ORF16-08 - Efficacy and Safety of Once-Weekly Canvuparatide in Patients with Hypoparathyroidism: Results from Avail, a Phase 2 Randomized Clinical Trial

Introduction: Hypoparathyroidism (hypoPT) is a rare endocrine disease characterized by low parathyroid hormone (PTH) levels and hypocalcemia, causing multiorgan complications and impaired quality of life. Canvuparatide is an investigational PTH analog for once-weekly (QW) hypoPT treatment.

Methods: Avail was a 12-week (W), multicenter, randomized, double-blind, placebo (PBO)-controlled study evaluating canvuparatide efficacy and safety in patients (pts) with hypoPT (NCT06465108). Pts were randomized 1:1:1:1 to canvuparatide 400 ug, 600 ug, 800 ug, or PBO SC QWx4, with optional 200 ug dose titration Q2W (maximum 1600 ug). Primary composite endpoint (PCE): albumin adjusted serum calcium (AdjCa) 8.2–10.6 mg/dL, independence from active vitamin D (aVitD), and oral calcium (Ca2+) supplements ≤ 600 mg/day (d) at W12. Secondary endpoints: change from baseline (CFB) to W12 in AdjCa, urine Ca2+ (uCa), and bone biomarkers; adverse events (AEs); and antidrug antibodies (ADA).

Results: Of 64 pts randomized, (87.5% female; pooled canvuparatide, n = 48; PBO, n = 16), 100% completed study treatment. A significantly higher proportion of pts achieved the PCE with canvuparatide (62.5%) vs PBO (31.3%; P = .043). At W12, the canvuparatide group experienced better outcomes than PBO in serum AdjCa normalization (81.3% vs 43.8%; P < .01), aVitD independence (97.9% vs 62.5%; P < .001), and oral Ca2+ ≤ 600 mg/d (75.0% vs 31.3%; P < .01). Mean AdjCa levels remained in the normal range at all visits in the pooled canvuparatide group. Mean 24-hour uCa decreased with canvuparatide at W12 (mean [SE] CFB: −91.8 [22.2] mg/d), with greater reductions in pts with baseline levels ≥ 250 mg/d (−203.1 [30.5] mg/d). Canvuparatide increased bone-specific alkaline phosphatase (+12 U/L), C-terminal telopeptide of type I collagen (+459 ng/L), and procollagen 1 intact N-terminal propeptide (+74 ug/L) vs minimal changes with PBO. Most AEs were mild or moderate. The most common AEs (canvuparatide vs PBO) were headache (20.8% vs 6.3%), hypercalcemia (18.8% vs 6.3%), arthralgia (14.6% vs 0%), and nausea (12.5% vs 6.3%). No deaths or drug-related serious AEs occurred. ADA incidence was minimal in 2 pts with preexisting baseline ADA.

Conclusions: Canvuparatide was generally well tolerated at all doses and provided conventional therapy independence (aVitD and oral Ca2+ supplements), normalized serum AdjCa levels, and was associated with decreased uCa excretion at W12 in most pts. The increase in bone turnover markers at W12 suggests enhanced bone remodeling with canvuparatide treatment. Current conventional therapy requires multiple daily doses of aVitD and Ca2+ with frequent monitoring. Together, these results support canvuparatide as a once-weekly PTH replacement therapy to reduce treatment burden and improve adherence while providing more physiologic Ca2+ homeostasis. Most pts (94%) enrolled in an open-label extension study.