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Insulin is the cornerstone of diabetes treatment, but compared with simple and convenient oral drugs, "subcutaneous injection", the current main mode of insulin administration, has many limitations
.
In order to better meet clinical needs, researchers are constantly moving forward on the road of research and development of insulin "oral dosage form"
.
Recently, the latest research progress of oral insulin ORMD-0801 was published
in the journal Diabetes, obesity and metabolism.
In patients with type 2 diabetes who use oral hypoglycemic agents but still have poor glycemic control, the efficacy and safety of different doses of ORMD-0801 (for 12 weeks) were evaluated, paving a solid path
for Phase 3 studies.
What are the difficulties in the research and development of oral insulin?
1.
The "three mountains" that need to be overcome in oral insulin research and development
Similar to the injectable form, the development of oral insulin began in 1922, but no product has been launched so
far.
The difficulty in research and development mainly lies in the "three mountains" composed of physical barriers, chemical barriers and enzyme action barriers in the human body, which affect the absorption and stability of drugs, making it difficult for oral dosage forms to give full play to their therapeutic effects
.
➤Physical barrier: the structure and function of the intestinal epithelium hinder insulin absorption and inhibit the osmotosis/absorption of insulin;
➤Chemical barrier: pH and other internal environment can affect the stability and effect of insulin structure;
➤ Enzyme action barrier: Proteases degrade insulin, resulting in its low
bioavailability.
Fig.
1 Barrier faced by oral insulin
2.
"Three ways" to break through barriers
In order to break through the above biological barriers, researchers have actively explored and made certain progress in recent years, and determined three new strategies to overcome research and development obstacles: 1.
enhance permeability; 2.
drug modification; 3.
mechanical transportation
.
A typical example of the "enhanced permeability" strategy - oral insulin ORMD-0801
ORMD-0801 is an oral recombinant human insulin enteric-coated capsule formulation that allows insulin to enter the systemic circulation
by inhibiting the hydrolysis of small intestinal proteins and improving the ability of polypeptides to pass through the intestinal epithelial lining.
In this study, 373 participants (7.
5% of T2DM patients receiving metformin or oral therapy with HbA1≥c) were randomly divided into the drug treatment group or placebo group (men accounted for about 60%, age about 56 years, HbA1c 8.
5%~9.
8%)
.
ORMD-0801 was randomized to receive ORMD-0801 8 mg (QD, BID) or 16 mg (QD, BID) or 32 mg (QD, BID, TID) for 12 weeks
.
What is the hypoglycemic effect of ORMD-0801? "Take 8mg before bedtime" has a good effect
At week 12, most dose groups achieved a significant reduction
in HbA1c compared to placebo.
ORMD-0801 was a greater reduction in HbA1c in the 8 mg QD or BID administration group, 0.
81% and 0.
82%,
respectively.
The effect of lowering fasting blood glucose and other blood glucose parameters measured by CGM is similar
to that of HbA1c.
This study supports the dose of "8 mg once daily at bedtime" as the most effective dosing regimen
for Phase 3 studies.
Fig.
2 Changes in HbA1c at week 12 with increasing dose of ORMD-0801 (after placebo adjustment)
How safe is ORMD-0801?
The overall incidence of adverse events and serious adverse events was similar in the ORMD-0801 and placebo-treated groups, with the incidence of drug-related adverse reactions <5% in all dose groups, no significant difference from placebo, mostly mild or moderate.
Adverse reactions: the most common adverse reactions were infection, followed by gastrointestinal diseases (mainly diarrhea, abdominal pain, 3.
7% in the placebo group and 4.
4%-6.
7% in the drug treatment group).
Hypoglycemic events: ORMD-0801 did not increase the incidence of
hypoglycemic events compared with placebo at the test dose.
Summary of this article
This Phase 2 study is designed to determine the optimal dose and regimen for ORMD-0801 to reduce HbA1c
in patients receiving metformin monotherapy (or in combination with other oral hypoglycemic agents) in patients with T2DM who still have poor glycemic control.
The results showed that ORMD-0801 was safe and well tolerated in most dose ranges from 8 mg QD to 32 mg BID
, significantly reducing HbA1c without significantly increasing the risk of hypoglycemia or weight gain.
Overall, based on primary and secondary efficacy results, this review supports the dose of "8 mg at bedtime" as the most effective dosing regimen for Phase 3 studies, with two Phase 3 trials currently ongoing
.
If these initial findings are confirmed by a Phase 3 trial, ORMD-0801 is likely to be an early oral option
for T2DM treatment.
Eldor R, Francis BH, Fleming A, et al.
Oral Insulin (ORMD-0801) in Type 2 Diabetes Mellitus: Dose-Finding 12-Week Randomized Placebo-Controlled Study[J].
Diabetes, obesity and metabolism.
2022 Oct 24.
DOI: 10.
1111/dom.
14901, PMID:36281496