Entera Bio Improving Its EB612 Add-on Therapy, Publishes Earlier Study

Entera Bio is developing a better formulation of EB612, its add-on therapy for maintaining normal blood calcium levels in people with hypoparathyroidism, and expects to launch a clinical trial next year.

The biotechnology company shared its plans while announcing the publication of an earlier Phase 2a study of EB612, an oral form of the human parathyroid hormone (PTH) that has received orphan drug designation from both the U.S. Food and Drug Administration and the European Medicines Agency.

“We are currently working on improved formulations of EB612 and the design of the next clinical trial which we expect to initiate in 2022,” Spiros Jamas, Entera’s CEO, said in a press release.

The Phase 2a study, conducted in 2015, found that add-on treatment with EB612 was well-tolerated and enabled a lesser use of calcium supplements to maintain normal blood calcium levels.

The results of the study are reported in “Safety and Efficacy of Oral Human Parathyroid Hormone (1-34) in Hypoparathyroidism: An Open-Label Study,” to be published soon in the Journal of Bone and Mineral Research.

“The publication of our Phase 2a EB612 study results in this leading peer-reviewed journal support our [hypoparathyroidism] development program and the value of our platform technology,” Jamas said.

EB612 consists of the first 34 amino acids — the building blocks of proteins — of the parathyroid hormone, or PTH, and is meant to mimic the natural hormone’s effects in the body.

“The availability of an oral PTH is expected to improve compliance, as well as therapeutic impact and may offer patients with [hypoparathyroidism] a much-needed alternative to the currently available parathyroid hormone replacement therapy options which are administered via daily injections,” Jamas added.

The Entera Bio-sponsored study (NCT02152228) enrolled 19 adults, of whom 15 completed the trial according to its protocol.

The participants received increasing EB612 doses up to a maximum of 12 daily tablets containing 0.75 mg each, for a total daily dose of 9 mg. The tablets were given four times daily over 16 weeks, or nearly four months.

The investigators monitored the participants for changes in calcium and alfacalcidiol use, blood levels of albumin-adjusted calcium (ACa) and phosphate, urinary calcium excretion, and quality of life. Of note, alfacalcidiol is an active form of vitamin D and albumin is the most abundant protein in blood plasma.

Overall, EB612 appeared safe and well-tolerated, and met all trial goals.

The results showed that treatment with EB612 led to a median 42% drop in the use of calcium supplements from the start of the study — a reduction Entera Bio called “significant.” Meanwhile, median ACa levels remained above the lower target level of 7.5 mg/dL.

A median 23% decline in blood phosphate levels occurred within two hours of the first dose and stayed within the normal range throughout the study. In turn, patients’ 24-hour urinary calcium excretion fell by a median of 21% between the first and last days of treatment, although this did not reach statistical significance.

In addition, the participants reported a significant (5%) increase in quality of life scores over the study period.

As for safety, four possibly treatment-related adverse effects (side effects) occurred. None were considered serious and all occurred to the same patient.

According to Entera Bio, a subsequent Phase 2 trial (NCT03516773) — involving 20 participants and completed in 2019 — tested different dosing schedules and dose strengths of EB612 in people with hypoparathyroidism.

The results showed a dose-dependent increase in the levels of active vitamin D with all dosing schedules. When used at 2.25 mg four times per day, the investigational therapy restored mineral balance and levels of active vitamin D in a similar way to Natpara — an injectable form of PTH for the treatment of low calcium due to hypoparathyroidism.

EB612 was granted orphan drug status by the EMA in 2016 for the treatment of hypoparathyroidism. That followed by two years a similar decision by the FDA in 2014. That designation is meant to expedite clinical development of a potential therapy for a rare disease by providing regulatory support and financial benefits, as well as a period of marketing exclusivity upon regulatory approval.