Psychiatric disorders already imposed a heavy burden on society before the COVID-19 pandemic. But now that we are dealing with COVID-19-related stress and the direct neuropsychiatric effects of the SARS-CoV-2 virus, the burden is beginning to feel all but crushing. We would welcome therapeutic relief, but so little is available. Why should so few drugs be available in this time of crisis? Until recently, neuropsychiatric drug development looked unpromising. Many pharmaceutical companies had stepped back from developing drugs for historically intransigent indications such as major depressive disorder, Alzheimer’s disease, and schizophrenia. However, advances in areas such as genomics and imaging, as well as breakthrough discoveries in the pathophysiology of neuropsychiatric diseases, have prompted a new round of innovation. What follows is a look at five companies—some large, others small—that are moving forward with novel therapeutics for patients who not only have unmet needs, but who also tend to be overlooked or marginalized in society. These companies delivered some of the most compelling presentations at the Fourth Annual Neuropsychiatric Drug Development Summit, a virtual event that was held September 28–30, 2021.

Targeting microglia

Mood disorders and inflammation have a complex relationship that has only recently become recognized as an area of investigation for drug discovery. Currently available therapeutics for conditions such as major depressive disorder don’t work for all patients, and among nonresponders, elevations of proinflammatory immunological markers are commonly observed. Injury or age-related changes can enable peripheral immune cells to cross the blood-brain barrier. However, even in the absence of a compromised blood-brain barrier, microglia within the brain can release proinflammatory cytokines, setting off a cascade of inflammatory events directly into the central nervous system. To counter inflammation, Anindya Bhattacharya, PhD, senior director, head of neuroimmunology discovery, Neuroscience Therapeutic Area, Janssen Research and Development, is focusing on P2X7, an ion channel receptor abundantly expressed on microglia that activates NLRP3-dependent IL-1β/IL-18 release and thereby initiates neuroinflammation and microglial activation. Data generated by Bhattacharya and his Janssen colleagues shed light on the role of P2X7 activation in the pathophysiology of mood disorders. “I have always been convinced that targeting the microglia with a brain-penetrant P2X7 antagonist is one of the many ways we can dampen neuroinflammation,” Bhattacharya says. Although P2X7 as a target has potential for a range of disorders including Alzheimer’s, traumatic brain injury, and epilepsy, Janssen’s program is prioritizing neuropsychiatric disorders. Bhattacharya says that a subset of patients with treatment-resistant depression who have been failed by classical treatments such as selective serotonin reuptake inhibitors (SSRIs) and antipsychotics have a heightened inflammatory tone. The indication and target population also offers an opportunity for a precision medicine approach, an approach that may also incorporate companion biomarkers such as C-reactive protein and IL-1β as well as imaging studies that show an inflammatory signature. Janssen has completed a Phase I study to assess the safety, tolerability, pharmacokinetics, and target engagement of a P2X7 PET ligand. The company is planning further human trials of the compound in mood disorders.

The brain’s reward circuit

Another company zeroing in on neuroinflammation for depression is INmune Bio. “We think of depression as an immune disorder,” says Jessica Malberg, PhD, the company’s director of neuroscience development. She notes that while there are more than 16 different generic antidepressants on the market, many people don’t respond to any. She adds that many nonresponding patients—patients who are “treatment resistant”—have an increase in inflammatory biomarkers.

INmune Bio develops immunotherapies that can reprogram a patient’s innate immune system and enhance its ability to fight cancer and Alzheimer’s disease. For example, the company is developing XPro1595, a next-generation protein biologic that neutralizes soluble tumor necrosis factor (TNF) without affecting transmembrane TNF. The biologic is meant to decrease neuroinflammation without the side effects seen with less selective TNF inhibitors.

INmune Bio is collaborating with Emory University researchers Andrew H. Miller, MD, and Jennifer Felger, PhD, who have identified a reward circuit in the brain that is sensitive to inflammation. “It really ties together inflammation, anhedonia, and a potential specific brain circuit in studies of these patients,” Malberg declares (Felger et al. Mol. Psychiatry 2016; 21: 1358–1365). Inspired by studies showing improved mood in patients with inflammatory diseases such as psoriasis and Crohn’s disease who have been treated with antitumor necrosis factor (anti-TNF) agents, INmune Bio is testing its anti-TNF compound XPro1595 in a Phase II trial. To be enrolled in the trial, patients must suffer from anhedonia, have a C-reactive protein level greater than 3 mg/L, and have failed two courses of antidepressant therapy. If successful, this drug would be distinguished by the use of C-reactive protein as a biomarker to determine which patients could benefit. Currently, there are no blood biomarkers available to aid in selection of depression therapies. In addition to providing safety and efficacy data about XPro1595, the study will help researchers to understand the pathophysiology of treatment-resistant depression by using magnetic resonance imaging to assess whether treatment restores functional connectivity between two areas of the brain involved in motivation and reward.

Stimulating neurogenesis

In an effort to search outside of the range of targets that have been previously tested in major neuroscience indications, NeuroNascent is studying compounds that promote neurogenesis in the brain, a natural process active throughout the lifespan of the human brain. To find those compounds, the company carried out phenotypic screens using human neural progenitor cells. Then, the company determined which of the neurogenesis-promoting agents were also neuroprotective. This process turned up hits for multiple families of small-molecule compounds, including NeuroNascent’s lead candidate for Alzheimer’s and Parkinson’s diseases, NNI-362.

NeuroNascent discovers and develops therapies that treat central nervous system disorders by replacing and enhancing neuron numbers, not just neural connections. One of the company’s small-molecule regenerative candidates is NNI-362. Evidence that NNI-362 promotes neuron regeneration from proliferation and expansion through differentiation and maturation supports the drug’s use to halt and reverse Alzheimer’s disease and other age-related neurodegenerative disorders.

Judy Kelleher-Andersson, PhD, president and CEO of NeuroNascent, explains, “Using a phenotypic screen, you’re allowing the modification of a cellular function to dictate the therapeutic as well as the target.” Although phenotypic screening is not exclusive to the neuroscience field, it is becoming popular as an alternative to target-based screening for neurodegenerative diseases because it does not require specific knowledge of the targets or pathways involved in the etiology of these diseases. Phenotypic screens can also point back to new, previously unknown pathways or mechanisms. Meanwhile, target-based drug discovery has repeatedly failed to produce disease-modifying therapies, even as the industry continues to carry the torch for targets like β-amyloid. NeuroNascent has completed a Phase Ia trial of NNI-362 in a healthy, aged population and found that the drug was safe and well tolerated. The next step, once funding is secured, will be a proof-of-concept, Phase II trial in Alzheimer’s or Parkinson’s patients. Keller-Andersson says that NeuroNascent scientists were able to observe neuronal regeneration in rodents that had received about six weeks of treatment. She adds that in aged humans, the corresponding treatment time would probably be six to nine months. Treated patients would be evaluated with volumetric magnetic resonance imaging to assess whether new neurons had been integrated in the brain. Also, treated patients would be assessed for reversals in age-related deficits. The company is also developing a compound called NNI-351. NNI-351 is undergoing IND-enabling testing for the treatment of rare pediatric disorder fragile X syndrome. Kelleher-Andersson says that this compound has reversed the hippocampal-related behavioral deficits in an animal model of fragile X syndrome.

A new schizophrenia target

Phenotypic screening has also been a key strategy for Sunovion Pharmaceuticals. In collaboration with PsychoGenics, Sunovion discovered ulotaront (SEP-363856), a TAAR1 agonist. Currently, Sunovion is developing the drug for schizophrenia. Like major depressive disorder, schizophrenia is a disorder for which few drugs and targets are available. Typical antipsychotics, or first-generation antipsychotics, were first developed in the 1950s. They block dopamine type 2 (D2) receptors. The second-generation drugs, or atypical antipsychotics, have a higher affinity for the serotonin 2A (5-HT2A) receptor, and a low affinity for dopamine receptors. About 30% of patients are resistant to typical and atypical antipsychotics, and about 60% of patients achieve only partial control of their symptoms. Besides being ineffectual in many patients, these agents are associated with significant undesirable side effects, including movement abnormalities, metabolic side effects, and cognitive effects. Consequently, a large unmet need remains within the indication. Using phenotypic screening in rodents, scientists working with Sunovion searched for compounds that have antipsychotic potential but act via a mechanism other than the one that enables some drugs to block D2 or 5-HT2A. The screening produced ulotaront, says Robert Goldman, PhD, chief, Medical Scientific Affairs, Sunovion. Last year, Sunovion published the results of a Phase II trial of ulotaront (Koblan et al. N. Engl. J. Med. 2020; 382: 1497–1506). The results showed that the ulotaront group had a greater reduction in symptoms than the placebo group, and that the drug was safe and well tolerated. “We’ve completed only the one pivotal study to date, and we know from that study that we had clinically meaningful effects on the positive symptoms on hallucinations, delusions, and disorganized thinking as well as on negative symptoms during the four-week trial,” Goldman states. The drug is now being tested in four Phase III clinical trials for schizophrenia.

Cancer is neuroscience, too

Cancer is a new and surprising therapeutic area emerging under the neuroscience umbrella. It is well known that nerves play an important role in the tumor microenvironment, and that there is communication between nerves and cancer cells. When nerves are present in the tumor, that communication tends to be correlated with worse cancer outcomes. However, until recently, technology has not been available to discover the mechanisms by which nerve cells stimulate the growth of tumors, and to target them with drugs. “Most neurobiologists will tell you that 98% of their field is really focused on the central nervous system: the brain and the spinal cord,” says Pearl Huang, PhD, president and CEO, Cygnal Therapeutics. “They have viewed the peripheral nervous system as an effector system, one that just does what the brain tells it to do. We wanted to look at the peripheral nervous system to see how it works independently to signal in human disease.” Cygnal Therapeutics was founded on the hypothesis that instead of being simple conduits of central nervous system commands, peripheral nerves are independent actors and decision makers. Because the termini where neurons communicate with immune cells or cancer cells are sometimes a meter or more away from the cell body of the nerve located near the spine, new tools were required to map which neurons are signaling in a diseased state. Cygnal’s exoneural platform for drug discovery includes proprietary imaging technology, functional genomics tools, bioinformatics tools, and a custom neuropharmacopeia. With this expertise, Cygnal scientists can grow nerve cells from stem cells, culture them, manipulate them, and observe signaling with cultured target cells. The company now has two programs poised to move toward candidate development in the near future, both aimed at downregulating signals exchanged between neurons and other tissues.

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