Ep. 13 - Nuances of NASH, COVID Vaccines and Real-World Data

Ep. 13 - 06JUL2020
Simone Fishburn: Hello and welcome to BioCentury This Week. I am Simone Fishburn, Editor in Chief, and I'm joined this week by
[00:00:07] Steve Usdin: Steve Usdin, Washington Editor,
[00:00:09] Lauren Martz: Lauren Martz, Senior Editor. I head Translation and Clinical Development.
[00:00:13] Simone Fishburn: And we will soon be talking with Lauren and Steve about NASH, about COVID, vaccines and real-world data. But first I want to start with yet another busy week for biotech financing. I'm sure all of our listeners are aware that this has just been a gung-ho environment for financing and biotech.
[00:00:35] This last week was headlined by two Asian companies: SK Biopharmaceuticals [SK Biopharmaceuticals Co. Ltd.] , which raised nearly $800 million on the Korean Exchange, and Gan & Lee Pharmaceuticals [Gan & Lee Pharmaceuticals, (Shanghai:603087) ] , which gained the maximum allowed by the Shanghai Exchange in its first day of trading to bring its market cap to more than $5 billion. On Thursday and next on file to go public on NASDAQ -- aiming to raise up to a hundred million dollars -- two days after raising a hundred million dollars in a series D round. On top of that, two preclinical companies submitted S-1's on Thursday to list on NASDAQ: Nurix [Nurix Inc.] and Inozyme [Inozyme Pharma Inc.] , which filed to raise up to $100 million and $86.3 million, respectively.
[00:01:20] And, this is something that is interesting. There's really just been a spate of preclinical companies going public in particular in the last month or two. So, stay tuned to our analysis at biocentury.com for more on that. And of course you can find there more on the financings I just discussed.
[00:01:38] So let's go to NASH. Lauren, NASH is an incredibly complex disease. It is prevalent and there is a huge amount of biotech activity. But, progress really seems to go in fits and starts. So, what's the latest in NASH?
[00:01:55] Lauren Martz: So last week, I think there were some pretty big ups and downs. We saw that Intercept [Intercept Pharmaceuticals Inc., (NASDAQ:ICPT) ] did not get approval. That would have been potentially the first approved disease modifying therapy for NASH. And I think that's important because it brings up some questions about endpoints.
[00:02:11] Intercept, I guess, was under the impression that they only had to meet one of their two primary endpoints in the trial. And, these are endpoints that FDA and EMA have both been looking for and asking for. So it is resolution of NASH without making fibrosis worse and resolution of fibrosis without worsening NASH. And so in Intercept's case, they were able to hit the fibrosis endpoint and they thought that would be enough for an approval and it turned out that it wasn't. So, I think that raises questions for a lot of companies in this space.
[00:02:43] Although Intercept's compound didn't perform -- it's hard to compare across trials but it didn't perform as well as some of the others in the late stages of development have. And, a few days later last week we also saw that Akero [Akero Therapeutics Inc., (NASDAQ:AKRO) ] had some positive data, which looked pretty good on both of those endpoints. So, I think there's still some positives to see in the NASH field coming out of last week.
[00:03:03] Simone Fishburn: So, does that suggest that there was miscommunication between Intercept and FDA about what endpoints would be acceptable?
[00:03:12] Lauren Martz: It sounds like from Intercept's perspective, that might be the case -- I obviously don't know for sure. Intercept has also had some safety issues arise so I think it came down to a question of the benefits vs. the risks. And in this case, these two histological endpoints that I mentioned are a really surrogate endpoint so I think there's just still some uncertainty about what exactly FDA may be looking for.
[00:03:36] Simone Fishburn: So, staying with FDA for the moment but moving away from NASH and [going to] COVID. FDA came out with guidance for COVID vaccines. We've had some high marks for some pretty influential names: Luciana Borio, who was previously FDA chief scientist, and Mikael Dustin, Pfizer's head of R&D.
[00:03:56] So Steve, can you give us a rundown on what was in their guidance and what these senior figures liked about it?
[00:04:04] Steve Usdin: Well look, basically I think what they liked about it was what wasn't in it as much as what was in it. So, there's a concern that FDA would kind of bow to the popular and the political pressure to get vaccines authorized quickly by allowing vaccines onto the market and wide exposure to them based on surrogate data. And, the guidance makes it very clear that they're not going to do that.
[00:04:29] They've committed to requiring clinical data of safety and efficacy prior to authorization of a vaccine -- that's really a key thing. They set a benchmark for what the minimum level of efficacy should be at 50% --basically vaccine has to be 50% better than placebo. That's the bottom threshold for getting something approved.
[00:04:49] And, they've made it clear that Phase III trials are gonna have to be quite large. And in order to meet the tests that FDA has required, Pfizer [Pfizer Inc., (NYSE:PFE) ] and some other companies have said that they're looking at Phase III trials on the order of about 30,000 people, randomized to either placebo or the vaccine candidate.
[00:05:08] Simone Fishburn: So Steve, a couple of things there. First of all, 30,000... Given the shape of the curve -- which I think we can still call it a curve -- in the U.S., is that going to be the primary site for recruiting individuals?
[00:05:23] Steve Usdin: FDA certainly hasn't made any kind of requirement that the individuals who are in trials be in the United States. Some of the companies have said that they plan to conduct their trials primarily in the United States but none of them are talking about exclusively conducting their trials in the United States.
[00:05:42] Brazil has emerged as one of the big places outside the United States for trials. And, most of companies are collaborating closely with NIH's National Institute of Allergy and Infectious Diseases, which has clinical trial networks in South Africa, Australia and South America. I would anticipate that they're going to try to enroll patients in all of those locations because the key thing to determining whether a vaccine is effective quickly is going to be conducting the trials in places where there's a raging outbreak.
[00:06:17] Simone Fishburn: Right. And so I just want to stay there for one minute. 50%. Some thought it should be lower, some thought it should be higher. Do we know how they came up with 50%?
[00:06:26] Steve Usdin: I don't know how they came up with 50%, but I think that it's a reasonable number. I haven't heard anybody suggest that it's an unreasonable threshold. The hope of course is for a much higher level of efficacy. I think the other thing to keep in mind is that this is all being compressed so much that whatever efficacy numbers come out of the initial Phase III trial is really going to be an approximation.
[00:06:50] And, the important thing is going to be not only the overall efficacy number, but [to] try to get some kind of granularity on who is protected and who isn't protected. For other kinds of vaccines, for other diseases... it's common that for example, the elderly are less well-protected than younger people.
[00:07:10] That would be particularly problematic in the case of a COVID-19 vaccine, of course, because the elderly are at greater risk. But, if you knew that the elderly were less protected, you could take measures in response to that. For example, either by increasing doses that you might give to the elderly or by creating an emphasis on vaccinating younger people and trying to protect the elderly by creating herd immunity.
[00:07:32] Simone Fishburn: And one last question on this: does it change the timeline? Everybody wants to know when, right? That's been the first question and continuing top question throughout this pandemic: when will there be a vaccine or a treatment -- and in this case, it was talking about a vaccine. Does this guidance put a different time course on when a vaccine might be available?
[00:07:53] Steve Usdin: I don't think it does -- except like I said to begin with -- it rules out the kind of reckless scenario of authorizing a vaccine based on surrogate markers. So it rules out the idea that you'd get a vaccine extraordinarily quickly.
[00:08:09] Beyond that... No, it doesn't really tell us when we're going to get a vaccine. That's going to be completely dependent on two factors. First, the efficacy levels that the vaccine creates. And second, whether the vaccine is tested in places where there's a high enough incidence to get the number of cases that are going to be needed to conclude the studies.
[00:08:30] Paul Stoffels from J&J, in public testimony said that a small difference in the level of the incidents of COVID-19 and the places where the trials are being conducted could lead to really large differences... meaning maybe up to six month differences in when you would get the results.
[00:08:48] So, that's what's really going to determine when these trial readouts come and when authorizations could happen.
[00:08:55] Simone Fishburn: So Lauren, BioNTech [BioNTech SE, (NASDAQ:BNTX) ] and Pfizer actually started to give some data and their vaccine showed that it yielded the highest titers to date. But, that benchmark itself is still an open question. Can you tell us what we learned from BioNTech and Pfizer last week? And of course theirs is an mRNA vaccine.
[00:09:16] Lauren Martz: Yeah, so as you said, these are the highest antibody titers that we've seen. So, I guess what we've learned is that this is able to induce a high antibody response and this is looking like it's higher than the levels of neutralizing antibodies in donors of convalescent plasma. Those average, I think, a little less than a hundred and we're looking at levels up near 200 for this vaccine. So, like Steve said, this would be a surrogate for efficacy.
[00:09:42] We don't know how these antibody levels are going to translate to protection against the virus. And of course, when you're comparing that to a patient who has been infected, the antibodies aren't the only protection that those patients have. So, it's not actually clear how high these levels need to be from the vaccines in order to be protective in patients.
[00:10:01] But, this is a really good sign and much higher than the clinical data that we've seen so far. What the company's also say is that they have a T cell response as well. And one of the reasons they've gone with this RNA vaccine format is that it is able to induce a pretty strong T cell response. But, we're not actually going to know the levels of T cells until a separate Phase I/II trial reads out.
[00:10:24] And again, we don't know what those T cell levels will mean in terms of protection. And personally, I'm skeptical about how long a T cell response would last although I hear that some people think it might even be longer than antibody responses. But, I guess we'll see.
[00:10:39] Steve Usdin: I'd like to jump in with just something that I think hasn't gotten very much attention. There's a notion that this is a race and that there's a certain number of vaccines that are under development. Now, they're going to cross the finish line and that's going to be the end. I think that it's going to be iterative. I think we're going to have a first generation of vaccines and they're going to have a certain level of efficacy, certain level of safety, and they're going to have certain dosing parameters...
[00:11:02] And then, very quickly after that, based on what we learned from the first cohort, there's going to be a second generation and it's going to be the same companies probably. Companies that are gonna have the first vaccines authorized... they're going to learn a lot from that. And then, they're going to probably jump in very quickly with second generation vaccines.
[00:11:23] Simone Fishburn: I agree. And I think we're already seeing companies with their backup molecules or backup vaccines in the pipeline. And I think that you're right. I think what 2021 is going to look like -- I think we should say hopefully actually -- but what 2021 is going to look like is a sort of wave of vaccines and a wave of therapies and sort of second waves and third waves of those sort of superseding.
[00:11:48] So that, you know, dexamethazone may already be used or whatever, but hopefully will be superseded by things that work in more patients and are even better than dexamethazone. But I think you're right and I think that the idea of single one winner takes all is probably not what we're going to go with.
[00:12:08] I want to spend just a couple more minutes on real world data and diagnostics. I think one of the things that's so interesting about this pandemic is that it's brought to the front these things that are normally the poor relation of the biopharma industry -- vaccines and diagnostics.
[00:12:22] Steve, you talked to Amy Abernethy. And you know, we talked about how tests actually perform in the real world rather than data from in vitro studies, which show how they could perform under idealized conditions. So, just give us some of the key takeaways of Amy Abernethy -- who obviously is FDA's principal deputy commissioner and acting CIO -- of where her attention is focused right now.
[00:12:46] Steve Usdin: It was really interesting speaking with her. One of the things that she said is that she's spending most of her time right now on COVID-19 diagnostics because diagnostics are really fundamental to making progress in every area from public health to treatments to vaccines. If you don't have good diagnostics and if you don't have good understanding of the sensitivity and specificity of diagnostics, you really can't make progress in all those other areas.
[00:13:17] So, what FDA and the Reagan-Udall Foundation for FDA and Friends of Cancer Research have done is to create something they call the COVID-19 diagnostics evidence accelerator. Basically what it's trying to do is to make it possible to match up data about what tests and individuals receive -- either the PCR diagnostic or the serological antibody -- with the results. Which sounds simple, right? You want to know they got a test and you want to know what happened.
[00:13:49] Unfortunately, at least in the United States, that turns out to be phenomenally difficult because different organizations and different kinds of organizations have the information about the test results and about the outcomes. What Amy Abernathy calls it is trying match up different size pipes and this is an effort to try to match up those pipes so that there can be this kind of end to end understanding -- at least for a large cohort of what tests people received and what the results were.
[00:14:19] Simone Fishburn: Particularly cool about this was that those pipes aren't just for COVID. She said this is not intended to be a COVID only activity.
[00:14:28] Steve Usdin: No, she's trying to set up something that will persist after COVID that will create an ongoing ability to generate real world data about the performance of diagnostics and tests.
[00:14:42] Simone Fishburn: Well, thanks very much for that, Steve and Lauren. We will, of course, continue to follow diagnostics, vaccines, COVID, financing and everything else at biocentury.com.
[00:14:52] Coronavirus analysis is open access at biocentury.com/coronavirus and our podcasts are all available at biocentury.com as well as Apple, Stitcher, Google and Spotify. Thank you.