ANNUAL REPORT 08/09
DIAMYD MEDICALANNUAL REPORT 08/09
DIAMYD IN bRIEf
Diamyd Medical is a Swedish public company focusing on the development of pharmaceuticals for the treatment of autoimmune diabetes and its complications. Diamyd currently has three clinical-phase products. Diamyd was founded in 1996. Since the mid-1990s several preclinical studies and four clinical trials have been conducted with the Diamyd
®diabetes vaccine, the most advanced of Diamyd’s development projects. Today the top priori- ties are the completion of the ongoing, global Phase III program of the Diamyd
®diabetes vaccine, and prepa- rations to apply for market approval. Diamyd employs an outsourcing model with low costs and an efficient organization, where some of its operations have been outsourced to qualified partners with expert qualifications.
Diamyd has offices in Stockholm, Sweden and Pittsburgh USA. Diamyd is listed on the Nasdaq OMX Nordic Market Small Cap list, as well as the OTCQX in the US.
Diamyd in brief ... 1
Important events during the fiscal year ... 2
Important events after the end of the fiscal year ... 2
CEO comments ... 3
Diabetes – a chronic disease. ... 4
Diabetes worldwide... 8
From research to results ... 10
Diamyd’s business model ... 12
Development platforms ... 14
Project portfolio ... 16
Clinical trials ... 20
A word from the researchers ... 24
Organization, employees and sustainable development ... 28
The Board ... 30
Key executives ... 31
Scientific and medical advisory board ... 32
Administration report ... 35
Group’s consolidated income statement ... 41
Group’s consolidated balance sheet ... 42
Change in shareholder’s equity – Group ... 43
Parent company’s income statement ... 44
Parent company’s balance sheet ... 45
Change in shareholders’ equity – parent ... 46
Cash flow statement ... 47
Accounting principles ... 48
Notes ... 53
Audit report ... 70
Corporate governance report ... 71
Diamyd on the stock exchange ... 76
Key ratios, definitions ... 79
Annual meeting of shareholders ... 80 Sources cited ... Inside of the back cover
TAbLE Of
CONTENTS
DIAMYD IN bRIEf
bUSINESS CONCEPT, ObJECTIVE AND VISION
Diamyd’s business concept is to license diabetes-related candidate drugs and refine them through development. Diamyd’s objective is to create a “Small Pharma Company” in the diabetes field. The vision is to be able to prevent and cure the autoimmune form of diabetes in the future.
PROJECT PORTfOLIO
Diamyd develops therapies from two independent technological platforms in the areas of diabetes and diabetes-related complications. One of the platforms originates from the GAD65 molecule and is the basis for the Diamyd® diabetes vaccine, while the second platform NTDDS (Nerve Targeting Drug Delivery System), utilizes gene therapy to deliver medication directly to nerve cells. As a result of the cumulative research efforts, Diamyd now possesses a portfolio of three clinical-stage candidate drugs: Diamyd® for type 1 diabetes (Phase III), Diamyd® for LADA (Phase II) and the NTDDS product NP2 for chronic pain (Phase I).
CLINICAL TRIALS
Phase III studies of Diamyd® for type 1 diabetes are currently under way in Europe and the US.
Diamyd expects to be able to begin reporting clinical results in the spring of 2011, after which applications for market approval can be submitted to the relevant regulatory agencies during the year. There are also several studies of Diamyd® initiated by research groups in progress, including a Swedish study where children at high risk of developing type 1 diabetes are vac- cinated to try to prevent the disease from developing. In addition Diamyd is conducting a Phase I trial in the US of the NTDDS product NP2 in the area of chronic pain.
PRODUCT STRATEGY
Diamyd may pursue the completion of current and future studies, market approval appli- cations and finally the market launch of its products independently to some extent, or in cooperation with other pharmaceutical companies. Diamyd’s ambition is to manage the com- mercialization of Diamyd® for type 1 diabetes independently in certain selected markets, while pursuing partnerships for other markets. Diamyd plans to out-license Diamyd® for LADA and NP2. Diamyd’s strategy for the NTDDS platform is to develop drugs related to diabetes complications on its own and out-license them after Phase II. Diamyd intends to out-license the application of the NTDDS technology for diseases other than diabetes at an early stage.
Diamyd Medical is a Swedish public company focusing on the development of pharmaceuticals for the treatment of autoimmune diabetes and its complications. Diamyd currently has three clinical-phase products. Diamyd was founded in 1996. Since the mid-1990s several preclinical studies and four clinical trials have been conducted with the Diamyd
®diabetes vaccine, the most advanced of Diamyd’s development projects. Today the top priori- ties are the completion of the ongoing, global Phase III program of the Diamyd
®diabetes vaccine, and prepa- rations to apply for market approval. Diamyd employs an outsourcing model with low costs and an efficient organization, where some of its operations have been outsourced to qualified partners with expert qualifications.
Diamyd has offices in Stockholm, Sweden and Pittsburgh USA. Diamyd is listed on the Nasdaq OMX Nordic Market Small Cap list, as well as the OTCQX in the US.
DIAmyD IN BrIEF
IMPORTANT EVENTS
DURING ThE fISCAL YEAR
IMPORTANT EVENTS AfTER ThE END Of ThE fISCAL YEAR
• Children from the age of 10 years were included and accelerated patient recruitment was initiated in the American Phase III study of the Diamyd
®diabetes vaccine.
• The first children were vaccinated in a prevention study with Diamyd
®intended to prevent type 1 diabetes in Swedish children at high risk of developing the disease.
• A study on Diamyd
®was published in Europe’s leading scientific diabetes journal, Diabetologia.
• Subscription for new shares supported by subscription warrant DIAM TO 2B provided a cash injection of MSEK 28.
• The rights to a novel endomorphin technology which can be used to treat conditions such as diabetes pain were in-licensed.
• A European Phase III study of the Diamyd
®diabetes vaccine was approved in all nine countries.
• The Swedish Medical Products Agency approved a follow-up study designed to follow Swedish children who were part of the Phase II study of the Diamyd
®vaccine and confirm the long-term effect of the vaccine.
• A pioneering prevention study of the Diamyd
®vaccine was ap- proved by the Norwegian Medicines Agency.
• The US FDA approved a combination study of the Diamyd
®vac- cine with the purpose of restoring the ability to produce insulin in patients with type 1 diabetes.
• The results of a Phase II study of Diamyd
®were published in the prestigious medical journal, the New England Journal of Medicine.
• The final patient was included in the European Phase III study of the Diamyd
®diabetes vaccine.
• The US Department of Veterans Affairs (VA) awarded a grant of MUSD 1.84 to support the development of Diamyd’s Nerve Tar- geting Drug Delivery System (NTDDS) for Diabetic Neuropathic Pain.
• An oversubscribed preferential rights issue brought in just over MSEK 219 before issue expenses to Diamyd.
• Diamyd executed a settlement agreement with Apoteket AB re- garding a clinical study in LADA patients, which was invalidated in 2007. As part of the settlement agreement, Diamyd received MSEK 11 in compensation for the deficiencies in Apoteket’s procedures and documentation that caused Diamyd to invalidate the study.
• An agreement was signed with patient recruitment firm Inclinix Inc. to accelerate the recruitment of patients for the US Phase III study of the Diamyd
®diabetes vaccine.
• A four-year follow-up of type 1 diabetes patients who were part
of the Phase II study of the Diamyd
®diabetes vaccine showed a
clear positive trend.
CEO COMMENTS
After a very eventful year, Diamyd stands stronger than ever. The first of our Phase III studies of the Diamyd® diabetes vaccine is fully recruited, and this fall’s oversubscribed new share issue will allow us to focus on our operations until the European clinical results become available in the spring of 2011. But we certainly won’t be twiddling our thumbs until then. We are making an all-out effort to quickly increase the number of recruiting clinics in the US, and to enroll all of the patients also in the US Phase III study. Once all of the new clinics are on board, we can better assess when recruitment for the study will end, and thus when we will be able to obtain the US clinical results. As it becomes possible to make more solid predictions concerning the future development of the Diamyd® project, our ability to sign partnership agreements that reflect the full potential of this revolutionary treatment will increase.
We are currently negotiating from a position of strength as a result of several events since autumn 2008. Our research has been met with great interest in the academic world, and has already resulted in several exciting studies initiated by research groups. We’ve had the results of our Phase II studies in type 1 diabetes and LADA published in leading scientific journals, and the long-term follow-up of the participants of the Phase II study of children and adolescents with type 1 diabetes has shown promising results. We’ve also reached a settlement agreement with Apoteket AB concerning the LADA study of 160 patients which was invalidated in 2007.
Last but not least, we have financial stability after completing a new share issue, which means that we can decide on the timing and structure of a partnership agreement that is the best for our shareholders and for Diamyd.
Going forward we will speed up the development of the NTDDS platform, which is being managed by our American subsidiary, Diamyd Inc. The NTDDS platform got put onto the back burner somewhat while the bulk of our resources was being focused on the Phase III studies of Diamyd®. Despite the faster pace of development, we expect the NTDDS platform to be nearly self-supporting in the future thanks to the large outside grants and orders for contract research that Diamyd Inc’s employees have landed. Moreover, in 2010 we expect the results from the Phase I study of our first NTDDS product, NP2, which may raise the entire platform to a new level.
We have a great deal of work ahead of us preparing to apply for market approval and the accom- panying market launch of the Diamyd® diabetes vaccine. Therefore we’ve already begun strength- ening the organization so that we will be able to manage everything that needs to be done so that no time is lost on the market. It’s a joy to relate how everyone who has encountered the project catches the Diamyd enthusiasm. We see an unbelievable spirit, both at the company and among our partners, which makes everyone deliver twice what we believed was possible.
Now more and more researchers, doctors, patients and both private and institutional investors are having their eyes opened to Diamyd. Nevertheless we are still relatively unknown in Sweden and abroad. The attention we receive will probably only increase in the coming year, as new ad- vances are reported and the Phase III results for the Diamyd® vaccine approach. Perhaps ten years from now those of you reading this today will tell your audience of impressed listeners that you were there way back in 2009, before the rest of the world discovered Diamyd.
Elisabeth Lindner President and CEO Diamyd Medical AB
CEO COmmENTS
DIAbETES
– A ChRONIC DISEASE
A ChRONIC DISEASE IN NEED Of NEW TREATMENT STRATEGIES Diabetes is a chronic disease. People with diabetes often develop serious complications result- ing in great suffering and premature death. Diabetes is one of the most common diseases in the Western world, and every year 3.8 million people die as a result of it. Apart from individual suf- fering and lifelong medication, the disease has an enormous financial impact on health services as well as on society, through loss of working hours. In 2007, annual global healthcare expenses for diabetes amounted to 232 billion USD (including treatment of complications)
1).
Diabetes is characterized by elevated blood sugar levels. Insulin is the hormone that regu- lates the level of sugar in the blood. In people with an autoimmune form of diabetes (type 1 diabetes or LADA), the body has stopped making insulin because the insulin-producing cells have been destroyed by the body’s own immune system. In those people with type 2 diabetes, the body still produces insulin, but no longer responds to it. The result, in all types of diabetes, is that sugar remains in the bloodstream and is not made available to the cells, which has several damaging consequences. Both very high and very low blood sugar levels are extremely dangerous and can lead to rapid and potentially fatal loss of consciousness. Consistently raised blood sugar levels cause typical diabetes complications, including kidney, eye and nerve dam- age as well as impaired circulation and cardiovascular disease.
DIffERENT TYPES Of DIAbETES
There are several types of diabetes. The three most common are type 2 diabetes, type 1 diabetes and LADA (Latent Autoimmune Diabetes in Adults). Type 1 diabetes and LADA are similar in that they are both autoimmune forms of the disease. This means that the body’s own immune system destroys the cells that make insulin, i.e. the beta cells of the pancreas. As the disease progresses, the patient will inevitably need to self-inject with industrially-manufactured insulin, as the patient’s own beta cells will have been destroyed in the autoimmune attack.
Type 2 diabetes, formerly known as adult-onset diabetes, is by far the most common form of diabetes and is rapidly increasing. In contrast to the autoimmune forms, type 2 diabetes is caused by impaired insulin sensitivity and is mainly related to age and lifestyle.
Type 1 diabetes
Type 1 diabetes, also known as juvenile diabetes, is an autoimmune form of diabetes that usu- ally occurs in children and adolescents. Type 1 diabetes is the result of a deficiency of insulin caused by an autoimmune attack on the body’s own blood sugar regulating beta cells in the pancreas.
The beta cells are thought to be gradually destroyed over a period of time, varying from a few months to several years. Symptoms only appear when this destruction has been going on for some time. Children and adolescents with type 1 diabetes usually don’t come into contact with the healthcare system until they become acutely ill. Usually by then, only 10-20 percent of the beta cells are left
2). This is not enough to maintain blood sugar control. At this point, the patient’s survival depends on starting insulin injections immediately. Even after the disease has been diagnosed, the autoimmune attack continues on the remaining beta cells, which in time will be completely destroyed. By then, the body will have no blood sugar control left. All of its insulin needs will have to be met by insulin injections or an insulin pump.
Estimated distribution of the different types of diabetes in the Western world
Type 1 diabetes LADA
Type 2 diabetes Diabetes
DIABETES
The trigger for the autoimmune attack remains unknown, but there are theories about different environmental factors such as virus infections. People with type 1 diabetes also have a genetic predisposition for the disease, and genetic testing can be used to estimate the risk of a newborn baby developing the disease later in life. About five percent of children who have a parent or sibling with type 1 diabetes also develop this type of diabetes
2). An ongoing autoimmune attack can be detected even before the symptoms of diabetes have appeared. This is done by measuring the level of various biomarkers in the blood, including antibodies against insulin, GAD and IA-2. There are several ongoing studies aiming to identify children and adolescents with a high risk of developing type 1 diabetes. These crucial studies will help us gain a better understanding of the disease and enable us to offer preventive treatment – preventing type 1 diabetes by blocking the autoimmune attack.
LADA
LADA (Latent Autoimmune Diabetes in Adults), also known as type 1.5 diabetes, is, like type 1 diabetes, also an autoimmune form of diabetes, but it strikes in adulthood. This disease is similar to type 1 diabetes in many respects and it, too, eventually leads to an absolute need for insulin treatment. However, the progress of the disease is slower than in type 1 diabetes.
Because the disorder mainly affects adults and does not immediately require insulin treat- ment, LADA is often incorrectly diagnosed as type 2 diabetes. Diamyd estimates that about 10 percent of all those diagnosed with type 2 diabetes actually have LADA
3). LADA patients char- acteristically have antibodies against GAD, which is a sign of the ongoing autoimmune attack on the blood sugar controlling cells. This means that LADA can be diagnosed with an antibody test. In the early stages, people with LADA often have significantly better insulin production and blood sugar control than those with type 1 diabetes, and therefore they do not necessarily require insulin treatment immediately. However, after a few years, people with LADA usually need daily insulin injections to maintain acceptable blood sugar levels. And, like people with type 1 diabetes, those with LADA often develop diabetes-related complications.
Type 2 diabetes
Type 2 diabetes, formerly known as adult-onset diabetes, is by far the most common form of the disease. There is a global epidemic of diabetes, mainly caused by modern lifestyle. Type 2 diabetes is characterized by insulin resistance, which means that insulin loses its effect on the body. The exact cause of insulin resistance in this type of diabetes has yet to be identified. Cell insulin receptors appear defective in some patients, whilst the insulin signal mechanism seems impaired in others. However, these patients seem to have a functioning insulin production.
Type 2 diabetes also progresses more slowly than type 1 diabetes and LADA. Type 2 diabetes is the result of a combination of many factors, including heredity, lifestyle and environment.
Type 2 diabetes mainly affects older people, but an increasing number of children are now developing the disease.
Living with type 1 diabetes
Type 1 diabetes is a chronic disease that has a huge impact on the life of both child and family. Insulin must be injected, and the blood sugar must be checked several times a day. It is extremely im- portant to manage the condition care- fully in order to avoid both high and low blood sugar levels. Both can lead to life- threatening coma. Prolonged elevation of the blood sugar also often leads to serious complications. Careful monitor- ing of blood sugar levels, combined with insulin treatment, reduces the risk of future diabetes complications. Neverthe- less, many people with type 1 diabetes go on to develop serious complications affecting blood vessels, nerves, kidneys and other organs. The timing and com- position of meals has to be regulated and balanced against the insulin dosage, which is especially difficult for small chil- dren. It is usually a traumatic experience for the whole family when a child devel- ops type 1 diabetes.
DIAbETES COMPLICATIONS
All types of diabetes can lead to associated diseases and complications.
Diabetes has both acute and long-term complications, and they can affect several different organs. Researchers have established that the risk of complications can be reduced by 60-80 percent in type 1 diabetes pa- tients who still have some remaining insulin production of their own
4). This clearly demonstrates the importance of at least partially preserving the ability of patients with type 1 diabetes to control blood sugar levels.
The Diamyd® vaccine aims to do just that, and therefore it may be of crucial importance for people with type 1 diabetes, in whom it could reduce the risk of developing complications.
Acute complications
Hypoglycemia – If the blood sugar level drops too low it can lead to acute hypoglycemic coma. The person becomes unconscious, and the body’s functions come to a halt as the brain suffers an acute lack of nutrients. This condition can be reversed with an intravenous injection of glucose. Less severe hypoglycemic events can be aborted by quickly eating or drinking something sweet, which brings the blood sugar level back up to normal.
Ketoacidosis – Markedly elevated blood sugar levels can lead to ketoaci- dosis. This condition arises when the body begins to break down its own cells to obtain nutrients, thereby releasing ketones and acids into the bloodstream. This is an extremely acute, life-threatening condition that requires intensive care.
Long-term complications
Cardiovascular disease – This is the most common cause of death in diabetes, and people with diabetes have a much elevated risk of develop- ing heart disease such as heart attack as well as stroke and other forms of cerebrovascular disease
5). Impaired circulation in the legs and feet, i.e.
peripheral vascular disease, can lead to leg ulcers and foot complications that may require amputation. A study carried out by the Karolinska Institute in Stockholm has shown that Swedes with type 1 diabetes run a risk of amputation 86 times greater than that of healthy people. 11%
of women and 21% of men with type 1 diabetes have to undergo an amputation before the age of 65
6).
Kidney damage – Diabetic nephropathy, i.e. kidney damage caused by diabetes, is the main cause of kidney failure in the Western world, sometimes requiring dialysis or a kidney transplant. About a third of all patients with diabetes develop kidney damage
5).
Nerve damage – Diabetes affects the nervous system in several different ways. The most common are loss of sensation and severe pain character- ized by a stabbing or burning sensation in the legs, feet and hands. The pain is caused by damage to the peripheral nervous system, neuropathy, as a result of diabetes. Diabetes pain leads to disturbed sleep, reduced mobility, and difficulty working and engaging in social activities.
Eye damage – People with diabetes may develop damage to the blood vessels in the retina. This can lead to retinopathy, with impaired vi- sion, and in some cases even blindness. People with diabetes may also develop cataracts resulting in impaired vision. Nearly everybody with long-standing type 1 diabetes will eventually develop retinal damage to some degree
7).
Eyes: Retinopathy
Long-term complications
Heart:
Cardiac disease
Kidney:
Nephropathy
Lower limbs:
Peripheral vascular disease
Peripheral nervous system: Neuropathy
Feet:
Ulceration and amputation Brain:
Cerebrovascular disease
DIABETES
Diabetes is a common disease globally, today affecting an estimated total of 246 million people. This figure is expected to rise to 380 million by 2025. Type 2 diabetes is on the increase worldwide, accounting for 85-95 percent of all cases
8).
Several studies have shown that around 10% of all those diagnosed with type 2 diabetes actually have LADA, which translates into an estimated total of at least 20 million people with LADA worldwide
4).
Type 1 diabetes is thought to account for about 5-10 percent of all cases of diabetes in the Western world
9). The prevalence of type 1 diabetes is highest in North America and the Nordic countries. Diamyd estimates that around 80 000 people develop type 1 diabetes annually in the USA and Europe alone, and this represents the primary market for the Diamyd® diabetes vaccine
10). In addition, new research shows that the number of children and adolescents that develop the disease in Europe is increasing by about 4% annually and that the age of onset of type 1 diabetes is falling
11). The reasons for this are unclear.
DIAbETES WORLDWIDE
Region
Percentage of the population with type 1 diabetes
Australia 0.2 - 0.3 %
Canada 0.4 - 0.5 %
Central Africa < 0.1 %
China < 0.1 %
Europe 0.2 - 0.3 %
India < 0.1 %
Japan < 0.1 %
The Middle East 0.1 - 0.2 %
North Africa 0.1 - 0.2 %
Russian Federation 0.1 - 0.2 %
Scandinavia > 0.5 %
South Africa 0.1 - 0.2 %
South America 0.1 - 0.2 %
South-East Asia < 0.1 %
USA 0.3 - 0.4 %
Percentage of the population with type 1 diabetes worldwide 12)
< 0.10 %
0.10 - 0.20 %
0.20 - 0.30 %
0.30 - 0.40 %
0.40 - 0.50 %
> 0.50 %
DIABETES
fROM RESEARCh TO RESULTS
The primary focus of Diamyd Medical’s research is the development of pharmaceuticals for the
treatment of autoimmune diabetes and its complications. Diamyd was founded in 1996 by former
CEO, now Chairman of the Board, Anders Essen-Möller as a spin-off from the sale of his previous
firm Synectics Medical AB to the American company Medtronic. The rights to GAD65, the active
substance in Diamyd’s most advanced project, the Diamyd
®diabetes vaccine, were licensed from the
University of California Los Angeles (UCLA) in 1994. Several preclinical studies and four clinical trials
of the Diamyd
®diabetes vaccine have been conducted since the mid-1990s. It has been demonstrat-
ed that Diamyd
®can slow or halt the progression of autoimmune diabetes. Today the top priorities
are the completion of the global Phase III program currently in progress and preparations to apply
for market approval.
1994-1998 In 1994 the rights to GAD65 are in-licensed, the active substance in the Diamyd® diabetes vaccine. In the later 1990s a large number of preclinical studies are con- ducted to ensure the substance’s safety and efficacy. Studies in models of autoimmune diabetes indicate that the substance is safe and can halt or prevent the immune system from attacking insulin-producing cells.
1999-2004 At the turn of the millennium, it is time to take the large step of testing the vaccine on human subjects. Within a few years, a Phase I safety study is conducted on healthy volunteers and a Phase II study is conducted on patients with LADA (Latent Autoimmune Diabetes in Adults), to see whether the vaccine is safe and to determine a suitable dosage for continued develop- ment. Both studies show positive and desir- able results. In the years following Diamyd conducts two more Phase II studies, one on adult LADA patients and the other on chil- dren and adolescents with type 1 diabetes.
2005-2006 Diamyd successfully conducts its Phase II study in type 1 diabetes, and can demonstrate that two single injections of the vaccine have slowed the autoimmune attack in the children and adolescents who were part of the study. In 2005 Diamyd acquires Nurel Therapeutics Inc., an American com- pany whose gene therapy research becomes the foundation for Diamyd Inc., a subsidiary of Diamyd Medical. In addition to research on the patented NTDDS platform, Diamyd Inc. is also managing the production of GAD65.
2007 At the end of 2007 company founder and CEO Anders Essen-Möller, who has been successfully running the company with
a clear vision since its inception, takes over as the acting company Chairman, and Diamyd comes under new operational management.
Elisabeth Lindner, with long-standing expe- rience in the pharmaceutical industry, takes over as President and CEO.
2008 Based on the results from the Phase II study in type 1 diabetes, in 2008 Diamyd re- ceives approval from the US FDA (Food and Drug Administration) and several European regulatory agencies to begin the decisive Phase III studies in type 1 diabetes. Diamyd takes this opportunity to strengthen the or- ganization in order to manage the extensive Phase III program. In the autumn of 2008 the prestigious scientific journal The New England Journal of Medicine publishes the 30-month results from the completed Phase II study of Diamyd® for type 1 diabetes, ac- companied by an editorial. The publication means a scientific validation of the clinical results and a tremendous breakthrough for Diamyd.
2009 Work intensifies on the project of recruiting patients for the Phase III stud- ies under way in Europe and the US. The European study is approved in the ninth and final European country, and the final patient is included at the end of the year. The US FDA approves lowering the minimum age for patients participating in the Ameri- can study from 16 to 10 years, which was permitted in the European study from the outset. Two pioneering prevention studies of the Diamyd® vaccine, one in Sweden and one in Norway, are approved this year by each country’s respective Medical Products Agency. The Swedish study has already begun vaccinating healthy children at high
risk of developing type 1 diabetes. In addi- tion, the FDA approves a combination study of the Diamyd® vaccine and two established drugs with the purpose of restoring the ability to produce insulin in patients with type 1 diabetes. TrialNet/NIDDK initiates an American study of Diamyd® at 15 leading diabetes clinics in order to investigate the vaccine’s mechanism of action in more detail.
The research receives further validation through a publication in Diabetologia, the leading scientific diabetes journal in Europe.
The article demonstrates that even after five years the Diamyd® vaccine reduces the risk that patients with LADA will need treatment with insulin. In the spring Diamyd hires an American consulting firm that specializes in managing out-licensing processes to explore the level of interest in the Diamyd® vaccine among the major international pharmaceuti- cal companies through a structured process.
A new share issue is completed in the fall, securing the financing for the next two years.
TODAY With the Diamyd® vaccine in Phase III and several NTDDS projects related to diabetes complications under development, Diamyd has evolved into a company focusing on diabetes with the object of becoming a market-oriented pharmaceutical company.
Diamyd’s opportunities and potential for growth have grown, and the business can expand in several different areas through new research as well as through acquisition and partnership agreements. By concentrating on the important Phase III studies while at the same time building a business focused company, Diamyd is taking care of both its product development and its future business.
FrOm rESEArCH TO rESULTS
DIAMYD’S
bUSINESS MODEL
Diamyd’s vision is to be able to prevent and cure the autoimmune form of diabetes in the future. In order to achieve this vision, Diamyd employs a dynamic business model that can be adapted to different scenarios concerning current and future trial programs, the commercial- ization of Diamyd’s products, financing of its business and partnerships and acquisitions.
bUSINESS CONCEPT
Diamyd’s business concept is to license and refine diabetes-related candidate therapies, which are to be subsequently commercialized, either independently or with a partner, or out-licensed.
VISION AND ObJECTIVE
Diamyd’s goal is to be able to treat children, adolescents and adults with diabetes and to vac- cinate in order to prevent the disease from developing. Diamyd’s objective is to create a “Small Pharma Company” in the diabetes field. Its vision is to be able to prevent and cure the autoim- mune form of diabetes in the future.
STRATEGY
The primary focus of Diamyd’s research is the development of pharmaceuticals for the treat- ment of autoimmune diabetes and its complications. Today the top priorities are the comple- tion of the global Phase III program of the Diamyd® diabetes vaccine currently in progress, and preparations to apply for market approval.
Diamyd Medical is managed using an outsourcing model where some of its operations have been outsourced to qualified partners with expert qualifications, and a limited number of permanent employees manage, lead and implement projects in areas such as clinical and pre-clinical research, regulatory affairs and production. This model leads to lower operating expenses than building up the operation in-house, and enables Diamyd to develop in a cost- efficient and flexible manner while ensuring high quality with an emphasis on results as the projects move forward.
In order to ensure that established targets are met and that Diamyd continually gets closer to its vision of being able to prevent and cure autoimmune diabetes, Diamyd works according to a strategic plan encompassing the areas of development and commercialization, financing and partnerships and acquisitions. The plan is a dynamic tool and the strategy is continuously evaluated as internal and external conditions evolve.
Development and commercialization
Diamyd may pursue the completion of current and future studies, market approval applica- tions and finally the market launch of its products, in cooperation with other pharmaceutical companies or independently to some extent. The path Diamyd chooses depends primarily on which resources are required to drive the development and market launch, which terms that can be reached in a potential partnership agreement and the capital needs at the time.
Out-licensing of development projects may be one way to finance and secure resources for the completion of trial programs or future market launches.
Klin
isk fo rsknin
g
PrekDIAMYDlinisk forskning Marknadsföring Regulatory
Production affairs
and
dev elopm
ent
and development and sales
Clin
ical resea
rch
Pre-clinical research Marketing
Diamyd’s outsourcing model
In general the rule is that the further along a product is in the development process, the better the terms that can be obtained in a licensing agreement. The optimal development phase and structure for a licensing agreement depend on several factors. There is a great future potential for Diamyd and its shareholders in retaining certain markets for itself. This will enable Diamyd to develop into a market-oriented pharmaceutical company under its own power. The following is a summary strategic overview concerning the commercialization of Diamyd’s products under development.
• Diamyd® for type 1 diabetes – In the Diamyd’s view the prospects for taking the Diamyd® for type 1 diabe- tes product through Phase III and potentially to market approval are good. Diamyd intends to manage the marketing and sales of the product itself, at least in the Nordic countries. This is possible because type 1 diabetes patients are treated by a very limited group of physicians, who primarily work at specialty clinics and university hospitals. As a result of the limited number of relevant physicians and hospitals, a smaller sales organization is sufficient to launch the Diamyd® vaccine for type 1 diabetes in certain key markets.
• Diamyd® for LADA – The intention is to completely out-license Diamyd® for LADA to other pharmaceu- tical companies. Unlike type 1 diabetes patients, LADA patients are predominantly treated by general practitioners, which significantly broadens the market and thus makes it more costly from a marketing perspective.
• NTDDS platform – Diamyd’s strategy for the NTDDS platform is to develop drugs related to diabetes complications on its own and license them out after Phase II. The target group for products developed in the NTDDS platform is primarily people suffering from chronic pain related to diabetes who are predominantly being treated by general practitioners. The intention is to out-license the application of the NTDDS technology for diseases other than diabetes at an early stage. The NTDDS technology is extremely broad, and there has been considerable interest in the platform from other companies with pharmaceutical substances that they would like to effectively deliver to neurons. The Phase I study in progress is validating the NTDDS platform as such.
• Other development projects – Diamyd plans to either partially or entirely out-license products for therapeutic indications outside the area of diabetes to external parties at an early stage. The application of GAD65 for the treatment of Parkinson’s disease has accordingly been out-licensed to the American com- pany Neurologix, Inc.
Financing
Diamyd has several options for financing its business, for example through out-licensing of com- plete or partial development projects on selected markets or through various types of share issues.
The development from preclinical studies to clinical Phase III studies, where Diamyd now finds itself, has been achieved at an extremely low cost by industry standards. Since its inception Diamyd has raised MSEK 463 in various share issues, which does not include the latest preferential rights issue of just over MSEK 219.
Partnerships and acquisitions
Partnerships with other pharmaceutical companies are a part of Diamyd’s future evolution, and various potential partnerships are continuously under evaluation. Diamyd is also evaluating the acquisition of development projects and companies with promising products under development.
Business discussions are held with international pharmaceutical companies concerning the out- licensing of several products in the research portfolio. The rights for the application of the GAD65 gene in the treatment of Parkinson’s disease have previously been licensed out on a non-exclusive basis to the American company Neurologix, Inc.
THE BUSINESS mODEL
DEVELOPMENT PLATfORMS
Diamyd’s research and development projects are mainly focused on the treatment of autoimmune diabetes and related complications. The therapies in development are based on two independent tech- nological platforms. One of the platforms originates from the GAD65 molecule and is the basis for the Diamyd
®diabetes vaccine, while the second platform, NTDDS (Nerve Targeting Drug Delivery System), uses gene therapy to deliver medication directly to nerve cells.
ThE GAD PLATfORM
Diamyd’s platform for research into autoimmune diabetes originates from the GAD65 molecule and forms the basis for the Diamyd®
diabetes vaccine. GAD65 (Glutamic acid decarboxylase isoform 65 kDa), is the active substance in Diamyd®. This is a human enzyme and an important autoantigen in autoimmune diabetes. GAD65 is found in the insulin-producing beta cells of the pancreas, although its function at this site is not yet fully understood. It is however clear that GAD65 is one of the most important targets when the immune system attacks the beta cells in autoimmune diabetes. The body’s own GAD65 can be found in the beta cells of the pancreas as well as in nerve and brain tissue. In nerve cells, GAD catalyzes the transfor- mation of the neurotransmitter glutamate to the neurotransmitter GABA. GAD65 is therefore thought to be an important drug candi- date for several neurological diseases, e.g. Parkinson’s disease, as well as for neuropathic pain.
Treatment with the Diamyd® vaccine is thought to induce toler- ance to GAD65, thereby intervening in the autoimmune attack and preserving the capacity to control the blood sugar in patients with autoimmune diabetes, i.e. type 1 diabetes and LADA. The vaccine works by immunomodulation and is antigen-specific, which means that it specifically aims to induce tolerance in the autoimmune T cells that attack GAD65 in the beta cells, without impairing the immune system either wholly or in part. This is in contrast to immunosuppres-
sion, a different treatment strategy that temporarily disables T cells and so suppresses and weakens the immune system. This increases the likelihood that Diamyd® treatment will not only prove effective but will also have few side effects. The safety profile is extremely important in the treatment of diabetes, as children and adolescents represent a significant proportion of people with type 1 diabetes.
GAD platform patent protection
Diamyd has secured exclusive patent licenses for the manufacturing and therapeutic use of GAD65 from the University of California, USA, and for the treatment of diabetes with GAD65 from the Uni- versity of Florida, USA. The GAD65 gene and its protein also have potential therapeutic applications in neurological diseases such as Parkinson’s disease. The licensed patents are believed to protect the use of GAD65 until 2021 in the USA and until 2016 in Europe. In ad- dition, the Diamyd® vaccine will receive further protection in Europe via data and market exclusivity for eight to eleven years after gaining marketing authorization by EMEA, the European Medicines Agency.
Furthermore, Diamyd has submitted its own patent applications,
which if approved, would further extend the patent protection for the
diabetes vaccine. In addition to the exclusive rights to therapeutic use
of GAD65, Diamyd also licenses non-exclusive rights to GAD-based
diagnostic applications.
ThE NTDDS PLATfORM
NTDDS (Nerve Targeting Drug Delivery System) is Diamyd’s second platform and currently consists of three products in preclinical and clinical development which are intended for the treatment of condi- tions that include chronic pain and cancer. Research and develop- ment based on the NTDDS platform is being carried out by the U.S.
subsidiary, Diamyd Inc., in Pittsburgh, focused on the development of products and treatments for pain relief in e.g. diabetic neuropathy.
NTDDS is a gene therapy delivery system, also known as a vector, which can deliver drugs directly to nerve cells, providing a direct effect in the cells targeted by the treatment. As the drug is delivered directly to the nervous system without first entering the bloodstream, side effects are likely to be fewer than with current treatments, such as morphine. The NTDDS vector, with a gene for a pain-relieving substance, e.g. enkephalin, is injected into the skin. The vector is then transported along the peripheral nerve pathways to the spinal cord where the gene can exert its effect by blocking pain signals to the brain. NTDDS can also be used in the treatment of cancer of the nervous system, glioma, where it can be used to transport cell-killing substances directly to the malignant tumor. The NTDDS vector is not integrated into the chromosomes of the host cell and it does not generate an immune reaction. This further reduces the risk of side effects compared to other gene therapy methods.
NTTDS can also be used to treat several other diseases involving the peripheral and central nervous systems, e.g. peripheral neuropathy – a serious condition affecting millions of people. There is currently no effective treatment for peripheral neuropathy. Local treatment using NTDDS with growth factors could become clinically very important if it can protect nerve cells and stimulate their regrowth.
Erectile dysfunction (impotence) is one example of the consequences of neuropathy in men with diabetes or men who have had prostate surgery. NTDDS combined with GAD could also prove effective in the treatment of a number of other diseases.
NTDDS platform patent protection
Diamyd has been granted exclusive rights to the NTDDS gene therapy platform by the University of Pittsburgh in the USA. The licensed patents and patent applications protect the NTDDS technol- ogy, production methods and components, e.g. cell lines and vectors.
Patent protection in the USA is considered valid until at least 2024.
European patent applications are under review.
An exclusive license for a novel endomorphin technology was acquired in 2008. This could potentially be used in the treatment of neuropathic pain, including diabetic neuropathy. This license includes a European patent. Patent applications for North America and Asia are under review.
DEVELOPmENT PLATFOrmS
PRECL I N IC A L PHAS E I PHAS E I I PHAS E I I I
Diamyd for type 1 Diamyd
®for LADA
NP2 NG2 NC3 PRODUCT
®
DIAMYD
®fOR TYPE 1 DIAbETES
The GAD-based vaccine Diamyd® for type 1 diabetes represents the research project that has reached the most advanced stage of develop- ment. The purpose of the vaccine is to prevent, delay, or stop the autoimmune attack on beta cells in type 1 diabetes, thereby preserv- ing the body’s capacity to regulate blood sugar. This is very important, as there is no such treatment available today.
A Phase II study of 70 children and adolescents with type 1 diabetes published in the highly respected medical journal the New England Journal of Medicine in the fall of 2008 showed that the Dia- myd® vaccine significantly slowed the course of the disease in subjects with newly-diagnosed type 1 diabetes for at least 30 months. The study also showed that the effect of the Diamyd® vaccine is greatest in the early stages of the disease. It was recently announced that the four- year follow-up of the study shows a clearly positive trend.
The treatment, which consists of only two to four injections, each administered in the arm on separate occasions, does not require
PROJECT PORTfOLIO
Diamyd has a portfolio of three drug candidates in clinical development: Diamyd
®for type 1 diabetes in Phase III, Diamyd
®for LADA in Phase II and NP2 for chronic pain in Phase I. In addition to these, the NTDDS products NG2 and NC3 are in preclinical development. The following is a description of the prod- ucts that Diamyd has under development.
hospitalization and has been well received by patients, parents and physicians alike. The Diamyd® vaccine has not been associated with any serious adverse effects in previous studies and is thought to have a uniquely favorable combination of efficacy and safety.
Project status
Two parallel Phase III studies of the Diamyd® vaccine, one in Europe and the other in the USA and each with 320 participants, have been in progress since the fall of 2008. Recruitment to the European study has been completed and it is estimated that the first results will be announced in the spring of 2011. If the results are positive, an ap- plication for market authorization will be submitted to the relevant medicinal products agencies during 2011, which may allow a market launch in 2012.
A three-year follow-up study to the completed Phase II study in
patients with type 1 diabetes is being carried out with the aim of
confirming the vaccine’s long term effects.
PrOJECT POrTFOLIO
There is currently no product on the market addressing the autoim- mune process that causes type 1 diabetes and LADA. Diamyd there- fore defines its competitors as other diabetes treatments in devel- opment that aim to prevent or slow down the autoimmune attack on the blood sugar regulating beta cells. This is a very active area of research and development, but there are two other main treat- ment strategies for type 1 diabetes that can currently be regarded as competing with the Diamyd® vaccine. These, like Diamyd®, have succeeded in reaching Phase III in clinical development, within reach of market authorization. The two alternative competing strategies that are currently undergoing Phase III trials are the monoclonal anti-CD3 antibodies, specifically the drug candidates Otelixizumab and Teplizumab, and the synthetic peptide DiaPep277®.
Otelixizumab – Tolerx Inc. is developing this monoclonal anti-CD3 antibody in collaboration with GlaxoSmithKline. Otelixizumab is an antibody to the CD3 receptor, which is present on all T cells. T cells are a sub-group of white blood cells called lymphocytes and repre- sent an important part of our immune system. In type 1 diabetes, certain T cells, called effector T cells, mistakenly attack and destroy the beta cells of the pancreas. Treatment with an intravenous infu- sion of Otelixizumab temporarily destroys the T cells and suppresses the immune system, a process called immunosuppression, which can have side effects such as flu-like symptoms and Epstein-Barr virus reactivation.
Teplizumab – Macrogenics Inc. is developing this monoclonal anti- CD3 antibody in collaboration with Eli Lilly. Teplizumab also binds to the T cell CD3 receptor, just like Otelixizumab. Temporarily de- stroying the T cells can modify the pathological immune response that lies behind several different autoimmune diseases other than type 1 diabetes. Adverse effects such as fever, headache, joint pain, muscle aches and rashes have been reported in previous studies with Teplizumab.
DiaPep277® – Andromeda Biotech Ltd, jointly owned by Clal Bio- technology Industries and Teva Pharmaceutical Industries, is devel- oping a synthetic immunomodulatory peptide, DiaPep277®, for the treatment of type 1 diabetes. This product is based on an immu- nodominant epitope from the autoantigen heat shock protein 60 (hsp60). Like Diamyd’s GAD65 molecule, this peptide modulates the immune system in type 1 diabetes, and could thereby reduce or prevent the destruction of the blood sugar regulating beta cells. No effect was observed in a Phase II clinical trial in children with type 1 diabetes.
Diamyd
®for type 1 diabetes – competing products In an ongoing prevention study of Swedish children aged four and
older, and another prevention study which is about to start in Nor- way, researchers are aiming to establish whether the Diamyd® vaccine can prevent type 1 diabetes in individuals at high risk of developing the disease.
Future market potential
The market for Diamyd’s diabetes products is global but primarily located in the Western world, where the prevalence of type 1 diabetes is at its highest.
Diamyd Medical does not provide forecasts and therefore cannot speculate on the size of any future sales figures or profits. The initial target group for the product closest to authorization, Diamyd® for type 1 diabetes, is newly-diagnosed patients. Estimates based on data from reports and articles about the number of people of different ages who develop type 1 diabetes, as well as on the rate of increase in dif- ferent regions, show that in the USA and Europe alone about 80,000 people develop type 1 diabetes annually
10). At an assumed selling price of 15,000 USD per treatment, this market would be worth over a billion USD annually.
Researchers have established that the risk of complications can be reduced by 60-80% in type 1 diabetes patients who still have some remaining beta cell function of their own
13). Based on this, together with information obtained from reports and publications about the prevalence and treatment costs of the different types of diabetes complications, Diamyd and its expert consultants estimate that there is a potential saving to society of more than 15,000 USD in treat- ment costs per patient if the rate of common complications in type 1 diabetes can be reduced
14). If additional complications are included in the calculation, this saving could be considerably greater. And this figure does not include the reduction in lost working hours or, indeed, individual suffering. Such health economic calculations will be used to justify the future pricing of the treatment.
If, in the future, Diamyd® for type 1 diabetes can be used for preven-
tion, i.e. to prevent the disease in individuals at high risk of developing
type 1 diabetes, as well as being used in those with already established
disease, the estimated sales potential is significantly greater.
Diamyd
®slows the autoimmune process
In type 1 diabetes, destruction of beta cells be- gins even before symptoms appear. For reasons that are unclear, the body’s own immune sys- tem starts to destroy the beta cells that regulate blood sugar levels. The symptoms of diabetes only become apparent when just 10 to 20 per- cent of beta cell function remains. By this time, the body does not have enough beta cells left to maintain blood sugar control.
Typical symptoms include increased urine vol- ume and excessive thirst, along with increasing fatigue, weakness, hunger and rapid weight loss.
Patients with type 1 diabetes don’t usually see a doctor until they become acutely ill. The condition can deteriorate rapidly, and if affected individuals don’t receive prompt medical care, they can lapse into a coma. The patient must have immediate insulin treatment and often has to stay in hospital for some time after diagnosis.
Despite insulin treatment, the underlying process of beta cell destruction continues unabated un- til virtually all the cells have been destroyed and the body has no remaining capacity to regulate blood sugar levels. The Diamyd® vaccine is in- tended to halt or slow the autoimmune attack and to save any remaining beta cells.
The next step - prevention
Studies have shown that the Diamyd® vaccine is most effective when given early in the course of the disease in patients with newly-diagnosed type 1 diabetes. If these results can be confirmed by larger studies, the next logical step is to extend testing of the vaccine to individuals who are at high risk of developing diabetes, i.e. to carry out prevention studies to see if the disease process can be prevented before it manifests.
One prevention study is already in progress, the aim of which is to evaluate the effect of the Diamyd® vaccine in children at elevated risk of de- veloping type 1 diabetes.
The autoimmune attack starts to destroy the beta cells Beta cell
mass 100%
80%
60%
20%
40%
0% Time
The autoimmune attack destroys the insulin-producing beta cells.
At the time of diagnosis only 10-20 percent of the beta cells remain.
Diagnosis of type 1 diabetes made
100%
80%
60%
20%
40%
0% Time
Diamyd® is given to stop the autoimmune attack, to preserve the remaining beta cells and the body’s own insulin production. The earlier treatment can start, the greater the remaining own production of insulin.
Diagnosis of type 1 diabetes made
Treated with Diamyd® Beta cell
mass
The autoimmune attack starts to destroy the beta cells
The autoimmune attack starts to destroy the beta cells 100%
80%
60%
20%
40%
0% Time
If Diamyd® is given at an early stage, the autoimmune process may be halted before the disease manifests. This means that if Diamyd® can be given as a preventive measure, it may be possible to completely prevent type 1 diabetes.
Treated with Diamyd® Beta cell
mass
DIAMYD
®fOR LADA
The GAD-based vaccine Diamyd® for LADA aims to prevent, delay, or stop the autoimmune attack on the blood sugar regulating beta cells that occurs in LADA (Latent Autoimmune Diabetes in Adults), a less aggressive form of autoimmune diabetes that affects adults.
Project status
Diamyd® for LADA has reached Phase II in clinical development, and in April 2009 the respected scientific journal Diabetologia published the results of a study that demonstrate that, even after 5 years, the Dia- myd® vaccine significantly reduces the need for insulin treatment in people with LADA. Only 14 percent of participants in the group that received 20 µg of Diamyd® needed insulin after five years, compared to 64 percent in the placebo group. No serious adverse events related to the Diamyd® treatment were reported.
Future market potential
Patients with LADA are a significant future target group for the Diamyd® vaccine. Several studies and Diamyd’s own clinical trials have shown that around 10 percent of all those diagnosed with type 2 dia- betes actually have LADA
15). In 2007 it was estimated that worldwide around 246 million people have diabetes, of which 85-95 percent have type 2 diabetes. This translates into an estimated total of over 20 million LADA-sufferers worldwide. The total number of people with diabetes is expected to rise dramatically to 380 million by 2025
16).
NP2
The NTDDS product NP2 is a method of treating chronic pain with enkephalin – a morphine-like substance. Preclinical studies show that a single dose of NP2 provides effective pain relief for several weeks.
The treatment works locally and can be repeated several times with- out causing dependence or tolerance to enkephalin. The treatment has also been shown to be safe and to be free of serious side effects, in contrast to conventional treatment, e.g. morphine.
Preclinical study results published in the scientific journal The Journal of Neuroscience in the fall of 2008 suggest that treatment with NP2 not only provides effective pain relief but could also potentially cure the pain, as it is partly due to inflammation caused by the pain itself. This means that in the future it may also be possible to administer local pain prevention.
Project status
Diamyd initiated a Phase I trial of NP2 in the USA in 2008. The aim is to establish the safety of the treatment in humans. The study encompasses 12 patients with severe cancer pain. The trial represents a safety study for the whole NTDDS platform and will form the basis for future studies of other substances and diseases.
Future market potential
The target group for NP2 is mainly people suffering from chronic pain, including pain related to diabetes and cancer. Current treatment regimens for chronic pain are generally associated with a number of
adverse effects such as constipation, psychological disturbances and impaired breathing. In addition, problems with drug tolerance and dependence occur, and when all this is taken into account, there is a clear medical need for new forms of treatment.
Drugs for diabetes-related pain are considered to have great market potential because diabetic neuropathy can occur in all forms of dia- betes – type 1, LADA and type 2. Cancer pain relief also represents a substantial market. About 30 percent of all cancer patients suffer from pain related to their disease. This figure rises to about 90 percent in patients with advanced cancer
17).
NG2
The NTDDS product NG2 delivers GAD locally to nerve cells. In disease models it has been shown to be effective in the treatment of chronic neuropathic pain resulting from nerve damage, as in e.g.
diabetes and spinal cord injury.
Project status
Preclinical studies are in progress. Clinical studies are being planned.
Future market potential
There is a clear medical need for new forms of treatment for neuro- pathic pain, with fewer side effects and avoiding the development of tolerance. About 4.7 million people suffer from neuropathic pain in the USA alone, and this populations is expected to increase to over 6.1 million by 2018. The American market for neuropathic pain relief is today estimated to be worth 2.6 billion USD, a figure that is expected to increase to 5.1 billion USD by 2018
18).
NC3
The NTDDS product NC3 is for the treatment of glioma, a type of malignant brain tumor produced by cancerous glial cells from brain connective tissue. Malignant glioma is one of the most aggressive types of brain tumor and has low survival rates. NC3 can induce high levels of therapeutic cell-killing substances for up to a week. The NC3 vector and the cell-killing substances work together to eliminate cancer cells locally without damaging healthy cells nearby.
Project status
Preclinical toxicological studies have been carried out with NC3, financed by grants from the US National Institutes of Health (NIH).
Future market potential
In Sweden, the annual incidence (number of new cases) of malignant glioma is 4-6 per 100 000 persons
19). The same incidence is thought to apply to the USA as well. The value of pharmaceutical sales for the treat- ment of glioma is expected to double to over 1.8 billion USD by 2017 in the USA, EU and Japan
20).
PrOJECT POrTFOLIO
CLINICAL TRIALS
Diamyd currently has three products in clinical development. The most advanced of these is the GAD- based vaccine Diamyd
®for type 1 diabetes which is undergoing Phase III trials in both the USA and Europe. In addition, Diamyd has initiated a clinical trial in the USA of the NTDDS technology within the field of chronic pain. Several externally funded and researcher-initiated studies of the Diamyd
®diabetes vaccine are in progress both in the USA and in Europe.
DIAMYD’S CURRENT AND RECENTLY COMPLETED CLINICAL STUDIES
Diamyd has a large Phase III program of the Diamyd® diabetes vac- cine in type 1 diabetes in the USA and Europe, as well as a Phase I study of the NTTDS product NP2. Completed studies include a Phase II study of Diamyd® for LADA and a Phase II study of Diamyd®
for type 1 diabetes. The latter has been extended by a further 3-year follow-up.
Phase III program – Diamyd
®for type 1 diabetes
Two parallel Phase III studies of the Diamyd® diabetes vaccine are now in progress in nine European countries and the USA. Both studies are randomized, double-blind and placebo controlled. Approximately 320 young patients with newly-diagnosed type 1 diabetes are included in each study. Recruitment for the European study has been completed.
The aim of the Phase III studies is to confirm and evaluate the ability of the Diamyd® vaccine to halt or slow the autoimmune destruction of the pancreatic beta cells, thereby preserving the body’s own ability to control the blood sugar in people with type 1 diabetes. Each study includes three treatment arms in which one third of the patients are treated with two injections of Diamyd® 20μg (days 1 and 30) and two placebo injections, one third are treated with four injections of Dia- myd® 20μg (days 1, 30, 90 and 270), and one third receive four placebo injections. The results of each study will be analyzed 15 months after all the participants have had their first injection. If the study results are positive, they will be used for market registration. The European study is led by Professor Johnny Ludvigsson of Linköping University Hospi- tal in Sweden, whilst the US study is led by Professor Jerry Palmer of the University of Washington in Seattle, USA.
Phase II study – Diamyd
®for type 1 diabetes
A completed 30-month randomized double-blind placebo-controlled Phase II trial of Diamyd® encompassing 70 children and adolescents with type 1 diabetes. Significant long-term efficacy in slowing the destruction of beta cell function, i.e. the body’s own ability to regulate blood sugar, was demonstrated. The treatment was well received by patients, their doctors, and family members. The results also strongly support the safety of the drug. No serious side effects related to the Diamyd® treatment were reported in the study. The results were pub- lished in the fall of 2008 in the prestigious journal The New England Journal of Medicine. The study has now been extended by a further three years in order to monitor the participants and confirm the long- term effects of the Diamyd® vaccine.
Follow-up of Phase II study – Diamyd
®for type 1 diabetes In February 2009, Diamyd received approval from the Swedish Medi- cal Products Agency to follow up the children and adolescents with type 1 diabetes who participated in the Phase II trial of the Diamyd®
diabetes vaccine. An initial analysis of the new data shows that still four years after the injections were given, the patients who were newly-diagnosed at the start of the study and who received Diamyd®
vaccine, had significantly better diabetes status than the correspond-
ing patients who received placebo. The safety data also continues to
look promising, without any serious adverse effects associated with
the treatment. The patients will also be followed with regard to quality
of life and diabetes complications. The follow-up study will continue
for three years, at which point the participants will have been moni-
tored for a total of seven years.
Phase II study – Diamyd
®for LADA
A completed randomized double-blind placebo-controlled Phase II study encompassing 47 LADA patients, where various doses of the vaccine were tested. Depending on their study arm, subjects received two injections, four weeks apart, of either 4, 20, 100 or 500 μg Diamyd® or placebo. The study was unblinded after six months and the patients were followed for another four and a half years. The study results show that the most efficacious dose of Diamyd® was 20 μg. A five year follow-up of the participants shows that the risk of a LADA patient having to start insulin therapy is reduced by Diamyd®
treatment. Only 14 percent of subjects in the group that received 20 µg of Diamyd® and completed the study needed insulin treatment five years after the initial injection, compared to 64 percent in the placebo group. No serious adverse effects associated with the drug were reported during the five year period. The results were presented in September 2008 at a conference organized by the European Association for the Study of Diabetes (EASD) and were published in April 2009 in Diabetologia, the leading European scientific journal dedicated to diabetes.
Phase I study - NP2 for cancer pain
A clinical Phase I study in progress in the USA to evaluate the safety of the NTTDS product NP2 in patients with severe cancer pain. The study is designed as a dose-escalating study in which various doses will be tested.
Diamyd® has demonstrated efficacy in a Phase II study of 70 children and adolescents with type 1 diabetes*). Patients who received Diamyd® lost significantly less of their meal-stimulated insulin-secreting capacity (as measured by C-peptide). C-peptide and insulin are produced in the body simultaneously and in the exact same quantities, and C-peptide is the best way to measure the body’s remaining capacity to secrete insulin. In patients treated within three months of being diagnosed with type 1 diabetes, the Diamyd® group on average even experienced an improvement in their insulin-secreting capacity over the first 15 months of the study.
*) Ludvigsson et al. N Engl J Med 2008;359:1909–1920 Change in meal-stimulated C-peptide, mean values Time since diagnosis at start of study: 0–18 months
0 5 10 15 20 25 30
Time in months pmol/ml/2 hours
Diamyd® injections -0.2 -0.4 0
p=0.02 p=0.01
p=0.02
p=0.04 -0.6
-1 -0.8
-1.2
Diamyd® n=35 Placebo n=34
Change in meal-stimulated C-peptide, mean values Time since diagnosis at start of study: 0–3 months
0 5 10 15 20 25 30
Time in months pmol/ml/2 hours
Diamyd® injections -2.0 -1.5 -1.0 -0.5 0.5
0
Diamyd® n=4 Placebo n=7
Dose placebo 4 µg 20 µg 100 µg 500 µg
Insulin-treated laDa patients 5 yrs after treatment
with Diamyd®*) 64% 71% 14% 14% 63%
*) Agardh et al. Diabetologia 2009;52:1363-1368
