Q&A: Tackling developmental disorders through the ERK pathway

DDN spoke with Dr. Michael Snape, chief scientific officer of AMO Pharma, to discuss drugs that target the ERK signaling cascade, and how these drugs might be able to treat a range of developmental disorders

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ERK signaling has been a well-known target for researchers focused on oncology. Now, researchers are figuring out how to use the ERK pathway in other ways.
Recently, DDN spoke with Dr. Michael Snape, chief scientific officer of AMO Pharma, to discuss drugs that target the ERK signaling cascade, and how these drugs might be able to treat a range of developmental disorders (e.g., congenital myotonic dystrophy and Rett syndrome).
DDN magazine: How did researchers discover that the ERK signaling cascade could have applications with developmental disorders?
Dr. Michael Snape: Research in this area began in a number of laboratories, mainly in the U.S. in the mid-2000s, with peer-reviewed studies on the ERK signaling cascade first published around 2008. Researchers were driven by an interest in how synapses in the brain can adapt as connections between neurons strengthen and weaken. The basic premise here is that the strength of connection between neurons and the CNS [central nervous system] is the fundamental unit of change that captures new information during learning and memory. 
Researchers investigated the signaling pathways within brain cells to try to determine the biochemical basis for information processing and eventually recognized the ERK signaling cascade as an important player in the regulation of plastic changes in synapses. Developmental disorders by definition involve a change in the way information is processed in the brain during development. It therefore made sense to investigate the role of systems involved in synaptic plasticity, such as the ERK pathway in developmental disorders.
Prior research efforts have focused on the role of the ERK pathway in developmental disorders including fragile X syndrome and autism spectrum disorders, two areas of interest for AMO, and the results were clear—in brain tissue of patients with these disorders the ERK pathway was aberrantly activated, including the glial cells that support neuronal function. Based on these and other study results, our team recognized the potential of the ERK pathway in the treatment of developmental disorders that currently have no approved treatment options.
 DDN: Can you tell us about AMO-01, and its method of action for targeting the Ras-ERK pathway? 
Snape: Our investigational therapy AMO-01 has been shown to inhibit activation of the Ras-ERK pathway in multiple preclinical studies, and in human trials. AMO-01 has demonstrated [that] it inhibits activation of the Ras protein specifically when Ras activity is stimulated within cells, rather than simply reducing the total amount of Ras protein. AMO-01 can also bind to a protein selectively expressed on activated astroglia—glia are cells within the brain that help coordinate and organize connections between neurons. 
When types of glia, such as astroglia, become activated their function changes [and] connections between neurons are impacted. Prior research has shown that astroglia are activated in a number of developmental disorders, including fragile X syndrome and Rett syndrome, and AMO-01 is well positioned to target the brain where astroglia activation occurs.
DDN: Why did AMO Pharma first choose to target Phelan-McDermid syndrome with AMO-01?
Snape: There are a number of developmental disorders where research has shown activation of the Ras protein—Phelan-McDermid syndrome is one of these disorders and one where there is a high unmet medical need for patients. There are currently no approved treatments for Phelan-McDermid syndrome.
Our team at AMO has known about this disorder for several years and learned about its characteristics that made it a desirable target. First, we learned that a significant proportion of people with Phelan-McDermid syndrome have epilepsy, a condition that can be serious and is not always responsive to treatment. We also learned of reports that Phelan-McDermid syndrome can be associated with developmental regression that occurs starting at about 12 years of age, a feature of the disorder that is particularly concerning for parents. 
Not long after AMO was founded in 2015, our team—along with collaborators—investigated the preclinical efficacy profile of a single administration of AMO-01 in a knockout mouse model of Phelan-McDermid syndrome. These data were very encouraging in showing a broad profile of efficacy that persisted for many days after a single treatment, and findings were similar to results seen in the knockout mouse model of fragile X syndrome.
Encouraged by these findings, AMO is supporting a Phase 2 clinical study in Phelan-McDermid syndrome being conducted at Mount Sinai School of Medicine in New York and Texas Children’s Hospital in Houston. These centers are world leaders in research in Phelan-McDermid syndrome, so this is a marvelous opportunity for AMO to further investigate AMO-01 as a potential treatment for this disorder.
DDN: Can you tell us about the clinical studies currently underway for AMO-01?
Snape: As mentioned, we are currently supporting a Phase 2 clinical study of AMO-01 in Phelan-McDermid syndrome being led by researchers at Mount Sinai and Texas Children’s Hospital. The Phase 2 open-label study is assessing the safety, tolerability and efficacy of AMO-01 following a single-dose administration in adults and adolescents with Phelan-McDermid syndrome who have also been diagnosed with epilepsy. About 10 patients will be studied and tracked over a number of weeks after the single-dose administration to assess whether AMO-01 offers any clinical, and lasting, benefit. 
We are excited to see whether the semi-persistent efficacy seen in preclinical studies translates into the clinic. We will also evaluate the safety profile of AMO-01 using a number of outcome measures that assess the characteristic clinical presentation of Phelan-McDermid syndrome, including both epilepsy and the developmental difficulties seen in this disorder.
Through these outcome measures our goal is to determine whether AMO-01 is able to address the fundamental nature of the disorder. Our team is eagerly awaiting the results of this study to determine whether AMO-01 is proven to be safe and provide therapeutic benefit in Phelan-McDermid patients who desperately need a treatment option.
DDN: How is AMO Pharma planning to use the ERK signaling pathway to target fragile X syndrome?
Snape: Based on prior research, there are actually multiple developmental disorders characterized by increased activity of the Ras-ERK pathway, and Phelan-McDermid syndrome and fragile X syndrome are just two. AMO and our collaborators initially prioritized these two conditions based on our prior knowledge and experience with them, and our connections with leading experts in clinical research in these conditions. 
Data to-date show the same AMO-01 profile in preclinical efficacy studies for both of these conditions — that is, a broad efficacy profile with essentially the whole phenotype of deficits either entirely or almost entirely reversed after a single administration of AMO-01. The clinical benefits of AMO-01 persisted for hours, even five to 10 days later, following a single dose in the mouse model of fragile X syndrome. 
Other academic groups have also shown that inhibition of the Ras-ERK pathway produces semi-persistent efficacy in similar experimental models of fragile X syndrome. In-vitro and in-vivo testing using knockout mouse models has also shown that AMO-01 could normalize the synapse abnormalities seen in neurons in fragile X syndrome, underpinning an effect on the underlying biology of this disorder. 
Taken together, these findings make our team excited to investigate the potential of AMO-01 to treat fragile X syndrome in the clinic. This is a route our team will consider once we have the safety and efficacy data from the ongoing Phelan-McDermid syndrome study.
DDN: What other developmental disorders might AMO Pharma be able to target via the ERK pathway?
Snape: There are a number of other developmental disorders characterized by increased Ras-ERK pathway activation—these are referred to as “Rasopathies” and are a recognized group of disorders. We also believe that there are more developmental disorders that involve this pathway than have been previously recognized. Prior research shows that epilepsy might also be impacted by increased Ras activity. Our team is currently designing a preclinical program to try to determine the potential scope of using this approach to target some other Rasopathies.
DDN: Is there anything else that you would like to tell us? What aspect of this research do you find most exciting?
Snape: For us, the data to-date on AMO-01 and the Ras-ERK pathway have been very promising in terms of the potential for therapeutic benefit. Of course, we are early in the journey into the clinical validation of targeting this pathway and so we have to temper our excitement as we wait for the early clinical data readout. But the potential of AMO-01 shown in preclinical studies is significant.
The fact that multiple groups have now shown that targeting the Ras-ERK pathway can potentially lead to semi-persistent benefit in specific developmental disorders is unprecedented in this field, or similar areas such as epilepsy. The potential to address the underlying biology and nature of developmental disorders would be a major advance. In addition, targeting the Ras-ERK pathway is similar to molecularly targeted approaches in oncology, which would be part of a paradigm shift currently evolving in neuroscience more broadly.

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