1. Afrezza® – inhaled human insulin
Manufacturer: MannKind Corporation
FDA Approval Date: June 27, 2014

2. Afrezza® – inhaled human insulin Clinical Application
Indications:
A rapid-acting, pre-meal time insulin for Type 1 and 2 diabetics.
Place in therapy:
An inhaled alternative to vial and syringe for meal-time insulins. Type 1 diabetics must use in combination with long-acting agent.

3. Afrezza® – inhaled human insulin Clinical Application
Contraindications:
During episodes of hypoglycemia
In patients who have chronic lung disease

4. Afrezza® – inhaled human insulin Clinical Application
Warnings and Precautions
Use with caution for patients who have recently (<6 months) stopped smoking
Decline in pulmonary function observed over time
Incidence of lung cancer was observed in controlled and uncontrolled trials
More patients using inhaled insulin experienced ketoacidosis
Life-threatening hypokalemia

5. Afrezza® – inhaled human insulin Clinical Application
Black Block Warning
Acute bronchospams reported in patients with asthma and COPD using inhaled insulin.
REMS established to ensure benefits outweigh risk
Contraindictation in patients with chronic lung disease
Before initiating Afrezza all patients need detailed medical history, PE and spirometry to identify potential lung disease

6. Afrezza® – inhaled human insulin Clinical Application
Pregnancy:
Category C
Lactation:
Excretion in breast milk unknown; use is not recommended

7. Afrezza® – inhaled human insulin Drug Facts
Pharmaceutics:
Combination drug-devices product
Human insulin produced by recombinant DNA technology
Insulin dissolved into carrier particles
Dry powder in packed in cartridges and dispersed through an inhaler

8. Afrezza® – inhaled human insulin Drug Facts
Pharmacology:
Recombinant regular human insulin lowers blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle fat and inhibiting hepatic glucose production.

9. Afrezza® – inhaled human insulin Drug Facts
Pharmacokinetics A
Tmax minutes
F= 37% compared to subcutaneously administered regular human insulin
Duration: minutes D
Vd = L/kg M
Same as endogenous insulin E
Any swallowed human insulin is eliminated unchanged in feces
Eliminated in 180 minutes

10. Afrezza® – inhaled human insulin Drug Interactions
Drug Interactions – Precipitant Drugs:
None
Drug Interactions – Object Drugs:
The hypoglycemic effect of Afrezza may be altered when used in combination with other drugs. These are pharmacodyamic effects.
Corticosteriods 
Diuretics 
Estrogens 
Niacin 
Oral contraceptives 
Ethanol 
Beta-blockers 
Clonidine 

11. Afrezza® – inhaled human insulin Adverse Effects
Afrezza vs. Placebo vs. Non-placebo
In type 2 DM patients
Afrezza vs Subcutaneous insulin
In Type 1 DM patients
Hypoglycemia: 67% (30%)
Cough: 29.4% [4.9%]
Cough: 25.6% (19.7%) [5.4%]
Throat pain/irritation: 5.5% [1.9%]
Throat pain or irritation: 4.4% (3.8%) [0.9%]
Headache: 4.7% [2.8%]
Severe hypoglycemia: 5.1% (1.7%)
Bronchitis: 2.5% [2.0%]
Headache: 3.1% (2.8%) [1.8%]
Urinary tract infection: 2.3% [1.9%]
FEV1 decline >15%: 6% [3%]

12. Afrezza® – inhaled human insulin Monitoring Parameters
Efficacy Monitoring:
Blood glucose, A1c
Toxicity Monitoring:
Pulmonary function tests before initiating, after 6 months of therapy and annually, even in absence of pulmonary symptoms.
Fluid retention and heart failure with concomitant use of thiazolidinediones
Hypokalemia

13. Afrezza® - inhaled human insulin Prescription Information
Dosing:
Insulin naïve patients: 4 units, titrate to blood glucose
Conversion chart available for patients currently using insulin
Dosing adjustments based on response
Cost:
Unknown
Comes to market early 2015

14. Afrezza® – inhaled human insulin Literature Review
Open-label, active-controlled, non- inferiority on Type 1 diabetics
Combination with basal insulin Afrezza or insulin aspart at every meal for 24 weeks. Titrated to glycemic goals.
52 week trial also looked at efficacy and safety of Afrezza vs. RAA
MannKind Corporation. FDA Briefing Document

15. Afrezza® – inhaled human insulin Literature Review
Primary endpoint
Absolute change in A1c from baseline to week 24
Secondary Endpoints
FPG
7-point glucose
Weight
Hypoglycemia
MannKind Corporation. FDA Briefing Document

16. Afrezza® – inhaled human insulin Literature Review
Parameter
Afrezza
Placebo
Age
37.0 (12.42)
39.1 (12.63)
Race
Caucasian (94.3%)
Caucasian (97.6%)
Sex
Male (44.3%)
Male (43.5%)
Weight
75.7 (15.75)
72.6 (15.28)
A1c
8.0 (0.77)
7.9 (0.75)
FPG
155.0 (67.62)
151.2 (67.43)
74.7% completed in the Afrezza group vs 88.8% of placebo
Withdrawl attributed to hyperglycemia (5); other adverse events (16); subject withdrew consent (17) and 1 lost to follow up
MannKind Corporation. FDA Briefing Document

17. Afrezza® – inhaled human insulin Literature Review
Intervention
A1c Goal Attainment
FPG
Weight
24 week Afrezza vs RAA
Afrezza + basal insulin
Goal %
(7.624) mg/dL
-0.39 (0.438) kg
p=0.4955
< 7.0%
18.3%
<6.5%
7.6%
RAA+ basal insulin
10.15 (7.396) mg/dL
0.93 (0.441) kg
p=0.0079
30.7%
12.7%
52 week Afrezza vs RAA
-35.5 (3.33)
mg/dL
-0.5 (0.32) kg
p=0.0009
< 8.0
51%
16.3%
7.4%
-20.6 (3.24)
1.4 (0.30) kg
56.2%
16%
7.3%
Afrezza relative to RAA – no significant difference. Determined non-inferior
Week 52 HbA1c  8.0%: Odds ratio = 0.658; 95% CI: (0.421, 1.028); p =
Week 52 HbA1c  7.0%: Odds ratio = 0.941; 95% CI: (0.536, 1.652); p =
Week 52 HbA1c  6.5%: Odds ratio = 0.942; 95% CI: (0.435, 2.039); p =
MannKind Corporation. FDA Briefing Document

18. Afrezza® – inhaled human insulin Literature Review
Open-label, active-controlled, non- inferiority on Type 2 diabetics
Combination with OAD or basal insulin
Two part trial
Afrezza vs inhaled placebo for 24 weeks
Afrezza vs BPR 70/30
MannKind Corporation. FDA Briefing Document

19. Afrezza® – inhaled human insulin Literature Review
Primary endpoint
Absolute change in A1c from baseline to week 24 or to week 52
Secondary endpoints
A1c goal attainment
Fasting Plasma Glucose
Weight
MannKind Corporation. FDA Briefing Document

20. Afrezza® – inhaled human insulin Literature Review
Parameter
Afrezza
Placebo
70/30
Age
56.7 (9.10)
56.7 (8.51)
55.9 (10.61)
55.9 (9.98)
Race
Caucasian (85.3%)
Caucasian (88.1%)
Caucasian (66.9)
Caucasian (68.0)
Sex
Male (46.3%)
Male (42%)
Male (50.7)
Male (43.4)
Weight
90.2 (17.22)
90.8 (17.34)
88.3 (17.39(
85.8 (17.96)
A1c
8.3 (0.68)
8.4 (0.78)
8.7 (1.12)
8.7 (1.08)
FPG
179.1 (43.72)
177.2 (46.40)
169.3 (65.78)
176.7 (67.35)
Required an A1c >7.5 to be included after nutritional and physical activity counseling
84.7; 64.7% completed in the Afrezza group vs 79;71.7% of placebo
Withdrawl attributed to hyperglycemia (1; 14); other adverse events (7;32); subject withdrew consent (8; 37) and lost to follow up (6;6)
MannKind Corporation. FDA Briefing Document

21. Afrezza® – inhaled human insulin Literature Review
Intervention
HbA1c Goal Attainment
FPG
Weight
24 week Afrezza vs inhaled placebo
Afrezza + OAD
Goal %
(3.776) mg/dL
0.49 (0.333) kg
p=0.0060
< 7.0%
37.7%
<6.5%
15.9%
Placebo +OAD
-3.78 (3.864)
mg/dL
-1.13 (0.347) kg
p=0.0001
19.0%
4.2%
52 week Afrezza vs. 70/30
Afrezza + basal
-26.7 (2.69)
0.9 (0.32) kg
P=0.0056
<8.0%
56.8%
22.1% 8%
BPR 70/30
-12.9 (2.56)
2.5 (0.29) kg
P<0.0001
60.9%
26.8%
12.4%
Significant difference when compared to placebo for reaching A1c goals and when compared to 70/30 in terms of FPG and changes in weight
Non-significance when compared to inhaled placebo in terms of FPG and when compared to 70/30 in A1c goals.
Vs. 70/30
TI relative to Comparator:
Week 52 HbA1c  8.0%: Odds ratio = 0.862; 95% CI: (0.580, 1.282); p =
Week 52 HbA1c  7.0%: Odds ratio = 0.774; 95% CI: (0.486, 1.231); p =
Week 52 HbA1c  6.5%: Odds ratio = 0.608; 95% CI: (0.318, 1.163); p =
Treatment difference (TI – Comparator) Adjusted mean change (SE): (3.58) mg/dL; 95% CI: (-20.8, -6.7);
p =
Treatment difference (TI – Comparator) Adjusted mean change (SE): –1.6 (0.41) kg; 95% CI: (-2.4 ,-0.7);
p =
MannKind Corporation. FDA Briefing Document

22. Afrezza® – inhaled human insulin Literature Review
Hypoglycemia
Type
Intervention
% (severe)
Type 1 DM
Afrezza
96%; 95% mild
RAA
99%
Less in Afrezza (OR=0.488 p=0.0124)
Type 2 DM
Afrezza + OAD
67.8% (5.1%)
Placebo + OAD
30.7 %
47.99% (4.33%)
70/30 + OAD
68.88 % (9.97%)
Hypoglycemia (mild) is a FBG level <70 mg/dl that was corrected with food
Severe hypoglycemia is FBG level <36
Hypoglycemia
For type 1 DM - 96% vs 99% when compared
95.4% mild with 24% experience a severe event
Afrezza saw 44.3% lower incidence of hypoglycemia when compared to aspart
67.8% vs 30.7% in type 2 DM
5.1% severe
47.99% vs 68.88%
4.33% vs 9.97% severe
MannKind Corporation. FDA Briefing Document

23. Afrezza® – inhaled human insulin Conclusions
In Type 1 DM, Afrezza was found non-inferior to RAA. There was a change in A1c in 24- week trial.
In Type 2 DM, Afrezza was found non-inferior to placebo and 70/30, with a -0.74% change in A1c in a 52-week trial
Hypoglycemia occurred less in Afrezza when compared to all other interventions
Afrezza patients saw less weight gain
Afrezza patients saw greater decrease in FBG
MannKind Corporation. FDA Briefing Document

24. Afrezza® – inhaled human insulin Summary
Afrezza is a dry powder human oral insulin inhaler.
Indicated for pre-meal time, rapid insulin delivery for type 1 and type 2 diabetics. Must be used in combination with long-acting agent for patients with type 1-diabetes.
Afrezza should be avoided in smokers, patients with chronic pulmonary and patients with increased risk of lung cancer.
Afrezza has a tmax of minutes and a duration of minutes.
Afrezza comes in 4-unit and 8-unit dose packs and cartridges.
Common side effects include hypoglycemia, cough, throat irritation/pain and a decline in FEV1

25. Afrezza® – inhaled human insulin References
Afrezza package insert. MannKind Corporation. June 2014.
Regular human insulin. Lexicomp Drug Information. Accessed through UpToDate. Accessed on Aug. 20, 2014.
Neumiller J, et al. A Review of Inhaled Technosphere Insulin. Annals of Pharmacotherapy 2010, July/August Volume 44.
Briefing Document for the Endocrinologic and Metabolic Drug Advisory Committee, FDA. MannKind Corporation. April 1, Accessed by fda.gov. Accessed on Aug 20,