DTC pharmacogenomics testing under scrutiny

Abstract

77 new-onset patients, a team led by Benaroya immunologists Alice Long and Peter Linsley probed gene expression profiles in the blood and identified a population of CD8-positive T cells, thought to be the cells that kill beta cells, with traits of exhaustion that increased in number among subjects who responded favorably to the therapy (Sci. Immunol. 1, eaai7793, 2016). For reasons that are not entirely clear, those T cells are more susceptible to teplizumab-induced activation than other immune subsets, Long explains. “Although [the antibody] hits all CD3 cells,” she says, “what it modulates most are exhausted cells.” The proliferation of those partially exhausted cells then creates a more tolerogenic immune landscape that safeguards beta cells from further attack. Long thinks the same mechanism is likely operating in the pre-diagnosis setting as well—which would explain why teplizumab proved so efficacious in the recently published trial, where the median time to type 1 diabetes diagnosis was just over four years in the teplizumab group; in the placebo group, it was half that duration. Side effects were mild, without any EBV-related complications. “But,” says Greenbaum, “we don’t yet know whether there’s something unique about this therapy as compared to other immune therapies.” Greenbaum and her fellow TrialNet investigators previously showed that oral insulin did not delay disease onset among autoantibody-positive relatives of people with type 1 diabetes. The group is now running prevention studies with two other immune-modulating drugs, the anti-malarial hydroxychloroquine and the cytotoxic T lymphocyte antigen 4 (CTLA-4) analog Orencia (abatacept), with plans to start two more trials—one involving antithymocyte globulin (a preparation of rabbitderived anti-human T cell antibodies), the other with the CD20-targeted antibody rituximab and Orencia. Janssen is also wrapping up a trial of its tumor necrosis factor-α blocker Simponi (golimumab), and several academic studies are looking at other putative beta cell–saving agents in at-risk individuals. These include a decades-old blood pressure medication called methyldopa, a concoction of probiotic bacterial strains, and the glucagonlike peptide-1 receptor agonist Victoza (liraglutide), commonly used to treat type 2 diabetes Tiziana Life Sciences, headquartered in London, also has a fully human anti-CD3 antibody called foralumab that binds to the T cell receptor complex to modulate regulatory and effector T cells, and could be used in diabetes prevention. But according to CEO Kunwar Shailubhai, the company first plans to evaluate an oral formulation of foralumab in healthy volunteers before advancing the drug for non-alcoholic steatohepatitis, Crohn’s disease and, if funding comes through from diabetesfocused non-profits, type 1 diabetes as well. Any prophylaxis will ultimately only be as good as the screening effort used to find children positive for islet autoantibodies, though, and researchers are still “trying to figure out the best way to reach kids,” says Kimber Simmons, a pediatric endocrinologist at the University of Colorado Barbara Davis Center for Diabetes in Aurora, who has helped screen over 20,000 children at doctors’ offices, emergency rooms, urgent care centers, pop-up clinics and community health fairs over the past three years. And in Germany, a coalition of some 650 pediatricians from across Bavaria and Lower Saxony—led by Anette-Gabriele Ziegler, an endocrinologist at Helmholtz Zentrum München—have tested for autoantibodies in nearly 100,000 children over a similar time period. Those kinds of population-wide screening efforts can help reduce lifethreatening complications but ultimately falter because “we’ve never had [a preventative drug therapy] to actually offer kids,” Simmons says. Should teplizumab enter the marketplace in 2021, as Provention hopes it will, “then we will be able to discuss screening more population-wide,” says Helena Elding Larsson, a pediatric endocrinologist from Lund University in Sweden. ❐