MannKind Corporation
ADVANCING CLINICAL CONCEPTS
2006 Annual Report
MannKind
+
STUDY 101
A Phase 2 clinical trial in
patients with type 1 diabetes
STUDY 014
A Phase 3 clinical trial in
patients with type 2 diabetes
DIABETES
from a patient’s perspective
HOW DOES THE TECHNOSPHERE®
INSULIN SYSTEM WORK?
MEASURING THE EFFECTIVENESS
OF DIABETES THERAPY
WE AT MANNKIND ARE FOCUSED ON THE DISCOVERY, DEVELOPMENT AND COMMERCIALIZATION OF
THERAPEUTIC PRODUCTS FOR DIABETES AND CANCER. OUR LEAD PRODUCT, THE TECHNOSPHERE®
INSULIN SYSTEM, IS IN PHASE 3 CLINICAL TRIALS IN THE UNITED STATES, EUROPE AND LATIN
AMERICA TO STUDY ITS SAFETY AND EFFECTIVENESS IN THE TREATMENT OF DIABETES.
CONTENTS
LETTER TO STOCKHOLDERS
A year of many accomplishments
DIABETES – from a patient’s perspective
The goals and challenges of current treatment
MEASURING THE EFFECTIVENESS OF DIABETES THERAPY
HbA1c levels and acute glucose fluctuations
HOW DOES THE TECHNOSPHERE® INSULIN SYSTEM WORK?
A closer look at our technology
STUDY 101
A Phase 2 clinical trial in patients with type 1 diabetes
STUDY 014
A Phase 3 clinical trial in patients with type 2 diabetes
1
2
4
6
8
10
Dear Stockholders
“Pivotal” is the only word to describe 2006. During the past year, we embarked on the final phase of our journey to become a fully
integrated biopharmaceutical company. We launched the remaining registration trials for our lead product, the Technosphere® Insulin
System. We backfilled our pipeline by moving a second product – an oncology therapeutic – into clinical development. We commenced
the expansion of our manufacturing facility in Danbury, Connecticut in order to meet our anticipated commercial production needs
for Technosphere® Insulin. We grew our workforce to 545 employees, bringing on board a number of experienced pharmaceutical
professionals. We also raised net proceeds of $497 million in simultaneous debt and equity offerings, giving us the financial resources
to move forward with our aggressive plans.
Among the many highlights of 2006:
(cid:127) We completed the first Phase 3 trial of our lead product, Technosphere® Insulin. In this study of patients with type 2 diabetes,
we demonstrated that our investigational product produced HbA1c improvements comparable to those seen in a group of patients
treated with a rapid-acting insulin analog (RAA) but with substantially less mild/moderate hypoglycemia
and no severe hyperglycemia. Strikingly, Technosphere® Insulin was associated with a significant weight
reduction compared to the weight gain observed in the RAA group.
(cid:127) We also observed that Technosphere® Insulin produced similar HbA1c and weight results in a Phase
2 study of patients with type 1 diabetes. In this study, we observed weight loss as well as substantially
reduced glucose fluctuations with Technosphere® Insulin following a meal – a finding that has important
implications for the ability of our therapy to reduce long-term complications of diabetes.
(cid:127) We completed enrollment of a two-year, pivotal, Phase 3 safety study of Technosphere® Insulin. We
closed the enrollment of Study 030 in early September 2006 with 2051 patients. With study completion
now targeted for September 2008, we remain on track to file a new drug application for Technosphere®
Insulin by the end of 2008.
(cid:127) We initiated the remaining pivotal Phase 3 efficacy studies of Technosphere® Insulin. Studies
009 and 102 are now enrolling patients at centers in the United States, Europe and Latin America. An
additional Phase 3 efficacy study, 103, is also enrolling patients.
(cid:127) We received clearance from the FDA of our investigational new drug application for MKC1106-PP, allowing us to begin enrolling
patients in a Phase 1 trial to evaluate this product for the treatment of a variety of cancers, including breast, lung, ovarian, pancreatic,
renal and colorectal cancers and melanoma.
While we build upon these accomplishments, we realize that our ambition level exceeds our current resources and capabilities.
Although we are confident that Technosphere® Insulin, once approved, will be a highly successful product, we realize that our
strength lies in discovery, development and manufacturing. We do not yet possess the sales and marketing capability required to
launch Technosphere® Insulin in the United States to large numbers of general practitioners as well as specialists, nor do we have
the resources to commercialize in Europe and elsewhere. For this reason, we continue to hold discussions with potential sales and
marketing partners who can provide this expertise and can help to accelerate the penetration of Technosphere® Insulin into the
diabetes market. We have a strong belief in the value of our lead product and we want to make sure that we do the right deal with the
right partner. We can afford to be patient.
That we can afford to be patient is because our stockholders have been tremendously supportive. Our simultaneous offerings of
debt and equity last fall were both oversubscribed and included many high-quality institutions. We sincerely appreciate this vote of
confidence in our product and our business plans and are working hard to ensure that your trust in us is justified.
The year ahead will be extraordinarily busy for us as we conduct our pivotal trials and advance our level of commercial readiness.
There may be few external signs of progress – we will not be in a position to report on our pivotal trials until 2008 – but we will be highly
engaged nonetheless.
Sincerely,
Hakan S. Edstrom
President and
Chief Operating Officer
Alfred E. Mann
Chairman and
Chief Executive Officer
MANNKIND | 2006 ANNUAL REPORT 1
Diabetes
from a patient’s perspective
Diabetes is a chronic condition resulting from the insuffi cient production of, or
lack of response to, insulin, a key regulator hormone of the body’s metabolism.
In a healthy body, the rise in blood glucose levels after a meal signals cells in the
pancreas—beta cells—to secrete insulin into the bloodstream. Insulin, in turn,
enables glucose to enter cells in the body where it is burned for energy or stored
for future use. People with diabetes either do not produce enough insulin or become
resistant to their own insulin. As a result, glucose builds up in the bloodstream.
2 MANNKIND | 2006 ANNUAL REPORT
Over time, diabetes can lead to a myriad
of life-threatening complications, including
heart disease, stroke, vision loss, kidney
disease and neuropathy (nerve damage).
Ultimately, if untreated, the disease can lead
to coma and death.
There are two forms of the disease.
Type 1 diabetes is an autoimmune disease
characterized by a complete lack of insulin
secretion by the pancreas. People with type 1
diabetes require insulin injections in order to
live. Their bodies produce little or no insulin
because their immune systems attack and
destroy the insulin-producing beta cells in
the pancreas.
In type 2 diabetes, the pancreas
continues to produce some insulin; but
insulin dependent cells become resistant
toward the insulin effect. Over time, the
pancreas becomes
increasingly unable
to secrete adequate amounts of insulin to
support metabolism.
Type 2 diabetes is the more prevalent form
of the disease, affecting approximately 90%
to 95% of people diagnosed with diabetes.
CURRENT TREATMENT
The goal of diabetes treatment is to
achieve and maintain blood glucose levels
within or near the normal range (90 to 126
mg/dL). Maintaining blood glucose levels in
this range can be very difficult with current
therapies. In order to effectively manage
their condition, diabetes patients must learn
to prevent their blood glucose levels from
plunging too low (hypoglycemia) or spiking
too high (hyperglycemia).
Day-to-day maintenance
for type 1
diabetes requires a strict daily treatment
regimen of multiple insulin injections together
with diet, exercise and blood glucose testing
(sometimes many times per day).
Unlike type 1 diabetes, type 2 diabetes
disease management, at least early in the
disease, is more dependent on lifestyle
choices
including healthful eating and
exercise, together with daily blood glucose
testing. Significant changes in diet and
exercise can temporarily enable patients with
early type 2 diabetes to eliminate the need
for medications. However, type 2 diabetes
is a progressive disease. In many cases,
patients with type 2 diabetes eventually
require medical treatment.
is the standard of care for patients with
diabetes, its use has certain shortcomings.
ANTI-DIABETIC MEDICATIONS ■
INSULIN CHALLENGES ■
There are several non-insulin diabetes
treatments that can be used to control blood
glucose levels, either alone or in combination
with insulin.
families
Today these drugs can be divided
including
into seven distinct
(e.g. Glucotrol®, Diabeta®,
sulfonylureas
Glynase®, Micronase®
and Amaryl®),
meglitinides (e.g. Prandin® and Starlix®),
biguanides (e.g. Glucophage®, Glucophage®
The primary challenge for insulin therapy
involves synchronizing the onset of insulin
activity with the absorption of mealtime
glucose. In healthy individuals, blood insulin
levels rise, and glucose production by the
liver stops, within minutes after glucose
from a meal enters the blood. These events
allow healthy individuals to maintain normal
glucose levels and avoid high blood glucose
levels for prolonged periods after eating.
20.8
APPROXIMATELY 20.8 MILLION PEOPLE
IN THE UNITED STATES SUFFER FROM
DIABETES. THAT NUMBER IS EXPECTED TO
RISE TO 48.3 MILLION PEOPLE BY 2050.
XR and Fortamet®), thiazolidinediones (e.g.
Avandia® and Actos®), alpha-glucosidase
inhibitors (e.g. Prandase®, Precose® and
Glyset®), incretin mimetics (e.g. Byetta®),
and inhibitors of dipeptidyl peptidase IV
(e.g. Januvia®).
The large number of such drugs is
an indicator of just how critical diabetes
treatment has become. However, most
treatments have significant side effects
and are not considered ideal for one reason
or another. Insulin replacement continues
to play a significant role in the treatment
of diabetes.
INSULIN ■
All individuals with type 1 diabetes
must use insulin to control their blood
glucose levels, and roughly 30% of those
with type 2 diabetes also require insulin.
injections
Until recently, subcutaneous
were the only way to administer insulin.
Many different insulins are available for
diabetes treatment. These insulins are
classified by the speed with which they
lower blood glucose and the duration of
glucose-lowering activity. While insulin
However, for patients with diabetes,
injected mealtime insulin enters the system
slowly, requiring up to three hours to reach
peak activity. During this time, the patient
may experience hyperglycemia until the
injected insulin takes effect and lowers
blood glucose. Typically, the insulin outlasts
the glucose ingested from a meal, which
then leads to hypoglycemia. This cycle of
extremes in blood glucose levels eventually
causes long-term organ damage.
This dilemma led to the development
of rapid-acting insulin analogs that start
working 15 to 30 minutes after injection
and reach peak effectiveness in 30 to 90
minutes; however, their action can persist
for up to 5 hours. Rapid-acting analogs are
an improvement over regular insulin, but
the need remains for a new form of insulin
that takes effect even more rapidly and has
a duration of action that does not exceed
the period of glucose ingestion from a meal.
An insulin therapy that mimics the body’s
natural insulin response would be ideal. We
believe that Technosphere® Insulin has the
potential to be that ideal insulin.
MANNKIND | 2006 ANNUAL REPORT 3
Glucose Levels:
Fasting and Post-meal Glucose Levels
Meal
Meal
Meal
400
350
300
250
200
150
100
50
)
L
d
/
g
m
(
e
s
o
c
u
l
G
0
0600
1000
1400
1800
2200
0200
0600
Illustration 4.a
Time of Day
M O D I F I E D F R O M H I R S C H E T A L . ,
C L I N I C A L D I A B E T E S 2 3 : 7 8 - 8 6 , 2 0 0 5 .
The red line illustrates the elevated fasting glucose and large glucose
fluctuations observed in uncontrolled diabetes. The blue line shows how
basal insulin lowers fasting glucose and reduces acute glucose fluctuations.
The black line shows how the addition of mealtime insulin to basal insulin
causes a reduction in acute glucose fluctuations.
Recent fi ndings have indicated
that diabetes therapy must strive
to manage acute glucose fl uctuations
in addition to average glucose levels
(see Illustration 4.a). The potential
value of MannKind’s Technosphere®
Insulin System can be seen in how
effectively it controls the extent of
acute glucose fl uctuations.
4 MANNKIND | 2006 ANNUAL REPORT
Patients with diabetes develop abnormally high levels of glucose,
a state known as hyperglycemia, either because they produce
insufficient levels of insulin or because they fail to respond adequately
to the insulin produced by the body. Over time, high levels of blood
glucose can lead to major complications, including high blood
pressure, blindness, amputation, kidney failure, heart attack, stroke
and death.
HBA1C LEVELS ■
There are two components to the hyperglycemia concern.
The first is related to the duration and magnitude of the chronic
sustained hyperglycemia associated with poorly controlled diabetes.
This component is assessed by measuring the level of glycosylated
hemoglobin (HbA1c), which is a reflection of the average glucose
levels in the bloodstream over the preceding three or four months.
HbA1c levels are an indication of the general degree of glucose control.
As can be seen in Illustration 4.a, the baseline or fasting glucose levels
can be a major factor in average glucose levels. An important goal of
all diabetes therapies is to lower HbA1c levels.
ACUTE GLUCOSE FLUCTUATIONS ■
The second component of hyperglycemia relates to the extent of
acute fluctuations primarily in blood glucose above and below the
average level. These fluctuations occur in response to meals. Over
time, excessive glucose fluctuations damage blood vessels and
surrounding cells. This damage shows up first in the fine capillaries
found in the eyes, kidneys, fingers and toes. This damage can lead to
blindness, kidney failure, amputation, heart attack and stroke.
DCCT/EDIC TRIAL ■
There is growing evidence that doctors and patients should place
greater emphasis on managing acute glucose fluctuations. In the
Diabetes Control and Complications Trial (DCCT), a group of patients
treated using conventional insulin therapy (1 to 2 insulin injections
per day along with daily urine glucose tests) was compared to a group
treated using intensive insulin therapy (either an insulin pump or at
least 3 insulin injections and at least 4 blood glucose tests per day).
In total, 1,441 patients were followed for an average of 6.5 years each.
The researchers found that intensive insulin therapy produced
a significant reduction in HbA1c levels compared to conventional
insulin therapy; the difference between treatment groups remained
evident for the duration of the study. Moreover, the patients who
had been intensively treated also showed significant decreases
in risk for kidney and eye damage compared to the conventional
treatment group. When these results were reported, the DCCT
was discontinued.
A group of 1,375 of these subjects (half from each of the original
treatment groups) was subsequently followed in the Epidemiology
of Diabetes Interventions and Complications (EDIC) study. After
seven years in the EDIC study, the HbA1c levels of the former
conventional therapy group did not differ from the HbA1c levels of
the former intensive treatment group – the HbA1c levels of the former
conventional therapy group had improved from the DCCT while those
of the former intensive therapy group had deteriorated.
However, the former conventional therapy group continued to
show an elevated risk of kidney and eye damage compared to the
former intensive therapy group. The implication of these results
is that intensive insulin therapy — which reduces acute glucose
fluctuations — can be beneficial for patients with diabetes, even
years after the therapy has been less intensified. However, the EDIC
also demonstrates how intensive insulin therapy is difficult for many
patients to implement in a home setting. Moreover, with intensive
therapy, the insulin products on the market today do not enter the
bloodstream fast enough to replicate the tight coupling between
changes in blood glucose levels and the release of insulin by the
pancreas that is seen in healthy individuals without diabetes.
MannKind’s Technosphere®
Insulin therapy addresses this
problem in two ways:
(cid:127) Insulin administration by inhalation is more convenient than
injection and also more amenable to intensive therapy.
(cid:127) The Technosphere® Insulin formulation delivers insulin monomers
to the deep lung. The insulin is absorbed rapidly and begins to lower
blood glucose faster than injected insulin, mimicking insulin action
in healthy individuals.
MANNKIND | 2006 ANNUAL REPORT 5
HOW DOES THE
TECHNOSPHERE®
INSULIN DELIVERY
SYSTEM WORK?
REPLICATES NATURAL PROCESS ■
In clinical trials to date, our Technosphere® Insulin System has produced
a profile of insulin levels in the bloodstream that approximates the post-meal
insulin profiles normally seen in healthy individuals.
Technosphere® Insulin has been shown to be rapidly absorbed into
the bloodstream following inhalation, reaching peak levels within 12 to
14 minutes. As a result of this rapid onset of action, most of the glucose-
lowering activity of Technosphere® Insulin occurs within the first three
hours of administration — which is generally the period
during which glucose becomes available from a
meal — instead of the much longer duration of
action observed when insulin is injected
subcutaneously.
We believe that the relatively
short duration of action of
Technosphere® Insulin reduces
the need for patients to snack
between meals in order to
manage ongoing blood glucose
excursions (rapid glucose level
elevations and depressions).
Indeed, in our clinical trials,
we have observed that patients
the Technosphere®
using
Insulin System have achieved
significant reductions in acute
glucose fluctuations and significant
decreases in HbA1c levels without
the weight gain typically associated
with insulin therapy.
FORMULATION TECHNOLOGY ■
Technosphere® Insulin’s rapid action may be related
to unique characteristics of both our carrier molecule
and the insulin in our formulation.
6 MANNKIND | 2006 ANNUAL REPORT
TECHNOSPHERE® INSULIN
ACTION
pH-Sensitive Carrier Particles
Dissolve instantly on lung tissue
Aerodynamic Carrier Particles
Navigation into deep lung
Insulin Monomers
Already in bioactive form
Our
Technosphere®
formulation
technology is centered on a class of
pH-sensitive organic molecules
that
self-assemble into small particles under
mildly acidic conditions. Certain drugs,
such as insulin, can be loaded onto these
particles by combining a mildly acidic
solution of the drug with a suspension of
Technosphere® material, which is dried
to a powder. This powder is then filled
into plastic cartridges and packaged.
To administer Technosphere® Insulin,
a patient loads a cartridge into our
palm-sized inhaler. By inhaling through
the inhaler, air is pulled through the
cartridge, which aerosolizes the powder
and pulls the particles into the air current
and out through the mouthpiece. The
particles are small and have aerodynamic
properties that enable them to travel
deep into the lungs.
When the particles contact the
moist lung surface with its neutral pH,
the Technosphere® particles dissolve
immediately. This releases the insulin
molecules, which then diffuse across a
the
that
indicate
thin layer of cells into the bloodstream.
Studies
insulin
absorption
is a passive process
that occurs without disruption of
either the cell membranes or the tight
junctions between cells.
INSULIN MONOMERS ■
When the Technosphere® particles
dissolve, the insulin that is released is
in a form that can readily be used by
the body.
In most pharmaceutical dosage
forms, regular human insulin exists
as a hexamer, a complex of six
associated insulin molecules. In order
to exert a pharmacological effect,
the hexamer must first dissociate
into
three dimers — complexes of
two insulin molecules — which then
further dissociate
individual
insulin molecules, or monomers. Only
these monomers exert a physiological
effect. Rapid-acting insulin analogs are
designed to be fragile hexamers that
into
dissociate more quickly than regular
insulin, thereby reducing the time
required to achieve an effect, but this
is still far slower than insulin that is
released from a healthy pancreas.
The
insulin
released
from
is already
Technosphere® particles
largely
in monomeric form. During
the manufacture of Technosphere®
Insulin, we cause hexameric insulin to
dissociate into insulin monomers before
being
loaded onto Technosphere®
particles.
These properties may explain why
the Technosphere®
Insulin System
produces such a rapid elevation in
insulin levels following inhalation. This
time-action profile approximates the
insulin profile normally seen in healthy
individuals
following
immediately
the beginning of a meal, but which
is absent in patients with diabetes.
MANNKIND | 2006 ANNUAL REPORT 7
Study 101 was designed to compare the
safety and efficacy (blood glucose control)
of Technosphere® Insulin and insulin aspart
(Novolog®), a rapid-acting insulin analog
Pulmonary safety was assessed by different measurements of lung
function, including forced expiratory volume (FEV1) – the volume of air
that can be forced out in one second after taking a deep breath – and
carbon monoxide lung diffusing capacity (DLco) – a measure of the gas
exchange capacity of the lungs.
(RAA), in patients with type 1 diabetes.
RESULTS ■
This study involved 110 patients with type 1 diabetes on basal/
prandial therapy, a dosing regimen used in the everyday intensive
management of diabetes. Patients were randomized into a group that
used Technosphere® Insulin (n=54) at mealtime or a group that used the
RAA (n=56) at mealtimes. Both groups used insulin glargine (Lantus®)
as a basal insulin.
The patients were followed for 12 weeks during which individual
adjustments of therapy were made as necessary. Standardized meal
tests were conducted at study initiation and after 8 and 12 weeks
of therapy. HbA1c levels and post-meal glucose fluctuations were
assessed at the initial visit, at the start of randomized treatment and at
study completion. Comparisons were made between the patient group
receiving Technosphere® Insulin and the patient group receiving RAA.
After 12 weeks of treatment, both patient groups achieved
a statistically significant decrease in HbA1c levels (0.83% in the
Technosphere® Insulin patient group and 0.99% in the RAA patient
group). However, during the standardized meal tests conducted at week
12, we observed a rather striking difference between the post-meal
glucose levels of the two groups. Graph 9.a shows that, in the group that
received the RAA, there was a sharp rise in blood glucose immediately
after the meal, followed by a gradual decline, reaching baseline in about
four hours. In the group that received Technosphere® Insulin, there was
a short dip in blood glucose immediately after the dose; subsequent
glucose fluctuations were considerably lower than with the RAA.
> See illustration 9.a – Glucose vs. Time
8 MANNKIND | 2006 ANNUAL REPORT
101
a Phase 2 clinical trial in patients with type 1 diabetes
these
We quantified
fluctuations by
measuring the area under each curve. Graph
9.b illustrates the significant reductions in
post-meal glucose
fluctuations achieved
following the use of Technosphere® Insulin.
> See illustration 9.b – Glucose Excursions
We were also intrigued by the observation
that, over 12 weeks of treatment, the RAA
patient group experienced an average increase
in weight of 1.8 lbs. whereas the Technosphere®
Insulin patient group experienced an average
weight loss of 2.0 lbs. This difference in
weight change between the two groups was
statistically significant (p=0.0018).
After 12 weeks of treatment, pulmonary
function, as measured by FEV1, and DLco, did
not differ from baseline for the Technosphere®
Insulin and RAA patient groups. The
results were consistent with the Company’s
previous studies of Technosphere® Insulin
that have demonstrated
in
overall glycemic control reductions in post-
meal glucose fluctuations, no deterioration
in pulmonary lung function and no weight
gain with Technosphere® Insulin at any of the
dosage levels tested.
improvement
CONCLUSION ■
in HbA1c
levels using
This study demonstrated that patients
with type 1 diabetes can achieve comparable
decreases
the
Technosphere® Insulin System as patients
injected RAA. The
treated with an
Technosphere® Insulin System was better
able to reduce post-meal glucose fluctuations.
Our study also found that patients using
Technosphere® Insulin lost weight during the
study in contrast to patients using the RAA
who gained weight. Moreover, after twelve
weeks of treatment, pulmonary function did
not differ between the two patient groups.
80
60
40
20
0
-20
-40
)
L
d
/
g
m
(
e
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c
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n
a
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C
)
n
i
m
*
L
d
/
g
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(
e
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u
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r
A
480
360
240
120
0
-120
-240
-360
Study 101 results:
Glucose levels after standard meal
RAA
Technosphere®
Insulin
0
50
100
150
200
250
300
350
400
450
Illustration 9.a
Time after meal (min)
Study 101 results:
Post-meal glucose excursions after standard meal
Above baseline
Below baseline
RAA
Technosphere®
Insulin
76%
p=0.02
Illustration 9.b
p=0.39
MANNKIND | 2006 ANNUAL REPORT 9
This study involved 308 patients with
type 2 diabetes. Patients were randomized
into a group that used Technosphere® Insulin
(n=150) at mealtimes or a group that used the
RAA (n=158) at mealtimes. Both groups used
insulin glargine (Lantus®) as a basal insulin.
Patients were followed for 24 weeks during
which individual adjustments of therapy were
made as necessary. Glucose control in both
treatment groups was assessed by periodic
determinations of HbA1c levels. We did not
conduct standardized meal tests in this study.
Pulmonary function was assessed by serial
measurements of FEV1 and forced vital capacity
(FVC), a measure of pulmonary capacity. After
the treatment period, patients reverted to their
conventional therapy and pulmonary function
was followed for an additional 24 weeks.
RESULTS ■
Both patient groups achieved statistically
significant improvements in HbA1c levels
(1.05% in the Technosphere® Insulin patient
group and 1.30% in the RAA patient group).
Pulmonary function, as assessed by FEV1 and
FVC, did not differ between the two patient
groups after six months of treatment and after
the six month withdrawal period.
Yet there were
important differences
between the treatment groups. Significantly
fewer patients experienced mild to moderate
hypoglycemia in the Technosphere® Insulin
patient group than in the RAA patient group
and there were no severe hypoglycemic
incidences. In addition, after six months of
treatment, the RAA patient group experienced
an average weight increase of 0.5 lbs. whereas
the Technosphere®
Insulin patient group
experienced a weight loss of 1.7 lbs. This
difference in weight change between the two
groups was statistically significant (p=0.0007).
> See illustration 11.a – Weight Changes
Study 014 was designed to compare the
safety and efficacy (blood glucose control) of
Technosphere® Insulin and the insulin aspart
(Novolog®), a rapid-acting insulin analog
(RAA), in patients with type 2 diabetes.
10 MANNKIND | 2006 ANNUAL REPORT
014a Phase 3 clinical trial in patients with type 2 diabetes
CONCLUSION ■
As in study 101, patients using Technosphere®
Insulin achieved comparable decreases in
HbA1c levels as patients treated with an
injected RAA. In addition, we observed no
adverse effect on pulmonary function in either
treatment group. However, unlike the injected
RAA group, Technosphere® Insulin patients
lost weight during the treatment period.
)
s
b
l
(
e
n
i
l
e
s
a
b
m
o
r
f
e
c
n
e
r
e
f
f
i
d
t
h
g
i
e
W
WHY NO WEIGHT GAIN? ■
We were surprised to observe no weight
gain, and even weight loss, in patients using
the Technosphere®
Insulin System
to
control their blood glucose. We believe that
this phenomenon may stem
from
the
synchronization of Technosphere®
Insulin
activity to meal digestion. Meal digestion
is somewhat variable, but generally
lasts
approximately three hours. Graph 11.b,
taken from our clinical data, illustrates that
over 80% of the glucose-lowering activity of
regular subcutaneous insulin is not exerted
until at least three hours after a meal. At
this point, patients run the risk of becoming
hypoglycemic. Typically,
this
situation
encourages patients to eat snacks between
meals, contributing to the weight gain often
associated with insulin therapy. By contrast,
approximately three-quarters of the action of
Technosphere® Insulin occurs within the first
three hours after a meal. After this point, there
is little insulin present to cause hypoglycemia,
thereby alleviating the need to snack.
y
t
i
v
i
t
c
A
g
n
i
r
e
w
o
L
e
s
o
c
u
l
G
4
3.5
3
2.5
2
1.5
1
0.5
0
Study 014 results:
Weight changes
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
RAA
Technosphere®
Insulin
-8
-4 0 4
8
12 16 20 24
28
Illustration 11.a
Time (weeks)
Time-action profi les:
Hypothesis: Better synchronization of insulin activity
to glucose absorption from a meal
180 min
i
c
Subcutaneous
insulin
insulin
Technosphere®
p
Insulin
0
100 200 300 400 500 600
Illustration 11.b
Time from Dosing (min)
MANNKIND | 2006 ANNUAL REPORT 11
t is
It is clear that the rising incidence of diabetes is creating a looming medical
crisis that will demand more effective treatments. The therapies of the last
80 years are not adequate to address the epidemic of diabetes.
What is not obvious is that the large number of diabetes therapies in
development do not address key issues critical to the management of the
disease. With Technosphere® Insulin, MannKind is assuming a leadership role
in insulin delivery with a product that represents the potential first offering
in a new class of insulins—supra-rapid acting insulins that provide real-time
control of glucose that mimics nature.
The growing diabetes market will ultimately require multiple therapies. With
Technosphere® Insulin, MannKind may bring clinicians a powerful new option
ew option
in diabetes therapy.
Jay S. Skyler, M.D., MACP
Professor, Division of Endocrinology, Diabetes, & Metabolism
Associate Director - Diabetes Research Institute
University of Miami
This annual report contains forward-looking statements relating to MannKind’s products under development that are subject
to certain risks and uncertainties that could cause actual results to differ materially from those projected. The words “believe,”
“expect,” “intend,” “anticipate,” “plan,” variations of such words, and similar expressions identify forward-looking statements,
but their absence does not mean that the statement is not forward-looking. These statements are not guarantees of future
performance and are subject to certain risks, uncertainties, and assumptions that are difficult to predict. Factors that could
affect MannKind’s actual results, the development of its proposed products and other risks and uncertainties described in
MannKind’s current and periodic reports filed with the Securities and Exchange Commission, including MannKind’s 2006 10-K.
12 MANNKIND | 2006 ANNUAL REPORT
BOARD OF DIRECTORS
Alfred E. Mann
Chairman and Chief Executive Officer
Richard L. Anderson
Corporate Vice President
and Chief Financial Officer
Hakan S. Edstrom
President, Chief Operating Officer
and Director
Kathleen Connell, Ph.D.
President
Connell Group, Inc.
*Director until May 2007
Ronald Consiglio
Managing Director
Synergy Trading
Michael A. Friedman, M.D.
President and Chief Executive Officer
City of Hope National Medical Center
Llew Keltner, M.D., Ph.D.
Founder and Chief Executive Officer
EPISTAT
*Director until May 2007
Kent Kresa
Chairman Emeritus
Northrop Grumman Corporation
David H. MacCallum
Managing Partner
Outer Islands Capital, L.P.
Henry L. Nordhoff
President and Chief Executive Officer
Gen-Probe Incorporated
EXECUTIVE OFFICERS
Alfred E. Mann
Chairman and Chief Executive Officer
Hakan S. Edstrom
President, Chief Operating Officer
and Director
Juergen A. Martens, Ph.D.
Corporate Vice President Operations
and Chief Technical Officer
Diane M. Palumbo
Corporate Vice President
Human Resources
Dr. Peter C. Richardson
Corporate Vice President
and Chief Scientific Officer
David Thomson, Ph.D., J.D.
Corporate Vice President
and General Counsel
ANNUAL MEETING
The Company’s annual meeting
of stockholders will be held:
Thursday, May 24, 2007
10:00 a.m. (Pacific)
28903 North Avenue Paine
Valencia, CA 91355
Tel +1.661.775.5300
TRANSFER AGENT
Mellon Investor Services, LLC
400 South Hope Street
Fourth Floor
Los Angeles, CA 90071
LEGAL COUNSEL
Cooley Godward Kronish LLP
4401 Eastgate Mall
San Diego, CA 92121
INDEPENDENT AUDITORS
Deloitte & Touche LLP
350 South Grand Avenue
Suite 200
Los Angeles, CA 90071
STOCK INFORMATION
MannKind Corporation stock is
publicly traded on the NASDAQ
Global Market under the symbol
“MNKD.”
CORPORATE HEADQUARTERS
MannKind Corporation
28903 North Avenue Paine
Valencia, CA 91355
Tel +1.661.775.5300
Fax +1.661.775.2080
www.mannkindcorp.com
REGIONAL OFFICES
1 Casper Street
Danbury, CT 06810
Tel +1.203.798.8000
Fax +1.203.798.7740
61 South Paramus Road
Mack-Cali Centre IV
Paramus, NJ 07652
Tel +1.201.983.5000
Fax +1.201.450.9982
INVESTOR RELATIONS
Reports regarding the Company
are filed electronically with the SEC.
You may access these reports and
additional information without
charge from our website at
www.mannkindcorp.com and from
the SEC’s website at www.sec.gov.
In addition, you may contact the
Company’s investor relations
department through “Information
Request” on the Company’s
website or by sending an email to:
IR@mannkindcorp.com.
Further data-related information can
be found on the Company website.
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28903 North Avenue Paine
Valencia, CA 91355
Phone: +1.661.775.5300
www.mannkindcorp.com