Treatment options for sickle cell patients are limited. In fact, until Endari was approved by the U.S. Food and Drug Administration in July 2017, hydroxyurea was the only sickle cell therapy. (Endari, the first new disease treatment in nearly 20 years, is designed to reduce complications associated with sickle cell anemia in patients age 5 and older.)
How Memantine works
Sickle cell disease results from a mutation in the gene that produces hemoglobin, the iron-rich compound that allows red blood cells to transport oxygen throughout the body. The defect causes hemoglobin to crystalize and red blood cells to assume a sickle shape and become “sticky” so that they adhere to vessel walls and block blood flow.
Calcium ions, along with other metals in blood, play a vital role in many functions. But in sickle cell patients, were shown in studies to be 10 times more likely to take up calcium than in cells of healthy individuals. Excess calcium in blood cells cause can cause the cells to dehydrate, and can further aggravate and worsen their sickle shape, stickiness and levels of oxidative or metabolic stress.
NMDA receptors are glutamate (an excitatory neurotransmitter) receptors on the surface of nerve and heart cells that were recently also found on blood cells. When this receptor is activated, calcium ions can enter the cell. In sickle cell patients, the NMDA receptor on red blood cells is over-active, leading too much calcium. Memantine inhibits — blocks — the receptor, preventing calcium ions from entering the cell. Laboratory studies have shown that memantine rehydrates red blood cells in patients with sickle cell disease, helping to prevent them from assuming a sickle shape.
Memantine in clinical trials
A pilot Phase 2 clinical trial (NCT02615847) of memantine took place in Switzerland between 2015 and 2017. Six adult sickle cell anemia patients received 20 mg a day for 12 months. Researchers studied its effectiveness and safety, and patients’ ability to tolerate it.
Study results showed that memantine was safe in these people, and that patients reported a significant improved quality of life. The therapy led to fewer red blood cells rupturing, allowing the cells to live longer, and decreased the production of abnormally shaped cells.
A larger Phase 2 trial (NCT03247218) is now underway at a single site in Israel, involving up to 40 sickle cell patients. They are being divided into two groups: one ages 10 to 17, and the other adults ages 18 and older. Participants will be given memantine tablets at doses of 5 mg, 10 mg, or 20 mg each day for year, then followed for another three months.
The trial’s primary objective is to assess how many adverse events the treatment generates, and their severity. A secondary goal is to determine if memantine benefits patients by treating the disease, as measured in hospital visits, needed transfusions, lost work days and the like during the trial period. This study is expected to conclude in June 2020.
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