In a review article published in April 2021, Profil’s Lead Scientist Dr. Tim Heise gives an overview on the future of insulin therapy (1).
When thinking of 100 years of insulin treatment since its first use, it is not surprising that one of the topics elaborated on in the article refers to oral insulin. Insulin injections into the subcutaneous tissue are considered inconvenient and could be related with fears and a consecutive time delay in starting an insulin therapy deemed necessary (2).
Characteristics of oral insulin
Fortunately, there are several ongoing clinical developments aiming to further improve insulin formulations – including oral insulins. One advantageous feature of oral insulin apart from the convenience aspect is its hepato-preferential action due to achieving high insulin concentrations in the portal vein before reaching peripheral tissues. Challenges related to oral insulin administration consist in high variability in absorption and low bioavailability – already mentioned in the first n=1 trial publication in 1923 (3). In addition, oral insulin preparations exhibit a pronounced food effect that has to be taken into account (4).
In the publication Dr. Heise introduces two prandial oral insulins currently in clinical development, insulin tregopil (or IN-105) and ORMD-0801, as well as one basal oral insulin formulation, oral insulin 338. Clinical trial data for the three insulins are summarized in his review.
Insulin tregopil is an insulin analogue with a polyethylene glycol side chain at position B29 and sodium caprate as absorption enhancer. Insulin tregopil is rapidly absorbed and has to be taken 10 to 30 minutes prior to meal ingestion (5). The primary endpoint of an early phase 3 trial in type 2 diabetes subjects – a placebo-adjusted HbA1c reduction of 0.7% - was not met, although significant improvements in early postprandial glucose control were observed (5). Dr. Heise stated that a trial in type 1 diabetes is still ongoing (6).
ORMD-0801 is an oral insulin in an enteric-coated capsule with further adjuvants not specified that shall protect the insulin from degradation in the gastrointestinal tract and enhance its absorption (5). Although the number of trials registered in clinicaltrials.gov is quite impressive (15 studies listed), publications of the most recent trials are sparse. In addition, none of the studies with available results used subcutaneous insulin as comparator and thus, interpretation of outcomes is difficult.
In July 2021 a type 2 diabetes study with ORMD-0801 was published (7) – again using placebo as comparator. In this trial 188 metformin-treated patients with type 2 diabetes received either placebo or 16 or 24 mg ORMD-0801, once-daily at bedtime for 28 days. Compared with the control group ORMD-0801 attenuated increases in night-time glycemia, 24-hour glycemia and HbA1c, without increasing hypoglycemic or safety events. Phase 3 trials in people with type 2 diabetes – approved by the FDA – are currently ongoing.
Oral insulin 338 (I338) is a long-acting basal insulin analogue formulated in a GastroIntestinal Permeation Enhancement Technology One (GIPET-1) tablet with sodium-caprate as absorption-enhancer (8, 9). Due to acylation with an 18-carbon fatty diacid via a linker I388 reversibly binds to albumin and exhibits a prolonged half-life of 70 hours at steady state, although it‘s absorption is comparably fast (9).
In an 8-week feasibility trial I338 improved metabolic control in insulin-naive people with type 2 diabetes without a significant difference to s.c. insulin glargine (8). This is the first study showing that it is possible to take a basal insulin as tablet and that it also provides comparable clinical efficacy as compared to s.c. basal insulin injections.
Further development of this specific oral insulin project, however, was discontinued and deemed not commercially viable, as I338 doses at the end of the 8-week treatment period were approximately 58 times higher than those of insulin glargine.
In Dr. Heise‘s opinion it will still take some time until oral insulins – together with other progress in the field of insulin formulations - will become the standard therapy. Although already introduced 100 years ago, insulin development has not come to its end yet. There are ongoing developments with the potential of further improvements concerning the safety and efficacy of insulin therapy in the future.
Our upcoming live online seminar titled: “Advancements in oral insulin development: are we nearly there yet?" will give you some more insights of the current status of oral insulin development and best practive for clinical trial design. Our expert Dr. Eric Zijlstra will present this online webinar, which takes place on November 2nd, 2021. Register or read more about this seminar here.