Sickle cell disease and the blood disorder beta thalassemia affect more than 180,000 Americans. Both diseases can be made milder or even cured by increasing fetal hemoglobin (HbF) levels, but current treatment to ramp up HbF has limited effectiveness. Researchers at Baylor College of Medicine and Texas Children’s Cancer and Hematology Centers discovered a gene, FOXO3, involved in controlling fetal hemoglobin production and were able to target the gene and “turn on” fetal hemoglobin levels in patient samples in the lab using the diabetes drug metformin.

This offers promising new treatments—the first new drug treatment for sickle cell disease in 30 years and the first ever for beta thalassemia.

“It was a major breakthrough to show that a common drug already in use for type-2 diabetes could be a treatment for sickle cell disease by inducing fetal hemoglobin, a type of hemoglobin that doesn’t become sickle shaped but is usually turned off in infancy,” said Vivien Sheehan, Assistant Professor of Pediatrics at Baylor and Texas Children’s Cancer and Hematology Centers and lead investigator of the research. “This is an exciting example of collaborative, bench-to-bedside research that has now resulted in a clinical trial that is already enrolling patients.”

Sheehan launched this research as a clinical fellow at Baylor College of Medicine in 2011 with the goal of identifying new drug targets to help sickle cell patients make more fetal hemoglobin. The only widely used drug to treat sickle cell disease, hydroxyurea, targets fetal hemoglobin by slowing red blood cells from maturing, but does not make enough HbF to help up to half of sickle cell patients and generally does not work in beta thalassemia.

Fetal hemoglobin is present in newborns until about 6 months of age and then is replaced by adult hemoglobin. Children with sickle cell disease produce a defective form of adult hemoglobin that causes red blood cells to become sickle shaped and get stuck in blood vessels, causing painful episodes and other symptoms. In beta thalassemia, patients simply do not produce enough hemoglobin, causing anemia, fatigue, and other serious complications.

Starting with 171 patient blood samples and later expanding to 400 more, Sheehan and her research colleagues were looking for genetic differences in sickle cell patients who make a lot of fetal hemoglobin versus those who do not. Collaborating with Baylor’s Human Genome Sequencing Center, they used whole-exome sequencing and discovered that the FOXO3 gene seemed to control fetal hemoglobin. They found that patients with mutations in the FOXO3 gene made less fetal hemoglobin. Researchers proved this association in the lab by knocking out FOXO3 in human bone marrow cells, which resulted in less fetal hemoglobin, and then overexpressing the gene, which increased it.

Next, researchers used a well-studied diabetes medication, metformin, to increase FOXO3 levels in human bone marrow cells from sickle cell patients. It was already known that metformin induces FOXO3, Sheehan said. When they increased FOXO3, the cells made more fetal hemoglobin. When they treated bone marrow cells with hydroxyurea and metformin, they made even more, up to 67%.

“Patients who make this much fetal hemoglobin would, in theory, be cured of sickle cell disease, and act like a sickle cell trait patient clinically. Metformin may also be an effective therapy for beta thalassemia patients, as it can help them make more hemoglobin by adding HbF, without slowing the production of red cells like hydroxyurea,” she said.

With funding from Pfizer, a clinical trial has been launched to further study the effectiveness of metformin in patients with sickle cell disease and beta thalassemia. The clinical trial will enroll patients 16 to 40 years of age from Baylor College of Medicine clinics, Texas Children’s Cancer and Hematology Centers, and the University of Texas Health Science Center at Houston. It will include patients with sickle cell disease not on any treatment, sickle cell patients being treated with hydroxyurea, and patients with beta thalassemia. They will be treated with metformin orally for six months, enough time to see a response in fetal hemoglobin, Sheehan said.

Source: Baylor College of Medicine; January 10, 2017.

Managed Care’s Top Ten Articles of 2016

There’s a lot more going on in health care than mergers (Aetna-Humana, Anthem-Cigna) creating huge players. Hundreds of insurers operate in 50 different states. Self-insured employers, ACA public exchanges, Medicare Advantage, and Medicaid managed care plans crowd an increasingly complex market.

Major health care players are determined to make health information exchanges (HIEs) work. The push toward value-based payment alone almost guarantees that HIEs will be tweaked, poked, prodded, and overhauled until they deliver on their promise. The goal: straight talk from and among tech systems.

They bring a different mindset. They’re willing to work in teams and focus on the sort of evidence-based medicine that can guide health care’s transformation into a system based on value. One question: How well will this new generation of data-driven MDs deal with patients?

The surge of new MS treatments have been for the relapsing-remitting form of the disease. There’s hope for sufferers of a different form of MS. By homing in on CD20-positive B cells, ocrelizumab is able to knock them out and other aberrant B cells circulating in the bloodstream.

A flood of tests have insurers ramping up prior authorization and utilization review. Information overload is a problem. As doctors struggle to keep up, health plans need to get ahead of the development of the technology in order to successfully manage genetic testing appropriately.

Having the data is one thing. Knowing how to use it is another. Applying its computational power to the data, a company called RowdMap puts providers into high-, medium-, and low-value buckets compared with peers in their markets, using specific benchmarks to show why outliers differ from the norm.
Competition among manufacturers, industry consolidation, and capitalization on me-too drugs are cranking up generic and branded drug prices. This increase has compelled PBMs, health plan sponsors, and retail pharmacies to find novel ways to turn a profit, often at the expense of the consumer.
The development of recombinant DNA and other technologies has added a new dimension to care. These medications have revolutionized the treatment of rheumatoid arthritis and many of the other 80 or so autoimmune diseases. But they can be budget busters and have a tricky side effect profile.

Shelley Slade
Vogel, Slade & Goldstein

Hub programs have emerged as a profitable new line of business in the sales and distribution side of the pharmaceutical industry that has got more than its fair share of wheeling and dealing. But they spell trouble if they spark collusion, threaten patients, or waste federal dollars.

More companies are self-insuring—and it’s not just large employers that are striking out on their own. The percentage of employers who fully self-insure increased by 44% in 1999 to 63% in 2015. Self-insurance may give employers more control over benefit packages, and stop-loss protects them against uncapped liability.