Potential New Therapy on Horizon for Sickle Cell Disease

Research is being conducted to identify novel therapies for sickle cell disease (SCD), including a phase 1 clinical trial that combines THU with Decitabine to decrease symptoms in an accessible and practical way.

Study investigates therapy to address limitations of standard SCD care

Investigators will present Combination with Thu to Address Pharmacologic Limitations of Decitabine: Interim PK/PD from a Phase 1/2 Clinical Trial of Oral Thu-Decitabine in Sickle Cell Disease at the 56th American Society of Hematologists Annual Meeting.

Decitabine (Dec) can deplete DNA methyltransferase (DNMT1), which is a validated molecular target for epigenetic therapy of sickle cell disease (SCD). Dec is an FDA-approved drug that can be positioned to deplete DNMT1 without off-target cytotoxicity. But Dec has pharmacologic limitations that impede translation into clinical epigenetic therapy.

For example, DNMT depletion requires that Dec levels overlap with certain phases of cellular growth cycles (‘S-phase’), but Dec is very rapidly destroyed in the body, within minutes, by an enzyme called cytidine deaminase (CDA). This significantly curtails any probability of overlap. Increasing the dose of Dec doesn’t solve this problem because off-target effects from higher peak drug levels kills dividing cells, causing toxicity that restricts the feasibility and frequency of therapy. Continuous infusion of Dec does not solve the problem either as Dec accumulates to toxic levels in some tissues while inadequate levels remain in others, because of widely divergent amounts of cytidine deaminase (CDA) in tissues. Destruction of Dec by CDA in the intestines and liver also means that oral administration is not practical, an important consideration for accessible, cost-effective multi-year or life-long therapy.

This research is addressing these limitations of Dec by combining oral Dec with a CDA inhibitor, oral tetrahydrouridine (THU), in people with high-risk, hydroxyurea refractory SCD.

At the time the abstract was written, 16 subjects had received placebo or THU-Dec, starting at mini-dosages of Dec with a gradual escalation. “We have not observed toxicity attributable to the experimental drug in the Phase 1 clinical trial thus far,” says one of the researchers, Yogen Saunthararajah, MD, Staff/Professor of Medicine in the Department of Hematologic Oncology and Blood Disorders at Cleveland Clinic. “We are seeing the pharmacology that we intended in order to decrease off-target toxicity and increase on-target effects; that is, low peak drug levels to decrease off-target effects, extended drug half-life, to hours instead of minutes, to increase on-target DNMT1-depletion,” he explains. In other words, the eight non-placebo subjects showed major improvement in bioavailability and the wide Dec concentration-time profile that is necessary for adequate DNMT1-depletion without cytotoxicity.

Too early to document improvement in clinical symptoms

The non-placebo patients at the highest dose level to date (0.08 mg/kg of decitabine) did have increased HbF levels, but since the phase 1 clinical trial only administers the experimental drug for eight weeks, there is insufficient time to document an improvement in clinical symptoms in patients, says Dr. Saunthararajah.

“We are measuring HbF as a surrogate end point that we expect to cause a decrease in symptoms if it can be sustained for an extended period of time – the intent is years to lifelong,” he says.

Positive preliminary results merit further study

Investigators hope to eventually gain support from the community for a multicenter clinical trial that randomizes symptomatic SCD patients to standard of care hydroxyurea versus oral THU-decitabine, says Dr. Saunthararajah.

Given these findings and future plans to continue the research along these lines, there is definitely hope on the horizon for much-needed new treatments for people with SCD.