Novel Drug Regimen Shows Promise for Sickle Cell Disease

Trial results reported for first molecularly targeted therapy

A new drug combination— tetrahydrouridine (THU) and decitabine — shows great promise in the treatment of sickle cell disease (SCD). Results from a phase 1/2 clinical trial suggest this novel oral therapy was well tolerated and produced the desired effect on red blood cells by increasing fetal hemoglobin (HbF) levels twofold.

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“We’ve known the molecular basis for this disease for decades, and now we finally have a rational, molecular-targeted therapy that addresses not just one or two symptoms of the disease, but the root cause of the disease,” says Yogen Saunthararajah, MD, a hematology expert and researcher at Cleveland Clinic. “This therapy can in principle address all the symptoms, all the complications sickle cell disease, so it’s very exciting.”

Dr. Saunthararajah is co-author on the study which was presented at the 2016 American Society of Hematology Annual Meeting in San Diego.

Despite longstanding knowledge about this devastating disease, effective treatments for SCD have remained elusive. Patients still contend with clinically significant complications and risk of early death despite the standard of care, hydroxyurea. The new regimen is a non-cytotoxic, normal stem-cell-sparing, rationally targeted approach to disease modification.

Overcoming clinical barriers

HbF is the hemoglobin produced by red blood cells at the fetal stage of life. HbF intersperses with mutated sickle hemoglobin and renders it more soluble, to prevent the greater than 10-fold reduction in red cell life-span and clogging of blood vessels caused by precipitation of mutated sickle hemoglobin, and which drives all the devastating manifestations of SCD. Thus, Iincreasing the production of HbF in patients with SCD could be the single most effective way to prevent the symptoms and complications of the disease, Dr. Saunthararajah notes, explaining that we already know from some observations in some individuals that replacing 20 to 30 percent of the mutated hemoglobin with HbF can make SCD  patients essentially asypmtomatic. The biochemical work of switching-off the gene for HbF from infancy onward is executed by DNMT1. DNMT1-depletion by decitabine thus increases HbF in RBCs even in adults, and even in patients who do not respond to current therapies.

Decitabine is FDA-approved for the treatment of a blood cancer myelodysplastic syndromes, but is administered for this indication at high toxic doses and by the intravenous route. Decitabine has a modified pyrimidine ring but natural sugar that enables depletion of the epigenetic enzyme DNA methyltransferase 1 (DNMT1) without terminating DNA chain elongation or causing cytotoxicity. Oral bioavailability and realization of this non-cytotoxic epigenetic effect in vivo, however, is severely curtailed by rapid decitabine degradation by cytidine deaminase (CDA). Administration of higher decitabine doses causes off-target anti-metabolite effects/cytotoxicity and does not solve these problems. Instead, in pre-clinical studies, co-administration of the CDA-inhibitor THU, that has not been found to cause toxicity to animals or humans, enables oral bioavailability of micro-dose decitabine, with the low decitabine Cmax and extended Tmax ideal for on-target non-cytotoxic DNMT1-depletion.  

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Depleting DNMT1 to increase HbF, without cytotoxicity

In this study, Cleveland Clinic and University of Illinois researchers collaborated to  DNMT1, the enzyme that turns off the fetal hemoglobin gene, Dr. Saunthararajah says.

The treatment was given twice a week for eight weeks, with THU given at a fixed dose of 10 mg/kg one hour before decitabine, which was started at extremely low (almost homeopathic) doses of 0.01, 0.02, and 0.04 mg/kg, and increased to very low doses of 0.08 and 0.16 mg/kg, all representing a fraction of the normal chemotherapy dose of the drug.

There were no significant adverse events compared to placebo and no Grade 4 adverse events. None of the patients either in placebo or treatment group discontinued the study prematurely.

Doses and treatment effects

Blood samples were obtained at 0, 2, 4 and 24 hours from 12 of 15 patients, and decitabine was detected in patients’ blood samples at the lowest dose of 0.01 mg/kg. The two highest doses produced a stable concentration that led to clinical effect, doubling the HbF levels in the red cells at the dose of 0.16 mg/kg, less than 10% of the FDA-approved dose of decitabine that is administered intravenously.

Total hemoglobin increased by more than a gram/dL at this dose, and improvement in hemolysis and thrombophilia markers was observed.

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Future directions

A phase 3 study is being planned, in which patients will take the two drugs for one year in the form of a new formulation consisting of a single capsule taken orally twice a week, delivering both drugs at the appropriate time interval, with THU being released first.

“We believe that this will be the kind of treatment that will be safe and effective enough that patients should be able to take it for their whole lives, to prevent pain and chronic organ damage, and to substantially increase quality and quantity of life — that is our goal,” Dr. Saunthararajah says. “Of course, we have to prove it.”