OR21-1 The PaTH Forward Trial: Efficacy and Safety of TransCon PTH Through Week 84 for Adults With Hypoparathyroidism

BACKGROUND: Hypoparathyroidism is a rare disease characterized by deficiency of parathyroid hormone (PTH), resulting in abnormal mineral homeostasis. Conventional therapy (active vitamin D and calcium) targets short-term symptoms, but fails to restore normal PTH physiology, and may lead to complications such as nephrolithiasis, nephrocalcinosis, and renal insufficiency. TransCon PTH is an investigational long-acting prodrug of PTH(1-34) dosed once-daily for the treatment of adults with hypoparathyroidism. In the phase 2 PaTH Forward trial of TransCon PTH, 82% of participants achieved independence from conventional therapy at Week 4, a trend observed through Week 26 and 58. Here we report the Week 84 results from PaTH Forward trial. METHODS: The phase 2 PaTH Forward trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 4-week clinical trial with an open-label extension (OLE) period planned through Week 214. Participants received 4 weeks fixed dose of TransCon PTH (15, 18, or 21 mcg/d) or placebo co-administered with conventional therapy, followed by an OLE period during which TransCon PTH dose was titrated to maintain normocalcemia. Efficacy assessments at Week 84 included levels of 24-hour urine calcium (uCa) and sCa and independence from conventional therapy (defined as taking no active vitamin D and ≤600 mg calcium). After Week 58, a subset of 12 participants had frequent blood and urine sampling over 24 hours for evaluation of pharmacodynamic effect on sCa and uCa level and active PTH pharmacokinetic assessment (PD/PK substudy). RESULTS: Fifty-eight of 59 participants continued in the trial through Week 84. The average dose of TransCon PTH at Week 84 was 22.8 mcg/d. Fifty-four of 58 participants (93%) at Week 84 achieved independence from conventional therapy. Baseline mean 24-hour uCa was above normal (428 mg/24-hour) but normalized at Week 26 (173 mg/24-hour), and sustained through Week 58 (144 mg/24-hour), and Week 84 (131 mg/24-hour). Average values for sCa baseline were 8.8 mg/dL and remained in normal range at Weeks 26 (8.9 mg/dL), 58 (8.5 mg/dL) and 84 (8.5 mg/dL). The majority of adverse events (AE) were mild and unrelated to study drug; no serious AEs were reported. No AEs led to discontinuation of the study drug, nor from the trial. In the PD/PK substudy, mean sCa and uCa levels were stable in the normal range at all time points. Active PTH levels reflected steady physiologic exposure throughout the 24-hour period. CONCLUSION: Week 84 results from the PaTH Forward trial investigating TransCon PTH for adults with hypoparathyroidism showed continued independence from conventional therapy for 93% of participants and maintenance of normal sCa and 24-hour uCa. Results from the PD/PK substudy demonstrated 24-hour stability of sCa and uCa levels and confirm infusion-like PK profile in a population of adults with hypoparathyroidism. TransCon PTH was generally well-tolerated through Week 84. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.