NDec for Sickle Cell Disease

(ASCENT1 Trial)

Recruiting at 99 trial locations

Overseen By Novo Nordisk

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Novo Nordisk A/S

Must be taking: Hydroxyurea

Must not be taking: Voxelotor, Crizanlizumab, L-glutamine

Disqualifiers: Chronic transfusion therapy, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

84 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new medicine called NDec for people with sickle cell disease. NDec combines two drugs to help manage the disease. Participants will take capsules regularly over several months to see how well the medicine works and if it is safe.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but if you are taking Hydroxyurea (HU), you may continue it during the study. However, you cannot participate if you have taken voxelotor, crizanlizumab, or L-glutamine within 12 weeks before the trial or plan to take them during the trial.

What data supports the effectiveness of the drug NDec for treating sickle cell disease?

Research shows that decitabine, a component of NDec, can increase fetal hemoglobin levels in patients with sickle cell anemia, which helps reduce symptoms. In a study, patients who did not respond to another treatment (hydroxyurea) saw an increase in fetal hemoglobin and overall hemoglobin levels without significant side effects. ^{1 2 3 4 5}

What makes the drug NDec unique for treating sickle cell disease?

NDec is unique because it combines decitabine with tetrahydrouridine to improve the oral availability of decitabine, which is usually broken down quickly in the body. This combination allows for a more effective and prolonged exposure to decitabine, potentially increasing fetal hemoglobin levels, which can be beneficial for sickle cell disease. ^{6 7 8 9 10}

Research Team

Clinical Transparency (dept. 2834)

Principal Investigator

Novo Nordisk A/S

Eligibility Criteria

Adults over 18 with sickle cell disease (SCD), having had 2-10 pain episodes in the last year, and specific blood criteria can join. Excluded are those on chronic transfusions, recent other treatments for SCD, certain blood counts outside normal ranges, pregnant or breastfeeding women, and those not using effective contraception.

Inclusion Criteria

Reticulocyte count above upper limit of the normal (ULN) at visit 1

I have had 2-10 painful episodes related to my condition in the last year.

My weight is between 40 and 125 kg.

Exclusion Criteria

I am a male willing to use a condom, and my partner uses effective birth control during the trial and for up to 12 months after.

Platelet count greater than 800 x 10^9/L at visit 1

I haven't taken voxelotor, crizanlizumab, or L-glutamine in the last 12 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NDec, NDec and placebo, or placebo. Participants on HU may continue HU or receive NDec treatments.

24 weeks

Twice weekly capsule administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

28 weeks

Treatment Details

Interventions

• NDec

Trial Overview The trial is testing NDec—a new oral medication combining decitabine-tetrahydrouridine—against a placebo and Hydroxyurea (HU) in people with SCD. Participants will be randomly assigned to receive either NDec capsules twice weekly or continue HU/placebo for about a year.

Participant Groups

Group I: HU-non-eligible - NDec plus placebo Experimental Treatment 2 Interventions

HU-non eligible patients randomised to treatment with NDec on one day and placebo on the other day

Group II: HU-non-eligible - NDec plus NDec Experimental Treatment 1 Intervention

HU-non eligible patients randomised to treatment with NDec on both days

Group III: HU-active - NDec plus placebo Experimental Treatment 2 Interventions

HU-active patients randomised to treatment with NDec on one day and placebo on the other day

Group IV: HU-active - NDec plus NDec Experimental Treatment 1 Intervention

HU-active patients randomised to treatment with NDec on both days

Group V: HU-active - HU Active Control 1 Intervention

HU-active patients randomised to continue on open-label HU treatment

Group VI: HU-non-eligible - Placebo plus placebo Placebo Group 1 Intervention

HU-non eligible patients randomised to treatment with placebo on both days

Who Is Running the Clinical Trial?

Novo Nordisk A/S

Lead Sponsor

Trials

1,578

Recruited

3,813,000+

Lars Fruergaard Jørgensen

Novo Nordisk A/S

Chief Executive Officer since 2017

MSc in Finance and Business Administration, Aarhus School of Business, Aarhus University, Denmark

Martin Holst Lange

Novo Nordisk A/S

Chief Medical Officer since 2021

MD from University of Copenhagen

Findings from Research

In a 9-month study involving 7 patients with sickle cell anemia, repeated dosing of decitabine significantly increased fetal hemoglobin (HbF) levels from a pretreatment average of 3.12% to a maximum of 18.35%, indicating its efficacy in patients who did not respond to hydroxyurea.

Decitabine was well-tolerated, with no cases of neutropenia or cumulative toxicity observed, suggesting that shorter treatment intervals could be possible, potentially leading to even greater improvements in hemoglobin levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. DeSimone, J., Koshy, M., Dorn, L., et al.[2021]

A study of 142 children with sickle cell disease showed that a lower initial dose of hydroxyurea (10-12 mg/kg/day) was effective in reducing hospital admissions due to vaso-occlusive crises, similar to higher doses (15-35 mg/kg/day).

Both low and high-dose groups experienced significant clinical improvements in laboratory markers and tolerated the treatment well, indicating that a cautious low-dose regimen is a safe and effective option for managing sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective. Sharef, SW., Al-Hajri, M., Beshlawi, I., et al.[2022]

In a study of 14 young children with sickle cell anemia, hydroxyurea was well-tolerated at a mean maximum tolerated dose of 28 mg/kg/day, showing significant improvements in laboratory parameters like hemoglobin and MCV over an average of 25 months.

Importantly, hydroxyurea treatment did not lead to any significant decline in kidney function or brain health, as indicated by stable transcranial Doppler velocities and no development of brain ischemic lesions, suggesting it may help prevent chronic organ damage in these children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. Thornburg, CD., Dixon, N., Burgett, S., et al.[2021]

The combination of tetrahydrouridine (THU) and decitabine shows promising pharmacokinetics, with decitabine being rapidly absorbed and maintaining high bioavailability (≥74%) when taken together, which is crucial for effective treatment in sickle cell disease (SCD).

The treatment was well tolerated across different sexes and fasting states, and despite variations in how the body processes the drugs, the desired pharmacodynamic effect of downregulating DNMT1 was consistent, indicating potential for effective oral therapy targeting SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine. Lau, H., Woost, PG., Friedrich, U., et al.[2023]

Caregivers of children with severe sickle cell disease (SCD) who accepted hydroxyurea (HU) were proactive in seeking information and viewed HU as a necessary preventative treatment, highlighting the importance of understanding the severity of the condition.

In contrast, caregivers who declined HU often did not perceive their child's SCD as severe and lacked engagement in discussions about HU with healthcare providers, indicating a need for better communication and education to improve acceptance of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxyurea therapy for children with sickle cell disease: describing how caregivers make this decision. Creary, S., Zickmund, S., Ross, D., et al.[2022]

The combination drug NDec, which includes oral decitabine and tetrahydrouridine, shows potential for safe administration alongside other medications that affect nucleoside transporters, as tetrahydrouridine did not inhibit key transporters at tested concentrations.

Tetrahydrouridine is actively accumulated in cells via the CNT3 transporter, with specific kinetic parameters identified, suggesting its mechanism of action is compatible with existing treatments for sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters. Säll, C., Koncsos, G., Klukovits, A.[2023]

The combination of decitabine (DAC) and tetrahydrouridine (THU) showed increased oral bioavailability of DAC, with THU enhancing DAC plasma concentration by approximately 10-fold, indicating a potential for improved therapeutic efficacy in treating sickle cell disease and β-thalassemia.

However, the therapy also revealed significant safety concerns, particularly in female mice, where high doses of DAC combined with THU led to severe toxicity, including bone marrow suppression and other harmful effects, necessitating careful monitoring and dose adjustments in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice. Terse, P., Engelke, K., Chan, K., et al.[2021]

NDec, a new oral formulation combining decitabine and tetrahydrouridine, shows promise for treating sickle cell disease without significant drug-drug interactions, as neither component inhibited key drug metabolizing enzymes or transporters.

Tetrahydrouridine demonstrated weak inhibition of the MATE2-K transporter, but this was not considered clinically relevant, indicating a favorable safety profile for NDec in terms of metabolic interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro drug-drug interactions of decitabine and tetrahydrouridine involving drug transporters and drug metabolising enzymes. Säll, C., Fogt Hjorth, C.[2022]

In a phase 1 study involving 50 patients with relapsed/refractory leukemias, decitabine was well tolerated at low doses, with myelosuppression being the main side effect.

The most effective response was observed with a dose of 15 mg/m2 for 10 days, leading to a 65% response rate, suggesting that lower doses of decitabine may be more effective than higher doses in treating myeloid malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Issa, JP., Garcia-Manero, G., Giles, FJ., et al.[2022]

The combination of tetrahydrouridine (THU) with decitabine (DAC) enhances the effectiveness of DAC by inhibiting cytidine deaminase, which normally breaks down DAC, thus increasing its absorption and exposure time in the body.

In nonhuman primates, this combination therapy was shown to be safe, not causing myelosuppression, while effectively increasing fetal hemoglobin levels, suggesting a potential treatment for hemoglobinopathies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Lavelle, D., Vaitkus, K., Ling, Y., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of an oral formulation of decitabine and tetrahydrouridine. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Hydroxyurea therapy for children with sickle cell disease: describing how caregivers make this decision. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

In Vitro Interaction of Tetrahydrouridine with Key Human Nucleoside Transporters. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice. [2021]

8. England pubmed.ncbi.nlm.nih.gov

In vitro drug-drug interactions of decitabine and tetrahydrouridine involving drug transporters and drug metabolising enzymes. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. [2022]