Technosphere Insulin Research Articles

Inhaled Technosphere Insulin for Individualized Diabetes Management: 3 Case Reports of CGM Outcomes

Inhaled Technosphere Insulin for Individualized Diabetes Management: 3 Case Reports of CGM Outcomes

Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P < 0.001; I2 = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P < 0.001; I2 = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P < 0.001; I2 = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P = 0.019; I2 = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P < 0.001; I2 = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.

Prandial Insulins: A Person-Centered Choice.

Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes.

1805-PUB: Results of a Two-Part Feasibility Study Assessing Inhaled Insulin for Meals with MDI or Automated Insulin Delivery (AID) Compared with Standard AID Therapy

Background: Technosphere Insulin (TI) is an ultra-rapid acting inhaled insulin and when used with basal insulin may be a safe and effective alternative to AID systems in type 1 diabetes. Methods: During study part 1, subjects using an AID were given an in-clinic standardized meal with either all meal insulin as TI (n=21) at meal start or rapid-acting insulin given via an AID (n=5) 15 minutes prior. Capillary glucose was measured at intervals for 2 hours. During study part 2, HbA1c was compared for 3 groups at baseline and 90 days: AID control (n=5), TI+AID (TI for meals only; n=9), or TI+insulin degludec (TI for meals and corrections, degludec for daily basal; n=10). Results: The figure shows in study part 1, TI led to significantly lower post-prandial glucose than AID control for the standardized meal. In study part 2, comparable HbA1c reduction from baseline was observed in all 3 groups. No events of severe hypoglycemia and one episode of diabetic ketoacidosis not related to TI per investigator were reported. Conclusion: This initial evaluation indicates that 1) TI had a more favorable glycemic response for 2 hours after the meal compared to AID control, and 2) HbA1c baseline to 90 days was comparable for the AID and the TI arms without serious safety issues. Adding TI for meals or switching to TI and basal insulin may provide comparable safety and efficacy to AID alone. Disclosure K.Kaiserman: Employee; MannKind Corporation, Research Support; Medtronic, Stock/Shareholder; MannKind Corporation. J.Ulloa: Employee; MannKind Corporation. J.Pleitez: Employee; MannKind Corporation. J.Sylvan: Employee; MannKind Corporation. K.Codorniz: Research Support; Medtronic, MannKind Corporation. S.Lee: Consultant; MannKind Corporation. C.Jacobson: Advisory Panel; MannKind Corporation, Medtronic. T.Blevins: Other Relationship; Medtronic, Research Support; Lilly Diabetes, Novo Nordisk, Dexcom, Inc., Abbott Diabetes, Tandem Diabetes Care, Inc., Medtronic, Speaker's Bureau; Lilly Diabetes, Novo Nordisk A/S.

Time-Action Profile of Technosphere Insulin in Children with Type1 Diabetes.

Technosphere insulin (TI) is aninhaled dry powder ultra-rapid-acting insulin. This report describes the results of the first study of TI in children with type1 diabetes (T1D). Pharmacokinetics (PK) of TI and the effect of TI on circulating glucose concentrations were evaluated in a single-arm study that enrolled children ages 8-17years with T1D for more than 1year, on a stable multiple daily insulin injection (MDI) regimen, and meeting pre-defined pulmonary function testing criteria (at least 70% predicted). To assess PK, subjects received an individualized single preprandial dose of TI (4-12U, in 4-U increments) via oral inhalation, basedon their usual meal-time subcutaneously injected rapid-acting insulin dose and meal content. Serum insulin and blood glucose were measured at -30 to 250min relative to dosing. Twenty-seven children with T1D participated in this single-dose PK study. Mean subject age was 13.3years (59% female; 81.5% White). Meanserum insulin Cmax (maximum concentration) was 77.3, 119.15, and 207.7µU/mL for doses of 4, 8, and 12U, respectively. Tmax occurred at 10.5, 13.9, and 14.6min post-dose for 4, 8, and 12U.Glucose lowering 30-60min post-dose was consistent with the PK profile. Serum insulin rapidly increased post-dose and returned to baseline by 120min. The data suggests the PK of TI in youth with T1D ages 8-17years was similar to that seen in previous adult studies. ClinicalTrials.gov identifier, NCT02527265.

Reduction in Postprandial Peak Glucose With Increased Technosphere Insulin Dosage.

Technosphere Insulin (TI) is an ultra-rapid-acting inhaled insulin. This study assessed the mean peak two-hour postprandial glucose concentration with the initial TI dose (dose 1) calculated per the current label (United State Prescribing Information) compared with a ~2× higher dose (dose 2). Secondary objectives were to evaluate hypoglycemia within the two-hour postprandial period, evaluate change in forced expiratory volume in one second (FEV1) before and after the two-hour postprandial period, and monitor for other adverse events. Twenty patients with diabetes, on basal-bolus insulin therapy, received an initial dose 1 of TI followed by the higher dose 2, one to three days later. Subjects received an identical meal for both visits, and TI doses were administered immediately prior to the meal. The higher dose 2 provided significant reductions in mean postprandial glucose excursion (PPGE) in the two-hour postprandial period starting from 45 minutes (P = .008) to 120 minutes (P < .0001). Mean peak glucose was reduced from 228.6 to 179.3 mg/dL (P < .001) at two hours. Two hypoglycemic events (one level 1, one level 2) were observed in a single subject during the two-hour postprandial period with dose 2. There were no significant changes in FEV1 after either dose of TI. The higher dose 2 reduced PPGE versus the current label recommended dose 1 within the two-hour postprandial timeframe without any new safety concerns. When confirmed with a larger study, this higher TI dosing recommendation may help patients and clinicians minimize immediate postprandial hyperglycemia when titrating TI for prandial glucose control.

1496-PUB: Augmenting Clinical Trial Data with In-Silico Evidence to Evaluate Initial Conversion Dose Changes for Technosphere Insulin (TI)

Background: TI is an inhaled mealtime insulin with ultra-rapid onset and short duration of action closely mimicking physiologic insulin. Clinical studies demonstrated a higher initial dose could result in faster titration to overcome a perceived lack of effect. The aim was to develop an in silico model to augment results of a study (NCT04849845) evaluating an increased initial conversion of TI from injected insulin vs. the current label in 20 adults with diabetes that showed significantly improved post-prandial control after 45 minutes. Methods: The in silico model characterizes blood glucose trends and outcomes utilizing published equations and distributions derived from real-world data sources. Inputs with the largest effects on glucose outcomes were combined to match study parameters to generate one million meal boluses. The model was validated using common modeling and simulation recommendations. Results: Model inputs were constrained to match clinical study parameters; in silico results substantiated and complemented in vivo safety and efficacy results with similar predictive values and acceptable hypoglycemia distributions. Conclusions: Clinical data augmented by in silico data support that an increased initial dose is not associated with any new safety concerns. Leveraging in silico data generates high quality evidence faster and with less risk to patients. Disclosure L.Desborough: Consultant; Luna, MannKind Corporation, Roche Diabetes Care, Securecell AG, Tandem Diabetes Care, Inc., Employee; Nudge BG, Inc. K.B.Kaiserman: Advisory Panel; Medtronic, Consultant; Medtronic, Employee; MannKind Corporation, Research Support; Medtronic, Speaker's Bureau; Medtronic, Stock/Shareholder; MannKind Corporation. J.Hanna: Employee; MannKind Corporation, Medtronic. K.Jaffe: None. J.Ulloa: Employee; MannKind Corporation, Medtronic, Stock/Shareholder; MannKind Corporation, Medtronic.

Comparison of Pharmacokinetics and Pharmacodynamics of Inhaled Technosphere Insulin and Subcutaneous Insulin Lispro in the Treatment of Type 1 Diabetes Mellitus.

BackgroundThis study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses.ObjectivesThis single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus.MethodsEach volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles.ResultsInsulin exposure was more than dose proportional, increasing with dose1.08 for LIS and dose1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect.ConclusionsTechnosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate.Clinical Trial RegistrationClinicalTrials.gov, NCT02470637; 12 June, 2015Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01084-0.

923-P: Tolerability and Time-Action Profile of Technosphere Insulin in Pediatric Subjects

Introduction: Technosphere Insulin (TI) is an inhaled ultra-rapid-acting dry powder prandial insulin. Reported are the results of the first study of TI in pediatric patients. Methods: PK/PD and safety of TI was evaluated in a single-arm, 4-week study in 30, 8-17 years old subjects with T1DM on a stable MDI regimen, meeting pre-defined pulmonary function testing criteria. On day 1, subjects received an individualized single prandial dose of TI (4-16 U, in 4U increments) based on their usual meal-time dose and meal content. Serum insulin and blood glucose were measured -30 to 250 minutes relative to dosing. Over the next 4 weeks, each subject’s dose of TI was titrated, targeting a 120-150 minute post-prandial glucose level of 110-180 mg/dL. Safety and tolerability were assessed over the course of the study. Severe hypoglycemia was defined as an event associated with coma, loss of consciousness, or seizure. Results: Mean age of subjects was 12.7 years (60% Female; 83.3% White). Serum insulin rapidly increased post-dose and returned to baseline by 120 minutes. Mean serum insulin Cmax was 77.3 µU/ml, 119.15 µU/ml, 101.29 µU/ml and 104.86 µU/ml for doses of 4, 8, 12 and 16U respectively. Tmax occurred at 10.5, 13.9, 14.6, and 20.0 minutes post-dose for 4, 8, 12 and 16U respectively. Glucose lowering during 30-60 minutes post-dose was consistent with the PK profile. Over 4 weeks of study, 23 subjects (76.7%) reported 41 TEAEs. One subject had an SAE of diabetic ketoacidosis that was considered possibly related to TI. The most common AEs were hypoglycemia (none severe) and cough. No subjects had a clinically relevant decline in pulmonary function. Conclusion: Inhaled TI demonstrated an ultra-rapid time-action profile similar to that observed in adults. These data suggest TI can be safely administered to children and adolescents ages 8-17 with T1DM. Disclosure M. C. Jones: Employee; Self; MannKind Corporation, Stock/Shareholder; Self; MannKind Corporation. M. J. Haller: Board Member; Self; SAB Biotherapeutics, Inc., Consultant; Self; MannKind Corporation, Other Relationship; Self; Janssen Pharmaceuticals, Inc., Sanofi. S. E. Ng: Employee; Self; MannKind Corporation. S. Bhavsar: Employee; Self; MannKind Corporation. K. B. Kaiserman: Advisory Panel; Self; Medtronic, Consultant; Self; Medtronic, Employee; Self; MannKind Corporation, Research Support; Self; Medtronic, Speaker’s Bureau; Self; Medtronic, Stock/Shareholder; Self; MannKind Corporation. J. A. Krueger: Employee; Self; MannKind Corporation, Stock/Shareholder; Self; Eli Lilly and Company. Funding MannKind Corporation

722-P: Inhaled Insulin Improves Daytime Time-in-Range in People with Type 2 Diabetes

Background and Aims: Technosphere Insulin (TI), an inhaled insulin with ultra-rapid onset and short duration of action that more closely mimics physiologic insulin, may improve patient outcomes. To address the challenge of prandial control of glucose in type 2 diabetes (T2D), this study aimed to determine real-world dosing requirements, safety, and efficacy of TI in patients with uncontrolled T2D. Methods: Twenty patients with T2D inadequately controlled with oral/injectable combination therapy excluding prandial insulin in a real-world setting with TI added to current therapy. Dosing started at 4 units of TI per meal and increased up to 12 units per meal over a week and then titrated weekly based on postprandial SMBG. HbA1c and CGM profiles were collected at baseline and 12 weeks. Results: Nineteen patients completed the study with baseline and treatment CGM data. For the daytime period (6:00-24:00), there were significant decreases in mean CGM values, significant decreases in time spent in hyperglycemia, and significant increases in time-in-range without a significant increase in hypoglycemia. Conclusions: Addition of TI in patients with uncontrolled type 2 diabetes results in a significant increase in daytime CGM time-in-range (from 38.7% to 62.1%, a mean of over 4 hours of increased daytime time-in-range per day) without an increase in hypoglycemia and a significant reduction in both Level 1 and Level 2 hyperglycemia. Disclosure L. Desborough: Consultant; Self; Diabetes & Glandular Disease Clinic, Diasome Pharmaceuticals, Inc., Luna Health, MODEL Clinical Research, Roche Diabetes Care, Securecell AG, Tandem Diabetes Care, Tidepool. P. Levin: Research Support; Self; MannKind Corporation, Mylan N. V., Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Sanofi. L. A. Bromberger: None.

Results of a 24-Week Trial of Technosphere Insulin Versus Insulin Aspart in Type 2 Diabetes

ObjectiveTo compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes. MethodsThis randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses. ResultsIn the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m2, weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant. ConclusionBoth TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes.

Ultra Rapid-Acting Inhaled Insulin Improves Glucose Control in Patients With Type 2 Diabetes Mellitus

ObjectiveTo determine whether the use of an inhaled insulin would improve HbA1c. MethodsThis study was performed in 20 type 2 diabetes mellitus (T2DM) participants with HbA1c values ≥7.5 (58) to ≤11.5% (102 mmol/mol) on a variety of glucose-lowering regimens. Prandial Technosphere insulin (TI) was rapidly titrated based on a treatment algorithm using postprandial blood glucose to calculate premeal doses. A 2-week baseline period was followed by 12 weeks of active treatment with TI. The primary outcome was change in HbA1c. Secondary outcomes included glucose time in range (time in range: 70-180 mg/dL) obtained by a blinded continuous glucose monitoring during the baseline period and at the end of 12 weeks. Goals were to assess how to rapidly and safely initiate TI intensification, determine dosing requirements, and establish an effective dose range in uncontrolled T2DM. ResultsMean HbA1c decreased by −1.6% (−17 mmol/mol) from 9.0% (75 mmol/mol) at baseline to 7.4% (57 mmol/mol) at 12 weeks (P < .0001). Mean time in range increased from 42.2% to 65.7% (P < .0002). Mean prandial doses of TI were 18 or 19 units for all meals. Time below range was 1.1% baseline and 2.6% post treatment (P = .01). ConclusionTreatment with inhaled TI dosed using a simple algorithm improved glycemic control measured by both HbA1c and time in range, with low rates of hypoglycemia. These data add significantly to understanding TI in the management of T2DM patients for whom prandial insulin is a consideration.

Long-Term Nonclinical Pulmonary Safety Assessment of Afrezza, a Novel Insulin Inhalation Powder.

Afrezza delivers inhaled insulin using the Gen2 inhaler for the treatment of patients with type 1 and type 2 Diabetes. Afrezza was evaluated in long-term nonclinical pulmonary safety studies in 2 toxicology species. Chronic inhalation toxicology studies in rat (26 weeks) and dog (39 weeks) and an inhalation carcinogenicity study in rats were conducted with Technosphere insulin (Afrezza) and with Technosphere alone as a vehicle control. Respiratory tract tissues were evaluated by histopathology and cells expressing proliferating cell nuclear antigen (PCNA) were quantified in lungs of rats. Microscopic findings in rats exposed to Afrezza were attributed to the Technosphere particle component, were confined to nasal epithelia, and consisted of eosinophilic globules and nasal epithelial degeneration. There were no Afrezza-related changes in pulmonary PCNA labeling indices in alveoli, large bronchioles, or terminal bronchioles. Microscopic findings in rats exposed to Technosphere particles included eosinophilic globules, mucus cell hyperplasia, and epithelial degeneration in the nasal cavities. PCNA labeling indices were increased in large bronchioles and terminal bronchioles but not in alveoli. There were no Technosphere particle-related findings in the dog study. Afrezza did not exhibit carcinogenic potential in the 2-year study in rats. These nonclinical inhalation studies support the use of Afrezza in humans over extended periods.

Understanding inhaled Technosphere Insulin: Results of an early randomized trial in type 1 diabetes mellitus.

Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action. Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation. The primary efficacy endpoint was a noninferiority of glycosylated hemoglobin (HbA1c) of 0.4% for TI compared with insulin lispro (LIS) in a 16-week phase 3 randomized clinical trial in type 1 diabetes mellitus. HbA1c values were similar in the TI and LIS groups at the beginning of the trial (7.8% and 7.6%, respectively) and at trial endpoint (7.7% and 7.6%, respectively). Least squares mean changes from baseline were similar between study groups. Glucose values after a standard meal were significantly lower with TI in the first 90 minutes post meal compared with LIS. Mild or moderate hypoglycemia event rates were also significantly lower with TI compared with LIS (5.97 vs 8.01, respectively; P = .0269). Cough was the most commonly reported adverse event with TI. Pulmonary function as measured by forced expiratory volume in 1 second was not different between groups at baseline, 16 weeks, or 4 weeks off study drug. HbA1c was unchanged and overall glucose control was comparable between groups. Treatment with TI resulted in improved post-meal glucose and a lower risk of hypoglycemia compared with LIS.

Comprehensive Pulmonary Safety Review of Inhaled Technosphere® Insulin in Patients with Diabetes Mellitus.

Background and ObjectiveTechnosphere® Insulin (TI), a human insulin powder for inhalation (Afrezza®; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety.MethodsPooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients.ResultsAmong 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images.ConclusionsPulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM.Electronic supplementary materialThe online version of this article (10.1007/s40261-020-00958-8) contains supplementary material, which is available to authorized users.

1024-P: Technosphere Insulin Added to Basal Insulin Is Associated with Less Weight Gain than Basal Insulin plus Insulin Aspart or Insulin Analog (Aspart) 70/30 Mixture in Type 2 DM

Technosphere Insulin (TI) is a dry-powder formulation of recombinant human insulin adsorbed onto Technosphere microparticles for oral inhalation. Data from two 52-wk randomized phase 3 trials in type 2 DM were combined to analyze the effects of TI on body weight. In one trial, patients on basal insulin were randomized to prandial TI or insulin aspart. In the other trial, basal insulin plus prandial TI was compared to 70/30 insulin analog mixture. Primary efficacy end point in each trial was change in A1C. Weight data were captured in each study. Weight and A1C data were analyzed based on modified Intention to Treat Analyses and LS mean changes from baseline. In these analyses, the TI arms were combined and comparisons were made between TI and each of the comparator arms. Aspart and 70/30 arms were not compared to each other. Data for 26 and 52 wk time points are reported. Results At both 26 and 52 weeks, TI was associated with less weight gain than either aspart or premixed insulin. Differences were significant for TI vs. each comparator. A1C differences among treatment arms were small and only statistically significant for TI vs. aspart at 52 weeks. Conclusion: In insulin treated T2DM persons, TI is associated with less weight gain than Insulin aspart or premixed 70/30 analog insulin. These weight differences appear to be independent of changes in A1C. Disclosure J. Manoukian: Employee; Self; MannKind Corporation. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

1023-P: Dose Titration and Clinical Effects of Inhaled Technosphere Insulin Compared with Mealtime Subcutaneous (SC) Analog Insulin Therapy in Type 1 Diabetes (T1D)

Insulin dosing has been a clinical challenge since the introduction of “islet extract” in the 1920’s. Route of administration, insulin preparation and peptide modifications alter clinical effects. With newer insulins, patients and clinicians must clearly understand effective dosing. Technosphere Insulin (TI) is a dry-powder formulation of recombinant human insulin adsorbed onto Technosphere microparticles administered by pulmonary inhalation. TI cartridges are labeled as insulin “units” (4, 8, 12 unit cartridges). With proper dose titration, TI achieves comparable glucose control, improves mealtime glucose, and lowers hypoglycemia risk vs. insulin analogs in T1D. Methods: These analyses compare doses of TI achieved after active titration in 4 randomized trials in individuals with T1D. The ratio of TI inhalation units (based on labeled cartridge content) to SC prandial analog in the comparator group was calculated for each trial at study endpoint. Results: Conclusion: The current analyses across 4 unique studies support the titration of individual patients to TI doses that are approximately 1.3 - 2.5x those of their comparable SC analog insulin doses. These data show that greater “unit doses” of TI should be used to achieve glycemic control in T1D and thus, insulins should be dosed based on glycemic responses rather than “insulin units.” Disclosure D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. J. Manoukian: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. M. Jones: Employee; Self; MannKind Corporation. R. Abaniel: None. P.M. Morey: Employee; Self; MannKind Corporation. M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

235-OR: Incidence of Significant Changes in Pulmonary Function during a 2-Year Study with Inhaled Technosphere Insulin

The impact of inhaled Technosphere Insulin (TI) on measures of pulmonary function remain an important component of clinical use. TI is an ultra rapid-acting prandial insulin delivered via deep pulmonary inhalation allowing for prompt absorption in the alveoli. Prior studies have demonstrated that, on average, changes in pulmonary function testing (PFT) are limited to small changes (∼1%) in forced expiratory volume in 1 second (FEV1). This comprehensive post-hoc analysis examined the incidence of significant decline in FEV1 over two years in subjects with type 1 and type 2 diabetes treated with TI. Subjects were included if they had at least five FEV1 measurements (including baseline and month 24). FEV1 must have been ≥70% of predicted at baseline. At each time point, subjects were classified as having a significant change in FEV1 if there was a ≥15% decline from baseline. Of the 377 subjects, 331 (87.8%) had no measure with ≥15% decline in FEV1 at any time point. Of subjects who had at least one measure with a decline of ≥15%, the majority (n=38) experienced this decline on a transient basis (defined as occurring at two or fewer time points). Eight individuals (2.1%) demonstrated a persistent decline in FEV1 (occurring at three or more time points). Four subjects in the comparator arm (0.7%, n=586) had persistent decline. In conclusion, persistent significant decline in FEV1 during the use of TI was uncommon. Disclosure M.C. Jones: Employee; Self; MannKind Corporation. T.S. Tran: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company.

Technosphere Insulin-Induced Pulmonary Infiltrate.

Technosphere Insulin-Induced Pulmonary Infiltrate.

151-OR: Technosphere Insulin Provides Better Early Postprandial Glucose Control than Subcutaneous Rapid-Acting Analog

In a recent study (STAT, NCT03143816), patients with type 1 diabetes mellitus (T1DM) treated with Technosphere Insulin (TI) demonstrated better early postprandial glucose (PPG) control than those on subcutaneous (SC) insulin aspart. The average daily dose of TI in patients who took TI as directed in the protocol was twice that of aspart (40.5 vs. 20.6 units). Despite the higher dose, the TI group experienced less time in hypoglycemia than the aspart group. These results prompted a retrospective analysis of mixed-meal tolerance tests (MMTTs) conducted in T1DM to further evaluate the 2:1 dosing ratio. In study MKC-TI-009 (NCT00308308), patients with T1DM underwent 1 to 3 MMTTs. A total of 1326 PPG profiles were evaluable: 674 MMTTs from 261 patients on SC aspart and 652 MMTTs from 264 patients on TI. On average, the area under the PPG excursion curve (PPGE AUC) decreased with increasing dose, and the mean (SE) ratio of the aspart slope to the TI slope was 2.1 (0.3), consistent with the results of STAT. This was confirmed when doses of TI 8, 16, and 24 units were compared with mean (SE) aspart doses of 4 (1), 8 (1), and 12 (1) units, respectively (Figure). The PPGE curves confirm the earlier onset and shorter duration of TI, while the tendency to drop below baseline in the late postprandial period reflects the longer duration of action of SC aspart. The timing of hypoglycemia (levels 1 and 2) follows the pattern of PPGEs. Disclosure M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Amgen Inc., MannKind Corporation. G. Sharma: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; Eli Lilly and Company, MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Spouse/Partner; Amgen Inc. Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. N. Zaveri: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Becton, Dickinson and Company. Funding MannKind Corporation