Inhaled Insulin Products

Delivered February 25th, 2018. Contributors: Nicole C., Kate H., Hans R. and

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Overview of Inhaled Insulin Products

After an extensive search, we found a list of inhaled insulin products that have been developed thus far: Exubera, AIR, Spiros, Technosphere, PROMAXX, Aerodose Insulin, and AERx Insulin. Technosphere was later renamed to Afreeza.

Because case studies for Exubera and Afreeza will be covered in a different Wonder request, the two companies will not be explained in full detail for this particular request.

Unfortunately, after extensive research, besides the product Afreeza, there are no other case studies of successful products nor current inhaled insulin products in development that are openly available to be found. Currently, Afreeza is the only inhaled insulin product that is FDA-approved and has not been discontinued. Its 4 biggest competitors, Exubera, AERx Insulin, Aerodose Insulin, and AIR have already been discontinued.

There is a lack of recent information publicly available for products Spiros and PROMAXX. This may be due to the fact that pharmaceutical companies may be guarding the development status of these products. PROMAXX completed phase I clinical studies in December 2005, and although additional clinical data was added in 2007, there haven't been any recent news on the status of its current development.

Under the company Alkermes, AIR, an inhaled insulin product using a dry powder form of insulin, was discontinued at Phase-III for Type-1 diabetes mellitus in 2008 after their funding partner, Eli Lilly, terminated the development and license agreement.

Case studies for AERx Insulin, which was discontinued after news of its competitor Exubera's failure, and Aerodose Insulin, which was discontinued due to lack of funding, were used as representatives of failed products and have been provided below. 

FailED CASE STUDIESCASE STUDY # 1: AERx Insulin Diabetes Management SystemThe AERx Insulin Diabetes Management System "delivers an aerosol of liquid insulin" into the lung. It features a unique system that only delivers the drug to the lung if the patient is breathing optimally and correctly. This is important since optimal breathing allows the insulin to be better deposited and absorbed by the lung. By using strips of liquid insulin, dosage can be adjusted to the nearest unit, similar to insulin injections. There is also a datadownloading and monitoring aspect that saves and monitors session data, allowing patients, physicans, and clinicians to review data on dose administration and breathing patterns, as well as information on patient compliance. Both type 1 and type 2 diabetes mellitus patients have been studied for this system.

PHYSICAL PRODUCT
To be more precise, the device was a "microprocessor-controlled inhaler" that monitored the patient's breathing patterns by actuating "when a combination of breathing parameters fell to a predetermined range." The insulin would move through a single-use nozzle that created a fine mist. In order to release the mist in a uniform manner, hundreds of 1 μm holes were contained in the nozzle.

STUDY RESULTS
"Compared with subcutaneous human insulin, the pharmacokinetic and pharmacodynamic profile of inhaled insulin with AERx iDMS is similar, but with a more rapid onset of action." Data from the studies demonstrated that using AERx iDMS is "as consistent and reproducible as subcutaneous human insulin." A study in 2007 concluded that, "no major safety concerns have been raised with respect to pulmonary function tests." In 2005, it was reported that according to the preliminary data at that time, patients transitioning from injections to AERx iDMS "showed higher compliance to therapy, demonstrated by improved glycemic control."

DISCONTINUED
However, in 2008, "Novo Nordisk elected to discontinue further study with the AERxiDMS system given the experience of Pfizer with Exubera." Further information on the reasoning for discontinuing AERx iDMS couldn't be found, however it was evident that the failure of the competitor product Exubera affected the owners of AERx iDMS to the point of discontinuing the product.

CASE STUDY #2: Aerodose Insulin Aerodose Insulin used a breath-activated inhaler to deliver liquid insulin. A cartridge was incorporated to be able to adjust the dosage based on insulin requirements. 

RESEARCH STUDY: METHODS
The product was studied in a small group of 15 patients (nonsmokers, 10 men, aged 47-77 years) with type 2 diabetes mellitus. The patients received two 240-unit doses of INH via inhaler and another "two 24-unit doses of SC under euglycemic clamp conditions on four separate study days." Over the next 8 hours, glucose infusion rates (GIRs) and serum insulin concentrations were closely monitored.

RESEARCH STUDY: RESULTS
When comparing the related coefficients of variation (CV), there were "no significant differences between the treatments during 0-3 hours (19% for INH versus 23% for SC) or 0-8 hours (22% for INH versus 16% for SC)." The INH, which again, were delivered via inhaler, "exhibited a shorter peak insulin concentration" and "shorter time to peak metabolic effect" compared with SC (P < 0.001). It was also reported that "no adverse events were observed." 

RESEARCH STUDY: CONCLUSIONS
The study concluded that the "comparable dosing reproductibility and shorter time to peak action" of the INH delivered via inhaler to the SC "suggest that INH delivered via the Aerodose Insulin Inhaler can provide reliable preprandial dosing of insulin in patients with type 2 diabetes."

DISCONTINUED
Although Aerogen Corporation saw promising results, the company  "failed to secure a financial partner and halted development of the product in January 2003."

ConclusionAfter an extensive search, we found a list of inhaled insulin products that have been developed thus far: Exubera, AIR, Spiros, Technosphere, PROMAXX, Aerodose Insulin, and AERx Insulin. Technosphere was later renamed to Afreeza. However, some lacked any current information on their development, while others had already been discontinued. AERx Insulin, which was discontinued after news of its competitor Exubera's failure, and Aerodose Insulin, which was discontinued due to lack of funding, were used as case studies for failed inhaled insulin products. The only truly successful product was Afreeza as the only inhaled insulin product that is FDA-approved and has not been discontinued.

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Competitive Analysis for Dance Biopharm

While information regarding market research analysts' perspectives on Dance Biopharm's inhaled insulin product is extremely limited due to the product still being in development, it is slated to be a commercial success based on the strong need for diabetes medication, the preference of inhaled insulin over injectable and oral forms, and positive reviews the company has already received from industry professionals. 
MARKET RESEARCH ANALYSTS' PERSPECTIVESAfter thorough research, we found one market research analyst's perspective on Dance Biopharm's new product. The analyst makes a thorough comparison of Dance Biopharm and its competitor Afrezza, and expects Dance Biopharm's new product to avoid the pitfalls of its competitor and be a commercial success. In addition, while Dance Biopharm is privately held, the analyst suspects that the company will go public in the near future, thereby gaining a dramatic increase in attention and garnering additional "deep pocket supporters." Key points of the analyst's perspective:

•	While Afrezza was forced to include a boxed warning on its packaging due to a lack of data concerning people with lung conditions, 
Dance Biopharm is currently in the midst of clinical trials with people suffering from chronic obstructive pulmonary disease (COPD) and expects to have results mid-2018, which can potentially offset FDA concerns.

•	Dance Biopharm already has the support of several investors and thus has the potential to maintain this support after its product is released.

•	Due to the exact dosing of Dance Biopharm's device, the company has the potential to attract the support of insurance companies, as the cost of treatment will be more easily regulated.
FACTORS CONTRIBUTING TO DANCE BIOPHARM'S POTENTIAL COMMERCIAL SUCCESSSTRONG NEED FOR DIABETES MEDICATION
The International Diabetes Federation (IDF) estimated that roughly 415 million people suffer from diabetes worldwide, and this number is expected to increase to approximately 642 million by 2040.  Based on the fact that diabetes is on the rise, we assume that there is and will continue to be a strong need for diabetes medication. 

PREFERENCE OF INHALED INSULIN OVER OTHER FORMS
 Dr. David Klonoff, Medical Director of the Diabetes Research Institute at the Mills-Peninsula Medical Center in San Mateo, California, states that "inhaled insulin works faster than injected insulin because it reaches the lung tissue immediately upon inhalation. From there it can diffuse into the bloodstream faster than an insulin molecule injected into the skin."  This faster rate of insulin absorption can eliminate the challenges diabetics often face at mealtime. Furthermore, according to a market research report by Technavio, insulin inhalers are among the most preferred forms of insulin administration by most diabetics. Based on these insights, we can conclude that there is a need for inhaled insulin and that it is preferred over injectable and oral forms. 

CURRENT POSITIVE REVIEWS
According to Bill Welch, Chief Technology Officer of Phillips-Medisize, technological advancements in how devices deliver drugs have improved reliability and adherence to therapy. He called Dance Biopharm's new breathable insulin device technology a "game changer" for individuals with diabetes. Dr. Augustine Chow, Chairman of Harmony Asset Management Group, also gave Dance Biopharm a positive review, stating, “[f]rom the first day I saw [Dance Biopharm's] technology, I knew they had a winner. We believe in the great potential that [their product] holds for the treatment of diabetes.”
KEY PIVOT FACTORS FOR SUCCESSAVOIDING THE PITFALLS OF COMPETITORS' PRODUCTS
Given that Dance Biopharm's product is still in the development stage, the company has the opportunity to analyze the pitfalls faced by competitors, such as Exubera and Afrezza, and avoid them.

Exubera's inhaled insulin product was abandoned due to safety concerns and patients' dislike of the large size of the delivery device, which they found cumbersome. Dance Biopharm, however, will likely avoid these pitfalls, as its product consists of a pocket-sized handheld electronic inhaler and "patented vibrating mesh technology, designed to produce consistently sized particles of liquid insulin in the form of a soft mist, allowing the efficient and consistent delivery of insulin into the lungs in a few breaths." The small size of the product will also allow Dance Biopharm to keep shipping, storage, and overhead costs low.

Afrezza's product, while still on the market, raises only $1M per quarter. The many ways in which Dance Biopharm's product differs from that of Afrezza suggests that Dance Biopharm can avoid the factors that lead to Afrezza's poor performance. For example:

•	While Afrezza's device delivers insulin in the form of dry powder that causes coughing in many patients, Dance Biopharm's insulin formulation is packaged as a liquid in a separate container and is administered in the form of a soft mist that mitigates coughing and will therefore avoid a primary complaint of Afrezza users.
•	Afrezza's device requires patients to buy cartridges containing a fixed dose that does not match the dosing needs of every patient (users are often left with extra insulin or do not have enough). However, Dance Biopharm's device can be dosed for the patient's exact needs, eliminating waste and allowing for a more exact cost of treatment. 
•	Unlike Afrezza's cartridges and inhaler, which must be purchased monthly, there is only a one-time cost for Dance Biopharm's device.

AVOIDING POTENTIAL PITFALLS SPECIFIC TO DANCE BIOPHARM
Several potential pitfalls could thwart the success of Dance Biopharm's inhaled insulin product should the company not address them. Firstly, while the device is smaller than Exubera's device, it is bigger than that of Afrezza. Secondly, the vials do not contain single doses which means users have no choice but to constantly carry multiple doses. Finally, the pharmacokinetic/pharmacodynamic (PK/PD) profile of the insulin the company has developed, which has not yet been published, could present a problem if patients' pharmacological response to the drug is not satisfactory.
CONCLUSIONIn conclusion, while information regarding market research analysts' perspectives on Dance Biopharm's inhaled insulin product is limited due to the product still being in development, available analysis strongly suggests that the Dance Biopharm device will be a commercial success. An increase in diabetes patients (leading to an increased need for diabetes medication), the preference of inhaled insulin over other forms, and positive reviews of Dance Biopharm by industry professionals also strongly suggest that the product will succeed in the market. Finally, Dance Biopharm has created a product that avoids many of the pitfalls that the failed inhaled insulin products Exubera and Afrezza faced. As long as Dance Biopharm can avoid the potential pitfalls specific to the company itself, its new product will likely succeed where its competitors could not.

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Exubera v Afrezza

The detailed compilation was done for the failure of Exubera which is mainly attributed to less volume of sales vs investment ($2.8 billion), due to the following: 
•	Not more effective over conventional therapies, 
•	Inconvenient design of inhaler for administration, 
•	Lack of safety profile with studies relating to the increase in incidence of lung cancer, and
•	No cost-effective provided over conventional therapies.

The launch of Afrezza in 2014 also didn't highlight much success mainly due to: 
•	Ineffective marketing with conflict of interest for other Sanofi's brands,
•	Lack of insurance coverage, and
•	Lack of patient and physician awareness.

Afrezza offered a significant advantage over Exubera and conventional therapies with the new design of inhalation device, better safety profile, and faster and more specific action. It is looking for the current developments and managements of future expectations like dedicated sales force as well as inclusion in 70% of insurance companies list without prior authorization, also Bluetooth connected inhalation device as a prospective offering.
EXUBERA
 According to NCBI, the Exubera insulin inhalation system was approved by the FDA and EC back in January 2006, making this the first inhalation system of this kind to be approved by the FDA and EC. This insulin inhalation system was designed to manage type 1 and 2 diabetes mellitus (DM) in adults. After less than two years of its approval, the product was taken out of the market, causing a setback for competitive new insulin inhalation systems that were already in various clinical development phases. As opposed to Pfizer, MannKind Corporation started developing Afrezza, an ultra-rapid-acting insulin in an audacious bid. Afrezza got FDA approved in June 2014 and has been marketed since February 2014. 

 Soon after Pfizer got the approval for Exubera, research showed that inhaled insulin “appears to be as effective, but no better than injected short-acting insulin”. Exubera, which was taken out of the market after a year of its launch, had a cost of $2.8 billion USD after having no success at winning over patients nor physicians. By 2007, it was taken out of the market due to poor sales and a possible association with lung cancer risk. 

 Studies demonstrated statistically that subjects taking Exubera had a greater decline in pulmonary function compared to those taking placebos, the decline stayed for the duration of the therapy (2 years). With this new information available, they had to increase precautionary actions such as, increased monitoring, a safety label change had to be issued regarding lung cancer when six new cases of lung malignancies where found on patients that were using Exubera. Although this evidence was not robust enough to show a correlation with Exubera, it instilled fear in patients and providers.  
AFREZZA
 Afrezza, a product developed by MannKind Corporation, is an ultra-rapid-acting insulin inhalation system that got its FDA approval in June 2014 and has been marketed since February 2015. MannKind Corporation admitted having a lower sales volume during the initial launch (first 21-week period) in comparison to Exubera’s launch. According to Matthew Pfeffer, the CFO of MannKind the reason for having lower sales than they should have initially, it was not a problem with the product, but on the sales efforts that were not up to the mark for marketing the product. Also, when it comes to new products there are barriers from insurers which require prior authorization for inclusions and also physicians take extra care when prescribing a new drug.  Due to these drawbacks, by the end of 2015, they only delivered $7.5 million in a total of sales. 

 In January 2016, Sanofi decided to drop the marketing of Afrezza, by November 2016 Mannkind’s stock fell from $7.25 USD to $2.05. By May 2017 it dropped even further to an all-time low of $0.67 USD per share.
WHY EXUBERA FAILED?There are a number of reasons that contributed to the failure of Exubera, which are given below:
•	Exubera was more expensive than the injectable insulin, costing $5 a day as opposed to $2 or $3 of the conventional treatment at that time.
•	The design was unappealing for patients, some sources describing it as “bulky and inconvenient”. 
•	The dosing was confusing; the foil powder packets that were measured in 3 or 9 milligrams were easily mixed up and confused the patients and doctors and made it complicated to equate to familiar dosing levels.
•	According to Healthline, the core problem was the unfeasible design of the inhaler.
•	It was the first inhaled insulin system, but they had to withdraw the product due to poor sales. 
•	They had a pretax loss of $2.6 billion on Exubera. 
•	The needle delivery technology had improved by that time, the improvement was such that physicians and patients were content to stick with the conventional treatment to keep diabetes under control. 
•	The FDA approval of Exubera came with the condition of conducting extensive clinical trials to understand the impact of administering insulin through the lungs and this led to a financial burden. 
•	In 2012, the FDA received final data on the FUSE study, this study was meant to follow patients who had been exposed to Exubera in clinical tries, and the study showed 12 cases of lung cancer in 11,180 patients-years exposed to Exubera, comparator-exposed patients — 3 cases of lung cancer in 10,468 patients-years, with an incidence density ratio of 3.75 (CI 1.01-20.68) 
AFREZZA OVER EXUBERA
 One of the main advantages that Afrezza has over Exubera is the formulation; it is fast-acting and the insulin comes in powder form. It is delivered in the arterial blood system instead of the capillary system. 

 The time it takes to act is also an advantage, Afrezza peaks within 12 to 15 minutes and it stays in the system for about an hour. If we compare this to the current fast-acting insulins that usually take at least 20 minutes to kick in, peak at 2-3 hours, and can last in the system for as long as five hours. We can see why this is a huge advantage that Afrezza offers as opposed to its competitors. 

The design, based on the design provided by Afrezza, also suggests that they learned from Exubera mistakes when it comes to inhaler designs. The Dreamboat inhaler can fit in the palm of one’s hand, it is convenient and makes you avoid injections without having to carry with you a bulky device. 

 Delivery system used by Afrezza is called “Technosphere” and allows for quicker and more complete clearance of insulin from lung tissue; whereas with Exubera, “the insulin concentration in epithelial lung fluid 12 hours after a dose was about 8 — 9% of the concentration immediately after a dose.” With Afrezza, “the concentration at 12 hours after a 60-unit dose was 0.3% of the concentration recorded immediately after the dose.”
 The Afrezza PI reports showed that there were also 4 cases of lung cancer in patients exposed to Afrezza in clinical trials while there are no cases reported in the comparator groups. 
 Research also showed that the few patients that used Exubera, quickly decided to go back to injections because administering the proper dosage was extremely complicated, while Afrezza addresses this problem by making the dosage way easier. 
 With Afrezza, the modifications of the design and the delivery system, allow for a more discreet administration process and a dosing regiment that is simpler for both patients and prescribers.  
 Afrezza showed superiority over conventional therapies, their insulin is broken its monomeric components. Thanks to this, they can significantly shorten the time to reach insulin peak levels compared to Exubera. For Afrezza it takes up to 14 minutes to peak while it can take up to 49 minutes for Exubera. 
 The monomeric formulation of Afrezza is also reputed to more closely mimic the natural insulin response of a healthy person as well as decrease the risk of gain weight or hypoglycemia. 
 As of February 2017, 70% of Americans with commercial health insurance had gained access to Afrezza. 
CONCLUSION
Afrezza offered a significant advantage over Exubera and conventional therapies with the new design of inhalation device, better safety profile, faster and more specific action.
Afrezza is looking for the current developments and management of future expectations like dedicated sales force as well as an already confirmed inclusion in 70% of insurance companies list without prior authorization, also Bluetooth connected inhalation device as a prospective offering.