21 Jan 2016

After months of public acrimony over the Alzheimer’s Disease Cooperative Study, the University of California, San Diego, announced on January 14 that Howard Feldman would take over the embattled clinical trials network as part of a broader appointment to UCSD’s School of Medicine. Feldman, currently the executive associate dean for research at the University of British Columbia in Vancouver, is among the most highly regarded clinician-researchers in the field of age-related neurodegenerative disease, and an Alzforum advisor. His appointment comes 25 years after the ADCS was founded by Leon Thal, a beloved visionary of AD research (see Alzforum obituary).

"Dr. Feldman has had a distinguished career in both academic medicine as well as in pharma, where he led important drug trials for Alzheimer’s disease. He is well respected and has superb scientific and administrative skills, which should prove to be a huge asset,” Tony Phelps of the National Institute on Aging told Alzforum. Feldman’s formal appointment to the ADCS is pending NIA approval. NIA supports the ADCS. For details on Feldman’s career, see UCSD press release.

The dispute that erupted last June over the departure of the ADCS’s previous director, Paul Aisen, to the University of Southern California subsequently devolved into lawsuits, countersuits, and an ongoing court battle over control of ADCS data. Along the way, the ADCS itself lost A4, its flagship clinical trial, as well as ADNI2 and other treatment trials to USC, and at present has few active trials on its docket.

Feldman has plenty of ideas—and the power—to revive it. Starting this April, he will assume a dual appointment at UCSD. Feldman will direct the ADCS and also take the newly created academic position of dean for Alzheimer’s and related neurodegeneration research at UCSD School of Medicine. In this role, he can support both the NIH-funded Shiley-Marcos Alzheimer’s Disease Research Center (ADRC) and neurodegeneration-related basic research at UCSD’s Department of Neurosciences. Researchers from both the ADCS and the ADRC will move into a new building UCSD is planning to open this spring.

Feldman envisions a future in which the ADCS stimulates and executes innovative designs, outcome measures, and other building blocks of successful trials for the first time, while also interacting in many more ways with the ADRC and research groups throughout UCSD and beyond than had been the case in recent years. “My goal is not to direct everything, but rather to create a really robust environment with successful programs in such a way that people see they are part of a larger whole,” Feldman told Alzforum (see Q&A below).

ADCS researchers, many of whom wanted nothing but to stay above the fray and focus on their work these past six months, universally welcomed the news. “Howard Feldman is outstanding. He is compassionate and genuinely interested in the future of ADCS. I hope to work with him,” said Michael Rafii, who leads the ADCS’s newest study, a Phase 1/2 trial of an anti-amyloid vaccine in adults with Down’s syndrome. Other ADCS staffers told Alzforum that they are elated, even “going bananas,” over Feldman’s move to La Jolla.

For his part, Aisen expressed a similar sentiment. “It is very good news that Howard Feldman is moving to San Diego. I have collaborated with Howard for many years; he is an esteemed member of the AD scientific community, with an unusually broad perspective from his experience in academia and industry. Most recently we worked together toward building international trial infrastructure in the U.S., Canada, and Europe; Howard’s leadership has been a driving force in this ambitious effort. I am optimistic that our research teams will work together toward our common aim of accelerating the development of effective AD therapy,” he wrote to Alzforum.

For a flavor of Feldman’s vision, read on below.—Gabrielle Strobel

Q&A with Howard Feldman

Q: You will be director of the ADCS and dean for Alzheimer’s and related neurodegeneration research. How do the two positions relate?

A: Together they afford the opportunity of bringing together all the pieces of the Alzheimer’s effort within the environment at UCSD. There is the Shiley-Marcos ADRC, the ADCS, and an incredibly vibrant neuroscience community. They started out as parts of a whole under Leon Thal, but over time have become less integrated. My title reflects a leadership role to take a programmatic view to rebuilding the efforts within UCSD and re-integrating them into a larger vision. I will think strategically about growing the efforts, and the mark of success will be to have a lot of interactions between the different parts of these groups and see that they are in regular contact with each other. For current ADCS programs, some are moving over to the ATRI, and for each program there is a plan to manage the intervening period. The new building will facilitate that because UCSD and ADRC researchers will be sitting next to each other for the first time in many years. Beyond that, I am excited about the proximity of the Scripps, the Salk, the Burnham, and J. Craig Venter research institutes. There is a lot of potential within the local environment for target identification, validation, and translation into early clinical trials.

Q: So you will work regionally to bring together research across different institutions?

A: Yes, it’s a unique environment to have this much intellectual horsepower accessible. Part of the opportunity is to bring groups together and create the forums by which the scientific changes will be enhanced with an eye toward clinical translation.

Q: Will there be a new ADCS funding cycle?

A: I expect there will be new funding opportunities, but they could be different. I do not know whether the next RFA will be open or closed, or take a different view. I have not yet had discussions with NIH on that. I could change to an open and competitive process rather than a renewal. Funding through the bypass grant offers opportunity to leverage the tremendous resources and capabilities of ADCS. It will be important for ADCS to have a crisp vision.

Q: What is your vision for the ADCS?

A: To prepare it for the future. At the moment the ADCS has its NIH deliverables. It is responsible for a grant that will run through end of 2017. This involves a number of clinical research trial programs, which will continue fully supported through the network. My goal for the coming two years is to create new programs to engage the network beyond the end of the grant.

Q: What will that look like?

A: We will create value from the ADCS’s rich trove of samples, brain imaging, data, as well as from its potential for modeling and long legacy of network capabilities. If we use all that, ADCS can make unique contributions to the field. I think there are things the ADCS can provide to the field that will not be done in industry. When I worked at BMS [Bristol-Myers Squibb], decisions would follow strategy, and strategy would be defined. Pharma often is an environment where there is less support for out-of-the-box, unproven ideas that lie off the main strategy. That creates sharp focus on one target and little focus on other targets. With ADCS, we can diversify the mix of targets and undertake novel trial designs.

Q: For example?

A: It has been said you cannot achieve clinical proof of concept in an early trial. I would like to disprove this using novel designs such as an adaptive clinical trials platform or highly tailored personalized approaches.

Another example from the recent past is moving into earlier-stage, prodromal AD trials. Many people argued you can’t do prodromal trials when we started with avagacestat. We actually showed you could do it. My point is that once a trial innovation is done, then the field expands. Whether it is showing a new design, or operationally opening up portions of the disease with new diagnostic criteria—once it’s been done it gets taken up more broadly.

Q: So ADCS comes in because …

A: … it can show new ways that then give industry confidence to invest heavily in them. The ADCS can be central to that. It can be a data testing ground for novel designs, novel outcomes, novel targets. That is how it started. I want to recommit ADCS to doing things that can’t be done elsewhere. That is the guiding principle.

Q: Originally, the ADCS’s vision was to test drugs that industry would not, because the patents had run out or for other reasons. There were many negative trials, and some criticism. More recently the ADCS partnered with industry on investigational drugs that were originally developed for AD. Under your leadership, will the ADCS revert to the original vision of trialing repurposed compounds?

A: The idea of doing things others won’t be able to do, and won’t do, is very important. Developing an amyloid-lowering monoclonal antibody is now in the mainstream of pharma interest. That is not is the best place for ADCS to be creating novel value. Taking a first-in-class or taking a repurposed compound is an attractive way of creating unique value.

Q: But you would do it differently than in the past?

A: I do think it’s critical to apply the lessons of pharma with the goal of increasing the likelihood of success and bringing down risk. We will ensure that each trial uses a pharmacodynamic biomarker that hits its endpoint before moving from early to a larger-scale trial. We will also use a second, disease-related biomarker that suggests there is some impact on disease before scaling up. Both criteria are equally important, and have not been always accomplished in the past. I’d like to re-conceptualize a decision tree for trials. That is an important part. My vision for ADCS is to apply what I learned in pharma and academia in the same setting. It is very exciting to have ADCS to both simulate and execute such trials, knowing that you have a well-established network behind it to conduct the research.

Q: Let’s talk about the movement in the field for the past seven years or so to skip over the classic Phase 2 proof-of-concept trial. ADCS has been doing Phase 3s of late. Where in the clinical pipeline do you see most bang for the buck in the next two to five years?

A: In clinical proof of concept. PoC is a curious term that gets bandied around and people potentially mean different things when they use it. The proof of concept I’d like to see has a staging around it. We would declare proof of concept when we have driven a pharmacodynamic biomarker and a disease biomarker in a way that met its pre-specified goal and you have transitioned into some level of clinical evidence to support a general directional sense that you are making progress.

Q: What trial design would you do this with?

A: For example, the adaptive trial platform is a way of seamlessly transitioning between those two things. I am very intrigued by that. There are inherent challenges, but I am attracted to the idea that this is a technique by which we could achieve proof of concept in new ways. We will closely watch the adaptive BAN2401 Phase 2 trial.

Q: What other designs interest you?

A: Combination trials. Achieving proof of concept with a therapy combination will be even more complex. That is a huge agenda of things to undertake, and do it with a diversified mix. That is where my passions reside. It would be thrilling to mount these on an adaptive trials platform. You would be working with a higher probability of success for Phase 3 if you could just get that proof of concept nailed down.

Q: This sounds like an adaptive platform for late-onset AD the way DIAN is trying to build for autosomal-dominant AD. Don’t you want to use the ADCS for things no one else is doing?

A: In some ways my vision is similar to DIAN, but no one has taken on late-life sporadic disease in this way. Sporadic late-life AD could be more complicated, with a greater variety of contributing factors, and LOAD may be less amenable to a single intervention than autosomal-dominant AD. We may end up in a different place in terms of what the trials and the therapies need to be. There is progress to be made in applying big data to selection of patients, and in actually working through levels of modeling and target identification and validation before moving into proof of concept trials. This is a large space to work in.

Q: Then how does your ADCS vision differ from EPAD's?

A: EPAD [the European Prevention of Alzheimer's Dementia Consortium] has put its imprint on prevention. I am very supportive of prevention and want to be involved, but I also want to find treatments for symptomatic patients. The huge interest in prevention makes it seem as if there is less attention on symptomatic AD. I see an ADCS helping to find drugs with a sustained benefit that really improve the quality of life of people with symptomatic disease.

Q: How will ADCS relate to GAP NET?

A: I do not have an answer yet. ADCS has well-established and mature capabilities. I hope it can be seen in that light in developing network partnerships, including working with GAP NET in a way that is enabling to GAP NET. I worked hard on developing the construct associated with the Global Alzheimer’s Platform and look forward to engaging in these efforts. Our collaboration can be non-denominational. We should work wherever we can benefit the process of developing new treatments. There is room for multiple networks in the work we all do. I don’t know that it needs to be one. There may be benefits in having several networks to really stimulate the field.

Q: I asked because I heard talk that once established, GAP NET may render ADCS obsolete.

A: If we had achieved five new successful treatments in the last 15 years, I would agree we may be looking at limited capacity. Progress being what it has been, there should be lots of opportunity and a stimulated development economy to be driving in multiple directions with the hope that we can actually succeed. Now is the wrong time to fold up a well-established network that has been built for 25 years. Even just its resources—the samples, imaging, data—renders it invaluable. It is a great set of capability. I have come to meet its people and they are dedicated and know a lot. Like all research networks, it has to be successful within whatever frameworks of competition there are. It is likely that the future landscape will be different than the past, and ADCS may have to reinvent itself.

Q: Will ADCS branch out to other dementias? It just took on a Down’s syndrome study. What about frontotemporal dementia (FTD) or dementia with Lewy bodies (DLB)?

A: I look forward to engaging with my colleagues in the FTD and DLB world about whether the ADCS could provide something very timely and useful. FTD and DLB trials are nascent efforts. Maybe there is something the ADCS can offer to create robust opportunities that help move more quickly? Imagine you have a choice between engaging with a mature network or building a new network. There is merit to saying, “I know it’s an Alzheimer network, but it really understands dementia trials. Maybe we could leverage its existing capabilities and expertise.” I see no a priori reason not to do it.

Q: Example?

A: Don Cleveland at UCSD has been involved with antisense oligonucleotides that are being developed in spinal muscular atrophy and Huntington’s disease. Those are very exciting. They offer us the possibility of choosing genetically defined circumstances and running well-constructed trials. The field of neurodegenerative disease needs a few wins. I see a unique opportunity in genetically determined diseases that are predictable and can be characterized and precisely targeted with therapies.

Q: The dispute between UCSD and USC over control of the ADCS database is not a problem of your making, but since you are going there, what is the situation you are going to deal with?

A: I am not coming to enter into that dispute, and I intend not to get involved. The dispute is being dealt with at the court and institutional levels on both sides. For current ADCS programs, some are moving over to the Alzheimer's Therapeutic Research Institute, and for each program there is a plan to manage the intervening period. Everyone is aware that the integrity of patient care is of paramount importance, so there is no disagreement over that. The well-being of research subjects within those trials is carefully managed because everyone realizes the downside of not looking after that properly. The programs that remain within ADCS will become my primary responsibility. Where I will assume responsibility is not where the dispute lies.

Q: You have known Paul Aisen for many years. You both are important to this research community. Can you work together?

A: I have enjoyed a very collegial relationship with Paul and expect that that will continue. I don’t see anything that would change that. We owe it to patients to do everything possible to advance and make sure our collaborations are in the best interests of the people we are trying to help. The dispute does not affect my relationship with Paul, and the ADCS can still have a relationship with the ATRI.

Q: Was the UC Cures for AD program already being developed when you started talking with USCD?

A: Yes. The idea had germinated and was ready to go.

Q: This program will award $4 million to two projects from within UC that focus on early proof-of-concept clinical studies. Is this significant?

A: Yes, insofar as it will stimulate groups across the UC system to start talking, collaborating, and thinking about things they can do that are unique.

Q: It could be seen as a shot in the arm of the ADCS, to give it new projects after some left for ATRI.

A: I see it more as stimulating new opportunities and collaborations that mobilize the capabilities of the ADCS.

Q: Can you define your vision for the deanship versus that for the ADCS?

A: The ADCS, ADRC, and the fundamental neuroscience research at UCSD are each distinct entities. If you go back historically, Leon Thal had a remarkable ability to integrate these seamlessly, as distinct programs under a large umbrella. My vision going forward is to rebuild the capabilities of each program while optimizing the relationships between each of these groups. That will involve retention, recruitment, and making USCS a great place to come to train, be educated, and network. My goal is not to direct everything, but rather to create a really robust environment with successful programs in such a way that people see they are part of a larger whole. I don’t want to see just islands of accomplished activity that are not leveraging each other.

Q: How will your appointment affect the Shiley-Marcos ADRC?

A: I want to strengthen it through recruitment, collaborative projects, engagement in trials, and other pieces of shared activity. I foresee a lot of interaction. This is another program with a long legacy, and I am committed to lend my efforts to it. I will live vicariously by seeing it succeed.

Q: Because you will not yourself direct a memory or dementia clinic anymore?

A: Right. I’d like to understand how the ADRC can create that supportive community of patients that feeds trials and research much more broadly. We have been successful with that at UBC by putting the clinic at the center of all of our activities. This is not straightforward to implement because the U.S. system of care is much more heterogeneous than the Canadian system, but we will see what we can do.

Q: Are you envisioning a closer integration of care in the memory/brain health clinic and research participation, along the lines of what Jeff Cummings is doing at the Lou Ruvo, Dave Morgan at USF’s Byrd, and John Morris has been doing at Washington University?

A: Yes, similar. I have to learn more about the economics and politics of doing this in the U.S., but let’s take the UBC model for a moment. We created an environment where patients arrive for the best possible care, but at the same time they can contribute to the research enterprise with their consent in any number of ways. They can add clinical data into the de-identified database, they can contribute bio-samples for development of biomarkers, they can consent to imaging studies, and to postmortem brain donation, etc. All of that is offered to every person walking in the door.

Q: And people do it?

A: Yes! We have been impressed by how interested people are. A huge majority of them are willing to contribute in some way. When people come in with AD or FTD, they often have concerns about the next generation. Many say, “Even if this does not help me, it could help my children.” We have been very rewarded by this program. We are the largest users of autopsy in the hospital. The pathway we have created includes brain autopsy as a service; it is part of our quality assurance for diagnosis and research. The research ethics board provides oversight. It took effort to move our model through the ethics approval process, but now that it is up and running it is working well.

Q: Why is this so useful?

A: Think about what this can do. We see thousands of patients every year. If we are permitted through consent to get information, we aggregate thousands of patients’ material. Over 10 years, this gets to be a huge amount of learning. We can recycle that back into care in ways your private physician cannot readily do. That is really powerful.

Q: You are leaving behind a lot of rain but also a beautiful new building.

A: As part of the agreement between UBC and UCSD, I will retain an affiliated faculty position at UBC to promote continued collaboration and research opportunities. Building a strong relationship between UCSD and UBS is a natural process, but beyond that I also want to think of ways of connecting some of the great Canadian initiatives to the ADCS. There have been Canadian sites in ADCS trials, but we are now in an era where Canada has the national Canadian Consortium for Neurodegeneration in Aging project [see CCNA] plus a nascent project to build a national trials network. Perhaps we can forge relationships?

Q: Care to sum up?

A: The goal is to create value for the field in ways that stimulate a breadth of approach. We should not be afraid to create new instruments, new designs, new targets, new methodologies, new trials. That is the unique contribution we can make from where we are positioned. Hopefully we will be talking soon about exciting new approaches to come out of UCSD.

Howard Feldman to Breathe New Life Into ADCS

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