How NKTT120 works
In sickle cell anemia, deformed and rigid red blood cells can become trapped inside small blood vessels. This can lead to a vaso-occlusive crisis (VOC), where the blood vessels become inflamed and narrowed. The blood flow is restricted by this blockage and inflammation, causing severe pain and potential organ damage.
NKTT120 acts to reduce inflammation. This should prevent or decrease the frequency of VOC in sickle cell anemia patients and may reduce the level of pain they experience.
Inflammation is an immune process that is controlled by a range of immune cells. One type of immune cell, called invariant natural killer T- (iNKT) cells, are known to secrete large amounts of inflammatory cytokines or immune proteins that stimulate inflammation. These may be activated as part of VOC in response to the repeated blockages caused by sickle-shaped red blood cells.
NKTT120 is an antibody, or a protein designed to bind to a specific target. It binds to a part of a type of protein called a T-cell receptor (TCR) that is found on the surface of iNKT cells.
When NKTT120 binds to TCR, it triggers the cell’s death. A preclinical study in monkeys, published in the scientific journal PLoS One, has shown that NKTT120 specifically binds to TCR on iNKT cells without affecting the levels of other immune cells. It is thought that through this mechanism, NKTT120 may reduce the numbers of iNKT cells that stimulate inflammation in sickle cell anemia.
NKTT120 in clinical trials
The safety and activity of NKTT120 have been investigated in a first-in-human Phase 1 clinical trial (NCT01783691) as a therapy for sickle cell anemia. The trial also aimed to find the optimal dose of NKTT120 to be used in a Phase 2 clinical trial.
In total, 21 patients were enrolled at several U.S-based sites and received a single dose of NKTT120. The dosage was escalated after the first three patients had been treated with no adverse effects, to determine a safe and effective dose for a Phase 2 trial.
The results for the first four patients given the lowest dose of0.001 mg per kg were published in the journal Blood after one month of follow-up. All patients had a confirmed depletion of iNKT cells, with no effect on other immune cells and no adverse events reported. This supported continuing the dose escalation.
The results following all 21 patients receiving treatment, also published in Blood, determined the recommended dosage of 0.3 mg per kg for a future Phase 2 trial.
In 2017, the final results for all 21 patients were published in PLoS One. The two highest doses of NKTT120 of 0.3 and 1 mg per kg achieved sustained depletion of iNKT cells for between two to five months. No significant adverse events were reported, and the treatment appeared to be well tolerated.
NKT Therapeutics is hoping to move on to a Phase 2 study to determine whether NKTT120 can successfully reduce the number or severity of VOC in sickle cell anemia patients.
NKTT120 received fast track designation from the U.S. Food and Drug Administration (FDA) in 2014, support speedier development of the therapy.
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