People in need of psychological or neurological care used to be subjected to bloodlettings, purgings, exorcisms, and even more extreme “treatments.” Fortunately, these interventions—which were usually justified as ways to rebalance humors or expel demons—have fallen out of favor. Today, pharmacological interventions predominate, even though some people are wary of “better living through chemistry.”
Chemistry, or rather molecular neuropharmacology, should be distinguished from feel-goodism, a reliance on illusory or superficial fixes. Molecular neuropharmacology goes deep. It is concerned with biological realities such as neurotransmitter concentrations, plaque deposits, and receptor polymorphisms. It has already benefitted millions, and it is poised to benefit millions more by addressing a widening array of conditions.
Several specialists in molecular neuropharmacology are highlighted in this article. They include scientists who are developing new drugs and drug delivery vehicles that press, ever more deftly, molecular levers that pertain to neurological and mental health.
Doubling up on bipolar depression
Most clinical studies that evaluate antidepressants exclude patients with acute suicidality—and for understandable reasons. Antidepressants have been associated with an increased risk of suicidal thinking, feeling, and behavior in young adults. Nonetheless, a Wilmington, DE-based company called NeuroRx, is committed to developing treatments for people with severe bipolar depression who also have serious thoughts about committing suicide.
NeuroRx may seem to welcome paradox. It certainly seemed that way to Robert Eric Besthof, a seasoned pharmaceutical executive, when he met NeuroRx’ founder and chief executive officer, Jonathan Javitt, MD, MPH, and heard about the company’s plans.
Besthof was intrigued. Like too many people, he had lost a friend to suicide. In March of 2016, he officially joined the fledgling NeuroRx as its chief commercial officer. Since then, the company has made rapid progress. In 2018, one of the company’s investigational drugs, NRX-101, received breakthrough therapy designation from the FDA. NRX-101, the company says, is the first oral treatment targeting suicidal bipolar depression after initial stabilization with ketamine or another therapy.
There’s clearly a need. In the United States, suicide is a leading cause of death, killing more than 40,000 people every year, according to the Centers for Disease Control and Prevention. Millions more attempt suicide or report having suicidal thoughts. The only FDA-approved treatment for suicidal bipolar depression is electroconvulsive therapy select ECT union brief electrical stimulation of the brain. While generally considered safe and effective, ECT can lead to confusion, memory loss, and other problems.
“Suicide is a very lethal condition,” Besthof emphasizes. “It’s also important that people tend to think of suicide as extreme depression, and that is not the case.” Suicidal brains look different, he notes, adding that suicidal bipolar depression requires a different treatment approach.
NRX-101 is a patented, oral, fixed-dose combination of D-cycloserine and lurasidone, which respectively target N-methyl-D-aspartate select NMDA) and 5-hydroxytryptamine 2a select 5-HT2a) receptors in the brain. Whereas most approved antidepressants work by raising serotonin levels, D-cycloserine increases the concentration of the neurotransmitters glutamate and glutamine.
Javitt was encouraged by evidence that NMDA-targeted drugs might work to reduce depression and suicide, but he was also aware that these drugs come with an increased risk of hallucination, requiring treatment with an antipsychotic. Preclinical studies suggested a combination of D-cycloserine and lurisadone, an approved antipsychotic, might strike the right balance, reducing depression and suicidal thoughts without introducing hallucinations.
Clinical studies so far are encouraging. In May, NeuroRx announced positive results of its Phase II study of NRX-101 for patients with suicidal bipolar depression after stabilization with ketamine. Patients who received the combination treatment versus lurasidone alone showed lower levels of depression. Relapses were observed in two of the five patients who received lurasidone alone, but no relapses were observed among the 12 patients who received the experimental combination. Also, NRX-101 was well tolerated.
In July, NeuroRx announced the launch of a larger Phase IIb/III study expected to enroll approximately 140 patients with severe bipolar depression and acute suicidal ideation and behavior after stabilization in the hospital with a single intravenous infusion of ketamine. Participants in the trial will be randomized to receive either NRX-101 or lurasidone alone for six weeks. Down the line, the company foresees other potential indications for its treatment approach for conditions including chronic depression, post-traumatic stress disorder select PTSD union and bipolar depression with lower suicide risk.
Peripheral neuropathy? Forget about it
Like NeuroRx, Switzerland-based Metys Pharmaceuticals is working on a treatment that targets glutamate signaling. However, Metys Pharmaceuticals’ drug, called MP-101, targets the signaling pathway in the spinal cord rather than in the brain. MP-101 is being developed to treat and/or prevent symptoms of peripheral neuropathy, including numbness, tingling, and pain.
Michael Scherz, PhD, the company’s founder and chief executive officer, explains that the orally administered drug has no effect on peripheral nerves. In other words, it isn’t expected to reverse peripheral nerve damage related to chemotherapy, surgery, diabetes, or other conditions. Instead, the drug acts on the processes that lead to spinal sensitization and the increasingly uncomfortable symptoms that come with the nerve damage.
“It’s like an amnesic agent,” Scherz says. “It helps the spinal cord forget.”
Scherz notes that patients receiving chemotherapy for the treatment of cancer often describe a strange sensation when they touch a sheet of glass or a cold drink. That sensation gradually becomes more persistent and painful over time. MP-101 is intended to interrupt that process by interfering with glutamate signals between nerve cells.
MP-101 has an intriguing chemistry. It consists of a 3:1 mixture of the enantiomers—the right- and left-handed mirror versions—of a molecule called dimiracetam. Dimiracetam was first developed decades ago along with other racetam drugs that appeared to make healthy rats smarter, Scherz explains. But that line of research later was abandoned. Then, the Swiss company Neurotune decided to pursue dimiracetam as a treatment for AIDS patients with neuropathic pain. That trial, too, ended in disappointment.
However, Scherz says, the trial data was hard to interpret. He launched Metys Pharmaceuticals with the goal of developing dimiracetam as a treatment for peripheral neuropathy. The original dimiracetam consisted of a 1:1 mixture of the molecule’s two enantiomers. But his team later made the unusual and fortuitous select for patent reasons) discovery that the drug appears to work better when in a 3:1 mixture. It’s this 3:1 optimized mixture of dimiracetam enantiomers that the company now calls MP-101.
Scherz reports that the company has been given the green light from the FDA to conduct a Phase II trial of MP-101 based on existing safety data obtained from studies of the original 1:1 ratio dimiracetam. All Metys Pharmaceuticals needs now, he says, is funding.
A metabolic approach to Alzheimer’s
Meanwhile, T3D Therapeutics aims to fill an unmet need in the treatment of Alzheimer’s disease select AD) following a series of disappointments targeting the amyloid plaques that are hallmarks of AD. The company, based in Research Triangle Park, NC, has been pursuing a strategy to tackle AD in essentially the same way one tackles type 2 diabetes, by targeting insulin resistance. T3D, however, targets insulin resistance in the brain.
Although many drug developers are focused on targeting the amyloid plaques that are a hallmark of Alzheimer’s disease, T3D Therapeutics is taking a different approach. Specifically, the company is trying to resolve metabolic abnormalities in neurons. According to T3D, poor energy metabolism and dysfunctional lipid metabolism in the brain can lead to neurodegeneration and brain “strangulation.” [National Institute on Aging/National Institutes of Health]
“Neurons in the brain are not getting adequate energy supply through glucose utilization,” explains John Didsbury, PhD, T3D’s president and chief executive officer. “You need insulin to process glucose. The inability to process glucose is a result of emerging insulin resistance in the brain.” As a result, the AD brain becomes “starved.”
The company’s lead drug candidate, T3D-959, was originally identified as a potential treatment for type 2 diabetes. But unlike most drugs, it has the ability to cross the blood-brain barrier. The molecule works through peroxisome proliferator-activated receptor select PPAR)-δ and, to a lesser extent, PPAR-γ, both central regulators of glucose and lipid metabolism.
The results of early clinical trials have so far shown that the orally delivered drug candidate is safe and well tolerated. Although sample sizes are small, Didsbury says that there’s some evidence the drug treatment might also lead to cognitive and motor improvements for people with mild to moderate Alzheimer’s disease.
In May, the NIH’s National Institute on Aging awarded the company $9 million to help fund a Phase II study of T3D-959. The Phase II PIONEER study select Prospective Therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration) is expected to enroll up to 252 adults with mild-to-moderate AD, beginning in early 2020.
Didsbury notes that his team holds out hope that the drug might ultimately treat people with more advanced AD too, as well as other neurodegenerative conditions. “There’s a sentiment in AD that once you reach a certain severity, there’s no possibility of effective treatment,” he points out.
An inhaler for epilepsy
The epilepsy community has lacked a viable rescue treatment for terminating a seizure. To introduce such a treatment, Engage Therapeutics, a biopharmaceutical company in Summit, NJ, isn’t developing a new drug. Instead, the company is applying a delivery technology that can rapidly bring an old drug to where it’s needed—the brain.
The technology is designed to allow the rapid vaporization of a drug into a small particle aerosol optimal for delivery via inhalation. Called Staccato, the FDA-approved technology comes from Alexza Pharmaceuticals. In 2017, Engage entered into an exclusive license and supply agreement with Alexza to advance Staccato Alprazolam select generic Xanax) as an emergency rescue treatment for epilepsy.
Company founder Greg Mayes has a personal reason for his investment in what he describes as an EpiPen-like “safety net” for people with epilepsy: his son was diagnosed with epilepsy in 2014. While there are treatments available to stop a seizure, he says, they take several minutes to start working.
A Phase IIa proof-of-concept trial showed that Staccato Alprazolam stopped seizures in less than two minutes in most people. Participants in the small trial included five people with photosensitive epilepsy, whose seizures could be triggered by visual stimuli.
“What we saw was good, but it’s not real life,” Mayes notes. “It really can stop a seizure quickly. Presumably, it can stop a naturally occurring seizure.”
To find out, Engage Therapeutics is now enrolling 123 patients into a multicenter, randomized, controlled trial to test Staccato Alprazolam in epileptic adults with regular, uncontrolled seizures that follow a predictable pattern.
A personalized, big data approach
For BlackThorn Therapeutics, in San Francisco, CA, the overarching goal isn’t to target any one particular disorder, but rather to move mental health toward personalized medicine, says Jane Tiller, MBChB, FRCPsych, the company’s chief marketing officer. “The problem in the field is we are diagnosing people through clusters of symptoms,” she explains, “but it’s not based on biology.”
Conditions such as depression or PTSD are surely made up of many different neurobiological impairments that produce behaviors and symptoms that appear similar, she continues. “When you think about neurobehavioral conditions that way, it’s not too surprising that everyone struggles to come up with innovative breakthroughs that make a difference.”
To address this shortfall, BlackThorn is applying what it calls a circuit-based approach to understanding neurobehavioral health—pursuing the discovery and development of novel treatments with advanced data science techniques and technologies to transform drug discovery. An important aspect of the approach is the use of artificial intelligence and machine learning to make sense of vast quantities of data.
BlackThorn claims that it has a growing pipeline of drug candidates. One of the two candidates the company has disclosed is BTRX-335140, a selective antagonist for the κ-opioid receptor, for use in mood disorders. The company has completed a Phase I study and expects to begin a Phase II study in 2020. The other candidate, BTRX-323511, is a selective antagonist for the vasopressin receptor 1a, which the company is pursuing for the treatment of social-emotional disorders such as autism spectrum disorder.
“We’ve gotten to a tipping point,” Tiller declares. “We can combine computational power with refined imaging and gene expression. We are pulling that package together with as much data as we are able to ingest … I think it’s putting us in a position to enable a new approach to drug development in neurobehavioral disorders, and within the next few years I hope to see a transformation in the field.”
Spatial Mapping of Brain Tissue Samples at Single-Cell Resolution
A new approach to in situ sequencing select ISS union a nucleic acid analysis technology, is being developed by Cartana in Sweden to meet the challenge identified by the Allen Institute and others of generating spatial maps of gene expression inside the brain with high resolution and throughput. To create high-quality atlases of brain cell types and model cell functions accurately, tools are required for characterizing and locating all the different CNS cell types inside the brain. Cartana’s ISS technology performs single-cell gene expression analysis directly inside brain tissue samples while preserving spatial information, thus enabling the creation of spatial human brain cell maps.
Cartana’s ISS starts with a tissue sample preparation kit with gene-specific, barcoded padlock probes. The sample preparation step generates 0.5–1 μm barcoded DNA spots at the original location of a detected RNA molecule. The barcode sequences in these DNA spots are then sequenced directly inside the tissue section, using decoding software and fluorescence imaging. During the ISS reaction cycles, fluorescently labeled probes are iteratively attached, imaged, and removed, making it possible to read the barcode sequences in the DNA spots. The high intensity and high signal-to-noise ratio enables imaging with low magnification objectives. Thus, ISS reactions over large tissue areas are imaged with high speed, significantly increasing throughput in comparison to other in situ transcriptome analysis techniques.
Due to this high-throughput, Cartana’s ISS is well suited for mapping of cell types in tissue sections defined by single-cell RNA sequencing. Generating large spatial cell atlases enables the analysis of unique gene expression patterns and relationships of different cell types constituting tissues and their architectures. The accompanying image shows 150 central nervous system marker genes spatially mapped in a mouse brain sample.