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

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

Introduction - Context Diabetes

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

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

Introduction - Context Types of insulin

Insulin secretion in individuals without diabetes At a low, basal level in the non-fed state, With increased, stimulated levels at mealtimes http://www.sanofidiabetes.in/apidra-doctor.aspx

Insulins Basal Intermediate-Acting : NPH Long-Acting Umuline NPH Insulatard HM Lantus Levemir Tresiba NPH : Neutral Protamine Hagedorn http://www.sanofidiabetes.in/apidra-doctor.aspx

Insulins Bolus Short acting = Regular Insulin Rapid-acting Actrapid Umuline Rapid Humalog Novo Rapid Apidra  http://www.sanofidiabetes.in/apidra-doctor.aspx

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

Insulin therapy : unmeet needs and non-adherence

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

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

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

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

History of the Inhaled Insulin & Exubera®

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

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 »

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) - 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 ! 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 http://www.nature.com/nbt/journal/v25/n12/full/nbt1207-1331.html

Exubera®: a bulky inhaler 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

Inhaled-insulin products in development in 2007 http://www.nature.com/nbt/journal/v25/n12/fig_tab/nbt1207-1331_T1.html

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

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

MannKind

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

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 http://www.mannkindcorp.com/about-us-executive-management-alfred.htm

Technosphere® Technology Dry powder formulation for inhalation

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 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 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 MannKind Corporation Technosphere® technology versatile drug delivery platform http://www.mannkindcorp.com/

Afrezza® Technosphere® Insulin Inhalation Powder (TI)

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 20140401-EMDAC-B1-02-MannKind_Backgrounder

Technosphere® Insulin 20140401-EMDAC-S1-02-MannKind_Slides

An inhaled formulation Advantages Painless Discrete Convenient Non invasive  Very fast absorption of insulin 20140401-EMDAC-B1-02-MannKind_Backgrounder

Afrezza® Medical Device

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

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 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: 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

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

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

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

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

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

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

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

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

Trials

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

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®

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

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

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

Efficacy Type 1 diabetes

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

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

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

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

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

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

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

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

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

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 ?

Efficacy Type 2 diabetes

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

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

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

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

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

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

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 ?

Safety Pulmonary Safety

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

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

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

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

Safety Non-pulmonary safety

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

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

Approval of Afrezza®

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

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

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

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

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 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 Afrezza® letter of approval FDA

REMS FDA REMS

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

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

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.

Letter for Healthcare Providers

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

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

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

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.

Sanofi & MannKind Partnership

« 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

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%.

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

Markets

Acceptance of inhaled insulin Among physicians

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

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

Estimation of Target population Excluded population Black box We assess this product as : Niche market product Target : 170 000 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

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/cgi-bin2/db/db.cgi?name2=Insulin

Sanofi’s Launch Strategy Recruit early users thanks to copayment reduction https://www.activatethecard.com/7055/

Europe

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

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 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. 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 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 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

Conclusion

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?

Thank you for your attention Any questions ?