I first learned about drug discovery and development in the mid-1990s when two of my sons were diagnosed with a brutal, untreatable genetic disease called ataxia-telangiectasia (A-T). Children with A‑T struggle with immune deficiency and lung problems, and have an extremely high cancer risk. But what hits them hardest is the relentless loss of muscle control caused by neurons dying in the brain’s cerebellum. In my desperation to help my sons and other kids with A-T, I started a nonprofit foundation and sought advisers to teach me how to develop new drugs for brain diseases like A-T.
In addition to moonlighting as the volunteer leader of a nonprofit research advocacy organization, I shifted my career from the food processing industry to the life sciences so I could focus on drug discovery and development full-time. Today I start and run biotechnology companies, the last two of which have been focused where my personal passion lies: brain diseases.
At first, I naively thought that drug discovery couldn’t be that difficult. But along the way I learned that discovering effective, safe drugs is vastly more difficult than most people would ever imagine. First, you need knowledge of the underlying disease mechanisms and an understanding of how the disease affects patients over time. Then, you need a tissue- or animal-model of the disease.
With those in hand, you need a specific and potent candidate drug that shows dose-dependent effectiveness and safety at multiples of the therapeutic dose, followed by translational studies and surrogate biomarkers that confirm the drug’s mechanism of action or that it is acting on its target. If you make it that far, you then need carefully designed clinical trials to show safety and effectiveness. Only if the trials are positive and the drug’s effectiveness exceeds its risks can it be approved and prescribed to patients.
It was still more sobering to discover that developing treatments for central nervous system (CNS) diseases, which affect the brain and spinal cord, is even harder to do. CNS drugs have longer development times and higher failure rates than non-CNS drugs, largely because of the brain’s enormous complexity. As a result, for CNS diseases like Parkinson’s disease, physicians are limited to prescribing symptomatic treatments like L-dopa and a long list of drugs developed more than 50 years ago for psychiatric disorders.
For common neurodegenerative diseases like Alzheimer’s, nothing has worked so far to slow the course of the disease in spite of billions of dollars of investment by industry and the nonprofit and government sectors. The failure rate has been an amazing 100%.
Fortunately, there have been a handful of recent partial successes in CNS drug development. A few pediatric diseases like spinal muscular atrophy are now being treated by replacing or silencing the disrupted genes that cause them. My foundation will be funding an N-of-one clinical trial at Boston Children’s Hospital this fall to test a new gene therapy approach in a girl who has my sons’ disease. But for later-onset brain diseases like Alzheimer’s and Parkinson’s that strike millions of people as they grow older, only a small fraction of patients carry disease-causing changes in their DNA, and gene-targeting strategies based on this knowledge are still largely unproven.
Most of the limited success in drug development for brain diseases has come from either “me too” medicines that merely tweak formulation or delivery, or “somewhat new” medicines that act on already proven targets.
The appeal of pursuing incremental improvements with medicines that act on old, familiar targets is understandable. Pursuing known targets and mechanisms is less daunting to investors and seems less risky to pharmaceutical company executives. But repeatedly filling drug-development pipelines with agents that act on the same handful of CNS targets has done little to help patients with neurodegenerative diseases. Our industry needs to accept, if not embrace, risk taking with new drug targets.
Industry veterans attribute the challenges of CNS drug development to many factors. Ensuring that a new drug can cross the blood-brain barrier is one challenge, but it is rarely the reason for late-stage failures with CNS drugs, since brain penetrance can be tested early on. Metabolic differences between animal models and humans can lead to erroneous predictions of human pharmacokinetic profiles, thereby misleading a drug-development program, but this obstacle, too, can typically be overcome. Safety concerns in clinical development can also present a challenging problem.
But the greatest reason for failure in CNS drug development by far is that the drug isn’t effective.
So how can we discover truly effective new medicines for CNS diseases? The first step is to identify a target protein and develop a hypothesis for how an increase or decrease in that protein’s activity will affect disease mechanisms and improve symptoms. The identification and biological validation of new targets represents a fresh chance to develop effective treatments, but this is exactly the point at which our industry eschews risk at the expense of finding potentially groundbreaking advances in treatments.
Two years ago, my colleagues and I started a company called Cerevance to apply a new technology for sorting cells and sequencing RNA in thousands of post-mortem human brain samples from healthy and diseased donors with the goal of identifying proteins that could be promising new drug targets. We are currently advancing preclinical and clinical programs that act on targets we have found to be changed in diseases or with aging, or that are selectively expressed in circuits disrupted by disease. All are targets that others have not (yet) pursued. In spite of the risks — or more accurately because of the risks of sticking with old targets — we are focusing on these new targets.
A new-targets-only strategy requires significant investment to validate new targets with little or no prior support from industry and academic efforts. Yet without a few of us swinging for the fence, there is simply no other way to create new medicines that can make a difference for millions of people awaiting treatments.
Many in the pharmaceutical industry assert that the new target discovery stage is too daunting or slow and prefer to call it a “precompetitive” endeavor, best suited to academics or consortia formed with other companies. Few seem to view the use of privately gained biological insights about a new target’s role in a disease as a competitive edge, as I do.
If we’re honest about it, old targets shouldn’t give us as much comfort as they do. We still don’t understand as much as we would like to about most CNS conditions. Even well-known CNS targets aren’t as well-validated as we tell ourselves they are. In particular, we don’t fully understand the expression or functional roles of many of our drug targets in human neuronal circuits, or whether modulation of a particular target — and that target alone — will be necessary and sufficient to significantly affect a disease. In many cases, we do not know how an ideal molecule should interact with its target, or whether modulating the target will produce the expected results.
The complexities of CNS diseases tend to reinforce the mindset to pursue longstanding drug targets rather than looking for new ones. And investors, particularly venture and crossover biotech investors, are often looking for shorter time horizons to return profits, which is generally shorter than the time needed to develop drugs against new targets. As a result, their investment dollars often go to companies that are focused on minor advances or on delivery systems, rather than to companies that are pursuing new targets and mechanisms.
But then what happens? Late-stage drug programs built on familiar targets produce headline-making failures with high frequency, leading global pharmaceutical companies to step away from neuroscience research altogether.
Companies that focus on identifying and pursuing new targets may help reverse this trend. New targets might, in fact, be less risky because the work that goes into finding them also generates new insights into CNS cell types, circuits, and disease mechanisms. Investors may ultimately find that it is less risky to invest in companies with truly new approaches than in companies pursuing existing, well-established targets.
While I’m hopeful that pursuing novel targets will yield effective new therapies for CNS disorders, I’m also aware of the many other challenges of drug development for these diseases. Validated biomarkers for stratifying patients early and tracking disease progression — rather than simply confirming target engagement or proof of mechanism — don’t yet exist. It is also possible that for complex CNS diseases, combination therapies with multiple targets may be required to achieve meaningful clinical efficacy. And clinical trials may need to be longer for disease-slowing therapies and may need to be designed differently and performed at earlier stages of the disease.
My colleagues and I started Cerevance to find and bet on new targets for brain diseases. For children with diseases like A-T, as well for the rest of us — especially as we grow older — I hope that this strategy will succeed and that others will join in this effort.
Brad Margus is co-founder and chief executive officer of Cerevance, a clinical-stage drug development company focused on brain diseases, and co-founder and volunteer chair of the A-T Children’s Project.