EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients

Abstract

The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of ³³Phosphate (³³P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of ³³P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future phase 2 and phase 3 studies.

Keywords: hemodialysis; intestine; phosphorus absorption; phosphorus radiotracer; sodium-phosphate cotransporters.

Figure 1 |. Schematic of study design.

Each study consisted of 2 sequences (arms) of 13–14 days duration with a 2-week wash-out between sequences. During the sequence, subjects had the study diet for the entire duration and the study drug began on day 4. The subjects were hospitalized in the Clinical Research Center on day 9 (first sequence for pharmacokinetics) or day 10 (second sequence) of each study. Patients underwent hemodialysis before admission and as the final event during the admission such that all of ³³P studies were done between dialysis treatments.

Figure 2 |. Pharmacokinetic (PK) analyses of EOS789.

Mean ± SD plasma EOS789 concentration at steady state (on day 10). PK sampling points were before morning dose and 1, 2, 4, 6, 8, 12, 24 hours after. Doses were given at 0, 4, and 8 hours. Only the first sequence was used for the PK sampling, with n = 5–7 per group. Individual PK curves for each dose are shown in Supplementary Figure S2. SEV, sevelamer carbonate.

Figure 3 |. Intestinal fractional P absorption by ³³P.

Fractional P absorption in individual patients in (a) study 1 (comparing placebo vs. 50 mg EOS789 3 times per day [t.i.d.] with meals) and (b) study 2 (comparing 100 mg EOS789 vs. 100 mg EOS789 with sevelamer t.i.d. with meals). Each line represents 1 patient, EOS789–50 = 50 mg EOS789 t.i.d.; EOS789–100 = 100 mg EOS789 t.i.d.; EOS789–100 + Sev. = 100 mg EOS789 + 1600 mg sevelamer carbonate t.i.d.

Figure 4 |. Dose efficacy of EOS789 in intestinal fractional P absorption.

In a planned secondary analysis, data from the 6 patients who completed both studies were analyzed to generate a dose response comparing placebo, 50 mg EOS789 3 times per day (t.i.d.) and 100 mg EOS789 t.i.d. There was a significant difference between placebo and EOS789–100 (P = 0.028).

Figure 5 |. Example of assessment of intestinal fractional P absorption with the use of a single isotope.

³³P was used to assess fractional P absorption. Staggering the oral and i.v. ³³P isotope administration by 1 day allows for the use of this single low-energy beta-emitter isotope. Kinetic modeling of the ³³P radioactivity counts by liquid scintillation counting of plasma samples allows for calculation of intestinal fractional P absorption. dpm = disintegrations per minute.