1. Afrezza®: Inhaled insulin approved by the FDA
Regulatory Seminar
AREIPS
March 2015
Cécile CAMINADE
Malika CUMZAIN
Anne-Charlotte DUBUS
Clémence GOUY
Cécile ROSELMAC
Louise TOURNOYS

3. Table of Contents Introduction - Context Approval of Afrezza® REMS
Diabetes
REMS
Types of insulin
Sanofi & MannKind Partnership
Insulin therapy : unmeet needs and non-adherence
Markets
History of the Inhaled Insulin & Exubera®
Europe
Conclusion
MannKind
Afrezza® : Technosphere® + Medical Device
Trials

4. Introduction - Context
Diabetes

5. Epidemiology of Diabetes Mellitus
Prevalence of diabetes in adults aged years range : 8,3 % (world, 2013)
The 7th leading cause of death in 2030 (1) (WHO projection)
FID Fédération International du diabète, Atlas du diabète 6ème édition

6. Diabetes Mellitus
10 %
90%
FID Fédération International du diabète, Atlas du diabète 6ème édition

7. Introduction - Context
Types of insulin

8. Insulin secretion in individuals without diabetes
At a low, basal level in the non-fed state,
With increased, stimulated levels at mealtimes

9. Insulins Basal Intermediate-Acting : NPH Long-Acting
Umuline NPH Insulatard HM
Lantus Levemir Tresiba
NPH : Neutral Protamine Hagedorn

10. Insulins Bolus Short acting = Regular Insulin Rapid-acting Actrapid
Umuline Rapid
Humalog
Novo Rapid
Apidra 

11. Insulin in Type 2 Diabetes Mellitus
Healthy eating, weight control, physical activity
Initial drug monotherapy: Metformin
2 then 3-drug combination: + SU/TZD/DDP4-i/GLP1 receptor agonist
Initiation with basal insulin: long-acting, or intermediate-acting NPH
If the HbA1c target is not met: intensification of insulin therapy: addition of bolus insulin
Individualization of treatment (multiple daily doses + 1 or 2 non-insulin agents)
Glycaemic Target: HbA1c < 7%
American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) ; Diabetes Care; 2012 : 35 :

12. Insulin therapy : unmeet needs and non-adherence

13. Effective insulin therapy
Four critical accomplishments:
involvement of both patient and healthcare provider
initiation
adherence
persistence
intensification
PUBMED : M. Peyrot1,2, A. H. Barnett3 , L. F. Meneghini4 and P.-M. Schumm-Draeger5
Article: Care Delivery Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study

14. Adherence
Adherence to insulin therapies is generally poor
Self reported rate of adherence ranged from 43% to 86% for insulin therapy with Type1 or Type 2 diabetes mellitus
Review Article : Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review
M. J. Davies1, J. J. Gagliardino2, L. J. Gray3, K. Khunti3, V. Mohan4 and R. Hughes5

15. Top 5 reasons for insulin omission/non-adherence1
Too busy 2
Travelling 3
Skipped meals 4
Stress (needle phobia, hypoglycemia, weight gain…) 5
Public embarrassment
Review Article : Real-world factors affecting adherence to insulin therapy in patients with Type 1 or Type 2 diabetes mellitus: a systematic review
M. J. Davies1, J. J. Gagliardino2, L. J. Gray3, K. Khunti3, V. Mohan4 and R. Hughes5

16. Ideal insulin therapy Minimize consequence of
Low number of injections
Minimize consequence of
a delayed or missed insulin
Easy to adjust insulin doses to respond to daily changes
Device who is not a burden for the daily life
No weight gain
No risk of hypoglycemia

17. History of the Inhaled Insulin & Exubera®

18. History of Inhaled Insulin
Since 1924 : various attempts have been made to get away from injectable insulin → upper nasal airways ; deep lungs ; stomach.
Deep lungs most promising → small physiological barriers + inspired aerosol deposited on a large area + absorption through extremely thin alveolar membrane.
2006 : Pfizer licensed the rights to a product that came to be known as Exubera®.

19. Exubera®: 1st approved inhalable insulin
Co-developped by Pfizer and Sanofi-Aventis
January 2006 : US/EU approval (Diabetes type 1 and 2: rapid-acting insulin)
Pfizer bought from Sanofi-Aventis $1.3 billion the worldwide marketing rights
Manufactured by Pfizer in collaboration with Nektar Therapeutics
18 October 2007 : Pfizer annonced that it would no longer manufacture or market Exubera®
Pfizer Chairman and CEO Jeffrey Kindler : Exubera® « failed to gain acceptance among patients and physicians »

20. Exubera®: a failure 1
No clinical advantage over injected insulin
April 2006 : 1st appraisal from NICE : the benefits of avoiding injections did not justifiy the higher cost (x5).
→ June 2006 NICE : cost effectiveness only for patients with needle phobia 2
Serious risk of dosing errors : - Exubera® is prescribed in mg (UI traditionally) mg ↔ 3UI but the increment is not linear : 3 mg ↔ 8UI ! - 3 consecutive doses of 1 mg = higher dose than a single 3 mg blister ! 3
Begin working within the body faster than injected forms Type 1 and 2 diabetics will still need an injection of longer acting insulin to maintain a basal level for a 24-hour period 4

21. Exubera®: a bulky inhaler

22. Exubera®: lung cancer concern
9th April 2008
Pfizer announced that Exubera® may have been associated with lung cancer : total of 7 cases
Clinical trials : 6 cases/4,740 patients who used Exubera® VS 1 case/4,292 in the placebo group not in a study, once Exubera® was on the market
=> Not significant and all had a prior history of cigarette smoking => CHMP could not determine if related to Exubera®

23. Inhaled-insulin products in development in 2007

24. Main inhaled insulin in development in 2007
2008 : Eli Lilly and Novo Nordisk both shelved their current programs on inhalated insulin.
AIR Insulin®
AERx® iDMS

25. Inhaled-insulin products in development in 2007
Afrezza® remains one of the last inhaled insulin products in development

26. MannKind

27. Alfred Mann M.S. degrees in physics, member of the Academy
of Engineering
Foundation of 14 companies
9 were acquired by high profile companies for a total of $ 8 billions
In medical devices
In aerospatial
Eg: MiniMed Inc. Acquired by medtronic development of continous Glucodose monitoring system

28. Biopharmaceutical company based in California
Founded in 1991 by Alfred Mann
Focus on:
discovery,
development,
commercialization of therapeutic products for diseases such as diabetes and cancer.
2001: Technosphere® technology purchased from Solomon Steiner
2004: IPO $70M offering
CEO: Hakan Edstrom since January 2015

29. Technosphere® Technology
Dry powder formulation for inhalation

30. Technosphere® Technology
« A versatile delivery system that mimics the pharmacokinetics of intra- arterial administration »
FDKP, polysorbate 80, acetic acid, water
Formation reproducible and well controlled
Particles ideally sized for inhalation to the deep lung (2μm)
MannKind Corporation Technosphere® technology versatile drug delivery platform

31. FDKP : novel & inert excipient
FDKP Matrix
Hydrogen bonds and electrostatic interactions
pH-linked release
Uniform distribution
Biologically inert
Renally excreted
Crystallline and amorphous particles
Characterized in a full panel of toxicology studies
Chronic inhalation toxicology in 2 species (rat 6 months; dog 9 months)
2-year carcinogenicity by the inhalation route in rats
Reproductive toxicology
Safety pharmacology
Genetic toxicology

32. Technosphere® Technology Advantages
Applicability to a wide variety of API
Molecular weight from 500 Da to 150 KDa (proteins, peptides, small molecules)
Anionic and cationic drugs
Hydrophobic and hydrophilic drugs
Rapid drug absorption
Dissolve extremely fast after inhalation and deliver the API directly into the arterial circulation
Excellent bioavailability
Improved convenience with patient-friendly, needle-free devices, self-adminitered medicines
MannKind Corporation Technosphere® technology versatile drug delivery platform

33. Afrezza®
Technosphere® Insulin Inhalation Powder (TI)

34. Technosphere® Insulin Inhalation Powder (TI)
Dry powder form, administered with an inhaler (Oral inhalation route)
Microparticles : fumaryl diketopiperazine (FDKP) + recombinant human insulin (monomeric)
Human insulin produced by recombinant deoxyribonucleic acid (rDNA) : a non-pathogenic laboratory strain of E.Coli (K12)
FDKP carries the insulin to the lung
EMDAC-B1-02-MannKind_Backgrounder

35. Technosphere® Insulin
EMDAC-S1-02-MannKind_Slides

36. An inhaled formulation
Advantages
Painless
Discrete
Convenient
Non invasive
 Very fast absorption of insulin
EMDAC-B1-02-MannKind_Backgrounder

37. Afrezza®
Medical Device

38. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
No major clinical trials, only bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM
MedTone
Model C and D

39. Afrezza® inhaler device
The Afrezza® Inhaler is breath-powered by the patient, when the patient inhales through
The device, the powder is aerosolized and delivered to the lung.
MannKind initially filed for marketing approval based on data from the MedTone device

40. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Inadequate titration
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
No major clinical trials, only bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM

41. Afrezza® inhaler device
In 2009, switch to the 2nd generation inhaler Dreamboat (Gen2)
Medtone
Gen2 device
Dreamboat

42. Reason of the change
Designed to be smaller, easier to load, handle and low-cost

43. Reason of the change
Need of less inspiratory flow pressure and duration
Only one inspiration
Very little change in performance over a wide range of relevant pressure drops (flow rates) and particule size
MannKind Corp Innovation in drug delivery by inhalation

44. Reason of the change
Medtone
Gen2 device
Dreamboat
Less cartridge load to deliver the same dosage of insulin as from MedTone Inhaler
Bioequivalence 20U delivered by Gen2 = 30U delivered by MedTone
90% of the powder is delivered to the patient,
almost 70% is delivered in the respirable range
Low maintenance (discarded and replaced every 15 days) of the device

45. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Inadequate titration
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
Bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM

46. Strategy of bridging
Issue of the 1st NDA: ECLIA method used for BE studies is not compliant du FDA guideline: Bioanalytical Method Validation
1-Show correlation of serum insulin concentrations between ECLIA and RIA method
The Relationship Between Two Insulin Assays Used to Determine Bioequivalence and Dose Proportionality of AFREZZA® Insulin Administered Using a Gen2 Inhaler Compared to a MedTone® Inhaler: Simulation of Clinical Trials and Actual Data »Mark » T. Marino, MD and James P. Cassidy, MS MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda

47. 2-Show bioequivalence between MedTone et Gen2 device device
« Bioequivalence and Dose Proportionality of AFREZZA® Inhalation Powder Administered Using a Gen2 Inhaler Compared to the MedTone® Inhaler » Mark T. Marino, MD; James P. Cassidy, MS; Chad C. Smutney, BSME; Michael Zupon, PhD; Joseph Kocinski, PhD MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda, MD

48. 3-Show dose linearity of Gen2 device
« Bioequivalence and Dose Proportionality of AFREZZA® Inhalation Powder Administered Using a Gen2 Inhaler Compared to the MedTone® Inhaler » Mark T. Marino, MD; James P. Cassidy, MS; Chad C. Smutney, BSME; Michael Zupon, PhD; Joseph Kocinski, PhD MannKind Corporation, Valencia, California Diabetes Technology Meeting, November 11-13, 2010, Bethesda, MD

49. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
Bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM

50. 4-Head to head comparison between Medtone and Gen2 requested by FDA
Aim: Bridging pulmonary safety data Gen2 vs Medtone in phase 3 studies
No significant difference in mean change in FEV1 (Forced expiratory volume in 1 sec)
Similar rate of pulmonary AE
Briefing Document Afrezza- Mannkind EMDAC

51. Need of clinical trials
Device - Conclusion
BE not performed with golden standard method
Show dose linerarity of of 2x10U cartridge VS 20U cartridge of Gen2
Resubmision with a new version of the device
BE performed between MedTone and Gen 2
Need of clinical trials

52. Trials

53. PK: Phase I in healthy subjects
Dose ranging study of Afrezza® with Gen2 inhaler : 10 U ; 30 U ; 60 U and 80 U
Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

54. PK: Phase I in healthy subjects
Bolus
Short acting = Regular Insulin
Rapid-acting
Technosphere® insulin
Peak : 1h- 3h
Duration : 5-8 h
Peak : min
Duration : 3-5 h
Peak : min
Duration : 3h
Actrapid
Umuline Rapid
Humalog
Novo Rapid
Apidra 
Afrezza®

55. PD: Phase I in healthy and T1DM subjects with Gen2 inhaler
Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

56. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
No major clinical trials, only bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM

57. Endpoints for clinical trials
Efficacy
Primary endpoint:
- Change in HbA1c
- Non inferiority margin for insulin 0.4% of difference in HbA1c
Secondary endpoint:
- Percent achieving HbA1c ≤7%
- Body weight change
Safety
Pulmonary:
- FEV1
- Asthma
- Lung cancer
Non pulmonary:
- Hypoglycemia
- Diabetic ketoacidosis

58. Efficacy
Type 1 diabetes

59. Phase 3 trials in the 2013 resubmission
T1DM on a basal/bolus insulin regimen:
One trial (009) with MedTone:
basal insulin + TI (n=277) vs basal insulin + aspart insulin (n=262)
52 weeks

60. First submission (009): primary efficacy endpoint (change in HbA1c)
Afrezza
Comparator
Non inferiority margin of 0.4%
 Afrezza® doesn’t meet the non inferiority criteria
Primary analysis results
MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

61. Regulatory history of Afrezza® program
2009
Original NDA
MedTone
T1DM: 1 trial
T2DM: 2 trials
Duration of 6 months or greater
Complete Response Letter 1:
Request:
Additionnal data for clinical utility
Inadequate titration
Safety data
Comparability between 2 types of MedTone
2010
Resubmission
Gen2 Device
No major clinical trials, only bioequivalence study
Complete Response Letter 2:
One trial with safety comparison with MedTone
Clinical trials with Gen2 device for T1DM and T2DM
2013
Gen2 inhaler
Medtone comparison
2 new Phase III trials in T1DM and T2DM

62. Phase 3 trials in the 2013 resubmission
T1DM on a basal/bolus insulin regimen:
One trial (171) with MedTone and Gen2:
basal insulin + TI (n=174) vs basal + aspart insulin (n=170)
24 weeks
EMDAC-S1-01-FDA_Slides_508

63. Resubmission: Study 171 design
7.5 % ≤ HbA1c ≤ 10%

64. Basal and Prandial Insulin Titration in T1DM
Titration during 12 weeks
Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

65. Resubmission (171): primary efficacy endpoint (change in HbA1c)
Afrezza
Comparator
Non inferiority margin of 0.4%
 Non inferiority of Afrezza® vs. comparator
MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

66. Secondary endpoint: HbA1c ≤ 7%
Greater achievement with comparator vs. Afrezza®
No significant difference between Afrezza® and comparator
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

67. Secondary endpoint: Body weight change
Significant difference in weight gain in favor of comparator
Significant difference in weight gain in favor of comparator
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

68. Efficacy T1DM: Conclusion
With Gen2 inhaler (new device):
Non inferiority in HbA1c reduction for Afrezza®
Lesser achievement of HbA1c ≤ 7% target with Afrezza®
No gain weight with Afrezza®
 FDA: Less effective insulin ?

69. Efficacy
Type 2 diabetes

70. Phase 3 trials For the 2013 resubmission, data from trials:
One trial (102) with MedTone: subjects on prior insulin therapy : basal + TI (n=302) vs premixed biphasic Rapid Acting Analog 70/30 (n=316), 52 weeks

71. First submission (102): primary efficacy endpoint (change in HbA1c)
 Non inferiority of Afrezza® vs. comparator
Afrezza
Comparator
 Non inferiority margin of 0.4%
Clinical trial MKC-TI-102
MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

72. Phase 3 trials For the 2013 resubmission, data from trials:
One trial (102) with Medtone: subjects on prior insulin therapy : basal + TI (n=302) vs premixed biphasic Rapid Acting Analog 70/30 (n=316), 52 weeks
One trial (175) with Gen2: insulin-naive failing Oral Anti-Diabetic (OAD) therapy: OAD + TI (n=177) vs OAD + TP (technospere placebo) (n=176), 24 weeks

73. Resubmission (175): primary efficacy endpoint (change in HbA1c)
 Superior HbA1c reduction when compared to placebo as add-on to oral anti-diabetics in insulin naive subjects
Afrezza
Comparator
Clinical trial MKC-TI-175

74. Secondary endpoint: HbA1c ≤ 7%
 Greater achievement with Afrezza® vs. placebo
No signicative difference between the 2 arms
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

75. Secondary endpoint: Body weight mean change
Significant difference in weight gain in favor of Afrezza®
 Small weight gain in Afrezza® arm
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

76. Efficacy T2DM: Conclusion
Vs. Active comparator:
Non inferiority of Afrezza®
Same achievement of HbA1c ≤ 7% target
Less increase of body weight
 FDA: Afrezza® less effective than comparator
Vs. Placebo, in add on to OADs:
Superiority of Afrezza®
More achievement of HbA1c ≤ 7% target
Small weight gain
 Therapeutic strategy ?

77. Safety
Pulmonary Safety

78. FEV1 FEV1 decline over duration of treatment with TI in T1DM and T2DM
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

79. Bronchospasm Original submission with MedTone :
Bronchospasm in patients with asthma and chronic obstructive pulmonary disease
Trial with Medtone in non-diabetic subjects : 17 asthmatics and 13 non-asthmatics :
2 serious adverse events (SAEs) of bronchospasm in asthmatics
Bronchospasm and wheezing AEs (29%; 5/17) compared to no events in non-asthmatics
MannKind data

80. Incidence of Common TEAEs (≥2%) Combined Type 1 & 2 DM Safety Population
Trials with MedTone and Gen2 devices
TEAE = Treatment Emergent Adverse Event
Reason for discontinuation: 2,8 % for cough
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

81. Lung cancer
Observed incidence: 0.8 cases [95% CI ( )] per 1,000 patient-years
In diabetic population : 1 – 2 cases per 1,000 patient-years (Gillian et al., 2005)
MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014

82. Safety
Non-pulmonary safety

83. Incidence of hypoglycemia
Diabetes (Trial-device)
TI n (%)
Comparator n (%)
Incidence total hypoglycemia
T1DM (171-Gen2)
167 (96.0)
170 (99.4)
T1DM (009-Medtone)
252 (86.0)
252 (92.7)*
T2DM (102-Medtone)
155 (48.0)
228 (68.9)*
Incidence severe hypoglycemia
32 (18.4)
50 (29.2)*
96 (32.8)
102 (37.5)
14 (4.3)
33 (10.0)*
T1DM
T2DM
*p<0.05 for difference between TI and comparator (favoring the TI in all cases).
Incidence of hypoglycemia in studies vs. active insulin comparator
Less incidence of hypoglycemia in Afrezza® arm
FDA : consistent with the finding that Afrezza® is less effective
 no clear, consistent evidence of Afrezza® benefit on hypoglycemia
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

84. Diabetic ketoacidosis
For the 2013 Resubmission Safety Population :
SYE = Subject-year exposure
Imbalance may be consistent with lesser efficacy of Afrezza®
Related to concurrent infection and treatment interruption and/or reduced dosing
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014

85. Approval of Afrezza®

86. Approval Afrezza® was approved on June 27, 2014
Indication: Rapid-acting inhaled insulin to improve glycemic control in adults with type 1 and type 2 diabetes mellitus
Dosage and administration
Oral inhalation
A single inhalation per cartridge (4 or 8 units)
At the beginning of the meal
Before initiating, medical history, physical examination, spirometry
Dosage adjustment is needed when switching from another insulin to Afrezza®
Prescribing Information Afrezza® MannKind

87. Equivalence between Dose of Cartridge and SC Insulin
4units injected  10U inhaled
A Cartridge labeled :
- 4 units contains 0,35 mg of Insulin = 10 U of insulin
- 8 units contains 0,70 mg of Insulin = 20 UI of insulin
Prescribing Information Afrezza® MannKind

88. Approval Limitation of use Contraindications
Used in combination with long-acting insulin in patients with T1DM
Not recommended for diabetic ketoacidosis
Not recommended in patients who smoke or recently stopped
Contraindications
During episodes of hypoglycemia
Chronic lung disease: asthma, chronic obstructive pulmonary disease,  risk of acute bronchospasm
Hypersensitivity to regular human insulin or Afrezza® excipients
Prescribing Information Afrezza® MannKind

89. Storage conditions
Inhaler must be discarded after 15 days of use and replaced with a new inhaler
Prescribing Information Afrezza® MannKind

90. FDA requirements Four post marketing studies:
Paediatric trials: 4 to 17 years old
Part 1: Open-label PK, and multiple-dose safety and tolerability dose- titration trial in T1DM patients
Part 2: Prospective, multicenter, open-label, randomized, controlled trial comparing the efficacy and safety of prandial Afrezza® to prandial SC insulin aspart + SC basal insulin in T1DM and T2DM patients
5-year, randomized, controlled trial in patients with T2DM, to assess the serious potential risk of pulmonary malignancy
2 PK/PD trials: to characterize the dose response relative to SC insulin and assess within-subjects variability
Afrezza® letter of approval FDA

91. REMS
FDA REMS

92. Risk Evaluation and Mitigation Strategy (REMS)
Approved in June 2014
Goal: To mitigate the risk of acute bronchospasm
1. Communication Plan
- REMS Letters - REMS Factsheet - REMS website
2. Submission of Assessments to the FDA

93. 1. REMS Communication Plan
To inform healthcare providers and professional societies of:

94. 1. REMS Communication Plan
By Letters for Healthcare Providers and Professional Societies:
Within 60 days and again after 1 year after REMS approval
If the commercial launch of Afrezza® occurs later than 90 days following REMS approval, an additionnal issuance of REMS Letters will be sent within 30 days of product launch
Letters distributed by . If an is marked as unopened, a 2nd will be sent within 14 days.

95. Letter for Healthcare Providers

96. 1. REMS Communication Plan
By Factsheet:
Distributed with the REMS Letter for Healthcare Providers
Made available to HCP through MannKind’s sales and medical representatives during initial discussion during the first 12 months after approval of this REMS
Will be prominently displayed at relevant scientific meetings where MannKind has a presence for the duration of the REMS

97. Distributed with the REMS Letter for Healthcare Providers
Factsheet
Distributed with the REMS Letter for Healthcare Providers

98. 1. REMS Communication Plan
By Website:
The Afrezza REMS website ( include a prominent REMS – specific link
Include the option to print versions of the PI, REMS Letter for HCP and the REMS factsheet
Will continue for the duration of the REMS

99. 2. Submission of Assessments
MannKind will submit REMS Assessments to FDA at 18 months, 3 years, and 7 years from the date of the initial REMS approval
The reporting interval covered by each assessment should conclude no earlier than 60 days before the submission date, to facilitate inclusion of as much information as possible while allowing time to prepare the submission
MannKind wills submit each assessment so that it will be received by the FDA on or before the due date.

100. Sanofi & MannKind Partnership

101. « The best case scenario partner »
Sanofi is looking for ways to buttress revenue and fend off competition from Novo Nordisk A/S when its top-selling product, the insulin Lantus, loses patent in February 2015.
Sanofi has a complementary product portfolio, a large presence on the insulin market and one of the first commercial infrastructure in the world.
Afrezza will help Sanofi compete with short-acting insulins in which Novo and Eli Lilly & Co. are the market leaders. VS

102. MannKind Corp. / Sanofi partnership
Worldwide exclusive licensing agreement for development and commercialization of Afrezza®.
August 2014
Sanofi is responsible for:
Global commercial
Regulatory
Development activities
MannKind will manufacture Afrezza at its manufacturing facility in Danbury, Connecticut.
Plan to collaborate to expand manufacturing capacity to meet global demand as necessary.
Sanofi and MannKind will share profits and loses on a global basis,
retaining 65%
receiving 35%.

103. MannKind Corp. / Sanofi partnership
August 2014
Sanofi paid $150 million up front and as much as $775 million if the drug, Afrezza, meets certain sales and development targets
January 2015
MannKind just received a $50M milestone payment from Sanofi

104. Markets

105. Acceptance of inhaled insulin
Among physicians

106. Acceptance of inhaled insulin
Among patients
Both for patients and physicians: ready to accept inhaled insulin
For insulin intensification: increase percentage of « no preference »

107. Sanofi’s Target population
National diabetes statistic report, 2014, CDC
Excluded population :
- Asthma 8%*
- COPD 3,75%**
- Smoker 18,1%***

108. Estimation of Target population
Excluded population
Black box
We assess this product as : Niche market product
Target : people
Estimated Sales : 450 millions USD a year
DT2 with OADs +/- GLP1 with uncontrolled HbA1c : 2 millions
And Needle phobia (8,5% of population*)
*YAEL NIR, ALONA PAZ, EDMOND SABO, AND ISRAEL POTASMAN FEAR OF INJECTIONS IN YOUNG ADULTS: PREVALENCE AND ASSOCIATIONS Am. J. Trop. Med. Hyg., 68(3), 2003, pp. 341–344

109. Sanofi’s Launch Strategy
Launch 3rd February 2015
Pricing similar to rapid insulin in pen
Copayment for patient depends on health inssurance
Comparison of price for 600UI of insuline: Afrezza versus Sanofi rapid acting insulin

110. Sanofi’s Launch Strategy
Recruit early users thanks to copayment reduction

111. Europe

112. Strategy Obtain EC certificate for the device : not mandatory
MA application : the centralised authorisation procedure
Guidelines : diabetes, inhaled products, insulin
Scientific Advice

113. Application for MA The centralised authorisation procedure
medicines derived from biotechnology processes
human medicines for the treatment of diabetes
Submitted directly to the Agency
Evaluation by CHMP : 210 days + clock stops
Opinion
The EC grants MA in the EU : 67 days

114. European specificities
The applicant submits a risk management plan (RMP) in its marketing authorisation application.
A safety specification and a PV plan
A RMP describes activities to minimize risks
Risk Management Plan (from Exubera®)
To obtain further data on cardiovascular risk as well as possible correlation with decline in FEV1.
Perform an epidemiologic study to assess the hypothetical risk of lung cancer associated with inhaled insulin.
EPAR Exubera®

115. European specificities
Paediatric investigation plan
Pharmacovigilance system
A detailed description of the system of pharmacovigilance
A qualified person responsible
The notification of any adverse reaction occurring either in the Community or in a third country has been provided

116. European specificities
Concerning CMC : Additionnal requirements
EU inspection of manufacturing site
Analyses to perform according to European Pharmacopoeia
Have an approved release and analyse site in Europe

117. Chances of approval in the EU
The similar inhaled insulin has already been approved by the EMA
Scientific Advice
Management of the application to the EMA by Sanofi which has expertise in diabetes
Safety management

118. Conclusion

119. Strengths Weaknesses Opportunities Threats
Faster action
No injection
Small device
Easy to use
Less hypoglycemia and less weight gain trend
Weaknesses
Cough and small decrease in air flow
Long term safety (lung cancer)
Opportunities
Change in therapeutic strategy (treatment line, subpopulation preference)
Early users could promote Afrezza®
Threats
Competitors in phase I (inhaled) and Phase II (oral)
Need of phase IV study for European approval?

120. Thank you for your attention
Any questions ?