Celebrated scientist and biotech entrepreneur Milton Werner believes that several key studies and recent research have revolutionized understanding of the biochemistry underlying the Parkinson’s disease process.

In fact, his company, Inhibikase Therapeutics, Inc., is taking a risk-reducing approach to CNS drug development by leveraging established understanding of marketed kinase inhibitor drugs to develop a new generation of targeted CNS therapies that may be administered chronically and systemically to patients with infectious or neurodegenerative CNS diseases.

Inhibikase is a clinical-stage specialty pharmaceutical company focused on developing and commercializing small-molecule kinase inhibitor therapeutics for the safe and effective treatment of CNS diseases, including diseases of the brain. Inhibikase’s lead small-molecule product candidate, IkT-148009, is an Abl kinase inhibitor that targets underlying disease mechanisms to reverse the course of Parkinson’s disease. The company believes that IkT-148009 is the only disease-modifying drug in development for Parkinson’s disease that is focused on a clinically validated target and that IkT-148009 has the potential to be the first disease-modifying therapy for Parkinson’s disease that blocks a checkpoint on the pathway that drives Parkinson’s disease progression.

Prior to founding Inhibikase, Werner rebuilt research at the cell-free immunotherapeutics company, Celtaxsys, which explores the role of proteins in controlling immune cell migration. Werner, an internationally recognized scientist, was also Associate Professor and Head of Lab at the Rockefeller University, where he focused on elucidating mechanisms of human disease in immunology, oncology, and infectious diseases.

As part of its latest series on new medical advances WuXi AppTec recently spoke with Werner about the state of Parkinson’s research, how his company’s research may hold the key to finding an effective treatment for this major unmet medical need, and the nitty-gritty science behind it.

WuXi: What are researchers learning about the causes of Parkinson’s disease, and are there implications for other neurological disorders?

Milton Werner: I believe sincerely that several key studies at Johns Hopkins and other universities, along with Inhibikase’s assessment of functional benefit from drug therapy, are revolutionizing understanding of the biochemistry underlying the Parkinson’s disease process. In the past two years, we’ve come to understand the enzymology of cell death in Parkinson’s and how it relates to the alpha-synuclein protein in a way that turns prior understanding of the disease course on its head—specifically, that while alpha-synuclein aggregation or misfolding is necessary for Parkinson’s disease to occur, this is not sufficient to cause disease. Rather, we believe that the cellular Abl kinase, c-Abl, serves as a “checkpoint” in the disease pathway that modifies alpha-synuclein to create a more toxic entity that drives Parkinson’s disease. So, my belief is that we now understand the role of alpha-synuclein as an initiator of the Parkinson’s disease process, and what we’ve learned suggests that intracellular pools of alpha-synuclein should be the focus of all therapeutic approaches. Extracellular pools of alpha-synuclein are not disease-causing when the intracellular processes are absent—a remarkable finding, in our view. So, as a company, we don’t believe that extracellular pools of alpha-synuclein are driving the disease. Rather, we believe that the intracellular pools of alpha-synuclein are driving the disease and can be tapped for multiple therapeutic interventions. I would say that this is a revolutionary development in our understanding of how the early phases of Parkinson’s disease take hold and progress.

WuXi: Is Parkinson’s disease caused by genetic abnormalities, environmental factors, or a combination of the two?

Milton Werner: Whether Parkinson’s is caused by a combination of genetic abnormalities and environmental factors is unclear to me, and the latter is hard to define. What’s clear is that the development of Parkinson’s arises from damage caused by aggregated or misfolding alpha-synuclein that accumulates in affected regions of the brain. It’s also true that point mutations, or other genetic abnormalities of genes encoding alpha-synuclein, are directly related multiple disease processes, but the occurrence of point mutations is quite rare. It’s curious that we don’t know the role of alpha-synuclein in normal human biology, though to my knowledge, lack of this protein is not a significant issue in the physiology of alpha-synuclein knockout mice. So fundamentally, it’s not clear what functional loss may occur in humans if they lacked alpha-synuclein. We do know that aggregated or misfolded alpha-synuclein intracellularly triggers a process of neuronal cell death that flows through the c-Abl checkpoint. And we do know that exposure to certain things can cause oxidative damage in the central nervous system that can lead to the creation of pathologic alpha-synuclein. But how and at what scale these processes occur in the context of the human brain, we just don’t know, to my knowledge. So, while I believe that environmental factors likely do contribute to the development of Parkinson’s disease, I think it’s still a mystery.

WuXi: What scientific breakthroughs are needed to better understand the causes and progression of Parkinson’s disease?

Milton Werner: As I mentioned earlier, we believe that the recent identification of c-Abl kinase as a primary driver of the disease process in Parkinson’s is a seminal discovery that provides a critical clue to the mechanics of Parkinson’s disease development and points to specific potential therapeutic interventions. As for other needed breakthroughs: One major unknown about Parkinson’s is when it starts. The lack of markers for early emergence and for disease progression are key drug development needs. Inhibikase and others have evidence that an old hypothesis put forth by Braak—that Parkinson’s disease initiates in the GI tract and then spreads to the central nervous system—may be true. Multiple labs have shown that it’s possible to recreate Parkinson’s by initiating the process in the GI tract. Our researchers have also shown that treating neurodegeneration in the GI tract caused by aggregated or misfolded alpha-synuclein can have an effect in the brain. The most important needs are not so much biochemical breakthroughs, but understanding of how the disease starts and identifying a sensitive marker for early disease recognition, before damage is done.

WuXi: What are the major challenges in treating Parkinson’s disease?

Milton Werner: I think the greatest barrier to Parkinson’s drug development is lack of an objective measure of patient response. Because we can’t get access to the brain to gauge target engagement of a drug with certainty, we have to rely on subjective measurements, such as how well a patient walks, talks, and turns around. While these types of measurements can be clinically informative, they can’t be correlated directly to whether a drug’s effects result in positive benefit. We have to rely on animal models to give us this information.

WuXi: Would a genetic target help?

Milton Werner: The genetic, inherited form of Parkinson’s is very rare—maybe 5-to-10 percent of cases. The most common form is sporadic, and the main challenge there from a development standpoint is how to monitor something in the brain that you’re trying to block. We don’t have well-established or easy-to-define tools to measure the impact of pharmacology treatment in the brain—even if you know the target in the brain, you can’t get access to it without a biopsy, which obviously you can’t do on living people when the biopsy would have to be done at the brain stem.

Would a genetic target help? I don’t think so. I think we need to know what alpha-synuclein is linked to that could provide an early marker. Our company is exploring whether a snapshot of “state of the brain” can be isolated from something pinched off from brain neurons that end up in the bloodstream. We and others have shown that these objects can be isolated from peripheral blood, and we have some indication that this approach might yield useful information, but we don’t know yet. And, of course, we have the age-old problem associated with treating diseases in the brain: Small-molecule drugs don’t get into the brain easily. So, a better understanding of transporter structural biology could have a major effect on the development of small-molecule drugs for Parkinson’s. From a large-molecule/biologic perspective: I’m aware of at least three antibody programs currently in clinical trials that are focused on removing extracellular alpha-synuclein from the brain. All require something that’s unprecedented in antibody therapy: Monthly dosing on the order of 12 to 15 grams per month, per patient. Most antibody drugs are delivered to humans at doses of 0.3 to 3 mg. So, you’re looking at providing these therapeutic antibodies to patients on the order of 1,000 times the normal amount of antibody drug delivered to a human. Though it’s not known, I would anticipate that this level of antibody load would create severe and long-lasting side effects.

WuXi: How is Inhibikase tackling Parkinson’s?

Milton Werner: Inhibikase has taken a strong view that there are well-defined biochemical pathways that govern the development of Parkinson’s in affected neurons. That pathway involves the transport of misfolded or aggregated alpha-synuclein into the affected neurons through the LAG3 and related receptors which, once inside the cell, triggers a biochemical cascade that has two effects: c-Abl kinase chemically modifies alpha-synuclein to create a toxic form that drives cell death processes inside each neuron, and the chemically modified alpha-synuclein is transported from one neuron to the next in the brain through LAG3 receptors, driving disease progression.

In addition, this transport of aggregated alpha-synuclein into cells inactivates the pathway that would normally get rid of the protein to preserve the affected neuron, a process that is also regulated by c-Abl. So, you have the creation of a toxic entity that can spread from cell to cell, and a block in the cell survival pathway when that toxin is present. This leads to three types of neuronal cell death. We believe that blocking c-Abl kinase will preserve that survival pathway as well as prevent further formation of the toxic form of synuclein, in turn preventing spreading from cell to cell; this is something that is undergoing extensive validation in multiple laboratories with which we collaborate.

So, Inhibikase is focused on developing an inhibitor of c-Abl as a disease-modifying therapy for Parkinson’s disease.

WuXi: What innovations and strategies are you using to de-risk your drug development process?

Milton Werner: We are using knowledge of a well-understood therapeutic target and drug class—c-Abl kinase inhibitors—as a new avenue for modifying disease progression in Parkinson’s. There’s a 20-year history of use of these molecules in human patients, though historically they’ve only been used in oncology. Inhibikase’s drug development platform enables us to preserve the established safety benefits of this known drug class in a new drug that is far more potent. We’ve shown that our drug development strategy leads to a potent new drug with exceptional activity in animal models of Parkinson’s disease.

WuXi: How does your company’s approach differ from others in this field?

Milton Werner: Our hypothesis is that the presence of misfolded or aggregated alpha-synuclein is the initiator of Parkinson’s disease, but is not sufficient to cause disease alone. This challenges prior notions of the disease course. We believe that initial strategies were largely based on the themes for treating Alzheimer’s disease. We now know that the Alzheimer’s strategy(ies) have no relationship to the Parkinson’s disease process. Instead, our company took the approach of participating in our university collaborators’ work to define the disease biochemistry in a detailed way. Then, using a combination of mouse transgenics and rigorous biochemistry to prove that the pathway we had defined is disease-relevant, our drugs were used to reverse the course of the disease. From there, we can show how our molecule affects each downstream event.

We believe that this is a revolutionary approach to drug development for central nervous system diseases in general. In the past, the approach was more like: We can’t get access to the brain, and so we don’t know where to look. We took the approach of asking: Is there a drug class that we believe is neuroprotective and then asked whether that drug class has a place in this disease. It turns out there was. Working in the brain is notoriously challenging, but collaborating with academic partners whose efforts had elucidated major parts of the pathway, we could systematically apply our drugs to interfere with the disease process in a predictable way. So, Inhibikase took a rather ambitious approach of marrying what we know about the biochemistry of the Parkinson’s disease process with established knowledge about a drug class that’s been in use for 20 years.

WuXi: How will Parkinson’s disease treatments evolve over the next five years?

Milton Werner: I suspect that within five years, a handful of companies will have unique therapies, each of which will modify Parkinson’s disease in a different way. As a company, we believe that a cure is possible, likely using a combination therapy strategy. I think leading a normal life with Parkinson’s disease is on a longer time horizon. If the disease is caught at an early stage, there’s a good chance such patients could have their progression stopped by taking a medication chronically, so that they’re in a persistent state of halted progression. As long as the medicine is well tolerated, that patient could live a more or less regular life. So, if we had markers to enable us to identify the disease at a much earlier stage, I can envision a chronic maintenance type of therapy—similar to the regimen of medicines used to treat HIV infection.

Overall, I think that within the next five to six years, Parkinson’s will cease to be a devastating disease of progressive deterioration and transformed into one of halted progression that trends toward an eventual cure.