Prologue. Sublin BV is a late-stage preclinical pharmaceutical product developing company, that focusses on a novel sublingual insulin modality (SLIM) as novel intervention for diabetes. This Case Study 2 addresses the treatment of diabetes and innovations therein. The general information around the pathology of diabetes mellitus are addressed in Case Study 1.
Since decades, treatment of insulin-dependent diabetes mellitus is based on daily subcutaneous insulin injections[1]. Insulin still largely depends on injections to be effective, since oral cavity uptake is not possible and subsequent gastrointestinal degradation and hepatic first-pass effects render the insulin inactive. The injections itself cause discomfort, poor patient compliance and increase the risk of several co-morbidities over time [2–4]. Alternative insulin routes of administration are desperately sought after and have been targeted by several pharmaceutical companies for decades[5–8]. Research has focused on the development of alternatives, based on galenic formulations for oral, nasal or pulmonary administration. Unfortunately, none of these alternatives to injections has been a commercial success and no oral insulin solution has been adopted vastly by the market yet. The largest pharmaceutical companies have invested several billions of dollars in developing other insulin administration alternatives, including; Sanofi, Eli Lilly, GSK, Astra Zeneca, Novo Nordisk, Medtronic, but also smaller companies were keen to penetrate the oral insulin market.
“Alternative insulin administration routes to injections have largely failed, so far !”
In general, the insulin administration routes can be discriminated between invasive and non-invasive routes. For the invasive routes, injections have been the oldest and most common means to provide diabetics with a subcutaneous dose of insulin. This was advanced to insulin pens, having multiple doses available and more sophisticated insulin pumps that provide automatic insulin dispensing to the body. All still depend on invasive needle/catheter-based administration routes, with all complications and risks associated. On the other hand, more patient-friendly non-invasive routes have been intensively explored, including pulmonary sprays, nasal sprays and oral cavity sprays[9]. These non-invasive routes pose little risk for adversity commonly associated with injection-based routes. Other complications however did lure along the way. Most of these sprays displayed several limitations i.e. lack of control over the administered insulin dosage, low bioavailability, since most of the insulin (up to 90%) did not reach the circulation in functional form, making it a very costly and ineffective routes with the current technologies [10]. Furthermore, patients were reluctant to substitute their injection schedule for a spray schedule, especially when multiple sprays (up to 40 per time) were needed to dose adequately. A poor reproducibility of administrated dose to reach a systemic insulin level, due to intra-individual fluctuating bioavailability, has hampered the adoption of new interventions even further. Lastly, the increased risk for adverse effects, including oncogenicity, vastly narrowed the percentage of the market penetration[11].
Overall, it can be stated that any truly effective oral administration route for insulin is superior to injections. Still, the most commonly used administration route is injection, either by syringe or pump needle/catheter. The insulin bioavailability this way is the highest compared with any other delivery route, making it reproducible, dependable, and relatively the cheapest method when calculating the net International units of insulin (IU insulin) consumption. This is however the only advantage of injections. Patient comfort is low, as for patient compliance, patient training is required, overall cost and maintenance are high and adversity is too often reported[12]. These adversities range from low-risk skin irritations due to injections to high-risk hyperinsulinemia, inflammation, bleeding and infection risks or catheter-site fibrosis for pumps, to name just a few.
Insulin sprays provide a non-invasive administration route, so it provides several advantages over injections. This explains the large interest of pharmaceutical companies and the number of different products under development in this category. Unfortunately, these administration routes mostly provide low bioavailability and poor reproducibility in dosing intentions versus reaching systemic insulin levels. The latter problems of these alternatives result in poor effectiveness. Furthermore, they present health issues after prolonged usage. For instance, although inhaled insulin seems a well-accepted new generation of insulin administration -as it is expected to have relatively good reproducibility in lung tissue- it largely failed to claim market value. Major concerns related to inhaled insulin were the indications of elevated health risks for some formulations, and a very low bioavailability in general, leading to high insulin spillage and a reimbursement refusal by US insurance companies since costs were too high compared to injections. The concerns led to a low treatment adoption for oral insulins, leaving the overall benefits of this route untapped by the previously developed products.
Sublin B.V. aims to address all these requirements and shortcomings by providing 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.
