One of our biggest difficulties is choosing the wrong target. No, really. We have all sorts of compounds that make it into human trials and then don’t actually work, because it turns out that our hypothesis about the underlying disease was just wrong. It’s hard to overemphasize this: we don’t know enough about human biology to make sure, much of the time, that we have grasped the right end of the stick. A few simple questions will illustrate the problem: what causes Alzheimer’s? What’s the best way to interrupt septic shock? What’s the underlying cause of Parkinson’s disease? What’s the best target to work on to deal with chronic pain? What’s the actual biochemical cause of major depression? If you wanted to reverse fibrosis in a given tissue, how would you best go about that?
You can do that sort of thing for quite a while. Some of these questions have slightly more plausible answers than others, but believe me, all of them will involve substantial risk as you go into Phase II trials in humans. Just look at the landscape around many of them – all the previous trials that have wiped out. So I think it’s fair to say that being able to do a better job of picking the actual disease-relevant targets for our drugs would be a great improvement. Unfortunately, there does not appear to be a general solution to this problem, since it involves a more detailed understanding of each individual disease.
Better models (animal and otherwise) of such diseases and conditions would be great to have, but that’s a high bar. The arguing over animal models of Alzheimer’s has been going on for decades, since the underlying difficulty is that humans are the only animal that actually gets Alzheimer’s. You might think that pain signaling would be a conserved process and that animal models would tell you a lot, but I have lost count of the number of compounds that work in such models but do not work in human trials, so there’s clearly something missing there. Model development in general sometimes runs into a chicken-and-egg question, since you would need to know a lot more about the disease before you can work up a good model to mimic it.
Here’s another: we would love to have a better warning system for toxicity in human trials as well. Many promising drugs have dropped out of the clinic due to unexpected tox effects, for sure – some of these turn out to be mechanism-related and some of them are just compound-related (where the compound does something else that you don’t want), but there are many instances where we can’t even make that distinction yet. Animal models for toxicity are extremely valuable, but they don’t get you all the way. You are still taking a risk every time a new compound or new mechanism goes into human trials, and it would be very useful if we could lower that risk a bit. The general solution would be some sort of system that exactly mimics human biology but doesn’t consist of a bunch of human swallowing pills. This is a difficult goal to realize.
To my mind, these are some of the biggest problems in coming up with new therapies. As a medicinal chemist, one of the things that you come to realize is that med-chem itself is often at the mercy of these things. You can deliver a potent, selective, bioavailable compound aimed directly at your disease target, only to find out in the clinic that whoops! That target doesn’t work. I have been involved in a good number of these over the years, and so has everyone else. No amount of compound optimization will fix that issue; the problem is bigger than the compounds.
So when you hear about a new technique that’s announced as speeding up the development of new drugs, ask yourself if it’s going to bear on the issues above or not. Now, that doesn’t mean that advances of that sort are useless, far from it. New techniques to screen compounds, or to find leads from the screening data, or to optimize them more efficiently into clinical candidates, new formulations and assays and delivery methods and mechanisms, all of that is useful. But all of those are upstream of the problems of target selection and unexpected toxicity. Finding out more quickly and with less expense that you have chosen the wrong target is no bad thing – but an even better thing would be to not choose the wrong target.
Real world evidence has the potential to support aspects of drug development and commercialization. It can expedite the generation of hypotheses, enable identification of sub-populations with higher risk-benefit ratios to target development efforts, support more efficient and targeted patient recruitment, reduce the burden of data collection and reporting, and lead to earlier conclusions about effectiveness and faster decisions about value and reimbursement. Real world evidence makes possible a new paradigm for closely monitoring the safety and efficacy of drugs prior to and after their approval. This close-monitoring during clinical trials, post-approval commitment phase, or after approval of a subset of patients (through a combination of personal monitoring devices, smartphone apps, phone calls and virtual visits) are likely to benefit patients, researchers and regulators. It is anticipated that the US FDA, European Medicines Agency (EMA) and other regulatory authorities are likely to increase the utilization of real world evidence in influencing the regulatory decisions associated with the safety and efficacy of medical products.
Real World Data Sources
Potential Applications of Real World Evidence
Real world evidence has enormous potential to contribute towards healthcare decision-making, in terms of pre-approval and post-approval guidelines. It can significantly decrease the time and cost of drug development, and can aid in the early stage research in order to discover new innovative treatments. Further, it eliminates the necessity of recruiting clinical subjects to analyze the safety factors of a treatment. If the data generated through real world evidence is of sufficiently high quality, then it can certainly influence the clinical decision-making processes of the regulatory authorities.
Growth Drivers and Challenges
Over the years, industry stakeholders are increasingly utilizing real world evidence in order to reduce costs and optimize operations of their product lifecycle. The numerous potential applications of real world evidence in establishing patient safety standards, ensuring effectiveness of a product and treatment paths, productive market assessment and the disease patterns have further augmented its necessity. Although real world studies have numerous opportunities in the healthcare sector, there are several associated challenges, which act as road blocks to their future growth. The major road block for optimum utilization of real world data is the availability of data in complex or scattered form that has to be structured in order to derive meaningful insights from it.
Due to regulatory opportunities and payer demands, the interest in real world evidence in the pharmaceutical industry is continuously increasing. The ongoing advances in compute power and data analytics are allowing stakeholders to gain accurate and reliable insights from EHR data in unique ways. These successful efforts are leading to specific advantages for a given therapy in patient sub-groups.
Check out our new Reports Here-
You may also be interested in the following titles:
- STING Pathway Targeting Therapeutics and Technologies
- Point-of-Care Diagnostics Market for Infectious Diseases by Indication
- Single-cell Sequencing Services and Technologies Market, 2020-2030
The post REAL-WORLD EVIDENCE: THE GAME CHANGER IN DRUG DEVELOPMENT appeared first on Blog.
- NVIDIA reports that it is building the “Cambridge-1” supercomputer, which will be an NVIDIA DGX SuperPOD system capable of delivering 400+ petaflops of AI performance and 8 petaflops of Linpack performance and 1s expected to come online by the end of 2020
- GSK and AstraZeneca will be the first company to harness Cambridge-1 for research. Additionally, Guy’s and St Thomas’ NHS Foundation Trust, King’s College London, and Oxford Nanopore Technologies also plan to take advantage of the system
- Cambridge-1 will be the first NVIDIA supercomputer designed and built for external research access and will provide researchers and academics the ability to tackle challenging AI training, inference, and data science workloads at scale. NVIDIA will invest ~ $51.7M in Cambridge-1
Click here to read full press release/ article | Ref: NVIDIA | Image: Medsmart App
The post GSK and AstraZeneca Plan to Deploy NVIDIA’s Supercomputer for Drug Development first appeared on PharmaShots.
Let’s take a few minutes to talk about biopharma stocks in general – or to be more precise, about some of the people who invest in biopharma stocks. There’s a lot of weird behavior in this area, and the pandemic has amplified it. I refer specifically to the “stock cult” mentality that will be familiar to anyone who writes about the market, about drug trials and approvals, anything that touches on the vital topic of whether Stock XYZ will take off like a rocket (or not).
We’ll stipulate up front that the very nature of biotech investing is that some stocks do take off in this way. Some of the charts you get in this business are wild indeed, total binary events that send previously obscure issues off into the skies and make the people who were holding them while they were unloved quite wealthy. I should mention that the opposite happens, too – there are plenty of biopharma stocks that have suddenly cratered on news of a regulatory rejection, suddenly toxicity in a Phase III trial, unexpected pullouts by larger partners, that sort of thing. But while there are always a few short-sellers looking for those events, the state of the market has always been hugely biased towards upside events – a constant raging thirst for upside.
With small biopharma companies, this gets mixed in with another psychological issue, a storyline. Human beings have a narrative bias. We often think in terms of stories, stories with beginnings and ends and plot lines and resolutions, with heroes and villains, with explanations that tie the threads together. But the natural world doesn’t have a narrative bias at all. I mean sure, there are causes and effects, but (1) they’re not always something that we are aware of, (2) they’re under no obligation to be relatable or even comprehensible to us, and (3) they’re similarly under no obligation to happen on the time scale of human attention or to be easily visible to our senses.
We also model events as if they were being done by other humans, and we ascribe intentions, emotions, and mental states to things. That can work, a little bit, with animals, because sometimes (not always!) those mental states overlap with things we can relate to: kitty wants food, doesn’t she? But it doesn’t work at all with things that don’t have any mental states at all. There is no god called Hurucan that assaults the Yucutan peninsula with high winds and rain, and lighting bolts are not sent by Jupiter. Earthquakes and comets are not signs of the displeasure of higher beings. That’s one of the problems with dealing with the coronavirus pandemic – the virus is beyond human concerns and it does what viruses do, which is make copies of themselves.
That’s all viruses do. They have no motivations and no storyline, and they don’t notice if we’re bored or frustrated or angry. While those copies are being made, the imperfections of that process mean that mutations will constantly occur. Most of those will do nothing, but if one of them turns out to help make more copies, it’ll stick around. Meanwhile, mutations that interfere with copy-making will vanish quickly. But don’t confuse with with any sort of intention; the virus didn’t “come up with a new strategy” or “respond” to anything, not in the way that we use those words. It’s very easy to speak that way, but it suggests abilities that a virus simply does not have. It makes copies. That error-prone mutation-throwing copy-making is, in fact, just another thing that in the past has turned out to be useful for making copies.
Back to stocks. The storyline, for many small investors, is a very simple one. It’s Us versus Them, a Manichean struggle of the forces of darkness against the forces of light. People get married to their ideas, in an emotional version of the Sunk Cost Fallacy, and when money is involved this process happens even more surely and strongly. So someone who becomes convinced that LittleTinyCorp, unappreciated by the world, has the answer to pancreatic cancer or to the coronavirus and then puts a good pile of their own money behind it . . .well, the last thing you should expect is for them to be continue being rational about that decision. Not everyone loses their mind, but plenty do.
In too many cases, every setback that LTC and their amazing therapy might encounter is ascribed not to the science just not working out, but to Evil Intentions. Paid “stock bashers” are at work – they want to shake the shares out of the weak hands, you see, so the “money managers” can pick them up cheaply to reap the huge, huge profits that are surely on the way. People have been bribed, suborned, paid off; it’s really the only reason that LittleTinyCorp hasn’t conquered yet. And remember, LTC are the good people who are fighting to bring a lifesaving therapy into the world. What does that make the ones who are fighting them, then? Who apparently want people to suffer and die so they can turn a buck? To arms, to arms, the forces of darkness are right there in front of you.
Well, as mentioned, you can see a lot of this going on during the pandemic. I’m not even going to mention the names of the drugs and the companies and the therapies – I’m sure that many readers will be able to fill them in. Just go back and look at the comments section here to find the accusation of bad faith and nefarious plans. Biopharma stocks have always had this problem because of the confluence of health, money, and the sheer fact that most ideas for new therapies simply do not work. But it’s worse than ever. Keep an eye out for this sort of thing, and adjust your worldviews accordingly.
We have a sudden influx over the last few days of preclinical rhesus challenge studies with various coronavirus vaccines, and it’s only natural to try to compare them. I have worked up a table with all four of the current results and the previously reported SinoVac inactivated virus vaccine, whose rhesus challenge numbers were officially published earlier this month. This is the closest to Phase II human data that we’re going to have until later in the summer, so let’s see what we can make of it!
Here is the Oxford/AstraZeneca vaccine, ChAdOx1, which is (as many have had the chance to memorize by now) a chimpanzee adenovirus repurposed with genetic material from the coronavirus Spike protein. This is the final published version of a preprint that came out earlier this year, whose results attracted wide comment and some criticism at the time. Since this one has already been discussed here, I’ll defer it to the comparison table I’m putting together.
And here we have Moderna’s mRNA-1273 results. The short readout is that the vaccine induced an antibody response in the monkeys similar to that seen in convalescent human serum, and a T-cell response that was heavily biased towards CD4+ Th1, with no detectable CD8+. That’s quite similar to what the company has reported in the human Phase I trials, which may add to one’s confidence in trying to learn something from the primate viral challenge studies. We’ll go into the actual numbers in the comparison table, but although the challenge in this case showed strong effects, it was not quite “sterilizing immunity” where the possibility of viral infection is completely shut down.
Then comes J&J, and I believe that these are the first numbers from their vaccine, which is another adenovirus vector, but an obscure human strain (Ad26) rather than a chimpanzee one. It’s been a bigger effort than we knew: the paper shows that they investigated seven different forms of an Ad26 vaccine, coding in various amino acid mutations for stability, different “leader sequences” to try to get the genetic material expressed more robustly once into cells, and different antigen sequences entirely. All of the latter are variations on the Spike protein, but some are full-length, while some had the cytoplasmic “tail” region or the transmembrane region deleted. They also tried mutations in the furin protease cleavage site and (like the first now-dropped Pfizer mRNA candidate), tried a foldon trimerization domain to present the antigen in multiple ways.
The one that stood out in antibody response was the “S.PP” candidate: wild-type leader sequence, full-length Spike protein, furin cleavage site mutated, and proline stabilizing mutations, so that’s what will be in the comparison below. Interestingly, this candidate had the lowest T-cell response of all seven that they tried (their paper’s Figure 3). After looking over the challenge data, the paper has some conclusions (their Extended Figure 6) on immune correlates (what markers are most indicative of efficacy): “these findings suggest that serum antibody titers may prove a useful immune correlate of protection for SARS-CoV vaccines. By contrast, vaccine-elicited ELISPOT responses, CD4+ ICS responses, and CD8+ ICS responses did not correlate with protection“. Which is interesting!
And finally, we have the Inovio DNA vaccine (INO-4800), which I’m glad to finally be seeing more data on. This is a DNA construct for the Spike protein, delivered intradermally. We need various technologies and routes of delivery to be running simultaneously, so the publication of this preprint is very timely. INO-4800 also produced antibody and T-cell responses, which will be summarized below.
There are a number of take-aways from this. I particular want to draw attention to the “Virus Challenge” row, since not all of these studies have been performed with an equivalent amount of virus. I have taken the various measurements as given in the papers and converted them all to Plaque Forming Units, using the conversion factor between that and the TDIC50 measurement given in the Moderna paper. You will note that Inovio’s challenge is the weakest of all those in the table, but at the same time their response is also the weakest: none of their animals ever go down to zero when measuring subgenomic RNA (which is more indicative of replicating virus). I am not optimistic, based on these numbers, about how their candidate will perform in Phase II/III human studies, both on the absolute scale and relative to their competition.
The second lowest is J&J. Their efficacy number are very good indeed, but one has to wonder if Moderna (whose viral challenge dose appears to have been tenfold higher) and the other competitors might have shown similar numbers at that same dose. On the other hand, that was only one dose of the J&J vaccine, which is impressive – they are the only company so far to report such a dosing protocol, and that’s a very big deal, from a logistics standpoint. But on the third hand, that single dose was tenfold more viral particles than the other adenovirus vector in the table (Oxford), so is J&J prepared to manufacture five times more active viral vector? They will, on the other hand, be using up only half as much fill-and-finish capacity after that. And so on – isn’t drug development a blast? Don’t you just wish that you could have decisions like this hanging over your head for a living?
I wish that we had similar primate challenge data for the Pfizer/BioNTech candidate, but I honestly don’t even know if they ran that experiment, or when we’ll see it. I still like that one from what we’ve seen of what we now know was its inferior competitor in Phase I, and I like the J&J vaccine as well. Those would be my personal front-runners, with Moderna and Oxford right behind them. Unknown factors in the human efficacy trials could rearrange that list in any direction, though, so my handicapping isn’t worth that much. That said, I don’t have similar hopes for the Inovio candidate based on what we’re seeing, and I don’t really know what to make of three-dose SinoVac inactivated-virus vaccine. Two boosters would be a major pain, and the data package on this one is, in retrospect, the thinnest of the bunch (although it does indeed appear to have worked). I’m not sure if anyone knows what they’re doing in their clinical trials.
On to Phase II!
As everyone knows, there have been a lot of attempts to repurpose existing therapies for the coronavirus pandemic. I’ve covered several of these along the way, but it’s time for some updates. The work that’s been going on not only adds to our knowledge about treatment for infected patients, but it should – ideally – also show what clinical research is like and why we have to do all these trials. Getting solid answers is a lot harder than it appears to be.
Antibodies Against IL-6 Activity
Case in point: the IL-6 story. Interleukin-6 is well-characterized as a pro-inflammatory cytokine signal, especially in the acute phase of the response, and that made this pathway a natural target for study after people realized that the “cytokine storm” immune reponse was getting coronavirus patients into trouble. Back in April, we had some numbers on the Roche/Genentech monoclonal antibody against the IL-6 receptor (Actema, tocilizumab) that suggested that it might be beneficial – in fact, the French team conducting the study said that deaths were “substantially reduced” in the treatment group. But at the same time, another antibody against IL-6R, Sanofi and Regeneron’s Kevzara (sarilumab) looked like it wasn’t working. That was puzzling at the time, and investigations on both of these continued.
Well, earlier this month sarilumab failed to reach its endpoints in a trial adding it to standard-of-care for hospitalized coronavirus patients, and that pretty well took care of it idea of using Kevzara as a therapy. Meanwhile, tocilizumab had failed to help patients a bit earlier in the disease progression in a study in Italy, which was disappointing after the French results, but there was still some hope that it could help the most severely affected patients. But just today, Roche announced that no, Actemra had no effect on clinical status or mortality. So much for that.
This is instructive on several levels, especially for folks who have been looking in on drug development from outside during the pandemic. The IL-6 hypothesis was a perfectly reasonable one, a solid idea from what we know about inflammation and about what was going wrong with patients who were being put on ventilation. But it’s wrong. A lot of perfectly reasonable medical hypotheses are wrong; this happens all the time and it’s why we have to run controlled trials rather than just running with what looks like it should work. And to go further, that first trial of tocilizumab looked like it worked, didn’t it? Deaths were “substantially reduced”, and how can you argue with that, right? But it was a small trial and it was only one trial, at that. Real treatments work again when you test them again, and they continue to work when you test them under more controlled and more statistically powerful conditions. Other results evaporate when you do that, and that’s what happened here. Those hopeful results early on were almost certainly an illusion, and this happens all the time. It’s why we run more than one trial, and why we make the later ones larger and more powerful.
You may be able to think of other high-profile therapeutic ideas that have had a similar course during the pandemic: promising early results in small trials followed by an inability to replicate them on a more robust scale. When such things don’t follow up, it’s not a conspiracy and it’s not malevolence and it’s not incompetence. Not usually. Because, and I cannot emphasize this enough, such things happen all the time. If you follow drug discovery and development, you’re used to it, because you’ve seen it happen over and over in all different disease areas. If you’re just tuning in, though, it can be hard to come to terms with.
There are plenty of other candidates out there. One that’s been getting attention is apilimod, a small molecule that’s been kicking around for some years now. It was originally investigated for its ability to lower IL-12 and IL-23 levels, a cytokine activity profile that looked like it could be useful in arthritis, psoriasis, and autoimmune diseases in general. If from that numbering you take away the idea that there are an awful lot of interleukins and that these cytokine signaling pathways must be rather a tangle, you are most extremely correct. The number of interactions in such systems (and with finer and finer distinctions of individual immune-responsive cell populations, too) is absolutely eye-watering.
But like many another small molecule, apilimod’s activity profile is a longer story than it first appears. It was identified in 2007 from a cell-based screen looking for modulators of interleukin activity. For some years, the only thing known about its mechanism was that it seemed to inhibit the activity of a transcription factor called c-Rel, preventing it from getting into the nucleus, and c-Rel was known to be essential for production of IL-12 and IL-23. But in 2017, a cell-based antiproliferative screen identified it further as an inhibitor of the enzyme phosphatidylinositol-3-phosphate 5-kinase (known as PIKfyve), and had just been found out (via other small-molecule PIKfyve inhibitors) that PIKfyve is essential for c-Rel activity, clearing up the mechanism a bit and giving apilimod a solid target and pathway to explain its actions. Apilimod has been suggested as an anticancer compound on the basis of such results.
So as for the pandemic, we’re back to inhibiting cytokine storms, right, this time by lowering IL-12 and IL-23 with this PIKfyve inhibitor compound, right? Maybe not! A recent paper in Nature (from a very large multicenter team) details another large-scale drug repurposing screen, this one done by looking for compounds that actually inhibit wild-type SARS-Cov2 virus infection of Vero-6 cells, a commonly used cell model from monkeys. Now, this is an in vitro screen, of course, but it’s a hard-core in vitro screen, because the team didn’t use a model for the virus itself (a pseudovirus or something of that sort), but rather went right to the real virus, which takes some serious screening facilities because of the serious containment needed. They followed up their best hits in human-derived cells and even in human lung tissue, so the results are quite solid.
And apilimod showed up as the best of the bunch, the only one to make it all the way through to good activity in the lung tissue assay. Not only did it inhibit viral replication strongly across all the whole screening cascade, but it also showed strong activity against the Ebola, Lassa, and Marburg viruses. (Told you that this was a hellacious containment facility, right? What a lineup.) That’s very interesting indeed, suggesting that this almost certainly has to be a host target involved in general viral infection mechanisms and not some specific protease or nonstructural protein of the pathogens themselves. Those viruses are all over the map phylogenetically; they really shouldn’t have much in common past their common use of an RNA genetic payload.
Indeed, PIKfyve has been shown to be an important regulator of endosome activity, particularly early endosome formation. That means that it could be right up there at the beginning stage of viral infection, because endosomes are how many viruses actually deliver their genetic material into a host cell. The data in this new Nature paper strongly suggest the apilimod be tested as a preventative of coronavirus infection and in patients who already have the disease.
But there’s more to the story – I haven’t seen this highlighted, but PIKfyve has also been shown (by the Bertozzi group at Stanford) to be a key part of the process whereby antigens are presented to the surfaces of dendritic cells (for T cells to then come along and recognize them). That is an absolutely crucial part of the immune response to new antigens, and that paper (which came out in January of last year) showed that apilimod and other PIKfive inhibitors do indeed impair immune function and T-cell activation. That’s just what you don’t want in a viral infection!
So clinical trials of apilimod are going to be rather interesting. Will it protect from viral entry, but make other (nonviral) infections more likely? The balancing act between the viral entry inhibition and immune system impairment is something that can only be evaluated for sure in human patients. It’s one of those little biochemistry jokes – there are several of these – that the relentless evolutionary repurposing of enzymes and mechanisms should come along and complicate the attempt to repurpose a drug when it’s needed the most.
Headlines appeared last night about Moderna losing a patent case that affects its coronavirus vaccine work. I know from long experience on this blog that any discussion of patent and IP issues has an effect on my readership traffic numbers that looks like I’m paying folks not to click on my links that day, but I’m going to brave this one. What’s going on?
For starters, it’s worth realizing that this dispute has been going on for quite a while. To an excellent approximation, all patent disputes have been going on for quite a while. The smattering of new ones are more than averaged out by the ones that have been Jarndycing their way through hearing after hearing. Here’s an article from 2016 and a followup in 2017 that go into some of the details in Moderna’s case. The issue is not about their coronavirus vaccine per se, nor is it quite about their own mRNA technology. It’s about what one has to do to get things like mRNA constructs to survive in the bloodstream so they can even be contemplated as drugs in the first place.
That takes you into modified RNA bases (for one thing) and very much into formulations, for another. Formulation science is one of those things that people outside drug development tend to not think much about (if they even know that it exists), but it’s really important. Getting an orally dosed drug out of the gut (or even just past the stomach) and into the bloodstream, and getting an injected one to circulate around in said bloodstream instead of being destroyed on contact – those can be big deals. It’s definitely a big deal for something like a small bundle of RNA.
Oral delivery is right out for those things – I don’t know what kind of wizardry you’d need to give someone an “mRNA pill” and have it be usefully absorbed into the circulation, but we sure don’t have anything like it yet. Nope, this is an injection from the very start, and even there you have serious problems. Here’s a paper that notes that if you add plain RNA to plasma samples, none of it is intact enough to be amplified after a wait of fifteen seconds. There are “cell-free” RNA species floating around in the blood, but your mRNA therapy is unlikely to share their characteristics, because there are a lot of different forms of RNA. Even those degrade easily enough.
And once into the bloodstream, whatever oligonucleotide species you’ve injected (be they mRNA, antisense DNA oligos, RNA interference species, etc.) that survive are highly likely to end up in the liver anyway, so you’d better be OK with that. Wherever they go, they are probably going to have to be taken up into cells and find their way to the right compartments once inside, and those can be rather high hurdles as well. It’s no accident that all of the neat ideas for dosing RNA and DNA-based therapeutics have taken so many years (and so many dollars) to be realized in practice – a huge amount of thought and experimentation has gone into getting us this far, and we’re still finding out new things.
Moderna, for its part, decided years ago that lipid nanoparticles (LNPs) looked like the way to go. This technique places the RNA constructs inside small lipid bubbles of lipid to protect them, and there’s an ever-growing list of variations on the idea and how to realize such species in practice. Moderna did a deal with a small company called Acuitas for access to this sort of thing, but Acuitas in turn had licensed it from another company, Arbutus. Whereupon Arbutus terminated their agreement with Acuitas, saying that they had no legal right to sublicense the technology to Moderna. They sued Acuitas in Canada in 2016, and ended up with a settlement in 2018 that allowed the Acuitas/Moderna sublicenses to stand (but no others). But. . .at just around the same time, Moderna launched an offensive at the USPTO to try to invalidate two Arbutus patents entirely. Earlier this year they asked for another review on a third Arbutus patent.
Moderna had been spending a lot of time talking about how well, you know, that Arbutus stuff was just OK, not really all that good, and how they’s moved so far past it that it really wasn’t a concern any more, etc. But the move to asking for inter partes review at the PTO is an example of what we call revealed preference, rather than stated preference. A general rule: always watch what people and companies actually do, rather than paying so much attention to what they say they’re doing. Speculation is that the 2018 settlement would have only covered uses in Canada, and that the far-more-lucrative US situation was therefore unresolved, so Moderna opened fire.
Inter partes review has been around since 2012, and it’s fair to say that overall it’s not a popular provision of US intellectual property law if you ask biopharma companies. Many of them consider the process as leaving too low a bar to initiate patent validity challenges – or at least they consider it so until it’s time for them to challenge someone else’s patent, and then it’s any weapon to hand. A big factor is that the IPR process doesn’t take place in the good ol’ Court of Appeals for the Federal Circuit, like such things used to, but rather goes before a Patent Trial and Appeal Board, the PTAB. This speeds things up and makes such challenges much less expensive, which as you’d imagine are only appealing features if you’re playing offense. Inter partes review last reared its shaggy head here during the 2017 Allergan/Mohawk fiasco – the entire purpose of that ridiculous strategy was, in fact, to make some of Allergan’s patents completely impossible to be touched by IPR at all because now (ta-daa) they were owned by a sovereign Indian tribe.
You can ask for such a review only on the patentability criteria of novelty and/or non-obviousness, sections 102 and 103, which come down in many cases to showing that some prior art exists that makes the patent under dispute either not novel or “obvious to one skilled in the art”. Relevant prior art can found in all sorts of stuff – other patents and patent applications, journal articles, public disclosures at scientific meetings, and so on. Moderna actually won their first patent challenge before the PTAB, getting all the Arbutus claims in it invalidated via such arguments. They had a partial win on the next one – some claims were tossed, but some stood. But yesterday they completely whiffed on their third challenge: all 22 claims in that Arbutus patent were upheld.
So what does this tell us? It seems clear that Moderna was worried about Arbutus waiting until such time as the coronavirus mRNA vaccine looked ready to take off, and then getting hit with a filing for infringement. The IPR challenges were an attempt at pre-empting that – can’t claim infringement of invalid claims, can you now? The situation now is unclear. I don’t know which of the upheld claims is the biggest threat to Moderna, and it would take me about a month of study to even have an informed opinion. Patent litigation is excruciating stuff. Neither do I know how much money Arbutus would come after them for, but clearly it was enough of a concern for Moderna to launch their own first strike (remember, Arbutus has never taken Modern to court directly at all).
This latest decision is expected by many to be appealed. That would take it to the Court of Appeals for the Federal Circuit, and that’s a much lengthier process. Moderna certainly seems to have standing for such an appeal (as that link will show, that issue has been the subject of much combat in the last few years), but the question is whether they want to do that now or wait until Arbutus comes after them.Or do they want to approach Arbutus directly and see if they can come to an agreement, rather than continuing to tango in the current fashion? Rather highly-paid lawyers are no doubt considering these questions right now.
You’d have to pay me an awful to to work it out, I can tell you right now. What seems certain is that Moderna will be pushing ahead with their vaccine, and that this issue will be hanging over them while they do. I don’t see this slowing down the vaccine development itself, since none of the lawyers are working in the labs. But it is a distraction for the higher-ups and perhaps a weight on the company’s stock price. But hey, Moderna’s executives seem to have unloaded plenty of their positions already, right?
The candidate vaccine will combine Medicago s recombinant coronavirus virus-like particles (
According to a July 7, 2020 press release, SGS has already initia
Approval for the therapy was based on the results
General chapter 2.6.32 Test for Bacterial Endoto
As we have discussed here previously, real-world data (RWD) and real-world evidence (RWE) offer many potential benefits in every stage of the drug discovery and development process, continuing on into post-market surveillance. With drug developers and other researchers becoming more interested in using RWD and the RWE that results from analyzing it, regulatory agencies have had to step up and work on producing guidance.
There are many
challenges that accompany RWD. Its various forms (e.g. EHRs, disease
registries, claims data) are not necessarily subject to the same
well-established regulations and protocols as clinical data. The data might be
inconsistent, unstructured, in multiple formats and it may not adhere to the
principles of FAIR data. As regulatory bodies consider RWE, they must think
about the quality of the data underpinning it.
The FDA offers
The Food and Drug Administration (FDA) took its first big step in December 2018 by publishing a framework for their real-world evidence program, which helped to lay out some of their goals and issues of importance to be addressed, such as how RWE will be used for regulatory decision-making for drugs, considerations for observational study designs and clinical trial design, data standards for submissions, regulatory issues around the use of electronic source data and more. Actual draft guidance for submitting documents using RWD and RWE for drugs and biologics then followed in May 2019.
The EMA grapples with real-world
Meanwhile in Europe, the European Medicines Agency (EMA) has also had to address the intense interest in RWD and RWE, though there are clearly concerns about whether real-world evidence can be credible evidence. In an article published in the journal Clinical Pharmacology & Therapeutics in October 2019, the EMA officials who authored it noted concerns that “acceptance of non‐RCT methodologies is tantamount to lowering the quality of evidence because these methods are prone to a myriad of undetected or undetectable biases.”
They remain optimistic
about the future for RWE, but are adamant about the importance of testing and
validation. “The ultimate key to achieving credibility is to start with an open
but ‘agnostic’ mind‐set and submit novel
methods to a fair, transparent, and prospective validation exercise,” they wrote.
The pharma response
The FDA has invited comments on its draft guidance, and the pharmaceutical industry has obliged. As reported in Policy & Medicine, a number of suggestions have come in from major players. Gilead, for instance, has proposed expanding the submissions list so that supplemental new drug applications and supplemental biologics license applications are included. Gilead has also suggested lab data be considered a source of RWD, and Novartis has suggested pharmacy claims should be considered a source for RWE.
What is quite clear is
that we are in the early stages of what will be a long process, as regulators
work to formulate policy and guidance for a type of data that they are still
trying to fully define. Real-world data and real-world evidence have much to
offer in drug development and post-market, and it will be important to have the
guidance and cooperation of our most influential regulatory bodies.
In our next piece on
RWE, we will discuss the role of real-world evidence in the fight against
COVID-19, including a new research project spearheaded by the FDA.