Ending the therapeutic drought
Of the longstanding technical difficulties in the drug development business, few have proven more intractable than crossing the blood brain barrier – evolution’s elegant system designed to protect the brain from harmful chemicals. A molecule must cross this barrier in order to effectively treat some of the world’s most devastating neurological conditions, including ALS, Parkinson’s and Alzheimer’s.
The failure rate for drugs targeting diseases of the central nervous system (CNS) has been dauntingly high. Over the past 20 years, most drugs have been based on the “amyloid hypothesis,” which began with a simple observation: Alzheimer’s patients have an unusual buildup of the protein amyloid in their brains. Thus, drugs that prevent or remove the amyloid should slow the onset of dementia. Roche’s gantenerumab and Eli Lilly’s solanezumab are just a few of the more than 100 potential Alzheimer’s drugs that have flopped in pursuit of a solution.
The prevalence of failure in treating neurological diseases is a testament to their unique challenges. Uncertain diagnoses, long progressive burdens of disease, multiple etiologies and complicated clinical trials are just a few factors that are impeding success. Given the history of failure it may seem that you would have to be either stupid, crazy or charitable to invest in this space. However, given macro and societal drivers, such as the global rise in the incidence of mental illness and the aging of the population, particularly in western societies, the payoff could be enormous.
An effective drug against Alzheimer’s disease, for example, would be a blessing for millions while also being hugely profitable for the company that invented it. Hence the excitement over any promising trial result, such as Lilly’s donanemab, and the intense interest in the FDA’s decision on Biogen’s aducanumab. According to Bernstein, US sales could amount to as much as US$50 billion a year for an effective Alzheimer’s treatment.
This has led a barrage of contrarian investors willing to fuel entrepreneurs to discover and develop novel therapeutic strategies across a range of neurologic conditions. There are now new ways of thinking about neurologic diseases, informed by human genetics and a better understanding of the brain, that are emerging out of basic and clinical research and they are very encouraging. These offer new paths to develop targeted medicines in specific subsets of patients.
Swiss-based AC Immune is one company working to pioneer advancements in personalized therapies for CNS diseases. The company’s co-founder and CEO, Dr. Andrea Pfeifer, noted: “We are reaching precision medicine in the neuro space. Precision medicine is based on the expression of misfolded proteins in the brain. We can look in the brain and dictate if you need an alpha synuclein or tau-targeted therapy.”
This represents a shift in recognizing that Beta-amyloid is just one protein that can mis-fold in the brain. Others, such as tau or alpha-synuclein, could hold clues to deciphering how Alzheimer's disease develops in the aging brain.
Tau, in particular, has intrigued many, earning recognition as another characteristic mark of Alzheimer's disease. Tangled clumps of the protein can stretch across regions of the brain, and its presence is correlated with worse cognition. Up to this point, the field could only diagnose Alzheimer’s when clinical symptoms were observed. This is a huge disadvantage akin to closing the barn door after the cows have left, because we now know that, by the time a patient has observable clinical symptoms, a lot of the neurons are already dead (estimates are that 70% of neurons are dead). The key then is to intervene when you still have all neurons intact. But up until today, this was not possible because there was no diagnostic means to identify people at risk. This has been one of the key developments over the past two years. We can now identify markers, such as phospho-tau 181 or phospho-tau 217, which allow you to identify people at risk, and begin treatment early on in the disease progression.
As an example, when you look at cardiovascular disease, a person goes to the doctor, gets checked for cholesterol and, if they have high cholesterol, then the doctor prescribes statins. The statins do not really treat heart disease but prevent it. There is now a recognition that risk markers for Alzheimer’s disease appear 10-20 years before the disease starts. By identifying these factors early on, a patient could receive a vaccine because it costs very little, it works for a long time and people would not lose their neurons, which is absolutely required in order to prevent the onset of the disease. This is where the field is headed today. Pfeifer continued: “This is precision medicine, which of course means specificity. It means safety, because you do not treat for something which you do not have, and it is cost effective because you do not treat something which costs a lot of money and does not really help you.”
The idea that developing combination therapies spanning several misfolded proteins rather than focusing on a single target will be more effective is gaining in popularity, and it is something that Dr. Trevor P. Castor, president and CEO of Aphios, has been pursuing for several years. He points to lessons we can take from the progression of HIV treatment. “Combinations allow us to have therapeutic solutions, whereas a single therapy may not work. Case in point is in HIV. There was a very high amount of single therapy failures caused by resistance being developed by HIV mutations, and it was a problem until Dr. Ho came up with the idea to use a triple drug therapy to prevent the virus from mutating,” said Castor.
Combination therapy, the basis for current antiretroviral therapy in the HIV world, is what made HIV a chronic disease rather than a killing disease, and, according to Castor: “The problem in neurodegenerative diseases like Alzheimer's is that we have not gotten any single therapies which have been effective in either suppressing or curing the disease. People ask, why use a combination therapy when we have not gotten the single therapy to work? The problem with a single therapy is that you hit only one target in a very complex biological system. For example, you inhibit one enzyme like beta secretase, and alpha secretase pops up as a contributing factor to Alzheimer’s disease. It is important to start thinking about how we can combine therapies that can impact different pathways simultaneously in treating Alzheimer's disease.”
On the back of this thesis, Aphios was granted a patent in 2020, titled “Combination Therapeutics and Methods for the Treatment of Neurodegenerative and Other Diseases.” The company’s findings were that the combination of Bryostatin-1 and retinoic acid is not merely additive to increase α-secretase, but synergistic, wherein the Bryostatin-1 and retinoic acid interact to form greatly elevated levels of α-secretase to make the treatment of neurodegenerative diseases more effective.
If you fund it they will come
A huge element of this expansion of basic neuroscience understanding has come from the explosion in National Institute of Health (NIH) funding for neuroscience in the first decade of the 2000s. In the 1990s, the NIH channeled US$954 million into neurology research. In the 2000s, this number spiked to over US$8 billion. This was a larger increase than any other therapeutic area and has created a wave of insights a decade later that we are in the process of translating into new therapies. Funding for the disease continues to increase dramatically, with NIA’s support climbing more than fourfold between 2013 and 2019. For fiscal year ‘21, Alzheimer’s research rose to US$3.1 billion
“Neuropsychiatric drug discovery has seen more money flow into it in 2020 than ever before and almost double 2019, both in terms of institutional investment and partnering. I think it was inevitable that we would see a resurgence of interest in CNS disorders as these are severely disabling conditions with poor or no available treatments that impact huge numbers of people worldwide.”
Emer Leahy, President & CEO, PsychoGenics
In neuropsychiatry there is also an abundance of companies thinking more outside of the box. For decades, the focus was on retreads of blocking dopamine in psychosis and modulating monoamines like serotonin, dopamine and norepinephrine in depression. Now there are many more new targets. And that is largely coming from early stage biotech rather than traditional large pharma who might be biased and set in their ways of thinking about things through a certain biological paradigm.
Emer Leahy, president and CEO of PsychoGenics, recognized: “Target-driven approaches to neuropsychiatric drug discovery, which biopharmaceutical companies were pursuing to the exclusion of other approaches, had serious flaws; confirmed decades later by the sparsity of new first-in-class treatments. We pioneered an alternative phenotypic approach that captures hundreds-of-thousands of behavioral and physiological datapoints from mice and employs machine learning to predict therapeutic applications for novel compounds.”
This target-agnostic approach has thus far shown promise, as it has delivered novel first-in-class clinical compounds, such as SEP-363856, with improved efficacy and side effect profiles for unmet neuropsychiatric needs such as Schizophrenia.
Driving the advancement of PsychoGenics’ pipeline is its robust CRO business that continues to grow on the back of the expanding number of newly formed, venture backed companies requesting its services. However, the future growth of the company will depend on the clinical success of SEP-363856, which could validate the company’s AI-driven discovery platforms.
In addition to advancements in the diseased brain, those with cognitive impairments are also receiving renewed attention. There is a movement afoot that says the immersive power of video games can be harnessed not only to entertain, but to enhance cognitive abilities. While educational games have been around a long time, some neuroscientists believe that games can act as therapeutic tools against conditions like ADHD and autism.
The field took a major step forward in June of 2020, when Akili Interactive was awarded FDA clearance for its EndeavorRx, a “digital therapeutic” developed to treat ADHD through a video game experience. The regulatory decision makes the Boston company’s product the first prescription therapy that comes in the form of a video game. When asked how the path forward may differ from that of a traditional pharma company, Akili co-founder and CEO Eddie Martucci emphasized: “Realizing the full potential of digital therapeutics to transform the patient experience requires imagination and creativity. DTx have the bandwidth to span multiple audiences and be easily accessible for download via a mobile device, which positions companies with innovative technologies to support more patients. We do DTx a disservice by applying a pharma model to this new industry.”
As a result, the company is developing a purpose-built distribution model designed specifically for digital therapeutics that can support the level of patient engagement and rapid product development this new category of medicine has the capability of delivering.
Image courtesy of CordenPharma