Despite significant delays related to COVID-19, in late 2020 BioKier completed a 4-week study of BKR-017 (orally administered colon-targeted, sustained-release 500 mg butyrate tablets) in type 2 diabetes (T2D) subjects. Dr. Kishore Gadde’s team at Pennington Biomedical Research Center (PBRC) enrolled 14 subjects in the study and all subjects successfully completed the 4-week treatment period. Data analysis was completed, and a high-level summary of the results is provided below

Summary: Fourteen T2D patients with good glycemic control (average weight = 115.04kg, range 67.7-185.8kg; average plasma glucose = 151.7mg/dL, range 112-233 mg/dL; average HOMA-IR = 4.87, range 2.82 – 7.52), treated with modified diet or oral agents, participated in this study to determine the effect of 28 days’ treatment of, BKR-017, on insulin resistance and other metabolic parameters. The study was a single-center, single-dose, open-label study. Each subject received 1.5g (three 500 mg tablets) BKR-01, twice daily. A mixed-meal tolerance test (MMTT) was administered at Day 0 prior to treatment and at Day 28 when treatment was completed. Blood samples were collected during the MMTT at defined time points for up to 4 hours for analysis of glucose, insulin, C-peptide, GLP-1, and triglycerides (TGs). Samples were also obtained at Day 0 and Day 28 to perform routine hematology and chemistry evaluations.

Treatment for 28 days with BKR-017 had no effect on fasting glucose, insulin, Cpeptide, HOMA-IR, GLP-1, TGs, hsCRP, 1,5-AG, adiponectin, RBP4, or weight. Small changes were seen in mean postprandial glucose, TGs, insulin, and C-peptide levels

BKR-017 (sustained-release formulation) decreased circulating cholesterol. The effects were both statistically and clinically significant for total cholesterol (174.7±34.2 to 148±23.8 mg/dL, mean ±SD, p=0.00244), LDL cholesterol (95.9±28.8 to 77.8±22.4 mg/dL, p=0.01636), HDL cholesterol (48.3±9.9 to 40.2±9.5 mg/dL, p=0.00049), and non-HDL cholesterol (126.4±29.8 to 107.8±22.8 mg/dL mg/dL, p=0.00732) levels. The changes in LDL cholesterol are provided in the figure below.

Figure 1: Changes (before – after) of LDL cholesterol resulting from 4 weeks of treatment with BKR-017.

BKR-017 statistically and clinically decreased circulating total cholesterol (174.7±34.2 to 148±23.8 mg/dL, mean±SD, p=0.00244), LDL-C (95.9±28.8 to 77.8±22.4 mg/dL, p=0.01636), HDL-C (48.3±9.9 to 40.2±9.5 mg/dL, p=0.00049), and non-HDL-C (126.4±29.8 to 107.8±22.8 mg/dL mg/dL, p=0.00732) levels. The changes in LDL cholesterol are provided in the graph below.

Levels of Apo A1, Apo B, Apo C-III, RBP-4 also decreased with BKR-017 treatment. The effects of BKR-017 on lipid parameters were greater in the GLP-1-responder subgroup.

BKR-017 had a small effect on liver markers AST and ALT that were normal range at baseline (5-40 U/L for AST and 7-56 U/L for ALT). However, one subject, 412 (female), had very high AST and ALT at baseline that returned to near-normal levels after the 4-week BKR-017 treatment. This subject was under observation by her primary care physician before the study for abnormally high AST and ALT values. The reductions in AST and ALT were accompanied by reductions in cholesterol, LDL-C, HDL-C, and hs-CRP and there were also marginal reductions in fasting glucose and insulin. One other subject, 410 (male), had an elevated ALT at baseline and was within normal range after the 4-week treatment period. Of note, Subjects 410 and 412 were two of the subjects who showed a significant improvement in postprandial GLP-1 secretion.

In summary, 28-day treatment with the colon-targeted, sustained-release butyrate tablet, BKR-017, improved the lipid, apolipoprotein, adipokine, and liver biomarker profiles in diabetic dyslipidemia. These effects suggest that BKR-017 has the potential to improve cardiometabolic health of T2D patients who typically exhibit various degrees of dyslipidemia, insulin resistance, diabetes, hypertension, and central adiposity. The current findings support the approach of using chronic administration of natural gut hormone secretagogues to the lower gut for the treatment of cardiometabolic syndrome. Additional studies will further elucidate how natural gut hormone secretagogues can influence glucose and lipid regulation.

Other ongoing activity

Multi-center T2D Clinical Study

Following on from the 4-week study at PBRC, BioKier is conducting a multi-site dose-response study of BKR-017 (orally administered colon-targeted, sustained-release 500 mg butyrate tablets) in T2D subjects. Three clinical sites are currently recruiting subjects: Pennington Biomedical Research Center with Dr. Kishore Gadde as PI, and Duke University Clinical Research sites at Kannapolis NC and the Pickett Road clinic in Durham with Dr. Kristin Newby as PI. After an initial slow start due to the COVID-19 pandemic, recruitment has accelerated will be complied by summer of 2022.

The study consists of four cohorts of 15 subjects each, treated with placebo or one of three active doses of BKR-017 (500 mg, 1 g, or 1.5 g BID) for 12 weeks. This study is designed to confirm results of the 4-week study and determine the lowest effective dose for commercialization. Outcomes to be measured are insulin resistance (HOMA-IR), total cholesterol, LDL, HDL, non-HDL, HbA1c, fasting insulin, glucose, triglycerides; exploratory endpoints are lipid particle size by NMR, 1,5AG, RBP-4, ALT, AST, Apo (A, B, and C), and hs-CRP.

Single-center T1D Clinical Study

Also, due to the beneficial effects of butyrate generated by fermentation of carbohydrates in the colon during treatment with α-glucosidase inhibitors in type 1 diabetes (T1D) patients, BioKier has recognized the potential of BKR-017 in helping mange glucose regulation in T1D patients. Although designed to initially target T2D, BKR-017 has the potential to improve insulin sensitivity, reduce insulin use, and reduce glucose excursions in T1D. The study, funded by a grant from JDRF, will be conducted in collaboration with Dr. Adrian Vella at the Mayo Clinic in Rochester MN. It consists of a single arm of 16 subjects treated for 8 weeks with a single dose of BKR-017. Treatment of patients will start in June 2022.

Outcomes include effects of BKR-017 as adjuvant therapy in TID subjects on insulin sensitivity, glucose control (variability), triglycerides, and cholesterol. Changes in these parameters will be compared to baseline values, measured during a 4-week run-in period.

Confirmation of BKR-017’s effects on regulation of glucose and lipids and its effects on augmenting postprandial secretion of GLP-1 imply that longer-term treatment can also positively impact weight-loss and fatty liver. Long-term plans are for BioKier to position its butyrate tablet for licensing by a corporate partner with the capacity to manufacture and market the product as a medical food.