INHALE-1 Trial: AFREZZA® Efficacy in Children and Adolescents

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Efficacy in children and adolescents

AFREZZA® is an ultra rapid-acting inhaled insulin option for ages 6 years and older with diabetes.1

Children and adolescents eating together — pediatric lifestyle imagery for INHALE-1 efficacy page
Children and adolescents eating together — pediatric lifestyle imagery for INHALE-1 efficacy page

Efficacy in children and adolescents

AFREZZA® is an ultra rapid-acting inhaled insulin option for ages 6 years and older with diabetes.1

Meal challenge

AFREZZA allows true mealtime dosing while improving postprandial glucose excursions1–4

INHALE-3: AFREZZA vs RAA glucose excursion in adults5

Subset analysis: As part of the RCT, an in-clinic standardized meal challenge was conducted to assess the postprandial glucose levels (CGM or SMBG) at the start of the INHALE-3 trial comparing AFREZZA with RAA in adult patients. Patients drank a bottle of BOOST® nutritional shake (240 calories; 37 grams of carbohydrates).6

INHALE-1: AFREZZA vs RAA glucose excursion in children and adolescents7

Subset analysis: As part of the RCT, an in-clinic standardized meal challenge was conducted at the start of the INHALE-1 trial to assess the effects of AFREZZA on postprandial glucose levels (CGM or SMBG). Patients consumed either a Clif Bar (250-260 calories) or drank a bottle of BOOST® nutritional shake (240 calories; 37 grams of carbohydrates).8
AFREZZA kept postmeal rises lower in adults vs RAA, and continued in children and adolescents.5,7
How does AFREZZA control postmeal glucose compared with injectable mealtime insulin?
AFREZZA is administered at the start of a meal and provides rapid postmeal glucose control comparable to injectable rapid-acting insulin analogs.1,3,4,9-11 In the INHALE-1 meal challenge, children and adolescents receiving AFREZZA showed postmeal glucose responses consistent with the rapid-onset profile previously observed in adults.5,7,8
• AFREZZA is taken at the start of the meal (0 minutes), whereas injected rapid-acting insulin analogs typically require dosing 5 to15 minutes before eating. This difference demonstrates the faster absorption profile of AFREZZA and supports true mealtime dosing6,8
Study design

Proven efficacy in children and adolescents1,12

INHALE-1: A Phase-3, open-label, noninferiority, randomized, controlled trial in those aged 4 to 17 years with A1C of ≥7.0% to ≤11.0%1,12,a

Primary endpoint: Change in A1C at Week 2612
Secondary assessments: DTSQ scores, weight/BMI, and hypoglycemia12

INHALE-3: The clinical trial evaluating AFREZZA in adults

VIEW STUDY DESIGN

aAFREZZA is indicated for patients as young as 6 years1; however, the INHALE-1 trial included children as young as 4 years.12

A1C control

Change in A1C with AFREZZA and RAA1,12

INHALE-1: Change in A1C from baseline (primary endpoint)12

INHALE-1 primary endpoint A1C change at Week 26: AFREZZA Baseline 8.22% (n=117) to Week 26 8.41% (n=105); RAA Baseline 8.21% (n=113) to Week 26 8.21% (n=105). P=0.091 noninferiority margin 0.4%. INHALE-1 primary endpoint A1C change at Week 26: AFREZZA Baseline 8.22% (n=117) to Week 26 8.41% (n=105); RAA Baseline 8.21% (n=113) to Week 26 8.21% (n=105). P=0.091 noninferiority margin 0.4%.
Sensitivity analysis: AFREZZA resulted in a nominally inferior change in A1C vs RAA based on the primary ITT analysis. A sensitivity analysis was conducted (removing a single patient outlier), resulting in an A1C treatment difference of 0.14% (95% CI: -0.10, 0.37); P=0.026.12
The CI of the between-group difference in mean reduction in A1C exceeded the prespecified noninferiority margin.1
Satisfaction survey

Higher treatment satisfaction with AFREZZA compared with RAA12,b-e

INHALE-1: DTSQs mean treatment satisfaction results from the analysis of adolescents and parents12,d,e

AFREZZA SCOREDb 4.99/6

The mean treatment satisfaction score in the RAA group was reported at 4.60/6 from adolescents and 4.55/6 from parents.12,c

Children and adolescents eating together — pediatric lifestyle imagery for INHALE-1 efficacy page

Components that the DTSQ survey assessed were the following:

Treatment
satisfaction14,15
Convenience
and flexibility14,15
Understanding of
the treatment14,15
Willingness to continue treatment14,15

What is AFREZZA?

AFREZZA (insulin human) Inhalation Powder is the only FDA-approved ultra rapid-acting inhaled mealtime insulin. It is indicated to improve glycemic control in children, adolescents, and adults 6 years of age and older with diabetes. AFREZZA is delivered as a dry powder through a small breath-activated inhaler with an onset of action of approximately 12 minutes.1

Are no injections needed with AFREZZA at mealtime?

Yes. AFREZZA is administered entirely by inhalation. There are no injections at mealtime. Patients who require basal insulin continue to administer that separately by injection. AFREZZA replaces only the mealtime (bolus) insulin component, eliminating mealtime injections.1

Which patients are appropriate candidates for AFREZZA?

AFREZZA is indicated for children, adolescents, and adults age 6 years and older with type 1 or type 2 diabetes who require mealtime insulin. It is contraindicated in patients with chronic lung disease, including asthma and COPD, due to the risk of acute bronchospasm. Spirometry (FEV₁) should be performed before initiating AFREZZA to identify potential lung disease in all patients, including those with no pulmonary history.1

A1C, glycated hemoglobin; BMI, body mass index; CGM, continuous glucose monitoring; COPD, chronic obstructive lung disease; DTSQ, Diabetes Treatment Satisfaction Questionnaire; FDA, US Food and Drug Administration; FEV1, forced expiratory volume in 1 second; ITT, intent-to-treat; PPG, postprandial glucose; PPGE, postprandial glucose excursion; RAA, rapid-acting analog; RCT, randomized controlled trial; SMBG, self-monitoring of blood glucose.

bAFREZZA: Mean treatment satisfaction in adolescents and parents was 4.63 (n=62) and 4.23 (n=53), respectively, at baseline and 4.99 (n=55) and 4.99 (n=42), respectively, at Week 26.12
cRAA: Mean treatment satisfaction in adolescents and parents was 4.62 (n=61) and 4.28 (n=52), respectively, at baseline and 4.60 (n=57) and 4.55 (n=51), respectively, at Week 26.12
dPooled treatment difference of AFREZZA vs RAA was statistically significant (P=0.004) for treatment satisfaction.12
eParticipants aged ≥13 years completed the DTSQ original status version (DTSQs) at baseline and 26 weeks, and the AFREZZA group also completed the DTSQ change version (DTSQc) at 26 weeks. A parent or guardian of participants aged <13 years completed the parent version of the surveys.12 Respondents were asked a series of questions, including “How satisfied are you with your current treatment?” or “How satisfied are you with your child’s current treatment?”14,15

References: 1. AFREZZA. Prescribing information. MannKind Corporation; 2026. 2. Caumo A, Bergman RN, Cobelli C. Insulin sensitivity from meal tolerance tests in normal subjects: a minimal model index. J Clin Endocrinol Metab. 2000;85(11):4396-4402. 3. Levin P, Hoogwerf BJ, Snell-Bergeon J, Vigers T, Pyle L, Bromberger L. Ultra rapid-acting inhaled insulin improves glucose control in patients with type 2 diabetes mellitus. Endocr Pract. 2021;27(5):449-454. 4. Data on file (PK/PD). MannKind Corporation. 5. Data on file (INHALE-3 Meal Challenge Randomized). MannKind Corporation. 6. Hirsch IB, Beck RW, Marak MC, et al; INHALE-3 Study Group. A randomized comparison of postprandial glucose excursion using inhaled insulin versus rapid-acting analog insulin in adults with type 1 diabetes using multiple daily injections of insulin or automated insulin delivery. Diabetes Care. 2024;47(9):1682-1687. 7. Data on file. (INHALE-1 Meal Challenge). MannKind Corporation. 8. Ekhlaspour L, Kanapka L, Dewan A, et al; INHALE-1 Study Group. Inhaled Technosphere insulin reduces postmeal glucose excursion in youth living with type 1 diabetes. Diabetes Technol Ther. 2026:15209156261432138. 9. FIASP. Prescribing information. Novo Nordisk; 2023. 10. LYUMJEV. Prescribing information. Eli Lilly and Company; 2022. 11. Grant M, Heise T, Baughman R. Comparison of pharmacokinetics and pharmacodynamics of inhaled Technosphere insulin and subcutaneous insulin lispro in the treatment of type 1 diabetes mellitus. Clin Pharmacokinet. 2022;61(3):413-422. 12. Haller MJ, Kanapka L, Monzavi R, et al; INHALE-1 Study Group. INHALE-1: a multicenter randomized trial of inhaled Technosphere insulin in children with type 1 diabetes. Diabetes Care. 2026;49(1):179-187. 13. Beck RW, Kanapka L, Monzavi R, et al; INHALE-1 Study Group. Inhaled Technosphere insulin in children with diabetes: the INHALE-1 extension study. Diabetes Technol Ther. 2026:15209156261420176. 14. Data on file (T-14 Scores of DTSQc-Teens). MannKind Corporation. 15. Data on file (MKC-TI-155 Part 2). MannKind Corporation.

© MannKind Corporation May 2026. US-AFR-2891

Indications and Usage:

Afrezza® (insulin human) Inhalation Powder is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus.

Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis, not recommended in patients who smoke or have recently stopped smoking.

Important Safety Information

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE

  • Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD.
  • Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients.

Indications and Usage:

Afrezza® (insulin human) Inhalation Powder is a rapid acting inhaled human insulin indicated to improve glycemic control in adult and pediatric patients 6 years of age and older with diabetes mellitus.

Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis, not recommended in patients who smoke or have recently stopped smoking.

Important Safety Information

WARNING: RISK OF ACUTE BRONCHOSPASM IN PATIENTS WITH CHRONIC LUNG DISEASE

  • Acute bronchospasm has been observed in AFREZZA-treated patients with asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • AFREZZA is contraindicated in patients with chronic lung disease such as asthma or COPD.
  • Before initiating AFREZZA, perform a detailed medical history, physical examination, and spirometry (FEV1) to identify potential lung disease in all patients.

Contraindications

AFREZZA is contraindicated: during episodes of hypoglycemia, in patients with chronic lung disease (such as asthma or COPD) because of the risk of acute bronchospasm, and in patients with previous severe hypersensitivity reaction to any regular human insulin product or any of the inactive ingredients in AFREZZA. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with AFREZZA.

Warnings and Precautions

Acute Bronchospasm in Patients with Chronic Lung Disease: In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following AFREZZA dosing was reported. Before initiating therapy, evaluate all patients with a medical history, physical examination, and spirometry (FEV1) to identify potential underlying lung disease. Do not use in patients with chronic lung disease such as asthma or COPD.

Hypoglycemia or Hyperglycemia with Changes in Insulin Regimen: Changes in an insulin regimen (e.g., insulin strength, manufacturer, injection site or type, or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. If clinically indicated, make any necessary changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. For patients with type 2 diabetes dosage modification of concomitant oral antidiabetic treatment may be needed.

Hypoglycemia: Hypoglycemia is the most common adverse reaction associated with insulins, including AFREZZA. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ across patients and change over time in the same patient. Advise patients to recognize and manage hypoglycemia and self-monitor glucose. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of glucose monitoring is recommended.

Decline in Pulmonary Function: AFREZZA causes a decline in lung pulmonary function over time as measured by FEV1. In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, AFREZZA-treated patients experienced a small (40 mL) but greater FEV1 decline than comparator-treated patients. Assess pulmonary function with spirometry at baseline, after the first 6 months of therapy and annually thereafter even in the absence of pulmonary symptoms. In patients who have a decline of ≥20% in FEV1 from baseline, consider discontinuing AFREZZA. Consider more frequent lung function assessment in patients with pulmonary symptoms, e.g., wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough. If symptoms persist, discontinue AFREZZA.

Lung Cancer: In clinical trials, 2 cases of lung cancer were observed in patients exposed to AFREZZA while no cases were reported for the comparators. In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer. Two additional cases of lung cancer (squamous cell and lung blastoma) were reported in non-smokers exposed to AFREZZA after the trial completion. These data are insufficient to determine whether AFREZZA has an effect on lung or respiratory tract tumors. In patients with active lung cancer, a prior history of lung cancer, or in patients at risk of lung cancer, consider whether the benefits of AFREZZA use outweigh this potential risk.

Diabetic Ketoacidosis (DKA): In clinical trials enrolling patients with type 1 diabetes, diabetic ketoacidosis (DKA) was more common in AFREZZA-treated patients (0.43%; n=13) than in comparator-treated patients (0.14%; n=3). Patients with type 1 diabetes should always use AFREZZA concomitantly with basal insulin. In patients at risk for DKA, such as those with an acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing AFREZZA and giving insulin using an alternate route of administration.

Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products. If hypersensitivity reactions occur, discontinue AFREZZA, treat per standard of care and monitor until symptoms and signs resolve.

Hypokalemia: All insulin products, including AFREZZA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Closely monitor potassium levels in patients at risk of hypokalemia and treat if indicated.

Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Observe these patients for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the TZD should be considered.

Adverse Reactions

The most common adverse reactions associated with AFREZZA are hypoglycemia, cough, and throat pain or irritation.

Drug Interactions

Certain drugs may affect glucose metabolism, increasing the risk of hypoglycemia, or decreasing or increasing the blood glucose lowering effect of AFREZZA. Dosage modification and increased frequency of blood glucose monitoring may be required. Co-administration of beta-blockers, clonidine, guanethidine, and reserpine with AFREZZA may reduce the signs and symptoms of hypoglycemia. For full list, see Prescribing Information.

To report SUSPECTED ADVERSE REACTIONS, contact MannKind Corporation at 1-877-323-8505 or FDA at www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088).

Please see full Prescribing Information, including BOXED WARNING for AFREZZA.