Pfizer & Biogen: The good, the bAD and what’s next

Editor in Chief Simone Fishburn discusses the Biden team’s newly named coronavirus task force, which she says will likely serve as the incoming administration’s coronavirus task force come Jan. 20. 

BioCentury Executive Editor Selina Koch breaks down why FDA’s advisers came out almost unanimously against approval for aducanumab, an Alzheimer’s candidate from Biogen Inc. (NASDAQ:BIIB), when the agency’s own reviewers came out in favor of the therapy. She also discusses what a potential additional trial of the therapy might look like.

A transcript of the episode follows.

[00:00:00] Jeff Cranmer: Welcome to BioCentury this Week I'm Jeff Cranmer, Executive Editor of BioCentury, and I'm joined by

[00:00:11] Simone Fishburn: Simone Fishburn, Editor in Chief,

[00:00:14] Selina Koch: Selina Koch, Executive Editor,

[00:00:16] Karen Tkach Tuzman: I'm Karen Tkach Tuzman, Associate Editor,

[00:00:19] Jeff Cranmer: The week is off to a fast start, Pfizer and partner BioNTech have released very promising interim data for their COVID-19 vaccine. President elect Joe Biden has unveiled a COVID task force that includes former FDA commissioner David Kessler, and BARDA whistleblower Rick Bright. And on any other week our top story that we'd be talking about is the roller coaster week that Biogen had as its Alzheimer's therapy aducanumab went up before the FDA. Quite a surprising turn of events with that - FDA and Biogen's viewpoints made from those of the FDA panel experts as wildly as those characters and Kurosawa’s Rashomon.

[00:01:14] But first, we kicked off our 7th China Healthcare Summit last night, which we are putting on in collaboration with our friends at BayHelix. It's the first time we've done the event virtually, which means there's still time to register, you don't have to get on a plane to Shanghai this year. All sessions will be available for 30 days after the event, and you can register at www.biocenturychinasummit.com.

[00:01:47] There's still time to set up virtual one-on-one meetings this week with top executives and investors from China. That means there's still time to register and get the McKinsey China Summit Reports on opportunities and challenges in China's biotech and medtech markets. This is a global event and you can meet and learn from China biotech, C-suite executives and investors. We are also expecting record attendance from Korean biotech executives and investors. So sign on up!

[00:02:27] Let's dig into this Pfizer data, Karen I know you've been looking at it, what are the key takeaways from this news?

[00:02:34] Karen Tkach Tuzman: Well first of all what is the news? Out of about 39,000 participants that they've dosed that could be evaluated, they have reported that they have 94 cases, and from that they were able to conclude that the vaccine was more than 90% effective, as of interim data. They didn't give us the exact number of cases in the placebo group versus treatment group. But it suggests that there may be nine or fewer cases that cropped up in the treatment group, and with the vast majority happening in the placebo group. Which is very encouraging news for a number of reasons - it suggests that this virus is in fact potentially addressable by a vaccine; it's good proof of concept for the target, which is the spike protein that many others are going after as well; promising proof of concept for the modality which is mRNA that Moderna is obviously and in some others are going after as well.

[00:03:30] One of the really interesting things about this is that, as recently as the end of October Pfizer CEO said [they] haven't reached 32 cases yet, [they were] not ready to give an interim data analysis, that was their original point at which they were going to share data. They ended up talking with FDA and shifting that point to 64 cases. But pretty quickly, within just a matter of short weeks, they got to 94 cases, from under 32. As we know, the cases are really surging around the globe in various places, if you know that was able to I think drive the early release of data. And what is also interesting is we might see more efficacy data from more companies coming up shortly behind it, because presumably this surge is impacting everywhere else as well.

[00:04:20] Simone Fishburn: I want to just add a couple of things Jeff just to take note, and Karen thanks for that really thorough overview and Jeff may have some more questions for you in a minute.

[00:04:29] I know others have said this, I think we definitely have to pay homage to the fact that this is remarkable, to come up with a vaccine in less than a year. I think it's also very encouraging that if this vaccine works chances are pretty good - as I understand that other vaccines will be going after the same protein. And there's a lot of logistics still to work out. But you know, asked by my son today "is this real good news, or does it sound like it?". I think it's really good news .

[00:05:03] You know I do want to just say that we know that President-Elect Joe Biden he has deep interest from personal experience in cancer, head of the Cancer Moonshot, and I think that this incoming administration will do everything on this front and they will be science friendly. I do look forward to being able to see whether there are innovation positive policies coming out of this administration that are good for our industry.

[00:05:37] Jeff Cranmer: What next should we expect on vaccine read out front, I guess next up might be Moderna which has a vaccine with a similar modality what are you looking for there Karen?

[00:05:50] Karen Tkach Tuzman: I think Moderna said that they would give interim data at 53 cases, so that might be something that we could see even as soon as sometime this week given the rate of uptick of cases that we saw in the in the Pfizer trial. So Moderna is like you said it's a similar modality it's mRNA, so it's the same as in the Pfizer case. There seems to be little daylight at this point that we can tell from available information between the two. They're going after the same protein I believe with the same mutations, but one key difference might be the formulation of the lipid nanoparticles that the mRNA's delivered in.

[00:06:27] That's something that we're looking forward to digging into and seeing what we can find. Because the formulation affects a couple of things one is the distribution does it need to be stored at what temperature and in cold chain, and what does that mean for how easily it can be distributed from a logistics point of view. Also the formulation could affect how the innate immune system responds for example even to the exact same vaccine antigen. So that's something that we'll be looking to see a differentiation, and frankly over 95% effectiveness this is a higher bar than what was anticipated based on sort of guidelines and protocols that companies had put out. We actually put together a graph of the number of cases that companies would have to see and at what efficacy, and you know 90% wasn't even on the axis. You can say that the bar has been raised, they'll be looking to see where other manufacturers fall in on that axis. I think Moderna will be the one that will be most closely scrutinized if can they meet this? Another question is when Pfizer looks to complete this trial at a 164 cases, will they still come out with that same over 90% number once all the cases in the trial are accounted for?

[00:07:43] Then looking beyond the RNA vaccines, we've got some other modalities coming up behind - Sinovac with their inactivated viral vaccine, and AstraZenica with their viral vector vaccine started late stage trials at around a similar time. It'll be interesting to see where other modalities fall in this space.

[00:08:01] One thing is that FDA has made clear they need to see at least two months of safety data from trial participants as a condition for filing for EUA. That is a benchmark that Pfizer has said they could reach within this month.

[00:08:20] Selina Koch: And in its guidance on EUA that's what FDA said it was looking for 2 months of safety data, plus evidence of efficacy and it left open the possibility of using interim readout to give an EUA so it could follow.

[00:08:34] Karen Tkach Tuzman: I think that especially given the surge of cases we might see a bunch more efficacy data come through quickly, perhaps even more quickly than reaching that safety time point. Yeah, keep your eyes peeled in the next couple of weeks...

[00:08:48] Simone Fishburn: Just a couple more things, just to emphasize the Pfizer and Moderna vaccines are a new modality that hasn't been used before. So there's going to be a lot of eyes on the safety there and that pointed out is one thing that could differentiate them. Probably the efficacy is going to be similar, against a similar protei en, though I guess delivery could make a difference. The other thing is that I think I have seen, am I correct that Moderna claims that its vaccine is stable at minus 20, rather than minus 80 degrees?

[00:09:21] Jeff Cranmer: Yeah, I think your right there.

[00:09:22] Simone Fishburn: So I'm not sure that that's a tremendous difference, but certainly shipping things at minus 80 is quite a burden, and minus 20 is quite a bit easier. If your thinking about hauling things around the country and around the world things like that..

[00:09:37] Selina Koch: There's infrastructure in place for the minus 20, but not for the minus 80, right. So when one case we can use an existing system.

[00:09:45] Simone Fishburn: And I think that at the end of the day, I think we've been saying all along, or we've been hearing all along that multiple vaccines are going to be needed.

[00:09:53] Jeff Cranmer: So clearly we have some good news here but there are many hurdles left to clear.

[00:10:01] And President-Elect Biden this morning named his COVID 19 advisory panel. Perhaps they will start digging into these issues right away. The co-chairs of this panel are Vivek Murthy, who served as surgeon general in 2014 to 2017; David Kessler, former FDA commissioner under George H. W. Bush and then later under Clinton; and Yale’s Marcella Nunez-Smith, some other notable names Atul Gawande, from Brigham and Women’s, he was a former Clinton advisor; Luciana Borio, a frequent BioCentury source is a former FDA official and NSC official; Ezekiel Emanuel, and of course Rick Bright, who was the BARDA whistleblower early on in the pandemic. Lots of big names at a glance I don't see any industry folks on this panel, we are analyzing the list and we'll report on it later today so look for that on our website.

[00:11:15] Simone, what do you expect from this panel?

[00:11:17] Simone Fishburn: Yeah, just a couple of points on this and we don't have Steve Usdin with us today to disagree with me and tell me how wrong I am, so I'm going to just go out and say what I think this is. First of all I just want to make the point that Zeke Emanuel also was a big voice behind the Affordable Care Act, in the Obama administration with Biden so a lot of these people are very familiar . The way I see this is the sort of germ of what will be Biden's version of a coronavirus task force. I think what he would probably do is create his own with a new name, maybe he'll take a couple of the non-partisan voices like Fauci, and some of the other scientists, or not just science, science regulators, but nonpolitical people into this. I think will be the transition for him and it will live as long as a coronavirus task force equivalent is needed. And I expect some of the members of this panel will go on, some but not all probably will go on to have roles in the Biden administration of one nature or another. But I see this as a sort of coronavirus transition team.

[00:12:29] Jeff Cranmer: Thanks for the thoughts Simone, I'm sure Steve would have agreed with every last word that you said there, but he'll get to speak his piece next week when he's back from the mountains.

[00:12:42] So let's turn to Biogen, as I said, in any other week, any other year, this would be the top story in life sciences. In its briefing documents FDA described the efficacy of Biogen's therapy for Alzheimer's as strong and extremely persuasive. And then fast forward to Friday, panelists roundly rejected that assertion in the vote.

[00:13:08] What happened here, Selina?

[00:13:11] Selina Koch: What happened is that the panelists felt FDA wasn't being an objective reviewer. Many of the panelists were, gosh... they were almost indignant that they'd been fed the data, and the voting questions were worded in such a way as to lead them to one conclusion, which is that the drug was positive.

[00:13:32] So there were two phase III studies in this program. One the company and FDA, said met it's primary endpoint with significance based on their calculations, although one of the reviewers didn't buy that argument, but they said okay this one's positive. The other one the high dose they said met in one trial and performed worse than placebo and the other one, so it bombed. All throughout the company's calculations and all throughout FDA's calculations because the company and the FDA in this case seemed to be in lock step of the briefing documents. The assumption that underlied all of the analyses was that the positive study was the truth the correct result, and that the negative study was a spurious finding.

[00:14:17] And they didn't even entertain the opposite possibility, so that's the thing that the panelists kept coming back to and kept saying scientists here we have to atleast acknowledge the possibility of the null hypothesis. Which is that the failed study represents truth and can we find support for that in the other study? Yeah, so they they didn't understand why FDA and Biogen jointly produced this briefing document, which isn't how it usually is.

[00:14:41] Simone Fishburn: Selena, the notion that Biogen could do another trial, it certainly can do another trial. But what's the bar it would have to meet? I mean it would have to be extremely positive really to overcome this sort of negative data that's already out there, so how do they go about doing that, I suppose in a subpopulation?

[00:15:02] Selina Koch: Yeah, I mean there's different ways of thinking about it -- one if the negative result was really spurious then you just do it again and you have your tiebreaker. But the panelists on the committee some of them didn't think it was so positive. So, if you wanted to optimize for a better outcome, you could say who carried the signal in the study, which seemed to be the APOE4 carriers on the high dose and you only enroll them. And then one of the panelists said you could do a withdrawal of the drug after the 18 months when it seems to start to show some small amount of efficacy, you can then do withdrawal and see if that rapidly reverses.

[00:15:46] Simone Fishburn: One of the reasons why the data have to be so convincing is that - sure FDA can approve it - but this is going to be a really expensive drug to reimbursement. I mean in the U.S., CMS would have to reimburse it, it's mostly Medicare population, right?

[00:16:03] Selina Koch: That's correct. And a really big one, there's something like 6 million patients in the U.S.. I think if it were approved, CMS is the one who gets stuck with the really hard decision then, and possibly being put in the role of the bad guy. Because you know if a large number of folks don't benefit, and that efficacy is marginal, and the expense is huge. But just because of the lack of options, this is a really severe disease with no good treatments patients are pretty desperate there's going to be a huge demand. They're going to be the ones who are going to have to say, well you can get it and you can't. I think there would probably have to be some restrictions on access.

[00:16:40] Simone Fishburn: Very, very thorny.

[00:16:42] Selina, if I remember correctly from your excellent story on Friday which I encourage people to read, did one of the panelists also refer to what this does to FDA's credibility?

[00:16:56] Selina Koch: Yeah, so actually that was in the public testimony. There was a whole string of, first patients calling for approval, but there were a couple of voices of dissent there . This idea that this threatens to damage an already damaged FDA credibility.

[00:17:11] Simone Fishburn: I'm going to turn to Jeff with this question because historically there have been some very contentious approvals where the adcomm went one way an FDA went another. And I know you lived this at BioCentury with Sarepta's.....

[00:17:28] Jeff Cranmer: The one that immediately comes to mind which I think we talked about a week or two ago is Sarepta I, and Sarepta II. Both of those decision's caused a furor in the life sciences community. I've been on panels where I've just mentioned something about that and I had an angry mob waiting for me after the panel finished. So I don't recall any others that top Sarepta but this feels a bit like that.

[00:18:00] Simone Fishburn: Selina, what are the chances that FDA ignores the panel and goes ahead and improve this drug.

[00:18:08] Selina Koch: I couldn't give a prediction there. It was clear from the briefing documents, the way they were organized, presented, the wording all throughout, the FDA really wants to approve this thing. I think having such a unanimous vote against it just makes that a lot more difficult. Certainly another possibility is to ask the company to run another trial.

[00:18:26] Simone Fishburn: Right.

[00:18:27] Jeff Cranmer: Some of the quotes that you cited in your story Selina, I'll just read a few here one panelists likened Biogen's data to quote, "shooting a shotgun at a barn and then painting a target around the bullet holes." That was Scott Emerson, of University of Washington, who also said "This is all terrifically one-sided." You know FDA, it's already in a place where its credibility has taken a bit of a knock during the pandemic. So I don't know what political capital it has right now to make a risky decision. Again, we don't have our FDA expert Steve Usdin here to weigh in...

[00:19:15] Simone Fishburn: Actually I have one more question on that front regarding the timing. I think we can assume that from January the 20 something... or however soon afterwards there'll be a new FDA commissioner, and I don't know whether that would affect this. And what are the chances of FDA making a decision before then Selina?

[00:19:34] Selina Koch: Well the PDUFA date's March. This ad comm, they held very quickly, which people took as a sign that FDA really had committed to reviewing this fast, sent Biogen the shares way up that day when it got scheduled. You know the FDA has been moving fast on this. Now that there's this negative vote I don't know if it's going to take more time.

[00:19:53] Jeff Cranmer: FDA might get a new commissioner even sooner than the next administration. I mean President Trump just this morning fired Defense Secretary Mark Esper, in a tweet naturally. There has been some chatter in Washington that Stephen Hahn's days were numbered. So we'll see what happens, any last thoughts on?

[00:20:17] Simone Fishburn: I think one thing that we should probably just finish the Alzheimer's story on is, you know this really just raises the ante for new targets, and new mechanisms in Alzheimer's disease. Selina, you've been following tau and more things after that, this is clearly not going to be the last word in this really big disease which is really a huge public health concern.

[00:20:41] Jeff Cranmer: So FDA has until March 7th is the decision date for this therapy, so they do have some time to think it over. I am curious Selina, I know you've written a lot about tau are there any other things you're looking out for in the Alzheimer's space?

[00:20:57] Selina Koch: Yeah, the first data to come in from a tau program in Alzheimer's were negative. We saw at CTAD on Friday that, that antibody had not decreased tau PET signals in the brain. So it may be that it didn't do what it was supposed to do, so maybe a molecule problem rather than a target problem. We will see there's a long lineup of tau antibodies, and other types of tau programs coming down the line that we should be getting data from the next year or two. After that of course, neuroinflammation, I think a lot of people are really excited about harnessing the immune system to deal with Alzheimer's. Those are big ones.

[00:21:36] Jeff Cranmer: We know you'll be following it closely, and here's hoping someone breaks through at some point on this. Of course we can't rule this molecule out either.

[00:21:46] Selina Koch: That's right, we absolutely can't. And there are many other amyloid targeted therapies coming behind it that some folks think, you know, it could be better.

[00:21:55] Jeff Cranmer: Simone, do you want the final word? I see you nodding there.

[00:21:58] Simone Fishburn: No, I think we've written and said enough for a little while. I do encourage everybody - and we can put this along with a written write up of this podcast - to go and look at some of the coverage that we've written about the journey of this molecule which's rollercoaster is probably an understatement, the [Amyloid] Hypothesis, why people have adhered to that. The other targets that are coming up, and then the Road of Tau which Selina has written about as well. And so we really have dug into this and we'll continue to do that.

[00:22:34] Jeff Cranmer: That's all we have time for this week. Thanks Karen, Selina and Simone, for all your thoughts. And I look forward to reading your article today, Karen. So get cracking.

[00:22:46] All of our podcasts are available at our website on Spotify, Stitcher, Apple, and Google

[00:22:53] Music for all of our podcasts is provided generously 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.