Novel Agent Hints at Bone Growth Boost Without Hematopoietic Risks

AUSTIN, Texas – A novel agent appeared to regulate bone growth signaling in early phase data that stirred hopes it could help osteoporosis and other diseases.

In a phase I study, KER-012 did not elevate hemoglobin or red blood cells — a problem with earlier drugs — but did appear to engage its target, the activin ligands that can increase or decrease bone growth, reported Simon Cooper, MBBS, chief medical officer of Keros Therapeutics of Lexington, Massachusetts. Keros is developing the agent for use in bone disorders and in diseases such as pulmonary artery hypertension.

In his oral presentation here at the annual meeting of the American Society for Bone and Mineral Research, Cooper explained that KER-012, an activin receptor type IIB ligand trap, is designed to inhibit transforming growth factor-beta superfamily ligands with specificity to minimally inhibit SMAD 2/3 signaling via activins, which can lead to bone destruction. At the same time, KER-012 would permit SMAD 1/5/9 signaling via bone morphogenetic proteins, which would promote bone formation.

Cooper said there have been other attempts to regulate the transforming growth factor-beta ligands, but a side effect of that work was an unwanted increase in red blood cell production. KER-012 did not show that effect in the study among healthy premenopausal women in the current trial, he said.

He did report that KER-012:

• Increased BSAP, a marker of osteoblast activity by almost 50% at the highest, 4.5-mg/kg dose of KER-012 compared with an increase of about 10% with placebo
• Increased procollagen type 1 N-terminal propeptide, an indicator of osteoblast activity compared with placebo
• Increased osteocalcin, another indicator of osteoblast activity

The study was performed in Australia in two parts, with Cooper providing information mainly on the second part, in which 20 subjects took ascending doses of KER-012 and six were assigned to placebo. The women were about 59 years old; and all but two were white. Their average weight was about 153 lb. One women who received placebo withdrew from the study on her physician’s recommendation; and another withdrew consent after receiving two doses of KER-012.

No effect on red blood cells or hemoglobin were elicited by any of the doses of KER-012. “The lack of effect on erythropoiesis in humans was consistent with lack of effect in multiple preclinical models,” Cooper said.

The agent was generally well tolerated at multiple doses up to 4.5 mg/kg, with adverse events classified as mild. The only serious adverse event occurred in a placebo-group patient.

“KER-012 has a tolerability profile suitable for further development in multiple disease states characterized by dysfunctional activin signaling, such as bone disorders and pulmonary arterial hypertension,” Cooper said.

The study caught the interest of oral session co-moderator Rodrigo Valderrabano, MD, of Brigham & Women’s Hospital and Harvard Medical School in Boston. “This is just fascinating research, and it is very promising,” he told MedPage Today.

“However, this is just a phase I study,” Valderrabano added.

“I really want to see the bone resorption results with this agent, but they didn’t have that yet. With that information we can get an idea of how it would play with existing therapies, he said. “So while this looks like a promising agent, these preliminary data don’t tell us yet where KER-012 will fit into treatment of bone diseases.”