Empagliflozin for Severe Congenital Neutropenia

Recruiting in Palo Alto (17 mi)

Overseen by David H McDermott, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: Renal failure, Type 1 diabetes, others

No Placebo Group

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Background: Severe congenital neutropenia (SCN) is an immune system disease. People with SCN do not have enough of a kind of white blood cell called neutrophils. This means they get sick easily from infections. Some drugs to treat SCN have lots of side effects. Researchers want to see if a the drug empagliflozin can help increase the number of neutrophils in a person with SCN. Objective: To see if a drug called empagliflozin can help people with SCN. Eligibility: Adults aged 18 and older with SCN. Design: Participants will be screened with a physical exam, medical history, and blood tests. They may have a pregnancy test. Participants will have study visits and local lab visits. They will repeat the screening tests. They will have heart and lung function tests. They will have an ultrasound of the liver and spleen. Their skin symptoms will be photographed. They may have consultations with specialists. They may give a stool sample. They may have an optional colonoscopy with tissue sample collection. They may have an optional bone marrow biopsy and aspirate. They may have an optional magnetic resonance imaging scan of their heart. Participants will be admitted to NIH for 5 7 days. They will start taking the study drug as a pill once daily. They will be monitored for side effects. Participants will take the study drug at home for 12 months. They will use a fingerstick blood glucose meter to measure blood sugar at home. Participants may be able to take the study drug through their local doctor after the study ends. Participation will last for 15 months.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the drug empagliflozin for treating severe congenital neutropenia?

Empagliflozin, a drug originally used for diabetes, has been shown to improve neutrophil counts and function in patients with certain genetic conditions causing neutropenia, such as G6PC3 deficiency and glycogen storage disease type Ib. In these cases, empagliflozin helped reduce infections and allowed some patients to stop or reduce other treatments like G-CSF, without significant side effects.

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How does the drug empagliflozin differ from other treatments for severe congenital neutropenia?

Empagliflozin is unique because it targets the underlying cause of neutropenia by reducing the levels of a specific compound (1,5-anhydroglucitol-6-phosphate) that impairs neutrophil function, unlike standard treatments that mainly focus on stimulating neutrophil production. This approach not only improves neutrophil counts and function but also allows for a reduction or discontinuation of other treatments like granulocyte colony-stimulating factor (GCSF), with fewer side effects.

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Eligibility Criteria

Adults over 18 with severe congenital neutropenia (SCN) due to G6PC3 deficiency, who have low white blood cell counts and agree to use two forms of birth control can join. Those with kidney failure, type 1 diabetes, fasting hypoglycemia, pregnancy or known allergy to empagliflozin cannot participate.

Inclusion Criteria

I agree to use two forms of birth control, including a condom, during the study.

Able to provide informed consent

My severe congenital neutropenia is due to a G6PC3 deficiency.

Exclusion Criteria

Fasting hypoglycemia (<60 mg/dL)

Any condition that, in the opinion of the investigator, contraindicates participation in this study

Pregnant

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase A

Participants receive 10 mg of oral empagliflozin daily for 2 months. Blood draws every two weeks for clinical lab evaluations and remote AE assessments.

8 weeks

4 visits (local lab), 4 remote assessments

Treatment Phase B

Participants may increase to 25 mg daily if needed. Blood draws and remote AE assessments monthly for the first 4 months, and bimonthly for the last 6 months. Outpatient visits at NIH at months 6 and 12.

10 months

6 visits (local lab), 6 remote assessments, 2 visits (in-person at NIH)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Participant Groups

The trial is testing if the drug empagliflozin can increase white blood cells in SCN patients. Participants will take the drug daily for a year and monitor their health at home and through visits including heart tests, liver ultrasounds, possibly colonoscopies or bone marrow biopsies.

Group I: Treatment Arm Experimental Treatment 1 Intervention

Patients with GCPC3 will receive daily Empagliflozin for 12 months.

Empagliflozin is already approved in European Union, United States, Canada, Japan for the following indications:

🇪🇺 Approved in European Union as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

🇺🇸 Approved in United States as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease
• Cardiovascular risk reduction

🇨🇦 Approved in Canada as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction
• Chronic kidney disease

🇯🇵 Approved in Japan as Jardiance for:

• Type 2 diabetes mellitus
• Heart failure with reduced ejection fraction

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID) Lead Sponsor

References

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

A molecular classification of congenital neutropenia syndromes. [2009] Current knowledge on the molecular pathogenesis of severe congenital neutropenia indicates that the clinical diagnosis includes a heterogeneous group of disorders following different patterns of inheritance. Similarly, multifaceted syndromes associated with neutropenia can be classified molecularly, which in turn allows for a better understanding of the basis of the neutropenia. Many of the neutropenia disorders can be treated with G-CSF (filgrastim) to increase the neutrophil count, thereby reducing infection morbidity and mortality. In some instances hematopoietic stem cell transplantation remains the only curative treatment currently available. This review describes and classifies, on a molecular basis, both primary congenital neutropenia and multifaceted syndromes associated with neutropenia.

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

Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5. [2022] Neutropenia and neutrophil dysfunction found in deficiencies in G6PC3 and in the glucose-6-phosphate transporter (G6PT/SLC37A4) are due to accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol present in blood. Lowering blood 1,5-AG with an SGLT2 inhibitor greatly improved neutrophil counts and function in G6PC3-deficient mice and in patients with G6PT-deficiency. We evaluate this treatment in two G6PC3-deficient children. While neutropenia was severe in one child (PT1), which was dependent on granulocyte cololony-stimulating factor (GCSF), it was significantly milder in the other one (PT2), which had low blood 1,5-AG levels and only required GCSF during severe infections. Treatment with the SGLT2-inhibitor empagliflozin decreased 1,5-AG in blood and 1,5-AG6P in neutrophils and improved (PT1) or normalized (PT2) neutrophil counts, allowing to stop GCSF. On empagliflozin, both children remained infection-free (>1 year - PT2; >2 years - PT1) and no side effects were reported. Remarkably, sequencing of SGLT5, the gene encoding the putative renal transporter for 1,5-AG, disclosed a rare heterozygous missense mutation in PT2, replacing the extremely conserved Arg401 by a histidine. The higher urinary clearance of 1,5-AG explains the more benign neutropenia and the outstanding response to empagliflozin treatment found in this child. Our data shows that SGLT2 inhibitors are an excellent alternative to treat the neutropenia present in G6PC3-deficiency.

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

Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. [2021] Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.

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

Sodium-glucose cotransporter type 2 channel inhibitor: Breakthrough in the treatment of neutropenia in patients with glycogen storage disease type 1b? [2022] Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by biallelic mutations in the SLC37A4 gene encoding microsomal glucose-6-phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. Ineffective G6P transport into the ER leads to hypoglycaemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hepato- and/or nephromegaly. Clinical manifestations of the disease include recurrent, severe infections and inflammatory bowel (Crohn-like) caused by neutropenia and diminished bactericidal and fungicidal activity of neutrophils. Granulocyte colony-stimulating factor (G-CSF) administration is currently a standard therapy to prevent adverse effects of neutropenia, but the treatment is associated with a high risk of severe side effects. On the other hand, short-treatment with sodium-glucose cotransporter type 2 inhibitor - empagliflozin (EMPA) was reported to act directly on the mechanism of neutropenia and neutrophil dysfunction in GSD 1b. We observed significant improvement in clinical and laboratory parameters after introducing EMPA to treatment, that is reduced frequency of infections, lower number of bowel movements, and improved postoperative wound healing. EMPA is effective in the treatment of neutropenia in our GSD 1b patients, which allows for dose reduction and even withdrawal of G-CSF. We did not observe any significant side effects of EMPA treatment in our patients.

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

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. [2019] The purpose of this review is to summarize pathogenic mechanisms and clinical implications of the most illustrative genetic entities of congenital neutropenia syndromes.

6. Belgium pubmed.ncbi.nlm.nih.gov

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. [2022] Empagliflozin is a new inhibitor of sodiumglucose cotransporters type 2 (SGLT2) for the treatment of type 2 diabetes mellitus (T2DM). Its specific action inhibits glucose reabsorption in renal tubules and thus promotes glucosuria. This effect results in a reduction in fasting and postprandial glycaemia and a decrease of glycated haemoglobin (HbA(Ic)), independently of insulin. Furthermore, calorie urinary loss promotes weight reduction and osmotic diuresis lowers arterial blood pressure. The efficacy of empagliflozin increases according to the level of hyperglycaemia but decreases in patients with renal insufficiency. In 24 to 104-week controlled trials versus placebo, empagliflozin reduces HbA(1c) (approximately 0.8%), without hypoglycaemia (except in patients already treated with insulin or sulphonylureas). This improvement in glucose control is rather similar to that observed with active comparators (metformin, glimepiride or sitagliptin), with the advantage for empagliflozin of reducing body weight (approximately 2 kg) and blood pressure (systolic approximately 4 mm Hg and diastolic approximately 2 mm Hg). Empagliflozin has shown a cardiovascular protection in the EMPA-REG OUTCOME trial. Mycotic genital infections occur more frequently, especially in women, while a negligible increase in mild urinary tract infections may be observed. The risk of hypotension and volume depletion is low, although it should be carefully checked in more fragile and at risk patients. Empagliflozin (Jardiance), which is commercialized at the doses of 10 mg and 25 mg once daily, is indicated for the treatment of T2DM and reimbursed in Belgium with conditions as add-on to a background glucose-lowering therapy.

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

Diabetes Drug Now Approved for Heart Failure. [2023] The diabetes drug empagliflozin (Jardiance) is now approved to reduce the risk of cardiovascular death and hospitalization in adults with heart failure, even if they do not have diabetes.Nurses and NPs should monitor patients for adverse effects, especially fluid deficits.