Empagliflozin for Severe Congenital Neutropenia

Overseen By David H McDermott, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

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

Disqualifiers: Renal failure, Type 1 diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

4 Participants Needed

What You Need to Know Before You Apply

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.

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. ^{1 2 3 4 5}

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. ^{1 2 3 6 7}

Who Is on the Research Team?

David H McDermott, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Empagliflozin

Trial Overview 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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

Severe congenital neutropenia encompasses a diverse range of disorders with different inheritance patterns, which can be better understood through molecular classification.

Treatment options include G-CSF (filgrastim) to boost neutrophil counts and reduce infection risks, while hematopoietic stem cell transplantation is the only curative approach available for some cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A molecular classification of congenital neutropenia syndromes. Boxer, LA., Newburger, PE.[2009]

SGLT2 inhibitors, like empagliflozin, effectively reduce levels of 1,5-anhydroglucitol and its phosphate form, leading to improved neutrophil counts and function in children with G6PC3 deficiency, allowing for the cessation of granulocyte colony-stimulating factor (GCSF) treatment.

In a study involving two G6PC3-deficient children, treatment with empagliflozin resulted in both children remaining infection-free for over a year, with no reported side effects, highlighting the safety and efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful use of empagliflozin to treat neutropenia in two G6PC3-deficient children: Impact of a mutation in SGLT5. Boulanger, C., Stephenne, X., Diederich, J., et al.[2022]

Empagliflozin, a drug typically used for type 2 diabetes, was successfully repurposed to treat neutropenia and neutrophil dysfunction in four patients with glycogen storage disease type Ib (GSD-Ib), leading to a decrease in harmful intracellular levels of 1,5-anhydroglucitol-6-phosphate (1,5AG6P).

The treatment resulted in significant clinical improvements, including resolution of frequent infections and inflammatory bowel disease symptoms, stabilization of neutrophil counts, and enhanced neutrophil function, all without causing symptomatic hypoglycemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. Wortmann, SB., Van Hove, JLK., Derks, TGJ., et al.[2021]

Empagliflozin (EMPA) significantly improved clinical outcomes in patients with Glycogen Storage Disease type 1b (GSD 1b), including reduced infection frequency and improved bowel function, while also enhancing postoperative wound healing.

EMPA effectively treated neutropenia in GSD 1b patients, allowing for a reduction or complete withdrawal of the standard therapy granulocyte colony-stimulating factor (G-CSF), without significant side effects.

NCBI (Pubmed)

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? Kaczor, M., Greczan, M., Kierus, K., et al.[2022]

Congenital neutropenia syndromes are linked to various genetic defects, including known entities like ELANE and novel ones like VPS45 deficiency, which enhance our understanding of neutrophil biology and function.

Recent advancements in genetic and biochemical techniques allow for more tailored treatment approaches, potentially leading to personalized medicine for patients with congenital neutropenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Hauck, F., Klein, C.[2019]

Empagliflozin effectively lowers blood sugar levels in patients with type 2 diabetes by inhibiting glucose reabsorption in the kidneys, resulting in an average reduction of HbA1c by approximately 0.8% without causing hypoglycemia, except in those already on insulin or sulphonylureas.

In addition to improving glycemic control, empagliflozin promotes weight loss (about 2 kg) and lowers blood pressure (systolic by approximately 4 mm Hg), while also providing cardiovascular protection, as demonstrated in the EMPA-REG OUTCOME trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. Scheen, AJ.[2022]

Empagliflozin (Jardiance) is now approved for reducing the risk of cardiovascular death and hospitalization in adults with heart failure, even in those without diabetes, highlighting its expanded therapeutic use.

Healthcare providers, including nurses and nurse practitioners, should closely monitor patients for potential adverse effects, particularly fluid deficits, to ensure patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diabetes Drug Now Approved for Heart Failure. Aschenbrenner, DS.[2023]

Citations

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

A molecular classification of congenital neutropenia syndromes. [2009]

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]

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

Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. [2021]

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]

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

Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. [2019]

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

[EMPAGLIFLOZIN (JARDIANCE) :Nw SGLT2 COTRANSPORTER INHIBITOR FOR TREATING TYPE 2 DIABETES]. [2022]

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

Diabetes Drug Now Approved for Heart Failure. [2023]