DIABETES SITUATION AROUND

THE WORLD

•Insulin is most effective

treatment for DM

•Over 67% of T2DM patients are

not achieving target glycemic

control

•Insulin therapy is initiated too

late in T2DM patients

•Intensive insulin therapy is

underutilized in both T1DM and

T2DM patients

Glycemic Control is Often

Suboptimal

Achieving Optimum Blood

Glucose Control

Implies avoidance of the extremes of high

& low blood glucose and maintaining

blood glucose towards normal range.

Will delay/prevent microvascular (retino/

nephro/ neuropathy) and macrovascular

(stroke, MI and PID) complications.

Needs Early and Intensive

Insulin Administration

PRACTICAL & POTENTIAL ROUTES OF INSULIN ADMINISTRATION

INJECTABLE INSULIN

INHALED INSULIN

A TALE OF TWO INSULINS

PAINLESS & EASY TO ADMINISTER

TREATMENT

FEW, DAILY PAINFUL

EXPERIENCES

Advantages

1)Large alveolar surface area

2)Avoidance of first pass metabolism

3)Absence of degrading gastric acid

and degrading GI enzymes

Disadvantages

1)CLD patients may not be able to

absorb the required dose

2)Some metabolism do occur in the

lungs

3)Mucocililary clearance

OPTING FOR INHALED INSULIN

Inhaled Insulin:

Indications and Usage

•For Treatment of adult patients

with T1DM and T2DM

As combination therapy with

inter-mediate/long-acting SC

insulin or OHA

As monotherapy (T2DM)

OPTING FOR INHALED INSULIN

OPTING FOR INHALED INSULIN

SAFETY ISSUES

Advantages:

*Easy to Carry

*Painless and Easy Intake.

Thus, No Hindrance Multiple

Doses

*Short and Rapid Action

*Specified Temperature Not

Essential To Store

*Reported Positive Impact

on Alzheimer’s Disease

Concerns:

*Special Groups

Excluded

*Fear of

Reduction of

lung capacity

*Fear of Lung

Malignancy - in

case of long-

term use

•Mild to moderate Cough (25 vs 5%)

•Effects on Lung Function (insigni.

to clinically relevant)

•Applicability for Ex-smokers and

Smokers; Special groups: Children

and Pregnant Ladies

• Insulin antibody formation

•Longterm safety not Established

OPTING FOR INHALED INSULIN

Potential Downsides of INH

OPTING FOR INHALED INSULIN

INH Development Program

Inhaled Insulin

Development Program

Should be as Efficacious as Short-acting SCI in Controlling PP Hyperglycemia

Should aid in Achieving Long-term Glycemic control

Easy to Administer and Acceptable

Should Have Good

Safety Profile:

Well Tolerated and Hypoglycemic Effect comparable to SCI

Low for Insulin Abs.

Negligible/Nonprogre-ssive & Reversible effect on FEV1,DLCo and Lung Tissue.

OPTING FOR INHALED INSULIN

INH Inhalation Device

Should be handy

and discrete to use

Should be able to

deliver a desired

dose in a simple

way

Should be easy to

maintain

Not more

expensive than SCI

*To be used as prandial medication

to treat PP hyperglycemia

*The basal insulin or OHA therapy

to be continued

*To be avoided in smokers and with

history of smoking

*To be avoided in special groups:

Pregnancy, extremes of age

*To be avoided in CLD patients

THE PLANNED THERAPY WITH INHWhen compared to INJ

INH Delivery Systems in Fray Before

Exubera Debacle

OPTING FOR INHALED INSULIN

INH and Delivery Systems

• Concept of using lungs as route for insulin delivery (INH) floated during 1920s.

• It took ~ 8 decades for the concept to become technically feasible.

• Pfizer & Aventis, Lilly, MannKind, Aerogen, Novartis, etc. tried to develop INH.

• Pfizer’s Exubera came, approved by FDA (Jan 2006), became available (Sep 2006).

• Pfizer pulled off Exubera in Oct 2007 because of poor sales/acceptability.

IDEA NURTURED FOR NEARLY A CENTURY WAS BLOWN OFF

INH - THE STORY OF A SHATTERED DREAM

1922: Banting and Best discovered

insulin. ‘Almost overnight outlook

for .. diabetic patient changed from

one of rapid decline and death to ..

nearly normal person’ (Guyton ‘91).

INH - THE STORY OF A SHATTERED DREAM‘History-made-lost’

1924: Gansslen experimented to deliver

insulin by inhalation. 1920s: Wigley et

al demonstrated hypoglycaemic effect

in rabbits by the inhaled insulin. These

researches were limited due to poor

bioavailability and lack of effective

inhalation devices. INH idea was born.

INH - THE STORY OF A SHATTERED DREAM‘History-made-lost’

1990s: Carl Leopold developed

method to preserve peptides like

insulin in glassy state. Allowing

pulverization in powder form to

make inhalable insulin.

Later research led to technologies to turn insulin

into particles suitable for inhalation. Inhalation

devices to deliver insulin to lung alveoli thence

into blood stream bypassing liver were made.

Nektar developed technology paving way

to begin testing & formulating INH. Late

1990s: Human tests began. Jan 2006:

FDA approved Pfizer’s Exubera.

INH - THE STORY OF A SHATTERED DREAM

THE EXUBERA DEBACLE

Jan 2006, FDA approved the firstINH, EXUBERA by Pfizer. It becameavailable in Sep 2006, till Oct 2007.

A Hexameric Recombinant-Huinsulin, Delivered via inhaler, Acted as rapid acting insulin.

Patients needed to take Longer-acting SCI

or to continue on OHA. It supplemented for

Post Prandial Requirements..

Oct 2007: Pfizer announced Exubera Pull-

off due to poor sales. Exubera debacle

amounted to >2.8 billion USD to Pfizer.

EXUBERA EXPERIENCE:The exhilaration and despair

Withdrawal of Exubera was like losing a Long-Hailed Dream, a ‘history-made-lost’. Work ofa long time was undermined.

Failed Exubera left the way difficult for otherINH. By 2008, Other pharma giants –Alkermes/Eli Lilly and Aradigm/Novo Nordiskwere abandoned their projects.

Exubera available - Sep 2006 to Oct 2007 - inUS as new method of delivering insulin forDM, was as effective as short-acting SCI but ata high cost. Pfizer discontinued it in Oct 2007due to poor sales/acceptability amongpatients and physicians.

EXUBERA EXPERIENCE:

Lessons From Exubera Debacle

Internal Sales Estimates/Forecasts are only imaginary numbers. They are guesses: some good, others real bad.

In pharma circles First Launch may matters. But a deficient, half-cooked & not-a-patient-friendly mode (Exubera inhaler) and not-fully-researched product (Exubera insulin) will not find way to consumers/healers.

Marketing is not everything. It alters people’s perception only a little.

Come Oct 2007: Imp. Lessons were to be learnt

Pharma industry is going through big overhaul. There are old player & new smarter players.

REALIZING THE DREAM:

Will Afrezza Succeed Where Exubera Failed?

Afrezza has Better Insulin/Advanced

Inhalation Device/Simple Dose Schedule

In 2-Yr Pulmonary Safety Study in T1DM andT2DM adults: Changes in PFT were comparableto changes seen in patients taking otherforms of insulin or OHAs.

Like HOPE survives hidden in crevices, efforts continued and belief persisted. INH was not

fully written off.Presently, Afrezza is under FDA review. Hasshown significant reduction in PP hypergl.,Lower risk of hypo., Better inh. device andLess weight gain than INJ.

Why Afrezza May Succeed

When Exubera Failed

Afr insulin is monomeric (Exuberawas hexameric) Has shorter timeto peak (14 min vs. 49 min forExu), Mimics natural insulin resp-onse. Hypo. & weight gain is less.

Afr inhaler, small ‘dream boat’

goes into pocket, discreet,

breath-activated, Has simplified

dose schedule. Exu inhaler was

large, use noticeable, dose

schedule complex, Required

activation by breathing.

Will Another INH Succeed Where

Exubera Failed?

VISIONS FOR FUTURE

LASTLY, Setbacks Might Have Delayed But INH is Right and Milder Way

To Administer, Subcutaneous is Definitely Not.

PRIME POINTS•Insulin is ideal drug for DM, Replacing the factor which is deficient.•Only viable routes are subcutaneously or Pulmonary •As technology develop, inhalation route will find ways to deliver longer acting insulins to replace fully SCIs and OHAs.