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New Hope for a Once Neglected Disease: Advances in Sickle Cell Treatments

When Kelly Knee was in graduate school in the early 2000s, she found it nearly impossible to secure grant funding for research on sickle cell disease, a rare blood disorder that historically has been a neglected area of medical research. But hearing stories from patients, who suffer severe pain episodes and frequent hospitalizations, kept her going. “I’ve been working on this since I started graduate school. It has been a bit of a moral imperative to see if we can help these patients,” says Knee, a senior principal scientist in Pfizer’s Rare Disease Research Unit, based in Kendall Square, Cambridge, Massachusetts.

It seems that her commitment is paying off. In recent months, a new wave of treatments has been approved by the FDA and others are entering clinical testing, both of which are giving patients new hope. For the first time in 20 years, the FDA has approved two new drugs for sickle cell disease. And at Pfizer, Knee is a part of a team of scientists who are bringing two new potential sickle cell drugs into clinical testing with the intent to further expand treatment alternatives. “Our hope is that there will be options so that physicians can have a sort of suite of medicines from which to select the most effective way to treat a patient,” says Knee.

Swimming against the tide

People with sickle cell disease have atypical hemoglobin molecules, a protein that carries oxygen in red blood cells, which can cause the shape of red blood cells to be distorted. When the atypical hemoglobin molecule is not carrying oxygen—called the deoxy form—it can polymerize, forming long fibers that cause red blood cells to take on a sickle shape. These distorted red blood cells can then clump in blood vessels and prematurely breakdown, causing anemia and severe pain.

While scientists have long understood hemoglobin’s critical role in the condition, historically they have not targeted it with medicines, because it is such an abundant protein in the blood. Any target that requires a large dose of drug comes with extra risk. “We were swimming against the tide,” says Knee. “A lot of people in the industry have said, ‘You can't do that. That's ridiculous. There's too much hemoglobin, you'll never get it to work.’”

Reaching more patients

But a few years ago, scientists at Pfizer decided to try to develop a medicine that could stabilize the oxygen-carrying form of hemoglobin so it would outnumber the deoxy form that causes the sickling in red blood cells. “The idea is to shift the ratio of the two different types of hemoglobin, so patients would have less of the deoxy form to polymerize,” says Knee.

As the potential new drug prepares to enter clinical evaluation in a few months, Knee is especially hopeful about one important aspect of the drug: It’s a small molecule medicine in pill form, which should be more convenient for patients to take. “Because it’s oral and shelf-stable, it’s an option that should more easily make it to patients in sub-Saharan Africa and other developing regions,” she says.

Caring enough to work on new treatments

Patients with sickle cell disease can experience painful episodes known as a vaso-occlusive crises, which often require them to be hospitalized. Pfizer is also developing a new anti-inflammatory biologic, or protein-based medicine, that is designed to lessen the frequency of these episodes.

Our hope is that there will be options so that physicians can have a sort of suite of medicines from which to select the most effective way to treat a patient.

Kelly Knee

The anti-inflammatory biologic targets E-selectin, an adhesion molecule that helps blood cells stick to the walls of blood vessels and to each other, an important part of wound healing and fighting infections. But in patients with sickle cell disease, there is an increase in these molecules, which can cause red blood cells to clump in blood vessels and block blood flow, leading to the pain episodes. “The sickling of red blood cells is what triggers inflammation and the increase of the E-selectin molecules,” says Janice Chin, an associate research fellow in Pfizer’s Rare Disease Research Unit, also based in Cambridge. “We’re hoping with our medicine that we can decrease the clumping of cells and the resulting pain episodes,” she adds.

And since the two potential new medicines target different drivers of the disease, scientists see the potential to combine them for more benefit. “It may provide patients with more options for treatments,” says Chin.

After participating in a recent sickle cell disease awareness walk, Knee connected with patients who are excited about the potential for new medicines. “These patients know that developing medicines takes time and that it’s extremely hard, but they’re excited that we care enough to work on potential new treatments,” says Knee.

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