Canvuparatide

Sprague Dawley rats^[1]

4-12 nmol/kg

s.c.; once daily; 28 days

No appreciable changes in body weight or food intake were observed after 28 days of daily SC dosing at 4, 8, and 12 nmol/kg.
Increased serum calcium less than 0.5 nmol/μL, with no dose response over the course of the study.

Sprague Dawley rats (female, parathyroidectomized, low-calcium diet)^[1]

10-40 nmol/kg (4 doses); 10-40 nmol/kg (10 days); 5-15 nmol/kg (10 days); 7.5-15 nmol/kg (28 days)

s.c.; daily; 4 or 10 or 28 days

Exhibited a dose-proportional increase in serum calcium after 48 h at 10, 25, and 40 nmol/kg; the calcium level in the 40-nmol/kg group slightly exceeded that in sham rats, and this relationship was maintained 72 h after the last dose.
Increased serum calcium dose-proportionally but exceeded sham levels at the higher doses after daily dosing for up to 10 days; on days 7, 10, and 11 significant differences were observed between vehicle and sham controls, the 25-nmol/kg group, and the 40-nmol/kg group, and between vehicle and the 10-nmol/kg group on days 7 and 11.
A dose-proportional increase in serum calcium occurred at 3 days and continued through the end of study at 5, 10, and 15 nmol/kg, at which time calcium in sham rats was statistically identical to the high-dose-treated PTX rats.
Restored circulating calcium levels similar to sham animals by day 14 and maintained through day 28 at 7.5 and 15 nmol/kg/day.
Decreased serum phosphate dose-proportionally at 10, 25, and 40 nmol/kg for up to 10 days, most evident on day 7 and day 10; significant differences were observed between vehicle and sham controls and the 40-nmol/kg group on days 3 and 11.
Reduced circulating phosphate closer to the upper limit of normal, similar to sham controls over 28 days at 7.5 and 15 nmol/kg/day.
No statistically significant changes in serum P1NP were observed after 4 and 28 days.
Resulted in a numerical reduction of trabecular BV/TV versus untreated PTX rats (not significant) at each dose.
Had significantly less cortical bone area compared with PTX vehicle controls at 15 nmol/kg, with a similar trend at 7.5 nmol/kg.
Had significantly higher BFR/BS than vehicle-treated PTX rats at 15 nmol/kg, and MAR, MS/BS, and BFR/BS did not differ from sham controls; the 7.5 nmol/kg dose had no significant effect on BFR/BS.
Oc.S/BS was significantly higher in PTX rats treated with canvuparatide 15 nmol/kg compared with sham rats.
Led to significantly lower displacement to failure and total work to failure versus PTX vehicle controls, and lower total work to failure versus sham controls at 15 nmol/kg, whereas 7.5 nmol/kg had no significant effect.