ASH preview & long shot drug pricing rules: a BioCentury podcast
On the latest edition of the BioCentury This Week podcast, BioCentury editors discuss how emerging targets, modalities and indications are stacking up at the upcoming American Society of Hematology meeting, as well as the uncertain fate of drug pricing rules released by the Trump administration on Friday, and the questions that remain as COVID-19 vaccines move towards authorization.
Associate Editor Karen Tkach Tuzman says the data from ASH are mixed on whether allogenic CAR Ts will be able to match or out-perform autologous therapies. “Should the efficacy get there, I think the cost advantages will be real, the accessibility advantages will be real, so it’s worth pursuing,” says Tkach Tuzman. “It’ll be about figuring out which candidates can really outshine their autologous counterparts.”
Tkach Tuzman also highlights clinical progress among BCMA-targeting candidates, CD47 inhibitors and sickle cell disease therapies unveiled in abstracts leading up to the ASH meeting, which will be held Dec. 5-8.
Washington Editor Steve Usdin and Editor in Chief C. Simone Fishburn discuss the final interim “most favored nation” rule, that caps Medicare Part B drug reimbursement for 50 drugs at the lowest price paid by any developed country, and a rebate rule that seeks to scrap rebate payments to PBMs and insurance companies for Medicare Part D drugs, both of which were released by the Trump administration on Friday.
“I think it’s not going to happen because it’s going to be blocked in court,” says Usdin. “But drug companies are taking the threat very seriously because nothing’s 100% certain in litigation, and if this were to go through, it would have enormous implications for all biologics.”
The last week has also seen progress on the COVID-19 vaccines front: on Friday, Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) became the first companies to submit their COVID-19 vaccine, BNT162b2, to FDA for emergency use authorization (EUA), and AstraZeneca plc (LSE:AZN; NASDAQ:AZN) on Monday reported interim data from its Phase III trials of AZD1222.
The partial-dose regimen of AZ’s vaccine was 90% effective in preventing development of symptomatic COVID-19 disease, while the full-dose regimen showed 62% efficacy.
Usdin expects rapid EUA decisions for BNT162b2, following a Dec. 10 advisory committee meeting to discuss the mRNA vaccine, and for mRNA-1273 from Moderna Inc. (NASDAQ:MRNA), which is expected to complete Phase III testing soon. The real question, he says, is whether FDA will require additional data from AZ, given the mixed data released today.
“A lesson from it is it’s really a good thing that we’ve got multiple vaccines that are created using multiple modalities, so that if there has to be a delay in the AstraZeneca vaccine, it isn’t going to be catastrophic,” says Usdin.
A transcript of the episode follows.
[00:00:00] Virginia Li: Welcome to BioCentury this Week, I'm Virginia Li, BioCentury Associate Editor, and I'm joined today by
[00:00:10] Karen Tkach Tuzman: Karen Tkach Tuzman, Associate Editor,
[00:00:13] Simone Fishburn: Simone Fishburn, Editor in Chief,
[00:00:14] Steve Usdin: Steve Usdin, Washington Editor,
[00:00:16] Virginia Li: Today Steve will give us an update from Washington after the Trump Administration on Friday released a series of rules that could reshape the drug pricing landscape in the U.S., if they can overcome the legal, and logistical challenges in place. But first Karen will give us a preview of data to watch out for at the upcoming American society of Hematology (ASH) meeting in early December.
[00:00:36] Karen, what are you seeing in the abstracts leading up to ASH this year?
[00:00:40] Karen Tkach Tuzman: What's really nice about these big conferences like ASH is it gives us the ability to home in on some hot topic emerging areas that we've been following and get a snapshot of who's doing what, and what it looks like. And so my colleague Lauren Martz did a great dive first on the BCMA data that's coming out, at ASH. So looking at the CAR T cells, and the bispecifics. One of the standouts there was J&J and Legends CAR T cell against BCMA, multiple myeloma, and in general we're seeing really good efficacy, good ORRs for this class of therapies going against this target. And one of the sort of steps away from that was from Allogene, the allogeneic CAR T cell that they had there. Which leads to some questions around can allogeneic T cells perform as well as autologous CAR T cells. We then did a dive on what's the allogeneic CAR T cell data. It's the modality that you know we're of course watching it offers the opportunity to have off the shelf therapies that you don't individually manufacture for each patient, but can they perform as well as autologous? And so looking now across a range of different targets, and indications what was the allogeneic data presented, looks like they're sort of a mixed picture.
[00:02:01] One of the standouts was this Chinese company called Bioheng, it's still in a small number of patients, but showed ORR of 83% in BALL and their allogenic CAR T is going after CD19 and CD22, so different indication. But one of the things that we are starting to see in the allogeneic CAR T space is the primary concern there had been can you make sure that these T cells won't go after the patients' host cells, to have graft versus host activity. And in general from the data we're seeing at ASH from Allogene, Cellectis and Bioheng, and other things we've seen reported, it seems like they've gotten around the GVHD question. But we're still actually seeing with these cells cytokine release syndrome that you see with autologous CAR Ts.
[00:02:50] Steve Usdin: So Karen, the question I have is bottom line how promising do the allogenic CAR T cells look like the CAR T therapies, and are there going to be advantages the obvious one in terms of money, are they going to be a lot cheaper to produce, and are there going to be some cancers that can be tackled with them that they'll be good enough?
[00:03:13] Karen Tkach Tuzman: Should the efficacy get there, I think the cost advantages will be real, the accessibility advantages will be real, so it's really worth pursuing. As far as, will they be good enough, there's a couple of different variables that are being tested here. One of them is around do you make these allogeneic CAR T's what do you use to edit are you using tailorings and CRISPR, are using shRNA? And then there's also some aspects around are you editing some other things in addition to just the TCR you're getting rid of to prevent graft versus host (GVHD), what other tweaks are you making?
[00:03:49] And so I think at this point it's too early to say if as a whole, the class is going to be able to perform. We've seen some cases actually, Allogene had a candidate some data for I think it was ALLO-501. That was a CD19 targeting CAR, and it did look like it was on equal footing with the marketed autologous CAR T cells when they were at a similar stage of development. But in the case of BCMA the Allogene's Car T cell was disappointing relative to the others at ASH. I think there's variables including what target and indication, and also how are these cells being tweaked and that we'll have to look out for.
[00:04:27] Simone Fishburn: Karen, I have another question on top of that looking at it they all seem after sort of a very limited number of targets BCMA, CD22, CD19. Do you think the field is just going to sort itself out with those targets before people really start going after new ones, or are you seeing the signs of it getting broader?
[00:04:45] Karen Tkach Tuzman: Well you always hear about with new modalities it's like can we reduce the target risk first while we sort out the modality, and then go after more interesting, and exciting targets that touch indications that haven't been touched yet. So I think we will continue to see these targets we've seen CD19, BCMA, CD22 being the proving ground for these allogeneic CAR Ts for a while.
[00:05:08] Simone Fishburn: And one more question on this front, you know it's one of those areas that has just for whatever reason become incredibly polarized in a nonpolitical sense, but still you're either an allogeneic believer, or you're a autologous believer and I've seen very heated sort of I'll never go there. Do you think the allogeneic cells have got enough traction now, are these data promising enough that you think you might sort of see people crossing over and saying well actually allogenics do have some advantages that are worth leaving autologous for?
[00:05:41] Karen Tkach Tuzman: We saw Cellectis's investors respond positively to their data in BALL is a 40% ORR, again these are all small numbers of patients. But I think in general despite the setback for the Allogene data they presented for ALLO-715 at this conference... I think we are seeing enough positive momentum forward that it's not grinding the space to a halt I think that people will continue pushing in this way and it'll be about figuring out which candidates can really out shine their autogolous counterparts.
[00:06:16] Virginia Li: Karen, beyond the allogeneic CAR T therapies are there any particular targets in any modality that will see transformative data at ASH?
[00:06:25] Karen Tkach Tuzman: It was a great time to check in on CD47, because this is a target that we've been watching for a while. It has the potential to be a myeloid checkpoint inhibitor in the vein of the PD1 PDL1's, it's about what's actually proving out here. So here we got a chance to double dip from ASH and SITC. One of the interesting things was from ALX Oncology, which is going after using their CD47 inhibitor in solid tumors as well as liquid tumors. It was interesting... they highlighted data from a pretty small number of patients smaller than what they'd shown before, but what they were saying is they're really homing in there on the combinations of the CD47 plus antibodies against tumor targets, plus chemotherapy regimens that's what they're going to be going forward with in their Phase II and they showed some promising data there. Then we got to see some data from Gilead, they acquired Forty Seven a couple months ago for a handsome sum of $4.9 billion. Here their lead indication is in myelodysplastic syndrome, but here they were showing off their AML data and specifically pointing to how it might be the CD47 inhibitor plus azacitidine might be particularly interesting in the p53 mutant patients.
[00:07:46] Another interesting one here was the first time we're seeing clinical data from I-Mab, Chinese company, they did a deal with AbbVie for their CD47 inhibitor. And it was one of the bigger upfront... I think 188 million up front that we were seeing for these cross-border deals in China, so they gave the first glimpse of the data. There's three patients, and one response so far it's still early but something that we're watching for.
[00:08:11] Simone Fishburn: And then on that front a while back we were sort of pegging is CD47 going to be the next PD1 I'm still not sure that we know that yet. But you've seen Gilead and AbbVie snap up a couple of deals, or in Gilead's case snap up a company. Early on you did a story on all the new companies that were being created around CD47, so do you expect this data to start triggering a bunch of deal activity?
[00:08:38] Karen Tkach Tuzman: Potentially, I guess from the companies that are presenting data at SITC, ASH that aren't perhaps partnered in the same way. We've got ALX Oncology, and Trillium and in both cases the data looks, there's a promising signal there. Trillium highlighted how they had some single agent activity from an IgG4, which people thought you might not be able to do that. So it's possible we might see more deals, or takeouts in this space.
[00:09:04] Virginia Li: One last thing on ASH Karen, your story also mentioned sickle cell disease as a hot topic at the meeting, can you give us a brief overview of what we should expect to see there?
[00:09:14] Karen Tkach Tuzman: Sure, the sickle cell disease data here it's kind of building on what we saw at the EMA meeting a couple of months ago. General companies were reporting positive data and so took the opportunity to look at what were the endpoints, what were the markers of positive data that they're showing? Because we are seeing this shift in the sickle cell disease field away from end points that are purely defined based on vaso-occlusive crises, so the number of VOC as they're called that, that a patient experiences, or things around the VOC rate. Also getting at endpoints that get at the hemoglobin and the sort of molecular basis of disease. Because we're seeing now this next wave therapies are directly hitting at that root cause of disease. We saw some data from these ex vivo gene therapies from bluebird, and Aruvant. bluebird in particular, they've had some data before, but in this case they're particularly highlighting it looks like the manufacturing method that they're going to be going forward with their optimized process there. There they were able to really show a range of both reduction in the VOC rate in addition to some of these molecular markers the sickling propensity of red blood cells.
[00:10:28] The CRISPR Therapeutics data stood out as well, I think in particular for the duration cause they are gene editing hematopoietic cells, putting them back in. And in this case, one of the things that was really striking was the fact that I think one patient had no VOC crises for I think over a year. That kind of duration data is really key, and it's a big signifier that things look promising.
[00:10:52] Then we've got some kind of earlier stage data from Agios, and Forma which they're going after it in a different way with small molecules that influence TKR, which they think improves metabolic flux in red blood cells. Here the data was earlier and they didn't have yet on the effect on vaso-occlusive crises, but they did have data around what's going on with the levels of hemoglobin that doesn't sickle, and what do the red blood cells look like.
[00:11:23] We're seeing a lot of momentum in the space after the approvals last year, from Novartis and Global Blood. It's definitely something to watch out for to see more and more data getting around the root cause of the disease.
[00:11:35] Virginia Li: All right, I'm going to switch gears now and turn to the latest drug pricing rules out of Washington. Steve, last week the Trump Administration released a final interim most-favored-nation (MFN) rule, as well as a rule that would eliminate rebate payments to PBMs and insurance companies for Medicare Part D drugs. So can you start by walking us through those rules, and what the implications are for the industry?
[00:11:59] Steve Usdin: The most important one is the most-favored-nation (MFN) the MFN rule. The White House waited till 60 days were left on its clock to try to slip this through. It's an enormously consequential change in the way that drugs are reimbursed. And really before I describe what they did, I have to say that there's a good chance that it's just not going to happen. There's probably a German word for something that seems like it isn't a big deal because it doesn't happen, but it didn't happen because people recognize it was a big deal, and they prevented it from happening. So...
[00:12:27] Simone Fishburn: A quick question, Steve is it not going to happen because it's not going to happen before the end of this administration, or is it not going to happen because it's going to get rolled back with the next one?
[00:12:36] Steve Usdin: I think it's not going to happen because it's going to be blocked in court.
[00:12:41] Simone Fishburn: Before it even gets there.
[00:12:42] Steve Usdin: Before it even gets there. But again, it's going to be blocked in court because people really care about this because it's really a tremendously important change. So the idea behind the most-favored-nation (MFN) idea for drugs is to create an international reference pricing system that would cap reimbursement under Medicare Part B at the lowest price paid by any developed country, any OECD country. Since Part B is primarily biologics, BIO and its members see this really as a dagger aimed right at the heart of their companies. If it goes into effect, tens of billions of dollars in revenues for biologics like Eyelea, Opdivo, and Keytruda would just evaporate. Again, I think it's not going to happen in part because the Trump Administration waited until the last minute, and then they took a shortcut. They issued something you mentioned at the beginning, an interim final rule. The courts are very likely to agree with drug companies that most-favored-nation (MFN) doesn't qualify for an interim final rule, if they do, then they'll just kick it out. And it will be up to the Biden administration to decide whether it wants to reinstate this. Drug companies are taking the threat very seriously because nothing's a hundred percent certain in litigation, and if this were to go through it would have enormous implications for all biologics.
[00:13:58] Virginia Li: And then what was the rebate rule that was also issued on Friday?
[00:14:02] Steve Usdin: So the rebate rule is something that the bio-pharmaceutical industry very strongly supports, but again is likely to be thrown out by the courts also. Basically what the administration is trying to do is to prevent PBMs and insurers from charging rebates to Medicare Part D drugs in exchange for putting drugs onto formularies, or for giving them favorable formulary placement. The drug companies, patient groups, and physician groups all support the idea of getting rid of the rebates, because they have perverse unintended consequences. One of those perverse unintended consequences is that they jack up the list prices and Medicare beneficiaries who have to pay a copay based on a percentage of the list price are hurt by that. Patients who don't have coverage and have to pay the full price are really devastated by it. The problem is that the PBMs and the insurance companies use those rebates in large part to subsidize premiums.
[00:15:12] So if the rebates are scrapped, premiums are going to go up. The Executive Order that President Trump signed allowing Alex Azar at HHS to revoke the authority for rebates specified that he could only do that if revoking the rebates wouldn't increase premiums. So what Alex Azar did was he just wrote a letter saying in my personal opinion this won't increase rebates. He didn't provide any data to substantiate that nobody who I've spoken with actually believes that it's true. The PBMs, the insurance companies are going to go after this. Democrats in Congress are not enthusiastic about it at all. I've heard that people who are in the Biden transition team are also not enthusiastic about it. The Trump Administration is trying to put it into effect starting January 1, so it would be already in effect if they complete it when the Biden administration takes office. I think it's likely the minimum that it's going to be delayed, and if it's delayed it's likely that the Biden aministration will scrap it. But again, you never know.
[00:16:22] Simone Fishburn: And Steve, there was one totally bizarre extra thing, right? Regarding old drugs on pharmacy shelves, just give us very quick overview of that.
[00:16:31] So the FDA from 2001, and in 2006 issued guidance creating what they call the Unapproved Drugs Initiative (UDI). The idea is that there are drugs that have been grandfathered in, that have been in use since before modern drug regulations came into effect. FDA wants to get rid of those it wants to kind of take them out of the shadows. The way that it does that it creates this incentive, it says if you're a drug company if you find an unapproved drug and you do the proper testing in order to get it approved, then FDA will kick all the other versions of it off the market, and you'll have a monopoly on that drug for some period of time. The theory is that creates a tremendous incentive for us to get the information about whether these drugs really work, or if they don't work, and who they work, and how they work. And also to have them manufactured at high quality. The downside of it is that a handful of companies have taken advantage of that, they've found unapproved drugs that are really important for a small niche. They've gotten them approved, FDA has kicked the other versions off the market, and then they jack the prices up exorbitantly and caused a lot of pain for patients and for the healthcare system. So the Trump Administration has basically said we're going to throw the baby out with the bath water, just get rid of the whole program, and leave it up to the next administration to figure out how they're going to police unapproved drugs going forward.
[00:17:55] Virginia Li: One last thing before we go, it's been another big week for COVID vaccines and therapeutics. On Friday Pfizer, and BioNTech became the first COVID vaccine developers to submit their vaccine for Emergency Use Authorization (EUA). And AstraZeneca released some interim data from its Phase III vaccine trial earlier today. What are some of the open questions that remain as the front runner vaccines move towards authorization?
[00:18:19] Steve Usdin: The decision points are going to be first December 10th there's going to be an advisory committee meeting for the Pfizer, BioNTech vaccine. Based on everything that we've seen so far it's quite likely that the advisory committee will recommend an Emergency Use Authorization (EUA) . FDA is likely to act extremely quickly after that to start distribution.
[00:18:41] We're going to see Emergency Use Authorization (EUA) requests from AstraZeneca, and from Moderna for their vaccines. I think the Moderna one is likely to also go through quite quickly. The real question about the AstraZeneca one is going to be about how regulators, and the advisory committee positions in the public interpret the data from it which is complicated. I think it's really a little bit too early to see, to determine whether that one's going to fly through, or whether there's going to be a requirement for additional clinical data to have more assurance on the efficacy levels around it.
[00:19:18] Karen Tkach Tuzman: The issue there was about the fact that the single dose did better than the double dose, right?
[00:19:23] Steve Usdin: Well no it wasn't the single dose versus a double dose. It was a prime boost strategy where they had half a dose, followed a few weeks later by a full dose, and they compared that to two full doses. The initial reading of the data is that half a dose followed by a full dose was far more effective than two full doses.
[00:19:47] But I think it's going to take some time to really dig through the data and determine whether, one whether that's really a real finding, and two what it means, and then three is there gonna be enough confidence around this data to authorize it based on the studies that have been completed, or a regulator is going to say that they need to have more data for more studies? And I think the maybe the bottom line lesson from it is, it's really a good thing that we've got multiple vaccines that are created using multiple modalities, so that if there has to be a delay in the AstraZeneca vaccine it isn't going to be catastrophic.
[00:20:27] Virginia Li: Okay, that's all we have time for today.
[00:20:30] BioCentury and BayHelix have just wrapped up the live portion of our 7th China Healthcare Summit. It's the first time we've done it virtually which means that there's still time to register and catch insights on financing, deal-making, and regulation in China from KOLs around the globe. All sessions are available until December 11th, you can register www.biocenturychinasummit.com.
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