Not done yet. The COVID R&D Alliance has plenty on its plate for 2021
Takeda’s Andy Plump and Theravance’s Brett Haumann discuss the consortium’s priorities, and what lessons carry forward for 2021 and beyond
Takeda’s Andy Plump and Theravance’s Brett Haumann discuss why master protocols make sense, how well — or not — data-sharing is going, and what’s next for the consortium.
With little fuss or fanfare, the COVID R&D Alliance was created early in the pandemic by the biopharma industry’s biggest players to solve one of the world’s most devastating problems in a century. Now, the looming question for this and the other COVID consortia is where do they go from here, as success on the vaccine front offers hope for an end to the emergency.
BioCentury sat down, virtually, with Andrew Plump and Brett Haumann, two members of the 22-strong COVID R&D Alliance, to discuss how the group views its mission in the coming year. Plump is President of R&D at Takeda Pharmaceutical Co. Ltd. (Tokyo:4502; NYSE:TAK) and Haumann is CMO at Theravance Biopharma Inc. (NASDAQ:TBPH).
What separates the COVID R&D Alliance from the two other major COVID consortia, ACTIV and the COVID-19 Therapeutics Accelerator, is that it was not coordinated by a public sector entity but was pulled together spontaneously by a group of pharma R&D heads looking to avoid redundancy of efforts and put competition aside to expedite the creation of countermeasures. ACTIV was created by NIH and the Foundation for the NIH (FNIH), and the CTA was launched by the Bill & Melinda Gates Foundation, the Wellcome Trust and Novartis AG (NYSE:NVS; SIX:NOVN), both as public-private partnerships.
Though all three consortia have overlapping memberships, that has been an asset rather than a hurdle, according to Haumann and Plump, because it has allowed the groups to focus their efforts to fill different needs. For example, COVID R&D stood down on vaccine development when it was clear that other initiatives were filling that need, and it put its greatest energy into identifying repurposed or new compounds that could treat COVID-19. The COVID R&D Alliance includes R&D heads from 15 pharmas, five large- to small-cap biotechs, and VC firms 5AM Ventures and Versant Ventures.
“We need to be forward-looking because this is not a one and done. This is something that is clearly going to happen again.”
The Alliance evaluated compounds from member companies’ portfolios, and coordinated with BioCentury to employ its COVID-19 Resource Center to channel candidate molecules from across the biomedical community into the group’s evaluation system.
In April, COVID R&D partnered with Quantum Leap Healthcare Collaborative, the consortium behind the I-SPY 2 breast cancer master protocol, to launch an I-SPY adaptive trial with the goal of evaluating 10-20 agents within a year to treat ARDS, the late-stage respiratory failure that can lead to death in COVID-19.
The trial, which started in July, is evaluating razuprotafib from Aerpio Pharmaceuticals Inc. (NASDAQ:ARPO), cenicriviroc from AbbVie Inc. (NYSE:ABBV), Otezla apremilast from Amgen Inc. (NASDAQ:AMGN) and Firazyr icatibant from Takeda, each in combination with Veklury remdesivir from Gilead Sciences Inc. (NASDAQ:GILD). The active comparator is remdesivir plus standard of care.
In November, COVID R&D launched its own master protocol trial, COMMUNITY, (COVID-19 Multiple Agents and Modulators Unified Industry Members), in a broad range of hospitalized patients. The blinded, placebo-controlled study is starting with immunomodulators that impact the vasculature, pursuing mechanisms that haven’t been tested in randomized controlled trials for COVID-19 before. Its first compounds are the PDE-4 inhibitor Otezla, Takeda’s Takhzyro lanadelumab, a mAb against plasma kallikrein, and zilucoplan from UCB Pharma S.A., a macrocyclic peptide that disrupts the complement cascade.
Plump and Haumann think the informal platform and fluid group dynamics — which involve various subgroups that meet as needed — have enabled fast decisions and represent a template that could be applied to other diseases.
Likewise, the experience of designing clinical trials under pressure has taught the group strategies that will prove useful elsewhere in drug development, says Haumann.
One area with mixed results is data-sharing, a priority for several of the group’s members who had hoped to see greater engagement. Though big strides have been made for sharing information, best practices and real-world data, Plump gives the industry a C-plus when it comes to sharing patient-level data from clinical trials, a topic he plans to continue pushing.
But both are convinced the success of the mRNA vaccines was not luck but the convergence of the investment in new modalities, the advance of science, and the power of competent execution under pressure.
A transcript of the conversation, edited for clarity, follows.
BioCentury: After an extraordinary year that has brought many of the industry’s biggest players together, and with vaccines now a reality, what is next for the Alliance, and what plans do you have for 2021?
Brett Haumann: We do recognize that the pandemic hasn’t disappeared, as fantastic as the progress has been. Just over 12 months ago, nobody in the world had even heard of COVID-19. So to see the progress in a year is absolutely phenomenal.
But I think the challenges do remain. During [the vaccine rollout], people will remain at risk. So, the potential exists still for therapeutics to be of value.
We’ve all within the Alliance felt that a broad swath of efforts — including diagnostics, therapeutics, monoclonal antibodies, vaccines — was all needed in order to deal with this pandemic.
So, in 2021, you'll see a continued effort, particularly on the therapeutic side. In particular, the Alliance has been invested in the COMMUNITY study, which will be evaluating the role of several therapeutic options in treating patients with confirmed COVID-19.
I think that that effort will be critically important. It’s likely that the insights that are gained through that and other platform studies will continue to have value through next year and into 2022.
One of the interesting things about therapeutics, and particularly anti-inflammatories, is that they’re likely to be future-proof. They will benefit patients, not just because of COVID-19–related lung injury, but likely they'll benefit patients who experience a similar sort of phenomenon in future pandemics, including flu or para-influenza.
Some of these efforts are investing clearly in the current crisis, but would have some longevity and some value beyond that.
Andy Plump: To underscore what Brett said — clearly we need to execute on what we’ve put in place, and that’s to continue to enable the vast array of activities that are ongoing by member companies.
Secondly, we need to be forward-looking because this is not a one and done. This is something that is clearly going to happen again. We know it, and we need to be better prepared. And all of us are thinking of how we can step up to ensure that when the next COVID-23, 29, 42 comes around we’re ready to deal with it.
“I don’t think it’s an accident that the first two vaccines are mRNAs. I think that this methodology, this mechanism, this tool, was waiting for its time and history.”
BioCentury: Do you plan to expand this effort to other areas such as Long COVID?
B. Haumann: Long COVID really is poorly understood at this stage. I don’t think we’ve got a good handle on it just yet. We know from SARS that there are chronic manifestations. It’s interesting that both fibrosis of the lung and avascular necrosis of long bones, like the femur, manifested after SARS. So, we do know that, probably driven by vasculitis, both of those are risk factors for COVID-19.
But it really is just too early to know for sure how this is going to manifest. We’re seeing some really interesting cardiac and neurological deficits that are emerging. And I do think that you’ll see perhaps the same players, but maybe different players, emerge, who may have different therapies to be able to apply to patients with Long COVID.
I think that the pre-competitive opportunities that we’ve applied and experienced this year could be applied in that setting as well.
BioCentury: This group came together spontaneously without wrangling over terms or lengthy agreements. How did that happen, and do you see situations outside of COVID where a similar structure might be deployed?
A. Plump: When we started this, it was really ad hoc, and there weren’t a lot of lawyers. There wasn’t a lot of process and wasn’t a lot of bureaucracy, but very early on two of us, Rupert Vessey [president of research and early development at Bristol Myers Squibb Co. (NYSE:BMY)] and myself, realized that we needed to put something in place to ensure that we were functioning in a legal way and in a precompetitive way.
We leveraged some documentation that came out from the Federal Trade Commission and the Department of Justice, allowing for closer collaboration within industry, given the emergency that we were in. And we asked our lawyers to come up with a memorandum of understanding in line with that.
The first document we got back was a vastly truncated, legal document; rather than 100 pages it was eight pages, single line, 10-point font. And I read about 30 seconds into it, and then I sent it back to my lawyer, and said, “One page, max.” And they came back with an MOU that was straightforward and simple. And it was a paradigm for how we’ve functioned.
“We’ve understood what is truly precompetitive information-sharing because there’s a lot more that’s precompetitive than not.”
As to whether we could do this in other settings, the answer is: absolutely.
We’ll have to figure out how we can best apply our collective efforts. There’s so many opportunities for us to work precompetitively in the life sciences.
We’ve understood what is truly precompetitive information-sharing because there’s a lot more that’s precompetitive than not. So, I think we really figured out as a broad ecosystem, how to do this, and I think there’s going to be great opportunities in the future to apply the same mindset.
Let’s go to a non-communicable disease that’s a huge challenge for the industry. Alzheimer’s disease has huge opportunities there for us to figure out how we work more efficiently and more effectively.
BioCentury: Early on, in collaboration with the Alliance, BioCentury created a portal to document molecules that could be candidates for COVID-19. How has that played into the team’s work and can you give an update on the effort?
A. Plump: So firstly, we can’t thank BioCentury enough for stepping up right from the very beginning and offering to help. One of the things that we were finding is that there was just so much information to access, and there was so much redundancy and inefficiency in the system. And very early on, we identified sharing in two ways, information-sharing and data-sharing.
BioCentury stood up the portal that allowed us to share information, not just on compounds that could be potentially repurposed, but on ongoing trials and access to assays, across the ecosystem.
B. Haumann: For the repurposed molecules, I think what we’ve seen is a fascinating, fairly eclectic group of molecules coming forward to tackle various elements of what might be missing in the armamentarium.
What’s impressed me is how rapidly the Alliance can respond to emerging data. We’re not the only group that are looking at large platform-type studies. Andy’s involved through ACTIV looking at the collaboration through NIAID and other groups as well.
The inputs from those are taken into consideration when we think about other mechanisms that may be of interest. So, we try not to replicate what’s already being done in other settings.
The mechanisms that you see coming through, mainly either approved or late-stage development assets with some safety information to support them, are really testing novel mechanisms.
One of the things that the Alliance has been working on is how do we think about earlier stage assets — assets that don’t have large safety databases, that haven’t been tested in other settings. How do we create a nimble approach to developing those in a COVID-19 setting as well?
BioCentury: The COMMUNITY trial, which launched recently, was some months in the making. Can you outline what went into the decision to create a master protocol? Why make a new one rather than join an existing one?
B. Haumann: The first three or four months of this year were defined by individual efforts. But I think very quickly people realized that if we were able to come up with platform studies, adaptive designs, integrated analyses, we could save time and patients because often these platforms studies have the value of using a common “placebo arm.” Really, it’s not placebo. It’s a standard of care, on top of trials.
One of the key things that I think was important to take stock of was a change in the regulatory environment. The initial design of the COMMUNITY study was actually open-label and had no standard of care reference arm. But the FDA were pretty clear, particularly by the late spring, early summer, that really to provide rigor and to support emergency use authorization, there needed to be additional statistical rigor placed on these studies, including the insertion of a control arm, and by extension, trying to blind these studies as well.
So that took a little bit of adaptation. I think the COMMUNITY study is stronger for it. But that took a bit of time to integrate into the thinking.
BioCentury: Data-sharing has been a big priority within the Alliance but is still a very thorny topic. How would you rate progress there?
A. Plump: When we think of data-sharing, let’s think of three buckets.
One is real-world evidence — datasets that exist in the outside world — how we approach those datasets, the kinds of questions that we ask, the methodologies that we use. It’s really important that we share methodology and approach.
Secondly, there’s clinical trial data, summary data and thirdly, clinical trial data — patient level data. There’s value in sharing all three.
I think the greatest progress that we’ve made during the pandemic has been in the first bucket. We’ve worked very closely together and with key stakeholders across the ecosystem, such as the FDA, and the Reagan-Udall Foundation, which has worked very closely with a number of biopharmaceutical companies to ask questions that you can get at using real-world data, like the natural history of this disease.
[For the second bucket], there’s been great intent around sharing summary level statistics.
That’s something that we’ve done as an industry already. It’s not done as well as it could be, but it’s something that we’ve already agreed to.
We were hoping to set up new platforms that would accelerate access to these shared datasets, given the acuity of the pandemic and make these datasets available as data, not text, but data.
I would say that there’s been great energy and engagement, but I think in the end, the results have been mixed to poor.
And then the last is patient-level data. It’s something that the industry has set up a capability with TransCelerate to share control arm data from clinical trials, which is great because it helps us understand the natural history of disease.
But we’ve not ever shared patient-level data. And that was something that we were hoping for in active arms — that was something that we were hoping to do with this pandemic. And we haven’t made headway there. So, I think there’s still a lot of room to grow.
Part of it is having the right infrastructure in place, but I think it’s still a behavioral adaptation.
So, I would say we get a C-plus. We’ve made some headway and that will carry forward, but I think there’s a lot more that we need to discuss and figure out how we can do better.
“What’s interesting is that a lot of our randomized protocols have become more real world, out of necessity.”
BioCentury: Do you think the pandemic has substantially changed the case for real-world data ?
B. Haumann: As a consequence of COVID, real-world evidence has often been spoken about as the opposite of clinical trial evidence because the population doesn’t represent the folks that you ultimately plan to treat.
What’s been interesting about COVID is the impact it’s had on randomized studies, as a response to needing to move quickly.
Both in COVID studies, but also in non-COVID studies, I’ve certainly experienced a dramatic change in the way that we consider protocols for our randomized studies.
Whereas previously we would have come up with a list as long as your arm of all the reasons why patients couldn’t participate, that hasn’t been the case in COVID. I think we’ve recognized that in order to respond quickly, we’ve needed to have a very short list of criteria that patients would qualify for.
What’s interesting is that a lot of our randomized protocols have become more real world, out of necessity.
Patients are unwilling to come into clinical settings in hospitals because of the risk of exposure. A lot of our efforts now are around making those studies more pragmatic, bringing the study to patients in their own homes, which I think is starting to reflect more real-world experience for these patients.
So, it’s probably an unintended consequence of the pandemic, but I think protocols as a rule will become a little bit more real world in the future.
BioCentury: The industry came up with two vaccines, at least, within a year, with the first being mRNA vaccines. Did we get lucky with that technology? What does this achievement mean in terms of the probability of being able to accelerate other therapies?
B. Haumann: I’m not an expert in vaccine development. But I think that in times of enormous stress — or, in this case, pandemics — you see an acceleration in new methodologies, new scientific efforts, new rigorous ways of doing things.
I don’t think it’s an accident that the first two vaccines are mRNAs. I think that this methodology, this mechanism, this tool, was waiting for its time and history. And I think we’ve demonstrated that this is it, that actually a clean, non-viral particle-derived approach could be done at pace and at scale.
So, it’s not an accident that these first two are landing where they are. They’re unprecedented, so there’s still this question in the long term about, did we miss anything? It will still take some time for people to build confidence.
But I do think though that it was that scientific advance that actually gave them the edge. I don’t think it was by accident.
A. Plump: I don’t know if we got lucky or unlucky. We’re unlucky to be in this situation. We’re unlucky that this virus is so potent and so has such a high R0 [R-naught] and is so transmissible.
But why is it that the most rapid vaccine out there is an mRNA vaccine? I think you have Pfizer as a powerhouse in vaccine development. They know what they’re doing, and I think that helps.
And stringing it together, nucleotides from a CMC standpoint, from a manufacturing standpoint is easier than purifying a viral protein and making a vaccine in a traditional way.
So in some ways it’s not a surprise that you have a new modality that can leapfrog all modalities and offer solutions to some of the challenges, particularly the manufacturing challenges.
It’s not easy to manufacture — I don’t want to suggest that — certainly at the scale, hundreds of millions and eventually billions of doses that are going to be necessary. But if you take someone who runs a manufacturing organization, and you ask which is an easier solution to solve, putting nucleotides together is much easier than purifying proteins.