Long-acting MBX 2109 mimics PTH with weekly dosing: Phase 1 data
Weekly MBX 2109 may offer more consistent, convenient symptom relief
Weekly treatment with MBX 2109, an experimental hormone replacement that MBX Biosciences is developing for chronic hypoparathyroidism, appears to be long-acting and to mimic natural parathyroid hormone (PTH) in healthy adults.
Data come from a Phase 1 clinical trial (NCT05158335) where side effects reported with multiple doses of MBX 2109, injected under the skin at increasing levels, were mostly mild and included reactions at the injection site, with no unexpected or serious side effects.
“MBX 2109’s long half-life [the time it takes for levels of the drug to be halved in the body] and flat exposure profile [suggesting more stable calcium control] demonstrated in the Phase 1 study may lead to a more consistent therapeutic effect and minimize symptoms from large fluctuations in calcium compared to PTH agonists with a shorter half-life,” Kent Hawryluk, president and CEO of MBX Biosciences, said in a company press release.
Findings were published in a study, “MBX 2109, A Once-Weekly Parathyroid Hormone Replacement Therapy Prodrug: Phase 1, First-In-Human, Randomized Trial,” in The Journal of Clinical Endocrinology & Metabolism. It was funded by MBX Biosciences.
Phase 2 Avail trial enrolling 48 adults with hypoparathyroidism
Recruiting now is Avail (NCT06465108), a Phase 2 clinical study that is testing the safety of MBX 2109 against a placebo and how well it works in up to 48 adults with hypoparathyroidism who are on standard treatment with calcium and vitamin D supplements.
Its main goal is to check how many patients can stop vitamin D, reduce calcium supplements to 600 mg/day or less, and still maintain normal levels of calcium in the blood after 12 weeks, or about three months, of treatment with MBX 2109. Dosing is ongoing, and top-line data are expected in the fall.
Hypoparathyroidism occurs when the body doesn’t have enough PTH, a hormone that the neck’s parathyroid glands release to control the levels of calcium and phosphorus in the blood. Without sufficient PTH, patients can experience a range of symptoms, from muscle cramps to fatigue and seizures.
MBX 2109 is a prodrug, which means it becomes active only after being converted by the body into a shortened form of PTH that works in a way similar to the naturally occurring, full-length hormone. This form of PTH is capped with a fatty molecule that helps it stay longer in the body, so it can be given once weekly.
The Phase 1 clinical study tested MBX 2109 to see if it was safe and how it worked in healthy adults. Of the 40 volunteers who joined the study, 32 received MBX 2109 at different doses of 200, 400, 600, or 900 micrograms, given as weekly subcutaneous injections for four weeks, and eight received a placebo.
Side effects of MBX 2109 were mostly mild
Most participants (77.5%) were men, and the mean age was 43.3 years. Side effects reported with MBX 2109 were mostly mild, with one treatment-related moderate side effect occurring with the highest dose. The most common side effect was erythema (reddening of the skin) at the injection site.
“Injection-site reactions were not dose related and were generally mild in intensity, red with a diameter of less than 50 mm [about two inches], flat, and resolved within 3 days without intervention,” the researchers wrote.
MBX 2109 reached peak levels in 48-60 hours and its half-life was up to 95 hours, or nearly four days. The higher the dose, the higher the exposure to MBX 2109. Variability was high at the lowest dose and moderate at higher doses.
The active form of PTH reached peak levels in 54-72 hours and had a half-life of up to 213 hours, or nearly nine days. Weekly doses provided stable levels between injections, and accumulation occurred over weeks, decreasing with each dose.
With the two higher doses, levels of calcium peaked after about 48 hours, or two days, while with lower doses, peak levels were reached at 48-72 hours. Calcium stayed within normal levels but dropped before the next injection. Higher doses resulted in greater increases in calcium compared with the placebo.
“These results, combined with its safety profile to date and pharmacodynamic activity [effects on the body], support the continued development of MBX 2109 as a potential once-weekly PTH prodrug for the treatment of [hypoparathyroidism],” Hawryluk said.
MBX 2109 has received orphan drug designation in the U.S. for hypoparathyroidism. The designation provides for tax credits, user fee exemptions, and a potential seven years of market exclusivity should the treatment be approved.
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