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Bristol Myers’ neuroscience research head explains the big pharma’s return to brain drugs

Republished By Plato
Republished By Plato

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Like many large pharmaceutical companies, Bristol Myers Squibb hasn’t made brain drugs a top priority over the last decade.

As a field, neuroscience represents a major opportunity for drugmakers. Alzheimer’s disease affects millions of people in the U.S. alone, and puts an enormous strain on the healthcare system. Patients with ALS, Huntington’s and other disorders hallmarked by the breakdown or nerve cells are in desperate need of new treatments.

Yet, the complicated biology of the brain and central nervous system has led once-promising medicines to fail time and again, leading developers to pursue other areas of research like cancer, the immune system and rare diseases.

The past couple years, though, have seen scientific and technological breakthroughs that have encouraged some of the most powerful and deep-pocketed pharmas to return to neuroscience. Bristol Myers is among them, having licensed experimental medicines from the biotechnology companies Prothena and Evotec. Last month, during a research and development event, Bristol Myers said it will be “re-establishing” neuroscience as a therapeutic area of focus.

BioPharma Dive sat down with Ken Rhodes, the company’s vice president of neuroscience research, to discuss this re-entry and where brain drug development is headed. The interview, which aired during an Oct. 26 event hosted by BioPharma Dive and PharmaVoice, has been lightly edited and condensed.

BIOPHARMA DIVE: Bristol Myers is reestablishing a therapeutic area of focus in neuroscience. What does that mean and why is the company making a statement of intent like that now?

KEN RHODES: We can all agree that disorders of the central nervous system are increasing in prevalence. They’re very serious diseases. There’s clear medical need. And they represent some of the greatest challenges of our time, both in terms of their impact on patients, on caregivers, on families and on the healthcare system.

So the desire to address devastating diseases like many of the neurodegenerative diseases is embedded within the DNA of the BMS organization.

BMS has been investing in neuroscience for several years now. Obviously, we have [multiple sclerosis medicine] Zeposia … but we actually have four programs that are about to enter Phase 2 development, all in the neuroscience disease area — one in Alzheimer’s disease, another in ALS and then two others. And so with Zeposia and with this emerging portfolio, we have the underpinnings of a robust neuroscience pipeline, which we’re looking to expand.

We have a dedicated discovery team within the organization. We have some outstanding neuroscientists focusing on our internal portfolio, as well as the work we do with our collaborators at Evotec and Insitro, with several of our academic collaborations and with our broader interactions with the biotech ecosystem. Those folks partner with our clinical development organization and our commercial colleagues to think about how we’re going to establish and ultimately deliver a robust portfolio of therapies to patients.

Richard Hargreaves, who is the senior vice president for the neuroscience thematic research center, set out on a mission several years ago to “put the CNS back in BMS.” And I think if you look at the portfolio that Richard [and] the broader BMS organization … put together, I think you quickly appreciate that that mission has been very successful.

You mentioned Alzheimer’s and ALS. What’s driving Bristol Myers’ investment in those areas?

RHODES: The themes are focusing around a well articulated construct that actually [Bristol Myers head of research] Robert Plenge articulated during the research and analyst day. And that is a strategy that focuses on causal human biology, matching therapeutic modality to the mechanism that’s driving disease, and having a path to evaluate mechanisms and get to relatively early decisions on clinical activity.

And that theme drives much of our decision making and how we make choices about what targets to pursue within the neuroscience area within BMS. If you look at the broader industry trends, some of the challenges that were faced in neuroscience drug discovery and development are when we drifted away from that central construct.

What steps can you take to improve the odds of success? Are the tools available different than what you had five or 10 years ago?

RHODES: The situation in drug discovery in neurodegenerative disease has changed dramatically even in the last five years, but certainly over the last 10 years. We have a much better and much deeper understanding of genetic drivers of neurodegenerative disease.

Causal genes — for Alzheimer’s disease, for inherited forms of ALS, for multiple sclerosis to some extent, Huntington’s disease — have been fairly well elucidated and present some clear opportunities for therapeutic intervention.

One of the things that has changed is our focus on those clearly defined mechanisms that are contributing to the initiation and progression of disease. This week in Boston is the Clinical Trials in Alzheimer’s Disease, or CTAD, conference. One of the things that clearly comes out of the sessions at that conference is the integration of biomarkers into how we select patients for trials, how we monitor the impact of our therapeutic intervention on the disease process.

Now with plasma biomarkers, with CSF biomarkers, with neuroimaging [and] PET imaging in particular, we can monitor the progression of disease longitudinally in living patients. And we can look at the impact of our drug candidates on the disease process using those markers as a way to be sure that our drug is in the target tissue and it’s modulating the biology in a direction we believe will have therapeutic benefit. Then we can tie that ultimately to clinical outcome.

Certainly the recent successes in Alzheimer’s disease have benefited from the tremendous investment that has been made in the industry and in academia … to enable a more biomarker-driven development strategy in neurodegenerative disease.

Looking back on it, that is really what changed drug development in multiple sclerosis: the appreciation MRI imaging could be used to monitor disease and used to assess the impact of drugs on inflammatory mechanisms in multiple sclerosis. That has now catalyzed much of the investment in Alzheimer’s disease and other neurodegenerative diseases, where we can use imaging and biomarker strategies to enable drug development in a way that just wasn’t possible until very recently.

One of the programs you mentioned is in Alzheimer’s. What biomarkers are you looking at?

RHODES: The program you’re referring to that’s about to enter Phase 2 is a program with a monoclonal antibody targeting the microtubule binding domain of the protein tau.

It’s well established now in the field — largely, again, as a result of imaging technology — that actually it’s the progression of tau pathology in Alzheimer’s disease that is most closely correlated with clinical progression. So the dementia, memory deficits and other deficits in patients with Alzheimer’s disease are tightly associated with progression of tau pathology and less tightly associated with the accumulation of amyloid.

We have now a tremendous suite of biomarkers related to tau biology and amyloid biology that we will integrate into our clinical development program along, obviously, with clinical outcome measures. But I think the imaging component of that will give us a lot of information about whether our antibody is interacting with the tau protein and leading to tau removal from the CNS in Alzheimer’s patients.

Should we expect more business development activity in neuroscience?

Rhodes: Most certainly you could expect to continue to see that.

As long as the program targets a mechanism and that causal biology that we think is important, for the initiation and progression of disease, we would be interested in hearing about it and having a conversation about it.

Together with our existing series of partnerships, we’re certainly interested in evaluating other high quality opportunities that are consistent with our strategy. And that strategy really focuses on disease-modifying therapies in neurodegenerative diseases like Alzheimer’s disease and ALS, in neuromuscular diseases and then neuroinflammatory diseases.

Tell me about Bristol Myers’ program in ALS. Are any of lessons learned in Alzheimer’s relevant to drug development in ALS?

Rhodes: Absolutely they are. It’s another area where biomarkers have proven to be extremely valuable. And central to the approval of some of the more recent medicines for ALS is a reliance on a biomarker called neurofilament light chain, which is a marker of axonal degeneration in the central nervous system.

Certainly an evaluation of neurofilament light chain would be part of any clinical development program we did in ALS, and likely a component of any clinical development program we did in any neurodegenerative disease. But it’s another case where focusing on causal human biology is central to the strategy.

This a program that targets integrated stress response. Protein misfolding is central to many neurodegenerative diseases, and as proteins misfold and accumulate they trigger a response called the unfolded protein response, which essentially shuts off protein synthesis within cells. [That’s] fine if it occurs transiently, but if it occurs chronically it can lead to profound stress on the cell, and cells will ultimately die and degenerate.

This mechanism allows you to turn back on components of the integrated stress response and allow the cells to continue to function normally and, ideally, clear misfolded proteins. There’s some really elegant pharmacology that was developed preclinically that set the stage for this program.

You were previously at Yumanity, a neuroscience-focused biotech. What can pharma companies like Bristol Myers learn from biotech?

RHODES: One of the things that small companies do very well is remain focused on their core mission. You commit to a platform, you commit to a target and you do everything possible to succeed and discharge risk and advance that program into the clinic. It’s essential for the life of the company in a way, but it’s really why everyone is there, working on these very difficult challenges.

I had the tremendous pleasure of working with the late Susan Lindquist, who is a pioneer in many aspects of biology, but particularly around protein misfolding and its role in neurogenerative disease. At Yumanity, we had a very vibrant discovery platform and a very focused effort that ultimately led to entry into clinical development of a potential disease-modifying therapy for Parkinson’s disease, which is now in the Johnson & Johnson portfolio.

One of the things I’d like to think we did well there was to remain focused and not chase too many shiny objects.

I’m confident in saying that David Altshuler at Vertex likely said [during an Oct. 25 panel discussion hosted by BioPharma Dive] that this idea of multiple shots on goal is a bit of an illusion. And, I think in some cases, a bit of a distraction from really focusing on targets and mechanisms that are grounded in causal biology and should bear the bulk of the focus of our drug discovery efforts across the industry.

I think that focus in a small company and everyone living or dying by the quality of the science is unique to a small company environment, and maybe something that could be learned from in large pharma.

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