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. 2017 Jan 17;5(1):e00292.
doi: 10.1002/prp2.292. eCollection 2017 Feb.

Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated with unexpected renal effects

Leonie van Meer  1 , Marloes van Dongen  1 , Matthijs Moerland  1 , Marieke de Kam  1 , Adam Cohen  1 , Jacobus Burggraaf  1
Affiliations

Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated with unexpected renal effects

Leonie van Meer et al. Pharmacol Res Perspect. .

Abstract

The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium-glucose cotransporter-2 (SGLT2) mRNA expression. It is developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administration of the drug were planned to be evaluated in healthy volunteers in a single-ascending-dose study (50-400 mg) and a multiple-ascending-dose study (6 weeks; weekly doses of 50-400 mg with loading dose regimen of three doses during the first week). The study was halted early because increases in serum creatinine occurred in the subjects participating in the 100 mg multiple-dose cohort. The pronounced changes in serum creatinine were accompanied by increased urinary excretion of beta-2-microglobulin and KIM1. The possible mechanisms for these findings remain elusive and are in contrast to preclinical findings as comparable treatment with ISIS 388626 of animals did not reveal similar changes. Although exposure was limited, there was an indication that glucosuria increased upon active treatment. Before the concept of antisense-mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations.

Keywords: Antisense; SGLT2 inhibitor; oligonucleotide; phase 1 study; renal toxicity.

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Figures

Figure 1
Figure 1
Average change from baseline of serum creatinine over time in the multiple ascending dose study with SD error bars. Timing of dosing is indicated with D's. The six subjects of the 50 mg cohort received all eight doses. In the 100 mg cohort, the first 4 doses were received by all 12 subjects. Thereafter, nine subjects received the fifth dose and four subjects received the sixth dose and no subjects in the 100 mg cohort received the seventh or eighth dose, due to the early halt of the study. In the 50 mg cohort, a minimal increase in average serum creatinine of 0.13 ± 0.09 mg/dL (13% increase) was observed during the first 3 weeks after treatment initiation. The values returned to baseline levels after the third treatment week, despite continued dosing. In the 100 mg cohort, an increase in average serum creatinine of 0.14 ± 0.12 mg/dL (16% increase) was observed during the first 3 weeks.
Figure 2
Figure 2
Box‐Whisker plot of urinary renal damage markers Pre‐Dose and Post‐Dose (after 4 doses). The bottom and top of the box are the 25th and 75th percentile, respectively and the band inside is the median. The ends of the whiskers represent the minimum and maximum of all the data. Dots are individual results, grey being pre‐dose measurements, black being values measured after 4 doses of study drug. After 4 doses, a dose‐dependent increase in B2M excretion was observed in nearly all ISIS 388626‐treated subjects. An average of 843 ± 1027.5 ug/24 hrs was observed for the 50 mg cohort and 2200 ± 2956.2 ug/24 hrs for the 100 mg cohort, versus 69.8 ± 27.6 ug/24 hrs in the placebo group. Also KIM 1 and aGST excretion increased upon ISIS 388626 treatment in the majority of treated subjects, although there were no clear dose relationships observed for these renal markers. No clear changes occurred in urinary NAG.
Figure 3
Figure 3
Profile of plasma pharmacokinetics during the first 48 h after a single dose of study drug. Average concentrations with SD error bars. Following single sc injection, ISIS 388626 was rapidly absorbed as demonstrated by reaching maximum plasma concentrations (C max) between 1.2 and 1.5 h.
Figure 4
Figure 4
Average ISIS 388626 urinary excretion (mg), with SD error bars after one dose of study drug during the first 24 h and during the 24–48 h interval. N = 3 subjects per dose level. The total amount of ISIS 388626 in urine increased more than dose‐proportionally
Figure 5
Figure 5
Average urinary glucose excretion time profile graph, with SD error bars. Repeated administration of 50 mg ISIS 388626 did not alter urinary glucose excretion after 6 weeks of treatment. At follow up, six weeks after the last administration of ISIS 388626, a possible trend towards an increased urinary glucose excretion was observed. EOT, End Of Trial; OGTT, Oral Glucose Tolerance Test.
Figure 6
Figure 6
Average inhibition of glucose reabsorption time profile graph, with SD error bars. Repeated administration of 50 mg ISIS 388626 did not alter inhibition of glucose reabsorption after 6 weeks of treatment. At follow‐up, six weeks after the last administration of ISIS 388626, a possible trend towards an increased inhibition of reabsorption was observed. W,week; EOT, end of Trial; OGTT, Oral Glucose Tolerance Test.
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