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Anti-CD3 drug keeps diabetes at bay No drug has ever delayed islet cell destruction. Now that teplizumab has, the challenge turns to identifying eligible recipients for the treatment.

he first drug to ever slow the progression from pre-diabetes to Tclinical is one step closer to reaching the market. On August 5, the US Food and Drug Administration (FDA) granted breakthrough therapy designation to teplizumab, a CD3-targeted from Provention Bio, to prevent or delay type 1 diabetes onset among children and adults at high risk of developing the disease. The regulatory distinction comes after a June report showing that teplizumab postponed the onset of symptomatic disease by a median of two years compared with placebo in patients who took the drug for 14 days (N. Engl. J. Med. 381, 608–613, 2019). “It’s a very prolonged effect after a single two-week course of the antibody,” says Lucienne Chatenoud, an immunologist from the Necker Hospital for Sick Children in Paris who was not involved in the study. “This is, in view of all clinical diabetologists, a real measure Should a treatment to push back the age of type 1 diabetes onset become available, screening programs of robustness... You are really delaying the to identify children at a markedly elevated risk will be critical. One such European effort is the Global onset of insulin therapy.” Platform for the Prevention of Autoimmune Diabetes, which has undertaken to screen 100,000 Although some researchers maintain newborns for disease-associated variants, including polymorphisms in human leukocyte (HLA) that larger confirmatory trials are still of the DR and DQ isotypes. Credit: KKStock / Alamy Stock Photo needed to prove the benefit of teplizumab, especially in younger children, Provention Bio’s chief executive Ashleigh Palmer says the company now intends to use the dependent on daily insulin injections. study. “I can assure you, if you talk to results of the 76-person study to support a Numerous approaches have attempted to people who have diabetes, they would jump marketing application for people who have prevent or stop islet cell destruction, but so up and down” for two years free of their autoantibodies against pancreatic islets or far, all have failed. Teplizumab now ushers disease. But, she notes, identifying would-be against insulin and are thus fated to develop in the possibility of offering a drug to people drug recipients in that preventative setting type 1 diabetes. Provention also has an who test positive for markers of beta cell remains a challenge. ongoing phase 3 trial evaluating the same autoimmunity but who do not yet have Teplizumab traces its roots back more drug in children and adolescents with newly symptoms of disease. 30 years to the laboratory of Jeffrey diagnosed disease. “I seriously can’t express enough Bluestone, an immunologist now at the Type 1 diabetes is one of the most what a landmark trial this is,” says Carla University of California, San Francisco. In common chronic diseases of childhood. It is Greenbaum, an endocrinologist at the the late 1980s, Bluestone began working prompted by the autoimmune destruction Benaroya Research Institute in Seattle, with Ortho Pharmaceutical to modify the of insulin-producing beta cells in pancreatic Washington, who leads TrialNet, the company’s OKT3, an agonistic CD3-directed islets and leaves affected individuals academic consortium behind the prevention murine that the FDA

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had approved a year earlier for reducing symptoms of EBV-related disease, but Lung Biotechnology tags acute rejection of transplanted organs. He neither did they do better than a placebo iBio for bioink production first mutated the Fc region of OKT3 to at preserving levels of C-peptide or other Lung Biotechnology continues making decrease binding of target receptors, thereby markers of diabetes control. After running inroads toward its goal of manufacturing minimizing crosslinking of the T-cell one last dose-finding follow-up study in 30 3D bioprinted lungs, with a newly receptor/CD3 complex that can trigger individuals, GlaxoSmithKline eventually announced partnership with iBio to scale cytokine release. He then humanized the halted further development last year. up bioink production. The partnership molecule to reduce its immunogenicity In the case of teplizumab, investigators ran follows a 2018 deal with the Israeli (Transplantation 57, 1537–1543, 1994) and a study that Eleanor Ramos, Provention’s chief regenerative medicine company CollPlant teplizumab was born. medical officer and chief operating officer, to license and develop technology for After initial testing in kidney transplant describes as “inherently flawed.” For starters, creating organ scaffolds from bioink recipients, Bluestone teamed up with the phase 3 Protégé trial enrolled a diverse derived from recombinant human Kevan Herold, a clinical immunologist global population, including patients from collagen. Lung Biotechnology, a public now at the Yale School of Medicine in New India who tended to have more advanced benefit corporation subsidiary of United Haven, Connecticut, to start evaluating disease than those from North America, Therapeutics, will use the scaffolds to teplizumab in patients with recent-onset Europe and Israel—and that heterogeneity create bioprintable lungs. iBio will use type 1 diabetes in 1999. Within a year, a “seemed to dilute any effect” of the drug, its FastPharma platform—an automated European group led by Chatenoud and Herold says. The study also had no minimum plant-based protein expression system Bart Keymeulen of the Free University C-peptide requirement: patients only had to combined with hydroponics and glycan of Brussels–VUB began its own study have detectable levels, an indicator of beta engineering—to scale up production of , another humanized cell function but not necessarily a plentiful of CollPlant’s bioink for fabricating Fc-mutated immunoglobulin G1 antibody reserve of insulin-producing cells. that, like teplizumab, targets the ε chain of lung scaffolds that can then be taken to “I can assure you, if you talk clinical trials. Additional collaborations the CD3 receptor. (The differ might be needed to optimize and expand primarily in how they limit to people who have diabetes, binding, with otelixizumab mutated the process for producing commercial they would jump up and down” quantities, iBio said. specifically to avoid glycosylation.) Recombinant human collagen bioink With either anti-CD3 agent, a short is being used with various bioprinting course of treatment started within a few But perhaps the biggest problem with technologies. CollPlant’s bioink— months of diagnosis helped preserve the trial was its primary outcome measure. extracted from the leaves of tobacco plants C-peptide levels, a byproduct of insulin MacroGenics came up with a composite genetically engineered with five human production that serves as an indirect measure defined by insulin usage and genes to produce collagen—includes light- measure of remaining beta cell function. glycemic control as defined by hemoglobin sensitive compounds that can modify the The benefits also lasted for years and the A1c (HbA1c). It ultimately doomed the study. bioink to match natural tissue properties, therapies proved generally tolerable. At One year after treatment, using these criteria, ranging from cartilage to adipose tissue. worst, teplizumab caused cytokine release a similar percentage of patients in the placebo Other groups, like the biotech syndrome–like toxicity in a minority of and teplizumab arms of the Protégé study met company Organovo, are using 3D recipients, owing to the modest T-cell the primary endpoint of low insulin usage bioprinting to generate a spectrum activation, and many otelixizumab recipients and HbA1C levels in a healthy range. of tissues, including liver, kidney and experienced transient symptoms of Epstein– C-peptide levels, however, were better intestine, mainly for lab-on-a-chip Barr virus (EBV) mononucleosis owing to preserved in teplizumab-treated patients, technologies. Bioprinting complex organs viral reactivation among patients with latent both one and two years out from treatment. has remained out of reach, and few prior infections. And there were subgroups—younger companies have attempted to produce In the mid-2000s, MacroGenics patients, those who were recently diagnosed lungs. But 3D bioprinted lungs took a step secured the rights to teplizumab and at the time of trial enrollment, participants forward in May, with the publication of Tolerx in-licensed otelixizumab. Both from the United States—that experienced findings in Science from a Rice University biotech companies then turned around and especially pronounced benefits. team demonstrating a stereolithographic inked co-development deals with larger After Provention acquired the asset from method of using photoactivated liquid pharmaceutical partners—MacroGenics with MacroGenics in May 2018, the company resins to create hydrogels with vascular Eli Lilly, Tolerx with GlaxoSmithKline— took the lessons of those post hoc analyses architectures that mimic lung air sacks. and launched phase 3 trials in new-onset to heart and designed a 300-person study The researchers cofounded Volumetric patients. (The recently published study recruiting only US-based children aged 8–17 last year to commercialize next- in at-risk individuals was not company- with C-peptide levels above a minimum generation biofabrication materials and sponsored but run in parallel with funding threshold. Furthermore, the trial defined systems based on their findings. from government and non-profit sources.) C-peptide responses at 18 months as At least one other company, 3DBio, The industry-backed studies for new- the primary outcome measure. Herold, is developing a collagen bioink for 3D onset disease would both end in failure, but a site investigator who has consulted for bioprinters. for different reasons. With otelixizumab, Provention, describes the trial as a “new and iBio declined to disclose financial the drug’s sponsors—seeking to avoid EBV improved Protégé.” terms of the deal. reactivation—dropped the cumulative dose In addition to better study design, of the therapy more than 15-fold, from 48 researchers today also have an improved Published online: 2 October 2019 milligrams in the academic phase 2 trial to understanding of how teplizumab https://doi.org/10.1038/s41587-019-0288-7 3.1 milligrams in the follow-up. No one in works on a molecular level. After an the low-dose otelixizumab study experienced earlier phase 2 trial with teplizumab in

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77 new-onset patients, a team led by bacterial strains, and the glucagon- Benaroya immunologists Alice Long and like peptide-1 receptor agonist Victoza DTC pharmacogenomics Peter Linsley probed gene expression profiles (liraglutide), commonly used to treat testing under scrutiny in the blood and identified a population of type 2 diabetes Since last October, the FDA has been CD8-positive T cells, thought to be the cells Tiziana Life Sciences, headquartered in signaling to patients and healthcare that kill beta cells, with traits of exhaustion London, also has a fully human anti-CD3 providers to exercise caution when that increased in number among subjects antibody called that binds to applying the results of direct-to- who responded favorably to the therapy the receptor complex to modulate consumer (DTC) pharmacogenomics (Sci. Immunol. 1, eaai7793, 2016). regulatory and effector T cells, and could be testing to prescribing drugs. That signal For reasons that are not entirely used in diabetes prevention. But according got stronger in April when the FDA clear, those T cells are more susceptible to CEO Kunwar Shailubhai, the company sent a warning letter to the genomics to teplizumab-induced activation than first plans to evaluate an oral formulation testing lab Inova, instructing it to modify other immune subsets, Long explains. of foralumab in healthy volunteers before labeling and marketing materials for “Although [the antibody] hits all CD3 advancing the drug for non-alcoholic several pharmacogenomics tests. Now cells,” she says, “what it modulates most steatohepatitis, Crohn’s disease and, if some genomics companies, among them are exhausted cells.” The proliferation of funding comes through from diabetes- Color, Genomind and OneOme, as well those partially exhausted cells then creates focused non-profits, type 1 diabetes as well. as the NIH-sponsored All of Us Program, a more tolerogenic immune landscape that Any prophylaxis will ultimately report that they are in discussions safeguards beta cells from further attack. only be as good as the screening effort with the FDA and in some cases have Long thinks the same mechanism is likely used to find children positive for islet already modified their informational operating in the pre-diagnosis setting as autoantibodies, though, and researchers materials. The tests at issue are mostly well—which would explain why teplizumab are still “trying to figure out the best way lab-developed tests, which typically proved so efficacious in the recently to reach kids,” says Kimber Simmons, a are exempt from regulatory review so published trial, where the median time pediatric endocrinologist at the University long as the testing lab is CLIA certified. to type 1 diabetes diagnosis was just over of Colorado Barbara Davis Center for However, FDA has the right to revoke four years in the teplizumab group; in the Diabetes in Aurora, who has helped screen that exemption in cases where public placebo group, it was half that duration. Side over 20,000 children at doctors’ offices, safety is at issue. With DTC marketing effects were mild, without any EBV-related emergency rooms, urgent care centers, of pharmacogenomics tests, the fear is complications. “But,” says Greenbaum, “we pop-up clinics and community health fairs that individuals will modify their drug don’t yet know whether there’s something over the past three years. And in Germany, use on their own. Whereas companies unique about this therapy as compared to a coalition of some 650 pediatricians from profess that the FDA is not clear on other immune therapies.” across Bavaria and Lower Saxony—led by which tests it considers dubious, the Greenbaum and her fellow TrialNet Anette-Gabriele Ziegler, an endocrinologist agency appears to be drawing the line investigators previously showed that at Helmholtz Zentrum München—have at tests not described in drug labels. So oral insulin did not delay disease onset tested for autoantibodies in nearly 100,000 far, 23andme is the only DTC genomics among autoantibody-positive relatives of children over a similar time period. testing company that has an approved people with type 1 diabetes. The group Those kinds of population-wide pharmacogenomics test: its Personal is now running prevention studies with screening efforts can help reduce life- Genome Service Pharmacogenetic two other immune-modulating drugs, the threatening complications but ultimately Report tests for multiple variants in anti-malarial hydroxychloroquine and the falter because “we’ve never had [a eight genes that affect the metabolism cytotoxic T lymphocyte 4 (CTLA-4) preventative drug therapy] to actually offer of some 50 drugs. Further confusing analog Orencia (), with plans to kids,” Simmons says. Should teplizumab the issue, United HealthCare in August start two more trials—one involving anti- enter the marketplace in 2021, as Provention announced that it will cover panels of thymocyte globulin (a preparation of rabbit- hopes it will, “then we will be able to genetic test for guiding the use of drugs derived anti-human T cell antibodies), the discuss screening more population-wide,” for major depression and other depressive other with the CD20-targeted antibody says Helena Elding Larsson, a pediatric disorders, although the American and Orencia. endocrinologist from Lund University Psychiatric Association’s research Janssen is also wrapping up a trial of its in Sweden. ❐ council last year concluded that the tumor necrosis factor- blocker Simponi α evidence for testing in those indications (), and several academic studies Elie Dolgin is not conclusive. are looking at other putative beta cell–saving Somerville, MA, USA agents in at-risk individuals. These include Published online: 2 October 2019 a decades-old blood pressure Published online: 3 September 2019 https://doi.org/10.1038/s41587-019-0283-z called methyldopa, a concoction of probiotic https://doi.org/10.1038/d41587-019-00025-4

“If I tell you I wasn’t disappointed, “Although none of our companies are working on “In a world without any discrimination, then I would be lying to you. But I’m also germline therapy, when I talk to people not involved in understanding human behavior is a noble willing to accept that there are certain the biotechnology business, one of the frst questions I goal, but we don’t live in that world,” said situations in which there are limitations to the get is: ‘Aren’t you worried about designer babies?’ I am Steven Reilly, researcher and member of technology.” Huang Yu, who paid $35,000 to spending more time on this kind of question than at the LGBTQ steering group at the Broad Institute. the Chinese company Sinogene to clone his any point in my career.” Jim Burns, CEO of Casebia and The publication of the largest genetic study ‘‘dead cat Garlic. The cat clone, the frst produced cochair of the Alliance for Regenerative Medicine task of same-sex sexual behavior by the Broad Institute in China, was missing a black patch on its force on gene editing. The group put out a statement raised the hackles of LGBTQ community, even chin that Garlic had. (The New York Times, in August that germline gene editing is currently from within the Broad itself. (The New York Times, 4 September 2019) inappropriate. (Financial Times, 26 August 2019) 29 August 2019) Nature Biotechnology | VOL 37 | OCTOBER 2019 | 1099–1109 | www.nature.com/naturebiotechnology ’’1101