A phase 2 trial presented at ASBMR provides insight into the effects of oral PTH tablets on bone health among postmenopausal women with osteoporosis.
Results of a phase 2 study presented at the American Society for Bone and Mineral Research (ASBMR) annual meeting suggest an oral osteoanabolic agent for the treatment of osteoporosis could eventually become a reality.
A 6-month, dose-ranging, placebo-controlled study, results demonstrate the oral formulation of human parathyroid hormone (1-34) was associated with increases in lumbar spine bone mineral density and produced comparable effects to the already approved subcutaneous PTH (Forteo).
“We are really excited by these full 6-month BMD data which show that our oral PTH 1-34 (EB613) for the treatment of osteoporosis produced results comparable with results observed in previously published studies utilizing injectable PTH 1-34,” said Spiros Jamas, DSc, CEO of Entera Bio, in a statement. “The data provides an excellent foundation for our Phase 3 registration trial, which we expect to commence in 2022.”
With an interest in filling the unmet clinical need for an oral osteoporosis treatment for elderly patients, the current trial was designed to assess the safety and efficacy, as well as the bioavailability, of an oral formulation of PTH. The study was designed to compare the oral formulation in 0.5, 1.0, 1.5, or 2.5 mg daily doses in a cohort of 161 postmenopausal women with low bone mineral density or osteoporosis.
All patients were recruited from 4 sites in Israel where the study was conducted. All subjects included in the study were white, the mean age was 61.3 (5.4) years, a mean weight of 66.6 (SD, 12) kg, and a mean height of 160.3 (SD, 5.8) cm. Of note, the total dose of oral PTH was administered as 1-5 0.5 mg tablets daily. A total of 6 arms were included in the study, of which 5 included treatment with oral hPTH (1-34) once daily. Treatment groups were administered oral hPTH (1-34) daily and received 0.5 mg, 1.0 mg, 1.5 mg, 2.5 mg constant, and 2.5 mg titrated.
Of note, a planned limit analysis of the first 80 subjects produced evidence suggesting a dose higher than 1.5 mg should produce greater effects. The 2.5 mg dose was added and enrollment of the 0.5 and 1.0 mg groups was ended after this. Adverse events typical of orthostasis were observed among those in the 2.5 mg constant group, which resulted in investigators providing additional subjects in the 2.5 mg with 1.5 mg doses for 1 month, 2.0 mg the net month, and 2.5 mg during months 3-6.
Endpoints of interest for the study included bone formation, which was measured according to procollagen 1 intent N-terminal propeptide (P1NP), and bone resorption, which was measured according to carboxy-terminal collagen crosslinks (CTX).
Upon analysis, results suggested a significant increase in P1NP was observed at month 3 in the oral PTH 2.5 mg group compared to placebo. Additionally, increases in P1NP observed from baseline to months 1 (32±7%) and 2 (12±5) were also greater compared to placebo (P <.0001 and P <.003). Investigators pointed out the increase in P1NP was dose-related.
Further analysis revealed a significant increase in osteocalcin at month 3 in the oral PTH 2.5 mg treatment group (15±4%) compared with placebo (1±3%) (P <.006). Similarly to P1NP, the increase in osteocalcin from baseline at months 1 (29±8%) and 2 (20±4%) were greater than those observed with placebo therapy (P <.0001). Investigators observed a significant decrease in serum CTX at month 3 among those receiving oral PTH 2.5 mg (-16±6%) compared to those receiving placebo therapy (10±7%) (P <.015). Investigators pointed out the decrease in CTX was sustained through month 3 and the decreases seen from baseline to months 1 and 2 were greater than those observed with placebo therapy (P <.0007 and P <.07).
In analyses examining safety and tolerability, results indicated the safety profile of oral PTH was consistent with the known profile of subcutaneous PTH. The most common drug-related adverse events observed in the trial were headache, nausea, dizziness, and presyncope. Investigators pointed out all of these events were mild to moderate and there were no serious drug-related adverse events observed in the trial.
“In this study, EB613 demonstrated reliable, consistent improvements in spine and hip BMD, overcoming a major challenge of earlier efforts to develop oral PTH agents. Additionally, EB613 performed comparably to injectable PTH 1-34 for increases in lumbar spine BMD, and also showed significant increases of BMD at the femoral neck and total hip. Change in BMD is the efficacy endpoint required for a 505(b)(2) approval pathway,” said study presenter Arthur Sanotra, MD, PhD, of the Robert Wood Johnson Medical School Interestingly, a decrease in CTX, a marker of bone resorption, was robust and continued through six months. This contrasts with the large CTX increase typically observed with injectable formulations of PTH 1-34 currently available and may reflect a favorably lower bone remodeling rate with EB613.”
This study, “A Six-month Phase 2 Study of Oral PTH in Postmenopausal Women with Low Bone Mass – An Interim Three-Month Analysis,” was presented at ASBMR 2021.