Takeda Development Center Americas, Inc.

THURSDAY, July 27, 2023 -- For patients with narcolepsy type 1, an orexin receptor 2 agonist, TAK-994, improves measures of sleepiness and cataplexy over eight weeks compared with placebo but is associated with hepatotoxic adverse events, according to a study published in the July 27 issue of the New England Journal of Medicine . Yves Dauvilliers, M.D., from Gui de Chauliac Hospital and the University of Montpellier in France, and colleagues conducted a phase 2 randomized, placebo-controlled trial of TAK-994 in patients with narcolepsy type 1. Seventy-three patients were randomly assigned to receive twice-daily oral TAK-994 (30 mg [17 patients], 90 mg [20 patients], and 180 mg [19 patients]) or placebo (17 patients). Owing to hepatotoxic adverse events, the phase 2 trial and extension trial were terminated early. Primary end point data were available for 41 patients. The researchers found that the least-squares mean changes to week 8 in average sleep latency on the Maintenance of Wakefulness Test were 23.9, 27.4, 32.6, and −2.5 minutes in the 30-, 90-, and 180-mg groups and placebo group, respectively. The corresponding least-squares mean changes to week 8 in the Epworth Sleepiness Scale were −12.2, −13.5, −15.1, and −2.1, respectively. The corresponding weekly incidences of cataplexy at week 8 were 0.27, 1.14, 0.88, and 5.83 (rate ratios versus placebo, 0.05, 0.20, and 0.015, respectively). "The outcomes described in the current report may be seen as a backward step because of the decision to terminate the trial," write the authors of an accompanying editorial. "However, the impressive efficacy is a major step forward in helping patients with narcolepsy type 1." The study was funded by Takeda Development Center Americas. Abstract/Full Text (subscription or payment may be required) Editorial (subscription or payment may be required) Posted July 2023

A team has developed a new tool that can predict how Parkinson's disease patients will fare over the course of a year based on their genetics, brain scans and physical examinations. Testing whether a new drug impacts the progression of Parkinson's disease takes years, in part because the disease often advances so slowly. Many Parkinson's patients don't have any worsening of their symptoms over the course of a typical clinical trial, even without treatment. Now, Scripps Research scientists have developed a tool that analyzes Parkinson's disease patients' genetic and clinical data to predict who is most likely to rapidly progress. The approach, described in npj Parkinson's Disease, will let clinical researchers select the most at-risk patients and design shorter, more powerful trials to assess Parkinson's drugs, they say. "If clinicians are able to enroll in trials only those patients predicted to progress, they can get much faster results and move this field along more quickly," says senior author Ali Torkamani, PhD, professor and director of Genomics and Genome Informatics at the Scripps Research Translational Institute. Parkinson's disease is a progressive disorder of the nervous system and affects about one million people in the United States. The earliest symptoms are often barely noticeable tremors, and over the course of many years the disease progresses, eventually impacting movement, posture, facial expressions, speech and eating, as well as causing pain and dementia. However, the order and speed at which these symptoms worsen varies greatly between people. Over a single year, for instance, many patients won't get worse, making it difficult and time-consuming to study the effectiveness of drugs at slowing this progression. Torkamani, along with Scripps Research colleagues and collaborators at Takeda -- who are developing investigational Parkinson's Disease treatments -- set out to better predict this short-term progression in patients considered for inclusion in clinical studies to slow down this disease. They analyzed the progression over 12, 24 and 36 months of patients enrolled in two existing cohorts -- the Parkinson's Progression Markers Initiative and the Parkinson's Disease Biomarkers Program. In all, the team used data including genetics, clinical exam information, brain scans and treatments, on 879 patients. Overall, 529 patients were found to be "progressors" over the first 12 months of the study, with their symptoms significantly worsening, while 350 were grouped as "non-progressors." Torkamani's group used a machine learning approach to develop a model that could predict, with 77% accuracy, which group patients belonged to. "This model worked by combining different aspects of comprehensive disease profiling," says Torkamani. "Genetic risk factors were the most powerful predictor, but other factors were important to include as well." Some of the strongest signals, he says, included whether a patient had a mutation in LRRK2 -- this known risk factor for Parkinson's disease makes patients more likely to develop early onset disease, but then their symptoms progress more slowly. For now, the model doesn't have clinical value for individual patients, since there are no drugs that have been shown to slow the progression of Parkinson's. However, the researchers hope that being able to choose "progressors" for clinical trials makes it easier and faster to pinpoint these kinds of drugs as the field moves forward. "Right now, these clinical trials are large and tend to take two to three years," says Torkamani. "We're hoping to empower smaller trials that are on the order of a one-year time frame." The Scripps Research scientists also plan to expand their model to try to predict other aspects of Parkinson's. For instance, can genetic markers predict which Parkinson's patients will develop psychosis or depression? The same approach they took in the current study -- integrating clinical and genetic information -- could also be useful in analyzing the progression of other neurodevelopmental disorders. This work was supported by funding from Takeda Development Center Americas, Inc., and the National Institutes of Health (R01HG010881).

T cells are capable of killing cancer cells, but tumors have tricks to evade their might. New research details one of these strategies, known as trogocytosis, in which T cells ingest a piece of cancer cell membrane, taking on a bit of cancerous identity. Blocking this process could improve the effectiveness of CAR T cell therapy. The immune system is equipped to respond not just to external invaders -- think viruses, bacteria, and parasites -- but also to internal threats, namely, cancer. Yet, frequently, malignancies overcome the immune system's defenses and evade detection. In a new study, researchers led by Serge Y. Fuchs of the School of Veterinary Medicine, have uncovered a detailed mechanism by which tumors can skirt both the immune system and cancer therapies that leverage its power, such as genetically engineered CAR T cells. Their investigation, published in the journal Cell Metabolism, revealed how tumor-derived factors stimulate trogocytosis -- a process derived from the Greek word trogo, which means "to gnaw" or "to chew." When T cells interact with cancer cells, they can sometimes "nibble" a piece of the cancer cell membrane. When that membrane segment includes an antigen, a molecule specific to the cancer, the T cells may then begin expressing that antigen on their own cell surface, making it appear to other T cells like a cancer cell. Trogocytosis can affect a patient's own T cells and those modified to become CAR T cells, an approach in which a patient's T cells are genetically engineered to specifically target cancer cells, grown in a lab, and then delivered back to the patient. "Trogocytosis can lead to three different things, and all three are bad for a person with a tumor," says Fuchs, the senior author on the work. "First of all, the tumor cell did not get killed and has lost an antigen, which may mean that even if another, better equipped T cell comes along, it will not recognize it, giving cancer cells a window of opportunity to grow unchecked. The second problem is, for reasons we still don't understand, once a T cell takes a piece of the tumor cell membrane, it becomes much less active. And the third problem is very ironic. Because now, a T cell that displays tumor antigen, this 'sheep in wolf's clothing,' may then become victim to 'fratricide,' killed by another T cell." Overall, the result is a decline in killer T cell numbers and activity and a bump in opportunities for the cancer cells to escape detection and grow. "What we see is that only a small number of cells undergo trogocytosis and then they disappear quickly because they're killed. So we're studying a vanishing act. It is hard to do -- very expensive and very tedious -- but it appears to be very important," says Fuchs. With a longstanding interest in how receptors on the surface of immune cells guide anti-cancer immunity, Fuchs and colleagues have made a variety of discoveries showing how tumors can manipulate T cells to escape being targeted and killed. A particular area of interest is what's known as tumor-derived factors, or the concoction of proteins, lipids, and other materials that cancer cells secrete into the body. In the current study, the Penn researchers found that collecting these secretions and exposing the resulting solution to T cells hampered the cells' ability to do their cancer-fighting job. "Just exposing them to this tumor-conditioned media caused them to kill fewer cancer cells, trogocytose more, and get killed more," Fuchs says. Trogocytosis was previously believed to have something to do with cancer's ability to hinder anti-cancer immunity, but the Penn-led team pinned down the mechanism, showing that T cells exposed to tumor-derived factors experienced a notable decline in levels of the gene CH25H. This gene is known to be involved in altering cell's lipid membranes and can inhibit two cell membranes from fusing together -- an essential process for trogocytosis to occur. When they added back a metabolite produced by CH25H, they could block trogocytosis. "That was an 'aha' moment," Fuchs says. Further characterization of the pathway helped the team identify another player, the gene ATF3, which opposes the activity of CH25H. Eliminating AFT3 prevented trogocytosis from occurring and restored the ability of T cells to kill tumor cells. Not only do the new insights suggest novel targets for anti-cancer therapies, but they may have immediate significance for CAR T therapy. Since trogocytosis could impair the effectiveness of the engineered T cells delivered in CAR T, the researchers surmised that blocking this could improve CAR T performance. "We figured, why don't we use what is cleverly known as an 'armored CAR' approach, and co-express CH25H in the CAR T," Fuchs says. "This turned out to be more efficient than the old CAR T cells." Indeed, delivering the CAR T cells adorned with CH25H improved the survival of mice with cancer compared to the unarmored CAR T cells. Though only a small percentage of T cells are involved in trogocytosis, Fuchs says it may be an underappreciated process when it comes to cancer immunity and other processes, such as those involved in autoimmunity. With future work, he and colleagues intend to explore the roles of ATF3 and CH25H and other molecules in trogocytosis. And he's hopeful that other researchers will pick up on these lines of work, bringing the findings closer to clinical application. "I can see this going into use in CAR T therapy quickly," Fuchs says. "It's ready to play." Serge Fuchs is the Elizabeth and William Whitney Clark Professor of Oncology at the University of Pennsylvania School of Veterinary Medicine. Fuchs' coauthors on the work were Penn Vet's Zhen Lu, Noreen McBrearty, Jinyun Chen, Vivek S. Tomar, Hongru Zhang, Gianluca De Rosa, and Daniel P. Beiting; the Perelman School of Medicine's Aiwen Tan, Aalim M. Weljie, Zhen Miao, Subin S. George, and Constantinos Koumensis; Takeda Development Center's Allison Berger and Gurpanna Saggu; and Case Western Reserve University's J. Alan Diehl. The study was supported in part by the National Institutes of Health (grants CA247803, CA240814, CA165997, and CA115299).