IGFBP1

A new study has identified that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy, highlighting a potential risk factor for the development of gestational diabetes. A new study led by the Harvard Pilgrim Health Care Institute has identified that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy, highlighting a potential risk factor for the development of gestational diabetes. The study, "Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes," appears in the April 16, 2024 edition of Nature Medicine. Gestational diabetes, a disease that can lead to multiple pregnancy and delivery complications, is the most common pregnancy metabolic complication, affecting 1 in 7 pregnancies. Existing research has shown that excess insulin resistance in pregnancy contributes to gestational diabetes, but the exact causes of this resistance remain unclear. "The placenta -- the major driver of changes in insulin physiology in pregnancy -- is likely a key source of hormones involved in the development of gestational diabetes," says Marie-France Hivert, Harvard Medical School associate professor of population medicine at the Harvard Pilgrim Health Care Institute and lead author of the study. "Our goal was to discover novel placental factors that are implicated in gestational diabetes, by studying all proteins expressed in placenta tissues, across the human genome. We identified placental insulin-like growth factor 1 (IGFBP1) as a secreted placental factor that is likely implicated in regulation of glucose in human pregnancy." The study builds on Dr. Hivert's extensive research into the determinants of gestational diabetes using genetics and other omics approaches, and their interaction with lifestyle and environmental factors. The study team conducted genome-wide RNA sequencing on maternal-facing placental tissue samples, and measured identified proteins in blood collected in multiple pregnancy cohorts with diverse backgrounds. The team identified 14 genes whose placental RNA expression levels were associated with insulin resistance, finding the strongest association with gene IGFBP1. By measuring the IGFBP1 protein levels in circulation, they found that IGFBP1 levels rise over the course of pregnancy and are 5 times higher in pregnant people compared to outside of pregnancy, arguing for the placenta being one of the major sources of this protein during pregnancy. Results also show that low levels of circulating IGFBP1 in early pregnancy could predict who is likely to develop gestational diabetes in late second trimester of pregnancy. Finally, the team found that the trajectory of IGFBP1 levels across pregnancy differs in people who have a subtype of gestational diabetes characterized by insulin resistance previously shown more likely to develop pregnancy complications. "Identifying a novel protein that characterizes a subtype of gestational diabetes is one additional step towards developing precision medicine for gestational diabetes," adds Dr. Hivert. "It's possible that measuring IGFBP1 in the first trimester could help identify people at risk of developing gestational diabetes early in pregnancy, potentially offering a window for prevention. We hope to conduct future research to address whether this protein plays a causal role in gestational glycemic regulation."

Pictured: Kathie Bishop, Ph.D./courtesy of Acadia Pharmaceuticals On February 28, Reata Pharmaceuticals won approval for Skyclarys, the first treatment for Friedreich’s ataxia, an ultra-rare neurological disease. This weekend, Acadia Pharmaceuticals hopes to follow suit with the first disease-modifying drug for Rett syndrome. If approved, trofinetide would also be the first drug approved to treat any neurodevelopmental disorder, Kathie Bishop, Ph.D., SVP and head of rare disease and external innovation at Acadia, told BioSpace. The FDA is set to make a decision on trofinetide, which Acadia is developing with partner Neuren Pharmaceuticals, on March 12. Rett syndrome is a multisystem neurodevelopmental disorder characterized by developmental regression, loss of language and hand function and impaired gait. It affects primarily female children, who develop normally until around the age of two, when they begin to miss expected milestones. They also begin to lose function, most notably verbal abilities and the ability to control hand function. Bishop said that while the disease affects neurons throughout the brain, it is not neurodegenerative. “What happens is that the connections between the brain cells are lost, so you still have the neurons there, but they can't communicate with each other.” Trofinetide restores those connections between cells, Bishop said. Because the disease is not neurodegenerative, Bishop said there is potential to intervene at any age. In clinical trials, Acadia saw improvements in both younger and older patients. The Case for Trofinetide Trofinetide, a novel synthetic analog of the amino‐terminal tripeptide domain of the IGF-1 protein, was assessed in the Phase III Lavender study. A 12-week study, Lavender compared the drug against placebo in 187 girls and young women between five and 20 years of age. The co-primary endpoints, change in Rett Syndrome Behavior Questionnaire scores from baseline and Clinical Global Impression-Improvement scale score, were significantly improved after treatment with trofinetide compared to the control group. Bishop shared that what parents mention most often is that their children can’t communicate with them. Throughout clinical trials, she said Acadia has seen an improvement in, particularly, non-verbal communication. “Parents talk about [how] the girls kind of become more awake. They're able to interact. They're able to indicate what they want,” she said. Acadia has also seen improvement in motor function. While the study did not include any boys, Bishop said that based on trofinetide’s mechanism, there is no reason to think the drug wouldn’t also help this minority patient population. A Reputation for Firsts If approved, trofinetide would be Acadia’s second commercial product. It would also be its second novel approval. In May 2016, the FDA greenlit Nuplazid (pimavanserin) as the first treatment for hallucinations and delusions associated with Parkinson’s disease psychosis. Acadia is currently studying pimavanserin in a Phase III trial for the negative symptoms of schizophrenia, another indication for which there is currently no approved drug. In this space, Acadia is competing with Karuna Therapeutics’ KarXT. Karuna has stated it plans to submit for approval of KarXT by mid-2023. Bishop has devoted 20 years of her career to the study of rare, neurological diseases, and she said this is a very exciting time in the space. “On the clinical side, with the advances in genetic testing, patients are being more readily identified and studied. Then on the science side, I think [there are] a lot of great discoveries and advancements. I think this is just the beginning of a lot more to come in neurologic rare diseases, especially genetic diseases.”

Pictured: Kathie Bishop, Ph.D._courtesy of Acadia Acadia Pharmaceuticals announced the approval of Daybue (trofinetide) as the first and only drug to treat Rett Syndrome, a rare, neurodegenerative disorder affecting primarily girls. Pictured: Kathie Bishop, Ph.D./courtesy of Acadia Pharmaceuticals Acadia Pharmaceuticals didn’t have to wait until March 12 to find out that trofinetide had been approved as the first therapy for Rett Syndrome. The FDA instead delivered the news late Friday evening. “Now, for the first time after decades of clinical research, healthcare providers finally have a treatment option to address a range of core behavioral, communication and physical symptoms for their patients living with Rett syndrome,” said Jeffrey L. Neul, M.D., Ph.D., professor at Vanderbilt University Medical Center and Phase III Lavender study investigator, in a prepared statement. Acadia will market the drug as Daybue and expects it to be available in the U.S. by the end of April 2023. The company secured a Rare Pediatric Disease Priority Review voucher along with the approval. Acadia developed Daybue in partnership with Neuren Pharmaceuticals . Speaking with BioSpace ahead of the decision, Kathie Bishop, Ph.D., SVP and head of rare disease and external innovation at Acadia, said that if approved, trofinetide would also be the first drug approved to treat any neurodevelopmental disorder. Rett syndrome is a multisystem neurodevelopmental disorder characterized by developmental regression, loss of language and hand function and impaired gait. It affects primarily female children, who develop normally until around the age of two, when they begin to miss expected milestones. They also begin to lose function, most notably verbal abilities and the ability to control hand function. Bishop said that while the disease affects neurons throughout the brain, it is not neurodegenerative. “What happens is that the connections between the brain cells are lost, so you still have the neurons there, but they can’t communicate with each other.” Trofinetide restores those connections between cells, Bishop said. Because the disease is not neurodegenerative, Bishop said there is potential to intervene at any age. In clinical trials, Acadia saw improvements in both younger and older patients. The Lavender Trial Daybue, a novel synthetic analog of the amino‐terminal tripeptide domain of the IGF-1 protein, was assessed in the Phase III Lavender study . A 12-week study, Lavender compared the drug against placebo in 187 girls and young women between five and 20 years of age. The co-primary endpoints, change in Rett Syndrome Behavior Questionnaire scores from baseline and Clinical Global Impression-Improvement scale score, were significantly improved after treatment with Daybue compared to the control group. Bishop shared that what parents mention most often is that their children can’t communicate with them. Throughout clinical trials, she said Acadia saw an improvement in, particularly, non-verbal communication. “Parents talk about [how] the girls kind of become more awake. They’re able to interact. They’re able to indicate what they want,” she said. Acadia has also seen improvement in motor function. While the study did not include any boys, Bishop said that based on trofinetide’s mechanism, there is no reason to think the drug wouldn’t also help this minority patient population. A Reputation for Firsts With the approval, Daybue becomes Acadia’s second commercial product. It is also its second novel approval. In May 2016, the FDA greenlit Nuplazid (pimavanserin) as the first treatment for hallucinations and delusions associated with Parkinson’s disease psychosis. Acadia is currently studying pimavanserin in a Phase III trial for the negative symptoms of schizophrenia, another indication for which there is currently no approved drug. In this space, Acadia is competing with Karuna Therapeutics’ KarXT. Karuna has stated it plans to submit for approval of KarXT by mid-2023. Bishop has devoted 20 years of her career to the study of rare, neurological diseases, and she said this is a very exciting time in the space. “On the clinical side, with the advances in genetic testing, patients are being more readily identified and studied. Then on the science side, I think [there are] a lot of great discoveries and advancements. I think this is just the beginning of a lot more to come in neurologic rare diseases, especially genetic diseases.”