technosphere® insulin

Technosphere� InsulinAn Inhaled Prandial Insulin Product

Joshua J. Neumiller1 and R. Keith Campbell2

1 Department of Pharmacotherapy, Washington State University, Spokane, Washington, USA

2 Department of Pharmacotherapy, Washington State University, Pullman, Washington, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

1. Background: Inhaled Insulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

2. Challenges and Issues with Inhaled Insulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

3. Technosphere� Insulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

3.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

3.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

3.3 Efficacy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

3.4 Adverse Events and Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170

4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Abstract Given the important role of insulin in the treatment of diabetes mellitus and in light of common barriers

to insulin use, new strategies for insulin delivery by routes other than intravenous and subcutaneous in-

jection have been investigated since the discovery of insulin in the 1920s. Most companies researching and

developing pulmonary administration systems for the use of insulin announced the termination of product

development following the failure of the first US FDA-approved inhaled insulin product, Exubera�. One

company in particular continued their pursuit of a useful inhaled insulin product. MannKind Corporation

has developed a powder formulation of insulin that allows for a high percentage of the administered insulin

to be absorbed via the lung. Their product, AFREZZA� (Technosphere� insulin), is currently under review

by the FDA for use in patients with diabetes. Technosphere� insulin appears to overcome some of the

barriers that contributed to the market withdrawal of Exubera� by the manufacturer. Studies with Techno-

sphere� insulin have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively

short duration of action, and is efficacious in terms of improved glycemic control without contributing to

increased weight gain or the incidence of hypoglycemia when compared with other prandial insulin

products. Additionally, Technosphere� insulin has demonstrated a favorable safety and tolerability profile

in clinical studies to date.

Insulin therapy is a medical necessity for all patients with

type 1 diabetes mellitus (T1DM), and with the prevalence of

type 2 diabetes mellitus (T2DM) increasing and with people be-

ing diagnosed at an early age, the use of insulin in T2DMwill be-

come increasingly important as patients develop severe insulin

deficiency as a result of pancreatic b-cell loss over time.One hur-

dle associated with the initiation of insulin is overcoming fear

and other misconceptions regarding insulin use on behalf of

the patient. Preconceived patient perceptions regarding injec-

tion pain, weight gain, regimen complexity and its impact on

quality of life, and risks and consequences of hypoglycemia

often hinder successful initiation of insulin therapy.[1] Given the

REVIEWARTICLEBiodrugs 2010; 24 (3): 165-172

1173-8804/10/0003-0165/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

important role of insulin in the treatment of diabetes and in light

of common barriers to insulin use, new strategies for insulin

delivery are being sought to improve ease of administration,

medication adherence, and overall glycemic control. In this

article, we briefly review the background history of inhaled in-

sulin development and discuss evidence available to date re-

garding a novel inhaled insulin product, Technosphere� insulin.

1. Background: Inhaled Insulin

The desire to administer insulin by routes other than intra-

venous and subcutaneous injection have been investigated since

the discovery of insulin in the 1920s.[2]While insulin delivery via

oral, sublingual, rectal, nasal, ocular, and transdermal routes,

among others, have been studied,[2] inhaled insulin has argu-

ably shown themost promise, with the first studies published on

insulin inhalation dating back to 1924.[3] Following advance-

ments in inhalation technology, largely driven by the asthma

therapy market, the technical requirements for inhaled insulin

delivery became a reality.[4] Several companies emerged an-

nouncing the development of pulmonary insulin delivery

technology suitable for clinical trial study.[4] Each company

began work with major insulin manufacturers to complete a

great deal of research and development to overcome insulin

formulation and inhalation device problems. At last, Inhaled

Therapeutic Inc., which had become Nektar, developed a de-

vice, which it sold to Pfizer, which then formed a partnership

with Sanofi-aventis for co-marketing. Pfizer eventually bought

out the Sanofi-aventis share to gain exclusive rights to the

product and conducted a clinical trial program that eventually

led to the first US FDA approval of an inhaled insulin product

in 2006. The product was marketed under the name Exubera�,

and Pfizer began an education and marketing program in

support of the commercial launch. Unfortunately for Pfizer,

Exubera� experienced hardships in terms of patient and health-

care provider acceptance, and Pfizer decided to cease manu-

facturing of the product in 2007.

2. Challenges and Issues with Inhaled Insulin

As noted previously, there were initial challenges associated

with the delivery of inhaled insulin prior to the advancements in

inhaler technology, which were realized in the 1990s.[4] While

technologic advancements have allowed for proper therapeutic

delivery of insulin to the lungs, the failure of Exubera� has

highlighted a variety of other more practical challenges asso-

ciated with pulmonary insulin delivery.

So why did Exubera� fail? The biggest factor was that it

simply was not embraced by healthcare providers, particularly

prescribers. The Exubera� inhaler was big and clumsy to use,

and it proved difficult to adequately train healthcare providers

and patients in its proper use. Furthermore, the inhalation

device required weekly cleaning in a special manner, with a

critical component of the inhalation device requiring replace-

ment every 2 weeks.[5] Many clinicians and patients alike were

dissatisfied with the product despite the anticipation of an in-

haled insulin product. The insulin used in the device also proved

problematic. The insulin was formulated as a dry powder, with

the extent of absorption via the lung being low, thus making the

insulin product inefficient and more costly to manufacture. To

add to the confusion, the insulin powder blisters were dosed in

milligrams rather than units, and those doses available did not

exhibit dose linearity. Exubera�was available in 1 mg and 3mg

blisters, and these were associated with providing a therapeutic

effect equivalent to 3 and 8 units of subcutaneous regular hu-

man insulin, respectively.[5] Likewise, while the lack of dose

linearity was confusing for some patients, the limitation of

dosing in increments of 3 and 8 units provided a limited ability

to fine tune therapy based on patient-specific needs. Most im-

portantly, the clinical performance of Exubera� offered no

advantages; it was not as effective as the commercial rapid in-

sulin analogs.

During phase III trials with Exubera�, the main respiratory

adverse events (AEs) reported were cough, dyspnea, increased

sputum, and epistaxis.[5] While these were the most common

respiratory-related AEs, clinical studies also demonstrated a

small but statistically significant decrease in pulmonary func-

tion that appeared not to be progressive. However, because of

the variability in patients, the manufacturer recommended

pulmonary function testing prior to the initiation of Exubera�

therapy. Pfizer agreed to a Risk Evaluation and Mitigation

Study of 5000 patients with periodic lung function testing over

5 years. Exubera�was not recommended for use in patients with

underlying lung disease, such as chronic obstructive pulmonary

disease (COPD) or asthma;[5] this limited the appropriate pa-

tient population and increased the need for provider-driven

monitoring and laboratory work.

Pfizer launched educational programs to train physicians,

nurses, pharmacists, and Certified Diabetes Educators about

how to train patients to use the product. While they developed

wonderful educational materials, they were still left with the

fact that the product had too many hurdles to overcome.

The death knell for the product was rung, and patients no

longer had the option of administering bolus insulin without a

needle and syringe. Six months following the October 2007

166 Neumiller & Campbell

ª 2010 Adis Data Information BV. All rights reserved. Biodrugs 2010; 24 (3)

announcement by Pfizer that they would cease the manu-

facturing of Exubera�, information linking Exubera� to lung

cancer was released. During clinical trials, six cases of lung

cancer developed in 4740 patients using Exubera� compared

with one case in 4292 control patients (incidence per 100 pa-

tient-years of study drug exposure: 0.13 vs 0.02).[6] All of those

patients who developed lung cancer had been smokers. The

company and the FDA both concluded that there were too few

cases to determine a link between Exubera� and lung cancer,

but the product labeling was updated to add the information on

incidence of lung cancer to the warnings section. With the

discontinuation of Exubera� and the potential link of its use to

lung cancer, it appeared that the pulmonary insulin market was

dead. Was it because pulmonary insulin was ineffective or un-

safe? Or was it because the product that was developed and

approved was poorly designed, inefficient in administering in-

sulin, and ineffectivelymarketed? These are certainly important

questions for any company pursuing the development of an

inhaled insulin product following the removal of Exubera�

from the market, and concerns and opinions stemming from

patients, diabetologists, scientists, and healthcare payers will

influence the future development and marketing of another

inhaled insulin product.[7]

3. Technosphere� Insulin

Most other companies researching and developing a pul-

monary administration system for the use of insulin announced

the termination of product development following the failure of

Exubera�. One company in particular, however, continued

their pursuit of a useful inhaled insulin product. MannKind

Corporation has developed a dry powder formulation of insulin

that allows a high percentage of the insulin to be absorbed via

the lung. Their product, AFREZZA� (Technosphere� insu-

lin), is currently under review by theUSFDA for use in patients

with T1DM and T2DM. Technosphere� insulin is a very rapid-

acting inhaled insulin with an action profile that mimics early

meal-associated insulin release. AFREZZA� is a drug-device

combination product consisting of Technosphere� insulin in-

halation powder pre-metered into single-use dose cartridges for

administrationwith anAFREZZA� inhaler. Figure 1 provides

several views depicting the two inhalation devices: the palm-

sized inhaler, whichwas used in the registration trials andwhich

has been approved (a and b); and the thumb-sized device, which

will be used in the full launch. Technosphere� insulin is a

prandial insulin product that dissolves immediately upon in-

halation into the lung to deliver insulin quickly, reaching peak

insulin levels within about 15minutes of administration. Newly

presented data from a clinical trial indicate that Technosphere�

insulin is well tolerated and efficacious after 4 years of con-

tinuous treatment.[8] The following discussion outlines the

pharmacodynamic and pharmacokinetic characteristics of this

insulin product, in addition to currently available efficacy and

safety data from clinical trials.

3.1 Pharmacodynamics

Technosphere� insulin is a dry powder formulation of in-

sulin adsorbed to Technosphere�microparticles for pulmonary

administration.[9,10] The product is composed of insulin with a

carrier comprised of fumaryl diketopiperazine (FDKP), which

is a proprietary excipient of MannKind Corporation.[9] The

excipient FDKP self-assembles via hydrogen binding in a

mildly acidic environment to form microspheres of small dia-

meter (2–5 mm) that are well suited for inhalation into the deep

lung.[11] During the precipitation process that is used to form

microspheres in solution, peptides and proteins can be in-

troduced into the solution, which are then microencapsulated

within the FDKPmicrospheres.[11] Technosphere� particles are

freeze dried following microsphere formation and drug en-

capsulation to form a powder suitable for inhalation. Upon

inhalation, Technosphere� particles are readily dissolved in the

neutral pH environment of the lung, thus allowing for the rapid

and efficient absorption of microencapsulated peptides or

proteins into the systemic circulation.[11] Technosphere� tech-

nology has been studied with a variety of therapeutic agents,

including insulin, felbamate, and parathyroid hormone.[12-14]

While the route of delivery and pharmacokinetic profile of

Technosphere� insulin differ from subcutaneous insulin prep-

arations, the mechanism of insulin action remains the same

once insulin is absorbed through the lung mucosa. Given the

pharmacokinetic differences between inhaled Technosphere�

insulin and subcutaneously delivered insulin, recently presented

data indicate that endogenous glucose production may be

suppressed earlier and more effectively following Techno-

sphere� insulin administration.[15] The open-label, single-

dose, three-way crossover study utilized a meal challenge in 18

insulin-treated participants with T2DM and normal lung

function. Measurement of endogenous glucose production

showed that Technosphere� insulin suppressed glucose pro-

duction earlier than insulin lispro and Exubera� (40, 75, and

130 minutes post-dose of the median endogenous glucose

production-time profiles, respectively). Statistically significant

differences were seen between insulin lispro up to 40 minutes

post-dose compared with Technosphere� insulin (p < 0.002),and for up to 2 hours for the comparison between Exubera�

Technosphere� Insulin 167


and Technosphere� insulin (p < 0.05). Overall, these data in-

dicate that compared with other insulin formulations, Techno-

sphere� insulin may convey a suppression of endogenous

glucose production that more closely mimics that seen in

healthy non-diabetic individuals.[15]

3.2 Pharmacokinetics

Technosphere� insulin demonstrates very rapid insulin de-

livery to the blood stream to achieve a time to maximum con-

centration (tmax) of approximately 15 minutes,[9] which is

notably earlier than that achieved with all current injected in-

sulin products.[16] In turn, the mean maximum insulin con-

centration (Cmax) achieved following Technosphere� insulin

administration is notably higher than that of injected insulin.[16]

Data show that Technosphere� insulin does not compromise

tight junction function or the plasma membrane in bronchial

cells,[9] indicating that FDKP does not act as a penetration

enhancer to promote insulin absorption. Technosphere� insu-

lin delivered with the new inhaler has a relative bioavailability

of approximately 37% compared with subcutaneously ad-

ministered regular human insulin.[12] In addition to the rapid

absorption of Technosphere� insulin, it exhibits a faster elim-

ination profile compared with injected insulin, which was evi-

denced by a shorter time to half-minimum serum concentration

than subcutaneous insulin administration.[16] These pharmaco-

kinetic characteristics lend to a prandial insulin product that

is both rapidly absorbed and eliminated, closely mimicking

normal early endogenous prandial insulin release.

Following inhalation of Technosphere� insulin, insulin and

FDKP levels decline over time in the lung, with values from

lung lavage studies measuring 12%, 1.6%, and 0.3% of max-

imum at 4.8 and 12 hours post-dose, respectively.[17,18] Accum-

ulation of insulin in the lungs with long-term use is thus

a b

c d

Fig. 1. AFREZZA� is a drug-device combination product consisting of Technosphere� insulin (MannKind Corporation, Valencia, CA, USA) inhalation powder

pre-metered into single-use dose cartridges for administration with an AFREZZA� inhaler. The inhaler that has been currently approved easily fits into the palm

of a hand (a) and (b). The full launch of AFREZZA�will bewith an even smaller thumb-sized device that is expected to be available this year (c) and (d). (Images

used by permission of MannKind Corporation, ª 2010. All rights reserved.)



unlikely with Technosphere� insulin. Technosphere� insulin

appears to have dose linearity as indicated in a study performed

in people with T1DM.[19] Participants were given Techno-

sphere� insulin as either a single 30-unit cartridge or as two15-unit

cartridges.Mean insulin exposures (areaunder the concentration-

time curve [AUC]360min) were similar, and tmax and half-life

for both insulin and FDKP were the same regardless of the

number of cartridges used to administer 30 units of Techno-

sphere� insulin.

Historically, inhaled insulin preparations have been asso-

ciated with a decreased rate and extent of absorption in patients

with COPD by 20–50% compared with those without

COPD.[20] A study in patients with and without COPDassessed

the pharmacokinetic profile of Technosphere� in these

populations.[20] Neither mean peak insulin levels (34.7 and

39.5 mU/mL, p= 0.285) normedian time to achieve Cmax (15 and

12 minutes, p = 0.241) differed in the COPD and non-COPD

groups, respectively. Additionally, mean insulin exposure

from time 0 to 240 minutes post-dose (AUC240min) was 2037

and 2270 mU/mL�min (p = 0.469) for the two groups, respect-

ively, indicating that Technosphere� insulin can be used suc-

cessfully in patients with COPD.

Smoking has been associated with increases in both max-

imum and overall insulin exposure when using inhaled insulin

formulations such as Exubera�.[21] A phase I, open-label,

single-dose, euglycemic clamp study was conducted, comparing

the pharmacokinetics of Technosphere� insulin in people with

T2DM who were smokers (n = 12) versus a cohort with T2DM

who were non-smokers (n = 12).[21] Participants were adminis-

tered 30 units of Technosphere� insulin while fasting and

4–6 hours after beginning an intravenous insulin infusion

during a euglycemic clamp procedure. When measured, the

Cmax in the two study groups were 22 and 24 mU/mL in the

smoker and non-smoker groups, respectively (p = 0.905). In

the non-smoker group, tmax values were reached faster, with

reported tmax values of 20 and 12 minutes in the two groups,

respectively (p = 0.010). The mean baseline adjusted AUC480min

was not statistically different between groups; however,

the smoking cohort achieved an AUC480min of 2100 versus

1700 mU/mL�min for non-smokers (p = 0.479). Given these

findings, the investigators concluded that the absorption of

Technosphere� insulin does not appear to be significantly

altered in those who smoke.[21]

3.3 Efficacy

A randomized, open-label, two-period, crossover study by

Rave et al.[22] was performed in 16 non-smoking subjects with

T2DM. Participants were 59– 8 years of age, had a body mass

index (BMI) of 29.6– 3.3 kg/m2, and had baseline hemoglobin

A1c (HbA1c) values of 7.5– 0.8%. The study protocol included a

screening visit for assessment of participant eligibility, followed

by an initial 24-hour in-house exposure to Technosphere� in-

sulin to establish the initial dosing needs for the patient. Parti-

cipants were then cycled through two 7-day periods of receiving

daily mealtime Technosphere� insulin or subcutaneous regular

human insulin in a crossover fashion. The two study periods

were separated by a 2- to 7-daywashout period.Meal challenges

involving a standard mixed meal containing 496 kcal were

performed at the end of each 7-day study period to obtain

endpoint data for experimental comparisons. Mean insulin

doses used for the meal studies were 48– 9 units and 14– 5 unitsfor the Technosphere� insulin and regular human insulin, re-

spectively. Participants were instructed to maintain their pre-

study diet, exercise routine, and basal insulin throughout the

study period. Results of the study showed that peak blood

glucose concentrations were significantly lower with the use of

Technosphere� insulin than with regular insulin (p= 0.002),with fasting blood glucose levels being similar with both treat-

ments. Postprandial blood glucose (PPG) excursions were lower

with Technosphere� insulin than those seen with regular insulin

at 30–120minutes followingmeal challenge,with theAUC240min

following Technosphere� insulin administration being ap-

proximately 52% of that observed with regular human insulin

(p= 0.007). Overall, Technosphere� insulin appeared to have

beneficial effects on PPG compared with regular human insulin.

Another study by Rave et al.[23] aimed to assess the vari-

ability in the time action profiles of Technosphere� insulin and

regular human insulin. Thirteen participants with T2DM were

enrolled in the study, with a mean age of 56 – 7 years, a mean

BMI of 30.4 – 3.0 kg/m2, and a mean HbA1c of 6.9 – 0.9%. This

six-period, crossover, isoglycemic clamp study randomized

patients to receive three single doses each of Technosphere�

insulin with the original inhaler or subcutaneous regular human

insulin given on separate study days. Measurements of 3-hour

insulin exposure (AUC3h) demonstrated comparable insulin

exposure with the administration of 48 units of Technosphere�

insulin with the original inhaler and 14 units of regular insulin.

The new inhaler is evenmore efficient, with about 32 units being

equivalent to 48 units with the earlier device. When compared,

the time to maximum effect was shorter (79 vs 293 minutes;

p < 0.0001) and the percentage of glucose disposal during the

initial 3-hour postprandial period was higher (59% vs 27%) with

Technosphere� insulin than with regular insulin.

A larger, prospective, double-blind, placebo-controlled,

multicenter study performed in 227 participants with T2DM



aimed to characterize the dose response of four doses of

Technosphere� insulin given three times daily in combination

with insulin glargine over 11 weeks of treatment.[24] Techno-

sphere� insulin doses tested were reported in dose-equivalent

units of regular human insulin, which were 3.6, 7.3, 10.9, and

14.6 units. Participants had a duration of diabetes ranging from

3 to 20 years, with suboptimal glycemic control despite treat-

ment with ‡1 antihyperglycemic agent and/or basal insulin at

baseline (HbA1c range of 7–12%). Participants were 18–80 years

of age, had a baseline BMI <38 kg/m2, and normal lung

function at baseline. Dose-dependent reductions inHbA1c were

-0.4, -0.5, -0.5, and -0.6% for the 3.6, 7.3, 10.9, and 14.6 unit

doses, respectively, compared with baseline HbA1c values

(p < 0.05 in all groups). When compared with Technosphere�

powder placebo, placebo-subtracted HbA1c reductions were

-0.4, -0.67, -0.7, and -0.78 for the four doses tested, respect-

ively (p < 0.04 for all groups). Statistically significant decreases

in peak PPG concentrations were seen for all groups compared

with baseline, excluding the 3.6-unit dose. Overall, this study

indicates that 11 weeks of Technosphere� insulin treatment

results in dose-dependent reductions in PPG andHbA1c values.

Another 12-week, randomized, double-blind, parallel-group,

placebo-controlled, multicenter study comparing the efficacy,

safety, and tolerability of Technosphere� insulin versus Techno-

sphere� powder placebo was conducted in insulin-naive pa-

tients with T2DM (n= 126) suboptimally controlled (HbA1c

range of 6.6–10.5%) with oral therapies, and similar findingswere

reported.[25] Patients receiving Technosphere� insulin were start-

ed on 6 nominal units before each meal and titrated to a max-

imum permitted dose of 48 units per meal in 6- to 12-unit

increments based on self-monitoring of blood glucose. HbA1c

changes relative to baseline at 12weeks were -0.72% and -0.30%,

respectively (p= 0.003). PPG excursions additionally decreased

by 56% from baseline with Technosphere� insulin treatment

(p< 0.0001), and peak PPG levels were reduced by 43% when

compared with Technosphere� powder placebo (p< 0.0001).Rosenstock et al.[26] recently reported findings from a

52-week, randomized, active-control, parallel-group study with

Technosphere� insulin. Participants enrolled in the study had

T2DM inadequately controlled (HbA1c 7–11%) with insulin

plus or minus concomitant oral antihyperglycemic therapy.

Volunteers were randomized to receive either a basal/bolusregimen consisting of Technosphere� insulin plus insulin glar-

gine (n = 323), or premixed biaspart 70/30 administered twice

daily (n = 331). Following 52 weeks of therapy, similar HbA1c

reductions were seen in the Technosphere� insulin and biaspart

insulin groups (-0.58 and -0.7%, respectively). Likewise, the

percentages of patients achieving an HbA1c <7% in the two

study groups were similar, at 22% and 27%, respectively. Sta-

tistically significant differences were seen, however, in terms of

fasting plasma glucose (FPG) [171 vs 208mg/dL, p = 0.0001]and 1-hour PPG levels (-32 vs -18mg/dL, p = 0.0029) betweenthe Technosphere� insulin and biaspart insulin groups, re-

spectively. Overall, this 1-year study demonstrated comparable

HbA1c reductions between the two treatment options, with

lower 1-hour PPG and FPG levels achieved with Techno-

sphere� insulin therapy. Reductions in FPG with Techno-

sphere� insulin therapy has been consistently observed, which

is remarkable since the insulin is completely depleted long

before fasting glucose measurements in the morning.

3.4 Adverse Events and Safety

Overall, clinical trial data to date have demonstratedTechno-

sphere� insulin to be safe and well tolerated in healthy volun-

teers and in people with diabetes. As can be expected, the most

common treatment-emergent AEs associated with Techno-

sphere� insulin use are hypoglycemia and cough. In a ran-

domized, open-label, two-period, crossover study performed in

16 non-smoking subjects with T2DM, 31% of the participants

receiving Technosphere� insulin experienced one or more AEs,

compared with 25% of those receiving subcutaneous regular

human insulin.[22] Hypoglycemia was reported in 25% of the

subjects upon receiving Technosphere� insulin, while 13% re-

ported hypoglycemia with regular insulin use. Nineteen percent

(3 of 16 subjects) reported treatment-emergent cough while

using Technosphere� insulin, with none of the participants ex-

hibiting abnormal flow-volume spirometry values at follow-up.

Another crossover, single-dose study involving people with

T2DM given both Technosphere� insulin and regular human

insulin reported similar event rates for AEs.[23] During the

study, seven treatment-emergentAEswere reported: two events

upon administration of Technosphere� insulin and five upon

administration of regular human insulin. Cough was reported

in six (46%) of the study participants following six of the 39 total

Technosphere� insulin doses administered during the study.

AE data from longer term studies are also available. An

11-week study involving T2DM patients tested four doses of

mealtime Technosphere� insulin versus a Technosphere�

powder placebo on safety outcomes and glycemic control.[24]

Hypoglycemia event rates (number of events/total subject

months) ranged from 0.13 to 0.88 for the Technosphere� in-

sulin doses tested versus a rate of 0.08 for placebo. Likewise, the

event rate for cough ranged from 0.04 to 0.21 for Techno-

sphere� insulin in the study versus an event rate of 0.15 for

placebo. Regarding other AEs reported during the trial, anemia



was reported in two subjects receiving Technosphere� insulin.

Seven subjects withdrew from the study due to treatment-

emergent AEs, which included toothache (n = 1), suspected

hypersensitivity (1), hyperglycemia (4), and dissatisfaction with

blood glucose reading during the placebo run-in period (1). No

deaths occurred during the 11-week study.

Safety data from a 52-week trial were recently presented in

abstract form from a study involving participants with

T2DM.[26] Participants were randomized to receive Techno-

sphere� insulin plus insulin glargine (n = 323) or premixed

biaspart 70/30 twice-daily (n = 331). Mean changes in respira-

tory parameters were reported as being similar between groups,

and participants in the Technosphere� insulin cohort gained

less weight than those in the comparator group at 52 weeks

when compared with baseline (+0.8 vs +2.4 kg, respectively;p = 0.0002). Likewise, the incidence of both mild to moderate

hypoglycemia (47.99 vs 68.88%, p< 0.001) and severe hypo-

glycemia (4.33 vs 9.97%, p < 0.007) were less in the Techno-

sphere� insulin group compared with the insulin biaspart

group, respectively.

4. Discussion

Insulin treatment is one of the most clinically useful and

cost-effective ways of treating diabetes. Insulin therapy is a

necessity in T1DM, and in T2DM it can meet the needs of most

patients and has the best outcomes related to HbA1c reduction.

Studies with Technosphere� insulin have shown it to be a

unique insulin formulation in that it is very rapid acting, has a

relatively short duration of action, and is efficacious without

the same degree of weight gain and incidence of hypoglycemic

events observed in studies comparing Technosphere� insulin

with subcutaneous regular human and rapid-acting insulins.

Technosphere� insulin has demonstrated a favorable safety

and tolerability profile in clinical studies to date, and the in-

halation device is small, easy to store and carry, and easily used

by healthcare practitioners and patients. The procedure for

loading the insulin powder units to administer the Techno-

sphere� insulin is simple when compared with previous de-

vices. In fact, three studies to date in patients with T1DM and

T2DM report significant treatment satisfaction for users of

Technosphere� insulin.[27-29] Given the challenges associated

with Exubera� that we have previously discussed, therapy ac-

ceptance is amajor concern for any new inhaled insulin product.

The characteristics of Technosphere� insulin make it a

viable treatment option for use in both T1DM and T2DM.

T1DM patients could conceivably administer basal insulin,

such as insulin glargine or insulin detemir, once daily in con-

junction with Technosphere� insulin for bolus administration

to cover prandial insulin needs. Given the pharmacokinetic

profile of Technosphere� insulin, this dosing paradigm would

closely mimic the physiologic insulin release in people without

diabetes. Correction doses for patients with elevated PPG levels

could likewise be administered using Technosphere� insulin.

Although the risk of hypoglycemia is inherent with any insulin

product, clinical data to date with Technosphere� insulin in-

dicate that this risk may be minimized compared with other

prandial insulin products.

Likewise, Technosphere� insulin could also be promoted as

an ideal insulin for use in T2DM patients, particularly those

who are resistant to initiating subcutaneous insulin because of a

fear of self-injection. The primary physiologic problem related

to insulin secretion in patients with T2DM is that the first-phase

insulin release fails as blood glucose levels rise secondary to

insulin resistance in fat, muscle, and liver. AT2DMpatient who

is still releasing basal insulin could utilize Technosphere� in-

sulin and overcome a deficient first-phase insulin response to

glucose intake. Many patients with T2DM could benefit from

the use of Technosphere� insulin before meals to manage

problematic postprandial glucose excursions. Although many

physicians opt to prescribe basal insulin alone in T2DM

patients, many patients may be better served by effectively

addressing prandial insulin needs. In turn, as T2DM patients

experience disease progression, a basal insulin product could be

added as a once-daily regimen as the need for basal insulin

becomes more evident in the face of worsening b-cell function.While many prescribers are reluctant to initiate prandial insulin

therapy in patients with T2DM because of the risk of hypo-

glycemia and the increased need for patient teaching and

monitoring, Technosphere� insulin has the potential to treat

the T2DM patient in a simpler fashion when compared with

other currently available choices.

5. Conclusions

The data available to date related to Technosphere� insulin

are promising and include the following: (i) Technosphere�

insulin is generally well tolerated with a low variability in effect;

(ii) it demonstrates a favorable pharmacokinetic profile that

more closely mimics normal prandial insulin release; (iii) it has

demonstrated efficacy in terms of postprandial and overall

glycemic control; (iv) it has shown promising user safety in

terms of pulmonary function; and (v) the absorption of Techno-

sphere� insulin is not significantly altered in patients with

COPD or in those who smoke. Additionally, despite the con-

cerns about the potential of lung carcinoma with Exubera�,



there has been no evidence to date of any link to the use of

Technosphere� insulin; however, continued monitoring is

warranted. Although Technosphere� insulin appears to be a

very promising new dosage form for administering insulin,

there are hurdles associated with the approval of pulmonary

insulin products. One of the main hurdles is the lack of support

for Exubera� that has already been discussed. Until a pul-

monary product is marketed for years and is able to demon-

strate long-term safety in regard to pulmonary function, the

concern over deleterious effects on pulmonary function may

continue to exist. However, the FDA is currently reviewing

Technosphere� insulin for use in both T1DM and T2DM.

Based on clinical trial data that indicate the product to be

safe and effective, this new product may soon be added to the

diabetes treatment armamentarium.

Acknowledgments

No sources of funding were used to assist in the preparation of this

review. The authors have no conflicts of interest that are directly relevant

to the content of this review.

References1. KorytkowskiM.When oral agents fail: practical barriers to starting insulin. Int

J Obes Relat Metab Disord 2002; 26 Suppl. 3: S18-24

2. Heinemann L, Pfutzner A, Heise T. Alternative routes of administration as an

approach to improve insulin therapy: update on dermal, oral, nasal, and

pulmonary insulin delivery. Curr Pharm Des 2001; 7: 1327-51

3. Siekmeier R, Scheuch G. Inhaled insulin: does it become reality? J Physiol

Pharmacol 2008; 59 Suppl. 6: 81-113

4. CefaluWT. Concept, strategies, and feasibility of non-invasive insulin delivery.

Diabetes Care 2004; 27: 239-46

5. Setter SM, Levien TL, Iltz JL, et al. Inhaled dry powder insulin for the treat-

ment of diabetes mellitus. Clin Ther 2007; 29: 795-813

6. Kling J. Inhaled insulin’s last gasp? Nat Biotechnol 2008; 26: 479-80

7. Heinemann L. The failure of Exubera: are we beating a dead horse? J Diabetes

Sci Technol 2008; 2: 518-29

8. Amin N, Boss A, Richardson P. Long-term sustained safety and efficacy of

continued use of technosphere insulin in subjects with type 2 diabetes [abstract

no. OP215]. Diabetologia 2009; 52 Suppl. 1: S94

9. Angelo R, Rousseau K, Grant M, et al. Technosphere� insulin: defining the

mechanismof action [abstract no. 428-P].DiabetesCare 2008; 57Suppl. 1:A128

10. Pfutzner A, Mann AE, Steiner SS. Technosphere/insulin: a new approach for

effective delivery of human insulin via the pulmonary route. Diabetes Technol

Ther 2002; 4: 589-94

11. Pfutzner A, Forst T. Pulmonary insulin delivery bymeans of the Technosphere�drug carrier mechanism. Expert Opin Drug Deliv 2005; 2: 1097-106

12. Steiner S, Pfutzner A,Wilson BR, et al. Technosphere/insulin-proof of conceptstudy with a new insulin formulation for pulmonary delivery. Exp Clin En-

docrinol Diabetes 2002; 110: 17-21

13. Pfutzner A, Flacke F, Pohl R, et al. Pilot study with technosphere/PTH(1-34):

a new approach for effective pulmonary delivery of parathyroid hormone

(1-34). Horm Metab Res 2003; 35: 319-23

14. Lian H, Steiner SS, Sofia RD, et al. A self-complementary, self-assembling

microsphere system: application for intravenous delivery of the antiepileptic

and neuroprotectant compound felbamate. J Pharm Sci 2000; 89: 867-75

15. Potocka E, Hovorka R, Baughman R et al. Technosphere insulin suppresses

endogenous glucose production earlier than a rapid-acting analogue (lispro)

and an inhaled insulin (Exubera) [abstract no. 952]. Diabetologia 2009; 52

Suppl. 1: S374

16. Rave K, Potocka E, Boss AH, et al. Pharmacokinetics and linear exposure of

AFRESA� compared with the subcutaneous injection of regular human

insulin. Diabetes Obes Metab 2009; 11: 715-20

17. Cassidy JP, Marino MT, Amin N, et al. Lung deposition and absorption of

insulin from AFRESA� (Technosphere� insulin) [abstract no. 433-P]. Dia-

betes Care 2009; 58 Suppl. 1: A115

18. Gotfried M, Cassidy J, Marino M, et al. Lung deposition and absorption of

insulin from technosphere insulin [abstract no. 955]. Diabetologia 2009; 52

Suppl. 1: S375

19. Cassidy JP, Baughman RA, Schwartz SL, et al. AFRESA� (Technosphere�

insulin) dosage strengths are interchangeable [abstract no. 425-P]. Diabetes

Care 2009; 58 Suppl. 1: A112-3

20. Richardson P, Potocka E, Baughman R, et al. Pharmacokinetics of techno-

sphere insulin unchanged in patients with chronic obstructive pulmonary

disease [abstract no. 954]. Diabetologia 2009; 52 Suppl. 1: S375

21. Baughman R, Cassidy J, Levy B, et al. Technosphere� insulin (TI) pharm-

acokinetics unchanged in subjects who smoke [abstract no. 427-P]. Diabetes

Care 2008; 57 Suppl. 1: A128

22. Rave K, Heise T, Pfutzner A, et al. Coverage of postprandial blood glucose

excursions with inhaled technosphere insulin in comparison to sub-

cutaneously injected regular human insulin in subjects with type 2 diabetes.

Diabetes Care 2007; 30: 2307-8

23. Rave K, Heise T, Heinemann L, et al. Inhaled Technosphere� insulin in

comparison to subcutaneous regular human insulin: time action profile and

variability in subjects with type 2 diabetes. J Diabets Sci Technol 2008; 2: 205-12

24. Tack CJ, Christov V, de Galan BE, et al. Randomized forced titration to

different doses of Technosphere� insulin demonstrates reduction in post-

prandial glucose excursions and hemoglobin A1c in patients with type 2

diabetes. J Diabets Sci Technol 2008; 2: 47-57

25. Rosenstock J, Bergenstal R, DeFronzo RA, et al. Efficacy and safety of

technosphere inhaled insulin compared with technosphere powder placebo in

insulin-naı̈ve type 2 diabetes suboptimally controlled with oral agents. Dia-

betes Care 2008; 31: 2177-82

26. Rosenstock J, Lorber DL, Petrucci RE, et al. Basal/bolus with prandial inhaledTechnosphere� insulin (TI) plus insulin glargine QD vs biaspart 70/30 insulinBID in T2DM inadequately controlled on insulin with/without oral agents[abstract no. 466-P]. Diabetes Care 2009; 58 Suppl. 1: A124

27. Rubin RR, Peyrot M. Patient reported outcomes in adults with type 1 diabetes

using mealtime AFRESA� (inhaled Technosphere� insulin) or rapid-acting

insulin with basal insulin [abstract no. 1881-P]. Diabetes Care 2009; 58 Suppl.

1: A484

28. Howard CP, Rubin RR, Peyrot M. Patient reported outcomes in adults with

type 2 diabetes using mealtime AFRESA� (inhaled Technosphere� insulin)

and basal insulin versus premixed insulin [abstract no. 551-P]. Diabetes Care

2009; 58 Suppl. 1: A148

29. Peyrot M, Rubin RR. Patient reported outcomes in adults with type 2 diabetes

using mealtime AFRESA� (inhaled Technosphere� insulin) or metfor-

min+secretagogue or both [abstract no. 552-P]. Diabetes Care 2009; 58 Suppl.

1: A148

Correspondence: Dr Joshua J. Neumiller, Department of Pharmacotherapy,

Washington State University, P.O. Box 1495, Spokane, WA 99210-1495, USA.

E-mail: [email protected]



technosphere® insulin

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