Prologue. Sublin B.V. is a late-stage preclinical pharmaceutical product developer, that focusses on a novel sublingual insulin modality (SLIM), and other drug classes, as a novel ‘oral’ intervention for diabetes. This Case Study 1 addresses all relevant information on diabetes mellitus. The treatment of diabetes and innovations therein are addressed in Case Study 2.
Diabetes mellitus (DM) is a disease that causes pathological high blood glucose levels and high risk of organ damage and other morbidities. It is a metabolic disorder caused by either too low insulin production (type I DM) or due to insufficient insulin signaling to trigger adequate cellular glucose uptake (type II DM). DM-I is caused by destruction of insulin-producing beta cells of islets of Langerhans in the pancreas, likely by autoimmune targeting and clearance. DM-II can be distinguished from DM-I as a disorder of both insulin function and secretion impairment leading to low insulin plasma levels.
Treatment of diabetes needs constant monitoring of blood glucose levels, and regulating it through controlled dietary carbohydrates intake, physical exercise and pharmacological interventions. Many DM-II patients can manage their disease by lifestyle alterations and non-insulin pharmaceuticals (e.g. metformin) to attain normal blood glucose levels. However, for all DM-I patients, and around 30% of DM-II patients, subcutaneous injections of insulin are mandatory multiple times per day. These injections consist of either a slow-acting insulin for an extended action during the day (maintenance dose) or a rapid action insulin injection before a carbohydrate-rich meal. Albeit necessary, these subcutaneous insulin injections increase the risk of e.g. too low blood glucose (hypoglycemia), too high insulin (peripheral hyperinsulinemia), skin-fat damage and deformation (lipoatrophy & lipohyperatrophy), obesity, insulin-induced neuronal damage (neuropathy) and eye damage (presbyopia). Furthermore, insulin injections are associated with discomfort and needle-phobia, causing psychological stress, none-publicly acceptable procedures. These often lead to non-compliance by many patients, hence an even higher risk of complications. Clinical studies showed that a significant percentage of patients failed to attain lasting glycemic control. A practical concern of insulin is the need for continuous cooling channels, making insulin distribution, patient traveling and storage in general expensive and limiting.
“‘SLIM’ technology from Sublin aims to be the next-generation treatment for diabetes mellitus”
According to the WHO report on April 2016, Diabetes is an important public health problem, one of the four priority non-communicable diseases (NCDs) targeted for action by world leaders. Diabetes has reached globally a pandemic scale. Both the number of cases and the prevalence of diabetes has been steadily increasing over the past few decades. Globally, an estimated 422 million adults are living with diabetes, compared to 108 million in 1980. The global prevalence of diabetes has nearly doubled since 1980, rising from 4.7% to 8.5%. According to the survey in low- and middle-income countries the number of people living with diabetes is expected to reach 585 million by 2035. Especially in the developing countries, diabetes has increased rapidly during the last decade. In the 21st century, diabetes has the risk to become a new epidemic in the Middle East, Sub-Saharan Africa, Latin America, India, and the rest of Asia.
Diabetes and its complications bring a substantial economic loss to the patients and their families, to health systems and national economies through direct medical costs and loss of work and wages. Next to being attributive to around 5 million deaths each year, also co-morbidities are prevalent, being leg amputations (60% of all adult amputations in US), cardiovascular disease, loss of vision and renal failure. These complications massively elevate patient burden and societal costs. According to the International Diabetes Federation (IDF), diabetes exceeded $727B in US health expenditure in 2017, making up 12% of the total spending on adults and exceeding oncology spending. In addition, in 2017 around 1.1 million children were living with type I diabetes as estimated by IDF. The global diabetes market is expected to reach over $56 billion in 2020 with a compound annual growth rate (CAGR) of around 8% and an insulin-specific annual market of over $51 billion with a CAGR of around 17%. The major factors contributing to this market growth are; the increase in prevalence of diabetic population, the rise in geriatric population, the rise in awareness of diabetes and the rise in prevalence of obesity.
Since decades, treatment of insulin-dependent diabetes mellitus is based on multiple subcutaneous injections of insulin daily. Injecting insulin is necessary since it is orally ineffective due to absence of oral cavity uptake and subsequent gastrointestinal degradation and hepatic first-pass effects. The injections cause discomfort, poor compliance and increase the risk of many co-morbidities over time. Alternative insulin administration means failed grossly on several parameters, as discussed in more detail in ‘Case-study 2’. An oral and effective route of insulin administration would be highly appreciated since it circumvents virtually all negative effects of injections. Furthermore, with increasing insulin prices, the oral formulation should have much higher bioavailability than what has been currently achieved. To increase patient comfort and to lower drug pricing even further, a new formulation would benefit tremendously from temperature insensitivity. Current insulins often need to be cooled continuously, making the transport and the temperature-controlled storage complicated thus expensive.
At Sublin B.V., we aimed to address all these requirements and shortcomings with our new Sub-Lingual Insulin Modality (SLIM), that is simply taken through the mouth. SLIM has a very high bioavailability and does not require cooling or temperature-controlled storage, based on preclinical data. With these achievements we foresee to fulfill the utmost desired insulin administration route, making SLIM the next-generation diabetes treatment modality.
“‘SLIM’ technology from Sublin aims to be the next-generation treatment for diabetes mellitus”
