10
Questions & Answers About MannKind Corporation and AFRESA™ Company Overview 1. What is MannKind’s purpose/mission? MannKind Corporation is a biopharmaceutical company focused on the discovery, development, and commercialization of therapeutic products for diseases such as diabetes and cancer. 2. What products are you working on currently? We recently completed pivotal phase 3 clinical trials of our lead investigational product candidate, AFRESA™. These trials were conducted in the United States, Canada, Europe, and Latin America. AFRESA™ utilizes our proprietary Technosphere® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. Currently we are conducting clinical trials to evaluate the safety and efficacy of another Technosphere® based product for the treatment of diabetes and are developing additional formulations of active compounds loaded onto Technosphere® particles, including a treatment of obesity. In addition to our Technosphere® platform, we are developing therapies for the treatment of different types of cancer. We are currently conducting clinical trials of our therapeutic cancer vaccines. We are also engaged in the discovery and development of drugs that selectively interfere with the cellular processes associated with cancer cells. 3. What is AFRESA™? AFRESA™ (insulin human [rDNA origin]) Inhalation Powder is the trade name that Mannkind has proposed to the FDA for it inhaled insulin product, formerly known as the Technosphere® Insulin System. 4. What is your overall strategy as a company? Our overall strategy is to: 1. Establish AFRESA™ as the preferred mealtime therapy for patients with diabetes. 2. Expand our proprietary Technosphere® platform technology and develop additional applications for the pulmonary delivery of other drugs. 3. Develop novel approaches to treating cancer and using our immunotherapy and targeted drug therapies.

Mannkind Q&A: About Afrezza

Embed Size (px)

Citation preview

Page 1: Mannkind Q&A: About Afrezza

Questions & Answers About MannKind Corporation and AFRESA™

Company Overview 1. What is MannKind’s purpose/mission?

MannKind Corporation is a biopharmaceutical company focused on the discovery, development, and commercialization of therapeutic products for diseases such as diabetes and cancer.

2. What products are you working on currently?

We recently completed pivotal phase 3 clinical trials of our lead investigational product candidate, AFRESA™. These trials were conducted in the United States, Canada, Europe, and Latin America.

AFRESA™ utilizes our proprietary Technosphere® formulation technology, which is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded. Currently we are conducting clinical trials to evaluate the safety and efficacy of another Technosphere® based product for the treatment of diabetes and are developing additional formulations of active compounds loaded onto Technosphere® particles, including a treatment of obesity.

In addition to our Technosphere® platform, we are developing therapies for the treatment of different types of cancer. We are currently conducting clinical trials of our therapeutic cancer vaccines. We are also engaged in the discovery and development of drugs that selectively interfere with the cellular processes associated with cancer cells.

3. What is AFRESA™?

AFRESA™ (insulin human [rDNA origin]) Inhalation Powder is the trade name that Mannkind has proposed to the FDA for it inhaled insulin product, formerly known as the Technosphere® Insulin System.

4. What is your overall strategy as a company?

Our overall strategy is to:

1. Establish AFRESA™ as the preferred mealtime therapy for patients with diabetes.

2. Expand our proprietary Technosphere® platform technology and develop additional applications for the pulmonary delivery of other drugs.

3. Develop novel approaches to treating cancer and using our immunotherapy and targeted drug therapies.

Page 2: Mannkind Q&A: About Afrezza

2

4. Enter into sales and marketing collaborations with other companies, if available on commercially reasonable terms, or develop these capabilities ourselves.

5. When was MannKind started?

The company was founded and incorporated in the State of Delaware in 1991. 6. Who is on the MannKind Board of Directors?

See attachment. 7. Who are your scientific advisors

See attachment. 8. Who is your executive leadership team?

See attachment. 9. Where are the company operations?

Corporate headquarters and certain clinical research and development facilities are located in Valencia, CA. Additional clinical research and development and regulatory affairs operations are located in Paramus, NJ. Technical operations and manufacturing are located in Danbury, CT.

10. How many employees do you have worldwide?

As of March 31, 2008, MannKind had 609 full-time employees. Diabetes 11. What is diabetes?

Diabetes is a major disease characterized by the body’s inability to properly regulate levels of blood glucose, or blood sugar. The cells of the body use glucose as fuel over the 24 hours of each day. Between meals, when glucose is not being supplied from food, the liver releases glucose into the blood to sustain adequate levels.

Insulin is a hormone produced by the pancreas that regulates the body’s blood glucose levels. 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 insulin produced by the body. Over time, poorly controlled levels of blood glucose can lead to major complications, including high blood pressure, blindness, amputation, kidney failure, heart attack, stroke, and death.

There are two major forms of diabetes, type 1 and type 2. Type 1 diabetes is an autoimmune disease characterized by a rapid and complete loss of insulin secretion by the pancreas, so

Page 3: Mannkind Q&A: About Afrezza

3

insulin must be supplied from outside the body in order to sustain life. In type 2 diabetes, the pancreas continues to produce insulin; however, 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.

12. How prevalent is diabetes?

According to the United States Centers for Disease Control, or CDC, approximately 20.8 million people in the United States, or 7% of the population, suffered from diabetes as of 2005. The CDC estimated that 14.6 million cases of diabetes were diagnosed and under treatment and that 1.5 million new cases would be diagnosed in 2005. More troubling is the fact that the incidence of diabetes is increasing. A study published by Diabetes Care in 2006 projected that in 2050 there would be 48.3 million people with diagnosed diabetes in the United States. According to the CDC, type 2 diabetes is the more prevalent form of the disease, affecting approximately 90% to 95% of people diagnosed with diabetes.

13. What are the consequences and costs to society of diabetes?

The CDC reported that diabetes was the sixth leading cause of death listed on death certificates in 2002, but that diabetes was likely to be underreported as a cause of death. Overall, the CDC found that the risk of death among people with diabetes is about twice that of people without diabetes of similar age. The economic costs of diabetes are high as well. The American Diabetes Association estimated that, in 2007, the total cost of diabetes in the United States was $174 billion, an increase of 32% since 2002. This amount includes $28 billion of direct costs for drug treatment for glucose control, of which approximately $6 billion were for insulin and delivery supplies and approximately $9 billion were for non-insulin oral medications.

14. What are the treatments for diabetes?

The primary treatment for type 1 diabetes is daily intensive insulin therapy. When patients with type 2 diabetes are first diagnosed, the initial therapy is typically lifestyle intervention, but ultimately many patients with type 2 diabetes will require insulin therapy in order to maintain appropriate levels of blood glucose.

15. What are the limitations of currently available insulin products?

Although insulin therapy is accepted as an effective means to control glucose levels, the available insulin products have limitations, including:

the risk of severe hypoglycemia, which is abnormally low levels of blood glucose that result from excessive insulin administration. Hypoglycemia can result in loss of mental acuity, confusion, increased heart rate, hunger, sweating and faintness and, at very low glucose levels, loss of consciousness, seizures, coma, and death;

the likelihood of weight gain;

inadequate post-meal glucose control;

the need for complex titration of insulin doses in connection with meals; and

Page 4: Mannkind Q&A: About Afrezza

4

the need for injections.

16. Are there other problems with currently available insulin therapies?

Because of the limitations mentioned above, patients tend not to comply with the prescribed treatment regimens and are often undertreated.

More importantly, even when properly administered, subcutaneous injections of insulin do not replicate the natural time-action profile of insulin. In a person without diabetes, blood insulin levels rise within several minutes of the entry into the bloodstream of glucose from a meal. By contrast, injected insulin enters the bloodstream slowly, resulting in peak insulin levels in about 120 to 180 minutes for regular human insulin or 30-90 minutes for so-called “rapid-acting” insulin analogs.

The consequence of these slower acting insulins is that patients do not have adequate levels of insulin present at the initiation of a meal and tend to be over-insulinized between meals. This lag in insulin delivery results in hyperglycemia early after meal onset, followed by a tendency for hypoglycemia to develop during the period between meals.

Physicians who treat patients with diabetes are concerned about the risks of hypoglycemia and, as a result, tend to undertreat the chronic hyperglycemia that is associated with the disease. However, the resultant extensive hyperglycemia significantly contributes to many of the long-term cardiovascular and other serious complications of diabetes.

AFRESA™ (insulin human [rDNA origin]) Inhalation Powder 17. What is AFRESA™ and how does it work?

We formulate AFRESA™ by loading insulin molecules onto our proprietary Technosphere® particles. These loaded particles are then aerosolized and inhaled as a dry powder into the deep lung using our proprietary inhaler.

18. What is different about AFRESA™?

We believe that a distinguishing characteristic of AFRESA™ is that it produces a profile of insulin levels in the bloodstream that approximates the insulin profile normally seen in healthy individuals immediately following the beginning of a meal, but which is absent in patients with diabetes. Specifically, AFRESA™ is rapidly absorbed into the bloodstream following inhalation, reaching peak levels within 12 to 14 minutes. As a result of this rapid absorption, most of the glucose-lowering activity of AFRESA™ occurs within the first three hours of administration — which is generally when 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 AFRESA™ reduces the need for patients to snack between meals in order to manage ongoing blood glucose excursions. In our clinical trials, we have observed that patients using AFRESA™ have achieved significant reductions in post-meal glucose excursions and significant improvements in overall glucose

Page 5: Mannkind Q&A: About Afrezza

5

control, as measured by decreases in glycosylated hemoglobin, or A1C, levels, without the weight gain typically associated with insulin therapy.

19. Why does AFRESA™ work this way?

We believe the rapid action of AFRESA™ may be related to the unique aspects of both the carrier molecule as well as the way insulin is stabilized in our formulation. When they contact the moist lung surface, AFRESA™ particles dissolve immediately, releasing the insulin molecules to diffuse across a thin layer of cells into the bloodstream. Moreover, the insulin released from AFRESA™ particles is already largely in monomeric form, the only form that can attach to the insulin receptor and exert a physiological effect. (In most pharmaceutical doage forms, regular human insulin exists as a hexamer, which first must dissociate into dimers and then further dissociate into monomers in order to be effective.)

20. How convenient is AFRESA™?

Our inhaler utilizes single-use, disposable, plastic cartridges containing drug-loaded powder. The inhaler is light and easy to use and fits in the palm of the hand. In our clinical trials, patients have reported a high level of satisfaction with the inhaler.

Because insulin is transferred to the bloodstream rapidly with our therapy, we believe that the optimal and most convenient time for patients to take a dose of AFRESA™ is right at the start of a meal. In contrast, with subcutaneous regular insulin it is recommended that the user try to time an injection 15 to 45 minutes before the expected mealtime, raising issues such as miscalculation of time or unanticipated change in meal availability, which could result in adverse events.

21. How safe is AFRESA™?

We have an ongoing program of safety surveillance and adverse event reporting for the purpose of evaluating the ongoing safety data related to the use of AFRESA™. All of our clinical trials are monitored by an independent data safety monitoring board that meets at regular intervals to review safety data. To date, the data safety monitoring board has fully endorsed continuation of the trials as planned. The data from long-term safety studies will be available late in 2008.

22. Where in the development process is the insulin product? Can you summarize

results? We are in the process of compiling all of the data from our clinical studies into a new drug application (or NDA) for AFRESA™. Our goal is to submit the NDA to the United States Food and Drug Administration by the end of 2008 or shortly thereafter.

23. Why is MannKind persisting with its inhaled insulin product when Pfizer,

NovoNordisk, and Eli Lilly have discontinued their inhalable products?

Page 6: Mannkind Q&A: About Afrezza

6

Pfizer’s Exubera was voluntarily withdrawn from the marketplace for commercial reasons. The Novo and Lilly products were investigational products whose development was terminated by the companies.

MannKind believes that in order to be successful in today’s health care market, a product must offer improved efficacy and safety, not just improved convenience. None of the competitors’ products mentioned offer any advantages over injectable rapid-acting insulin analogs.

By contrast, in clinical trials to date, AFRESA™ has shown important advantages over rapid-acting insulin analogs, currently the most effective mealtime therapy. These include:

A significant reduction in post-prandial glucose excursions, approaching the levels seen in normal people, which are believed to be an important risk factor in the development of complications from the disease;

The ability to achieve comparable levels of overall glucose control compared with present "state of the art" treatment, as measured by HbA1c, which is considered the standard measure of a treatment's effectiveness in diabetes;

A lower risk of hypoglycemia, which is considered to be a major problem for patients using presently available insulins and many oral treatments, limiting their ability to optimally treat their disease;

No weight gain and even weight loss in patients treated with AFRESA™, in contrast to the weight gain that is usually considered a major downside of insulin therapy for many patients;

No need for complex meal titration, as utilized in our studies to date, significantly simplifying treatment and reducing the training typically needed for insulin therapy;

No adverse effect on the measures of pulmonary function that have been reported to occur with other inhaled insulins.

24. What about concerns that Exubera causes lung cancer?

Pfizer stated that over the course of Exubera's clinical trial program, 6 of the 4,740 patients treated with Exubera developed lung cancer. Pfizer concluded that there were too few cases to determine whether this observation was related to Exubera, and we are not aware of any specific carcinogenicity studies of Exubera to evaluate the potential of cancer risk.

In contrast, the safety profile of AFRESA™ has been examined in an extensive pre-clinical program including multiple carcinogenicity studies, all of which were negative. Furthermore, our clinical program is designed to provide data on safety and efficacy in a broad group of patients with diabetes. We have not observed a higher incidence of lung cancer in AFRESA™ patients than that expected in the general population. Our independent Data Safety Monitoring Board (DSMB) regularly reviews all potential safety issues with our clinical trials and has consistently recommended that the trials continue without changes.

Page 7: Mannkind Q&A: About Afrezza

7

Other Company Products 25. What is the Technosphere® technology?

Our proprietary Technosphere® formulation technology is based on a class of organic molecules that are designed to self-assemble into small particles onto which drug molecules can be loaded.

26. Other than AFRESA™, what other products do you have in the pipeline based on

the Technosphere® technology? Our product MKC253 is a proprietary formulation of human GLP-1 loaded onto Technosphere® particles. GLP-1 is an incretin, a hormone that stimulates release of insulin by the pancreas, slows stomach emptying, and reduces food intake. Its effects are less pronounced in patients with type 2 diabetes. Results from a Phase 1 trial support the hypothesis that inhalation of MKC253 may be able to simulate the incretin effect that is lost in patients with type 2 diabetes. Currently we are conducting a second Phase 1 trial to assess the safety of MKC253.

Our next proposed candidate for development is MKC-180, a novel Technosphere® formulation of a natural hormone to control satiety for addressing obesity, using pulmonary delivery. The toxicology studies are underway in order to support a Q2 2009 CTA filing in Europe. Preclinical animal studies show remarkable reductions in food intake.

27. What products are you working on that are not based on the Technosphere®

technology? Our cancer program is focused on immunotherapy (inducing the immune system to kill tumor cells instead of tolerating them) and targeted drug therapies (small molecules that selectively interfere with a cellular process associated with cancer cells).

The lead compound in our immunotherapy program, MKC1106-PP, is intended for the treatment of several solid-tumor cancers, including ovarian, colorectal, pancreatic, renal, breast, non-small cell lung and prostate carcinomas, glioblastoma and melanoma. We are currently continuing to enroll patients in an open-label Phase 1 clinical trial of the compound. We have also initiated an open-label Phase 1/2 clinical trial to evaluate a second immunotherapy compound, MKC1106-MT, in patients with advanced melanoma.

As part of our effort to develop innovative cancer therapies, we have built a drug discovery group that qualifies targets for high-throughput screening, identifies and optimizes lead compounds and develops initial preclinical data. We have identified a novel lead class of compounds that selectively antagonize in vitro an enzyme known as IRE-1. This may lead to therapies effective for myeloma cells and possibly other malignancies. We have received a research award from the Multiple Myeloma Research Foundation that will help to support our optimization and preclinical studies of an IRE-1 antagonist.

Our drug discovery group has identified and optimized a unique class of molecules that selectively inhibit, in vitro and in vivo, a protein known as ITK. We have received an award

Page 8: Mannkind Q&A: About Afrezza

8

from the Leukemia & Lymphoma Society in support of our development of potential ITK clinical candidates.

CT Operations 28. How many employees in CT?

Currently there are 352 employees at the Danbury location. 29. How much have you invested in CT facilities so far?

In 2001, we acquired the facility in Danbury. It included two buildings comprising approximately 190,000 square feet encompassing 17.5 acres. In 2007, we commenced construction of new manufacturing space. The 263,900 sq ft manufacturing facility includes 213,000 sq ft of new and renovated space and brings the company’s total investment in plant and equipment at the Danbury site to about $200 million. With the expansion complete, our Danbury facility now has two buildings with a total of approximately 328,000 square feet, housing research and development, administrative, and manufacturing functions, primarily for AFRESA™ formulation, filling, and packaging.

30. What investment in CT are you planning going forward? As you expand operations,

will you locate additional facilities in CT? We believe the Danbury facility will have sufficient space to satisfy potential commercial demand for the launch of AFRESA™ and, with the expansion completed, the first few years thereafter for AFRESA™ and other Technosphere®-related products.

31. Was CT’s R&D tax credit exchange a factor in your decision to locate in CT? How

much has the credit been worth to you? The State of Connecticut provides certain companies with the opportunity to exchange certain research and development income tax credit carryforwards for cash in exchange for forgoing the carryforward of the research and development income tax credits. The program provides for an exchange of research and development income tax credits for cash equal to 65% of the value of corporation tax credit available for exchange. The value of this program was one of the factors the company considered in deciding to locate operations in Danbury. Estimated amounts receivable under the program are recorded as a reduction of research and development expenses. At June 30, 2008, the estimated amount receivable under the program was $2.25 million.

32. What other factors attracted you to CT?

A number of factors affected our decision to locate our technical operation and manufacturing facility in Connecticut. These included the existence of a core bioscience industry in the state, including numerous pharmaceutical and biotechnology companies and a vibrant university sector; competitive real estate costs, both for the company’s operations and

Page 9: Mannkind Q&A: About Afrezza

9

for employee housing; the existence of a highly educated workforce well trained in bioscience; and the state’s pleasant environment and high quality of life.

Manufacturing 33. What exactly goes on and will go on at the Danbury manufacturing facilities?

We formulate AFRESA™ from recombinant human insulin and Technosphere® particles, then fill the AFRESA™ powder into plastic cartridges and commercial operations are planned to have each cartridge packaged within a foil overwrap.

34. How is your new manufacturing facility flexible, efficient, and cost-effective?

The new facility features state-of-the-art equipment and processes and redundant utilities. It includes expansion space that will allow us to more than double production capability as needed. We believe the Danbury facility will have sufficient space to satisfy potential commercial demand for the launch of AFRESA™ and, with the expansion completed, the first few years thereafter for AFRESA™ and other Technosphere®-related products.

35. Who designed the facility? Who built it?

The architect was Kling Stubbins and the engineering firm Clark Richardson Biskup. The construction manager was Torcon. On August 21, 2008, at the Ninth Annual Constructech Vision Award ceremony in Chicago, MannKind received the “2008 Bronze Vision Award” in the Corporate Owner: Industrial/Manufacturing category. The Constructech Vision Awards honors construction and engineering projects that have solved critical business issues through the use of innovative technology solutions.

36. Who supplies your insulin?

We have a long-term agreement with N.V. Organon to supply us with recombinant human insulin. They are a Dutch company recently acquired by Schering-Plough.

37. Who supplies the inhaler?

We have a long-term supply agreement with Vaupell, Inc. for the manufacture and supply of our MedTone® inhaler and the cartridges that are inserted into it. Headquartered in Seattle, Vaupell provides precision plastic assemblies to the aerospace, medical, and electronics industries. We are in the process of qualifying a second manufacturer to supply us with commercial quantities of these components.

38. Who supplies the Technosphere® raw material?

Currently, we obtain the raw material from which we produce Technosphere® particles from Evonik Industries (formerly Degussa AG), a major chemical manufacturer with facilities in Europe and North America. We are in the process of evaluating a second manufacturer to supply us with commercial quantities of this raw material. We also have the capability of manufacturing this chemical ourselves in our Danbury facility.

Page 10: Mannkind Q&A: About Afrezza

10

Marketing & Sales 39. Under what name will you be marketing your lead product?

We have submitted the name AFRESA™ (pronounced uh-FRESS-uh) to the FDA for review.

40. How did you select that name?

AFRESA™ was selected because it scored well with physicians and pharmacists as a name that was a good fit with our product positioning and was associated with positive images. In addition, most felt that the name did not sound or look like an existing product name.

41. What are the next milestones in commercializing AFRESA™?

Once we have analyzed the data from our Phase 3 programs and have achieved operational readiness in our commercial manufacturing facility in Danbury, we intend to submit an NDA for AFRESA™ to the FDA. We plan to request a Priority Review of the NDA.

We also plan to submit AFRESA™ to the European Regulatory authorities after we submit our NDA to the FDA.

For Further Information 42. How can I learn more about MannKind Corporation?

We invite you to visit our website at http://www.mannkindcorp.com. The company’s stock is traded under Nasdaq:MNKD.

###