Transcript Afrezza®: Inhaled insulin approved by the FDA

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
2
Table of Contents
 Introduction - Context
• Diabetes
• Types of insulin
 Insulin therapy : unmeet
needs and non-adherence
 History of the Inhaled
Insulin & Exubera®
 MannKind
 Afrezza® : Technosphere® +
Medical Device
 Trials
 Approval of Afrezza®
 REMS
 Sanofi & MannKind
Partnership
 Markets
 Europe
 Conclusion
3
Introduction - Context
Diabetes
4
Epidemiology of Diabetes Mellitus
 Prevalence of diabetes in adults aged 20-79 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
5
Diabetes Mellitus
10 %
90%
FID Fédération International du diabète, Atlas du diabète 6ème édition
6
Introduction - Context
Types of insulin
7
Insulin secretion in individuals
without diabetes
 At a low, basal level in the non-fed state,
 With increased, stimulated levels at mealtimes
8
http://www.sanofidiabetes.in/apidra-doctor.aspx
Insulins
Basal
IntermediateActing : NPH
Long-Acting
Umuline NPH
Insulatard HM
Lantus
Levemir
Tresiba
NPH : Neutral Protamine Hagedorn
http://www.sanofidiabetes.in/apidra-doctor.aspx
9
Insulins
Bolus
Short acting =
Regular Insulin
Rapid-acting
Actrapid
Umuline Rapid
Humalog
Novo Rapid
Apidra 
http://www.sanofidiabetes.in/apidra-doctor.aspx
10
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 : 1364-1379
11
Insulin therapy : unmeet
needs and non-adherence
12
Effective insulin therapy
Four critical accomplishments: involvement of both patient and healthcare provider
intensification
initiation
persistence
adherence
13
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
Adherence
Self reported rate of
adherence ranged from
43% to 86% for insulin
therapy with Type1 or Type
2 diabetes mellitus
Adherence to insulin
therapies is generally poor
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
14
Top 5 reasons for insulin
omission/non-adherence
1
• 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
15
Ideal insulin therapy
Low number of
injections
No weight gain
Minimize
consequence of
a delayed or
missed insulin
No risk of hypoglycemia
Easy to adjust
insulin doses to
respond to daily
changes
Device who is not a
burden for the daily
life
16
History of the Inhaled
®
Insulin & Exubera
17
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®.
http://www.lef.org/Magazine/2015/2/Vinpocetine-Brainshrinkage-Brain-Injury-and-Bioidentical-Hormones/Page-05
http://www.fool.com/investing/general/2013/09/11/will-the-new-inhaler-replace-injections-for-diabet.aspx
18
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 »
19
Exubera®: a failure
1
No clinical advantage over injected insulin
2
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
3
Serious risk of dosing errors :
- Exubera® is prescribed in mg (UI traditionally)
- 1 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 !
4
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
http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1331.html
20
Exubera®: a bulky inhaler
21
http://www.nytimes.com/2007/11/16/business/16mannkind.html?pagewanted=1&_r=2&fta=y&
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.
+ 1 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®
http://www.lepoint.fr/actualites-sante/2008-04-10/l-insuline-inhalee-exubera-liee-a-des-cancers-du-poumon-selon/1409/0/237289
22
Inhaled-insulin products in
development in 2007
http://www.nature.com/nbt/journal/v25/n12/fig_tab/nbt1207-1331_T1.html
23
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
24
Inhaled-insulin products in
development in 2007
Afrezza® remains one of the last inhaled insulin products in development
http://www.nature.com/nbt/journal/v25/n12/fig_tab/nbt1207-1331_T1.html
25
MannKind
26
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
http://www.mannkindcorp.com/about-us-executive-management-alfred.htm
27
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
28
http://www.mannkindcorp.com/about-us-executive-management-alfred.htm
®
Technosphere
Technology
Dry powder formulation for inhalation
29
®
Technosphere
Technology
« A versatile delivery system that mimics the pharmacokinetics of intraarterial administration »
• FDKP, polysorbate 80, acetic
acid, water
• Formation reproducible and
well controlled
• Particles ideally sized for
inhalation to the deep lung
(2μm)
30
MannKind Corporation Technosphere® technology versatile drug delivery platform http://www.mannkindcorp.com/
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
31
http://www.mannkindcorp.com/
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
32
MannKind Corporation Technosphere® technology versatile drug delivery platform http://www.mannkindcorp.com/
®
Afrezza
Technosphere® Insulin Inhalation Powder (TI)
33
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
34
20140401-EMDAC-B1-02-MannKind_Backgrounder
®
Technosphere
Insulin
35
20140401-EMDAC-S1-02-MannKind_Slides
An inhaled formulation
 Advantages
Painless
Discrete
Convenient
Non invasive
 Very fast absorption of insulin
36
20140401-EMDAC-B1-02-MannKind_Backgrounder
®
Afrezza
Medical Device
37
Regulatory history of Afrezza®
program
2009
Complete Response
Letter 1:
Original NDA
MedTone
2010
Complete Response
Letter 2:
2013
Request:
Resubmission
Request:
Resubmission
Gen2 Device
T2DM: 2 trials
Safety data
One trial with safety
comparison with
MedTone
Gen2 inhaler
T1DM: 1 trial
Additionnal data for
clinical utility
Duration of 6 months
or greater
Comparability
between 2 types of
MedTone
Clinical trials with
Gen2 device for
T1DM and T2DM
2 new Phase III trials
in T1DM and T2DM
MedTone
Model C and D
No major clinical
trials, only
bioequivalence
study
Medtone
comparison
38
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
39
www.mannkindcorp.com
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:
2010
Additionnal data for
clinical utility
Resubmission
Inadequate titration
No major clinical trials,
only bioequivalence
study
Safety data
Comparability
between 2 types of
MedTone
Gen2 Device
Complete Response
Letter 2:
2013
Request:
Resubmission
One trial with safety
comparison with
MedTone
Gen2 inhaler
Clinical trials with
Gen2 device for T1DM
and T2DM
Medtone comparison
2 new Phase III trials in
T1DM and T2DM
40
Afrezza® inhaler device
 In 2009, switch to the 2nd generation inhaler Dreamboat
(Gen2)
Gen2 device
Dreamboat
Medtone
41
www.mannkindcorp.com
Reason of the change
 Designed to be smaller, easier to load, handle and low-cost
42
www.mannkindcorp.com
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
43
MannKind Corp Innovation in drug delivery by inhalation
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
44
www.mannkindcorp.com
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:
Complete Response
Letter 2:
2013
Resubmission
Gen2 inhaler
Additionnal data for
clinical utility
2010
Request:
Resubmission
Inadequate titration
Gen2 Device
Safety data
Bioequivalence study
One trial with safety
comparison with
MedTone
Comparability
between 2 types of
MedTone
Clinical trials with
Gen2 device for T1DM
and T2DM
Medtone comparison
2 new Phase III trials in
T1DM and T2DM
45
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
46
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
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
47
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
48
Regulatory history of Afrezza®
program
2009
Complete Response
Letter 1:
Original NDA
Request:
MedTone
Complete Response
Letter 2:
2013
2010
Request:
Resubmission
Resubmission
T2DM: 2 trials
Safety data
Duration of 6 months
or greater
Comparability
between 2 types of
MedTone
Bioequivalence
study
One trial with safety
comparison with
MedTone
Gen2 inhaler
T1DM: 1 trial
Additionnal data for
clinical utility
Clinical trials with
Gen2 device for
T1DM and T2DM
2 new Phase III trials
in T1DM and T2DM
Gen2 Device
Medtone
comparison
49
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
50
Briefing Document Afrezza- Mannkind EMDAC
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
51
Trials
52
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
53
PK: Phase I in healthy subjects
Bolus
Short acting =
Regular Insulin
Rapid-acting
Technosphere®
insulin
Peak : 1h- 3h
Duration : 5-8 h
Peak : 30-90 min
Duration : 3-5 h
Peak : 10-15 min
Duration : 3h
Actrapid
Umuline Rapid
Humalog
Novo Rapid
Apidra 
Afrezza®
54
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
55
Regulatory history of Afrezza®
program
2009
Complete Response
Letter 1:
Original NDA
MedTone
2010
Complete Response
Letter 2:
2013
Request:
Resubmission
Request:
Resubmission
Gen2 Device
T2DM: 2 trials
Safety data
One trial with safety
comparison with
MedTone
Gen2 inhaler
T1DM: 1 trial
Additionnal data for
clinical utility
Duration of 6 months
or greater
Comparability
between 2 types of
MedTone
Clinical trials with
Gen2 device for
T1DM and T2DM
2 new Phase III trials
in T1DM and T2DM
No major clinical
trials, only
bioequivalence
study
Medtone
comparison
56
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
57
Efficacy
Type 1 diabetes
58
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
59
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
60
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:
2010
Additionnal data for
clinical utility
Resubmission
Inadequate titration
No major clinical trials,
only bioequivalence
study
Safety data
Comparability
between 2 types of
MedTone
Gen2 Device
Complete Response
Letter 2:
2013
Request:
Resubmission
One trial with safety
comparison with
MedTone
Gen2 inhaler
Clinical trials with
Gen2 device for T1DM
and T2DM
Medtone comparison
2 new Phase III trials in
T1DM and T2DM
61
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
20140401-EMDAC-S1-01-FDA_Slides_508
62
Resubmission: Study 171 design
7.5 % ≤ HbA1c ≤ 10%
63
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
64
Resubmission (171): primary efficacy
endpoint (change in HbA1c)
Afrezza
Comparator
Non inferiority margin of 0.4%
 Non inferiority of Afrezza®
vs. comparator
65
MannKind Corporation, and Jean‐Marc Guettier, MD CM, Division of Metabolism and Endocrinology Products, FDA, CDER, Advisory Committee April 1, 2014
Secondary endpoint: HbA1c ≤ 7%
Greater achievement
No significant
with comparator vs.
difference between Afrezza®
Afrezza® and
comparator
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014
66
Secondary endpoint: Body weight
change
 Significant difference in weight
gain in favor of comparator
 Significant difference in weight
gain in favor of comparator
67
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014
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 ?
68
Efficacy
Type 2 diabetes
69
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
70
First submission (102): primary
efficacy endpoint (change in HbA1c)
Afrezza
Comparator
 Non inferiority margin of 0.4%
 Non inferiority of
Afrezza® vs. comparator
71
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
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
72
Resubmission (175): primary efficacy
endpoint (change in HbA1c)
Afrezza
Comparator
 Superior HbA1c reduction when compared to placebo as
add-on to oral anti-diabetics in insulin naive subjects
Clinical trial MKC-TI-175
73
Secondary endpoint: HbA1c ≤ 7%
 Greater
achievement with
No signicative difference
Afrezza® vs. placebo
between the 2 arms
MannKind Corporation, Endocrinologic and Metabolic Drugs, FDA Advisory Committee April 1, 2014
74
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
75
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 ?
76
Safety
Pulmonary Safety
77
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
78
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
79
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
80
Lung cancer
Observed incidence: 0.8 cases [95% CI (0.09-2.8)] 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
81
Safety
Non-pulmonary safety
82
Incidence of hypoglycemia
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
83
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
84
Approval of Afrezza®
85
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
86
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
87
Approval
 Limitation of use
• 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
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Storage conditions
Inhaler must be discarded after 15 days of use and replaced with a new inhaler
Prescribing Information Afrezza® MannKind
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FDA requirements
 Four post marketing studies:
• Paediatric trials: 4 to 17 years old
• Part 1: Open-label PK, and multiple-dose safety and tolerability dosetitration 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 8 000-10 000 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
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Afrezza® letter of approval FDA
REMS
FDA REMS
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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
92
1. REMS Communication Plan
 To inform healthcare providers and professional societies of:
93
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 email. If an email is marked as unopened, a 2nd
email will be sent within 14 days.
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Letter for
Healthcare
Providers
95
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
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Factsheet
Distributed with
the REMS Letter
for Healthcare
Providers
97
1. REMS Communication Plan
 By Website:
- The Afrezza REMS website (www.AfrezzaREMS.com) 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
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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.
99
Sanofi & MannKind
Partnership
100
« 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 shortacting insulins in which
Novo and Eli Lilly & Co.
are the market leaders.
VS
101
MannKind Corp. / Sanofi
partnership
August 2014
Worldwide exclusive licensing agreement for development
and commercialization of Afrezza®.
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%.
102
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
103
Markets
104
Acceptance of inhaled insulin
Among physicians
105
Acceptance of inhaled insulin
Among patients
Both for patients and physicians: ready to accept inhaled insulin
For insulin intensification: increase percentage of « no preference »
106
Sanofi’s Target population
National diabetes statistic report, 2014, CDC
Excluded population :
- Asthma 8%*
- COPD 3,75%**
- Smoker 18,1%***
http://www.cdc.gov/asthma/asthmadata.htm http://www.cdc.gov/copd/
http://www.cdc.gov/tobacco/campaign/tips/resources/data/cigarette-smoking-in-united-states.html
107
Estimation of Target population
Excluded population
Black box
We assess this product as : Niche market product
DT2 with OADs +/- GLP1
with uncontrolled
HbA1c : 2 millions
And Needle phobia
(8,5% of population*)
Target : 170 000 people
Estimated Sales : 450 millions USD a year
*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
108
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
http://rxusa.com/cgibin2/db/db.cgi?name2=Insulin
109
Sanofi’s Launch Strategy
Recruit early users thanks to copayment reduction
https://www.activatethecard.com/7055/
110
Europe
111
Strategy
1. Obtain EC certificate for the device : not mandatory
2. MA application : the centralised authorisation procedure
• Guidelines : diabetes, inhaled products, insulin
• Scientific Advice
112
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
113
http://www.ema.europa.eu/ema/
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.
114
EPAR Exubera®
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
115
http://www.ema.europa.eu/ema/
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
116
http://www.ema.europa.eu/ema/
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
117
Conclusion
118
Strengths
Faster action
Weaknesses
No injection
Cough and small
decrease in air flow
Small device
Easy to use
Less hypoglycemia and
less weight gain trend
Opportunities
Change in therapeutic
strategy (treatment line,
subpopulation
preference)
Early users could
promote Afrezza®
Long term safety (lung
cancer)
Threats
Competitors in phase I
(inhaled) and Phase II
(oral)
Need of phase IV study
for European approval?
119
Thank you for your
attention
Any questions ?
120