The Paper was presented at World Congress on Diabetes & Metabolism at Philadelphia during December 2011. It was later published in Cardiology Today.

3. DIABETES SITUATION AROUND
THE WORLD

4. •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

5. 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

7. PRACTICAL & POTENTIAL ROUTES
OF INSULIN ADMINISTRATION
INJECTABLE INSULIN
INHALED INSULIN

8. A TALE OF TWO INSULINS
PAINLESS & EASY
TO ADMINISTER
TREATMENT
FEW, DAILY
PAINFUL
EXPERIENCES

9. 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

10. 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

11. 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

12. •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

13. 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.

14. 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

15. *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 INH
When compared to INJ

16. INH Delivery Systems in Fray Before
Exubera Debacle
OPTING FOR INHALED INSULIN
INH and Delivery Systems

17. • 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

18. 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.

19. 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.

20. INH - THE STORY OF A SHATTERED DREAM
THE EXUBERA DEBACLE
 Jan 2006, FDA approved the first
INH, EXUBERA by Pfizer. It became
available in Sep 2006, till Oct 2007.
A Hexameric Recombinant-Hu
insulin, 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.

21. EXUBERA EXPERIENCE:
The exhilaration and despair
Withdrawal of Exubera was like losing a Long-
Hailed Dream, a ‘history-made-lost’. Work of
a long time was undermined.
Failed Exubera left the way difficult for other
INH. By 2008, Other pharma giants –
Alkermes/Eli Lilly and Aradigm/Novo Nordisk
were abandoned their projects.
Exubera available - Sep 2006 to Oct 2007 - in
US as new method of delivering insulin for
DM, was as effective as short-acting SCI but at
a high cost. Pfizer discontinued it in Oct 2007
due to poor sales/acceptability among
patients and physicians.

23. 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.

24. 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 and
T2DM adults: Changes in PFT were comparable
to changes seen in patients taking other
forms 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. Has
shown significant reduction in PP hypergl.,
Lower risk of hypo., Better inh. device and
Less weight gain than INJ.

25. Why Afrezza May Succeed
When Exubera Failed
Afr insulin is monomeric (Exubera
was hexameric) Has shorter time
to peak (14 min vs. 49 min for
Exu), 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.

26. 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.