Investigators are first looking at a second drug to combat sickle cells

AGUSTA, Ga. (May 11, 2023) – A class of drugs used for their ability to stop tumor cell division is now being studied for their potential to reduce pain and damage caused by sickle cell disease, researchers report.

The drugs are called HDAC inhibitors, and researchers have early evidence called panobinostat can reactivate after birth a gene that produces fetal hemoglobin, which can’t take a sickle shape, says Abdullah Kutlar, MD, director of the Center for Blood Disorders at the Medical College of Georgia and Augusta University Health.

Hemoglobin is the oxygen-carrying component of red blood cells, and with sickle cell disease, this basic function is inefficient. The potentially devastating consequences include frequent bouts of pain from blockages primarily in the small blood vessels produced by red blood cells which are also oddly shaped and sticky. Many patients experience rapid breakdown, or hemolysis, of their red blood cells. Anemia, major organ damage and shortened life expectancy may occur.

Histone deacetylases, or HDACs, are enzymes that are among the many ways of expression of rejected genes, a natural process for some genes, such as the gamma-globin gene that makes fetal hemoglobin, as we move from childhood to adulthood.

Fetal hemoglobin allows the developing baby to capture oxygen from the mother’s blood while the beta-globin gene produces mature hemoglobin which carries oxygen. In the first few months after birth, most babies have little or no fetal hemoglobin.

Kutlar and Betty Pace, MD, Francis J. Tedesco Distinguished Chair of Pediatric Hematology and Oncology and sickle cell investigators, are co-principal investigators in a new $2.3 million three-year grant (R33HL162681-01) from the National Heart, Lung and Blood Institute , funded early-stage clinical trials to see if the HDAC-inhibiting panobinostat could revive the fetal hemoglobin gene in adults to directly address the underlying problem of inefficient oxygen delivery.

“HDAC inhibitors are drugs that are known to alter the expression of certain genes,” says Kutlar. “When you inhibit histone deacetylases, what you are doing is enabling some genes that have been turned off by certain mechanisms to be re-expressed. That’s important for sickle cell because we know in adults that the fetal hemoglobin gene is turned off and we know fetal hemoglobin does very well as a disease modifier.”

Two HDACs are involved in silencing the fetal hemoglobin gene and panobinostat is a pan-HDAC inhibitor, meaning it silences more than one HDAC.

Hydroxyurea, the first sickle cell drug to be approved by the US Food and Drug Administration in 1998, also increases fetal hemoglobin, although exactly is not clear, and is also used for some types of cancer. Kutlar notes that if panobinostat continues to show promise, the next step will be pairing the two fetal hemoglobin promoters to see if there is a beneficial synergy.

For now, the phase 1 trial he is leading will explore the safety and efficacy of panobinostat in 18 patients taking either 15 or 20 milligrams several times per week. Researchers will monitor study participants’ levels of non-lipped fetal hemoglobin as well as levels of F-cells, the red blood cell subpopulation that contains fetal hemoglobin. Kutlar noted that higher doses have been used in other conditions and were well tolerated by patients. But at higher levels, side effects like diarrhea, nausea, and fatigue become a problem.

Researchers will also work with study participants to develop better ways to ensure they are taking their medications as they should now and in the future. And they’ll be looking for indicators that the treatment is a good choice for the individual patient. This includes looking at what happens to non-histone proteins like NFkB, a regulator of our innate immunity, and p53, a protein in cells that is important for controlling division and death. Histones are the proteins that make up the tightly coiled coils of our DNA, which are also important for gene regulation.

Researchers have early evidence that the drug, taken in pill form, should directly target the hemoglobin problem in sickle cell disease. Pace has shown panobinostat increases fetal hemoglobin expression both in red blood cells in culture and in a mouse model of sickle cell disease by activating reactivation of the fetal hemoglobin gene. An early and small trial by Kutlar showed a slight increase in fetal hemoglobin levels by giving 10 milligrams of the drug to patients and it was well tolerated.

For this study in humans with sickle cell disease, she will be looking at the drug in patients not taking hydroxyurea, to confirm that the increase in fetal hemoglobin results from the newer drug. He notes most of the study participants will likely come from the roughly 120 patients he currently has at the Center for Blood Disorders, who choose not to use hydroxyurea.

Results of the Multicentre Study of Hydroxyurea in Sickle Cell Anemia are published in Journal of the American Medical Association in 2003, demonstrated the use of hydroxyurea, the only drug approved at the time, reduced mortality by reducing pain crises and increasing fetal hemoglobin.

But concerns about reported side effects from long-term use such as decreased infertility in men and increased risks of skin cancer and leukemia as well as weight gain lead some patients to refuse to take the drug, Kutlar and colleagues report, necessitating more treatment options. .

Kutlar says the potential for additional therapy is exciting. “It’s not going to be a cure for sickle cell disease but it’s going to be a significant disease modifier, which is going to keep these patients going longer without a lot of organ damage and hopefully without so much pain,” he said.

Other treatment options include bone marrow transplant, which is considered curative for sickle cell disease, and gene therapy is another exciting option being studied, including the use of gene-editing techniques such as CRISPR to increase fetal hemoglobin expression or correct the genetic cause of the condition, said Kutlar. While this approach also holds promise, more drugs are still needed because it will likely be years, if ever, before advanced techniques like these become widely available where sickle cell disease concentrations are most significant such as Africa or India, said Kutlar. Also, every drug doesn’t work for every patient.

The three other drugs currently approved by the FDA for sickle cell disease include L-glutamine (Endari), which helps protect red blood cells from damage, and was approved in 2017. The monoclonal antibody crizanlizumab (Adakevo), which helps prevent red blood cells from shrinking. not sticking to blood vessel walls, and voxelotor (Oxbryta), which helps prevent creasing that makes it easier for cells to carry oxygen and slows their breakdown, both approved in 2019.

MCG is the study center for hydroxyurea and the largest registrar for participants in the crizanlizumab study. For more information about the new panobinostat study, call the Center for Blood Disorders at 706-721-2171 and ask the lead research coordinator and attending physician LaTanya Bowman or Kutlar.

Panobinostat (Farydak) has been used in this country and is still used in Europe for multiple myeloma, and has been studied as a possible drug for HIV infection, so there has been significant experience in humans.

Kutlar notes that while there are some adults with naturally high fetal hemoglobin levels who are sickle cell resistant as a result, there is more evidence that drugs that increase those levels are beneficial.

MCG, AU Medical Center and Children’s Hospital of Georgia followed approximately 1,500 adult and pediatric patients with sickle cell disease.

The genetic disorder affects about 100,000 people in the US, according to the Centers for Disease Control and Prevention, and occurs mainly in individuals whose ancestors come from sub-Saharan Africa; the Spanish-speaking regions of the Western Hemisphere, including South and Central America and the Caribbean; Saudi Arabia; India; and Mediterranean countries like Türkiye and Greece. Closer to home, about 150 babies are born in Georgia each year with sickle cell disease, about 3,000 born nationwide.