think that too many patients have been treated who aren't that advanced in their disease at this point it seems to be holding up. What we're also seeing is the long-term durability data come up which I think is really interesting, because that's one of the most important things when you're treating cancer. And we've got four year data now showing that these CAR T's in patients who are responding they seem to keep responding. That kind of makes the case for moving it earlier too I think.

[00:13:09] Simone Fishburn: That's interesting cause I was speaking to a pharma company recently about deals in oncology -- and one of the things that we've been thinking about and observing is that for deal-making in the inflection point or the value creation point is often thought of as the sort of Phase II data traditionally and in some modalities like CAR T cell therapies, maybe gene therapies that's moving earlier so with Phase I you start to get some level of efficacy. They said the big sort of caveat to that is that you don't have durability data with Phase I. You know I think if the genre if the whole class is starting to actually settle the concern of durability then that might also change people's thinking in terms of the valuation of a therapy or proof of concept when does that come and drug development. Lauren, I also wanted to ask you how this jives for the other thing you've been reporting which is that bispecific antibodies are starting to upstage or as we say in the U.K. where I am right now "pipped to the post" cell therapies. And so if you've got people first-line, second-line do you think that bispecifics are just going to shove out CAR Ts now, would you maybe you can just give us your overview on that?

[00:14:28] Lauren Martz: When you think about these earlier line settings the difference between a CAR T and a bispecific is that in general the CAR Ts have been a little bit more effective you're going to get slightly higher response rates in these. But do you go into these patients with a bispecific that also has a really good chance of working, or do you go right to the CAR T. So I don't know how payers are going to necessarily respond, I don't know how physicians are going to respond, but it makes sense to me to go for a bispecific first. This is a modality that we know how to manufacture, you can do it at a cost that's a lot less than a CAR T you don't have to design a therapy that's specific for each patient which is what you still have to do with these autologous CAR T's. It seems like every company has a bispecific now it's becoming a very standard modality.

[00:15:16] Virginia Li: So Lauren is as car T developers are moving into earlier settings. What indications are they starting with and how do those data looks so far?

[00:15:25] Lauren Martz: It sounds like the general strategy is not to just go for every newly diagnosed patient. It makes sense that these companies are going for the patients who are at a high risk of not responding to the standard of care in the first, and second-line. The companies that are most advanced with CAR Ts all seem to be taking that strategy they're going for the diffuse B cell lymphoma with the CD19 CAR Ts in the patients who are high risk. In the second line setting a lot of these companies are looking to put their CD19 CAR Ts head to head against STEM cell transplant. We're also seeing I think there's one BCMA CAR T that's also looking earlier, but the trend is definitely see how this works in the patients who don't have other options first and then go from there.

[00:16:18] Virginia Li: And what do these companies need to show in the first and second line setting to make the case for better reimbursement, given that market access issues? Still an issue today,

[00:16:27] Lauren Martz: If you're looking at the patients who are unlikely to respond to better therapies I guess it's just going to come down to how the response rates look, and this is about the budget impact to the payers. And that's not just that's not just response rates that's how does the cost of the CAR T and all the associated costs of delivering that compare with the cost of you know a patient getting all of these other therapies first.

[00:16:56] All right. Thanks Lauren. That is all we have time for today.

[00:17:01] This is our final episode of 2020. So we hope you have a wonderful holiday and we'll be back in the new year. All of the podcasts are available at our website, Spotify, Stitcher, Apple, and Google 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.

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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