Novel drug suggests bone growth spurt without hematopoietic risks

AUSTIN, Texas — A novel drug appears to regulate bone growth signals in early stages of data that have sparked hopes that it could help osteoporosis and other diseases.

In a phase I study, KER-012 did not increase hemoglobin or red blood cells – a problem with previous drugs – but appeared to achieve its goal of targeting activin ligands, which can increase or decrease bone growth, reported Simon Cooper, MBBS, Chief Medical Officer of Keros Therapeutics of Lexington, Massachusetts. Keros is developing the compound for use in bone disorders and diseases such as pulmonary arterial hypertension.

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

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

He reported that KER-012:

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

The study was conducted in Australia in two parts, with Cooper primarily providing information on the second part, in which 20 subjects took increasing doses of KER-012 and six were assigned placebo. The women were about 59 years old; and all but two were white. Their average weight was about 153 pounds. One woman receiving a placebo withdrew from the study on her doctor’s recommendation; and another withdrew consent after receiving two doses of KER-012.

There was no effect on red blood cells or hemoglobin at any dose of KER-012. “The lack of effect on human erythropoiesis was consistent with the lack of effect in several preclinical models,” said Cooper.

The active substance was generally well tolerated at multiple doses up to 4.5 mg/kg, with side effects classified as mild. The only serious adverse event occurred in one patient in the placebo group.

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

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 shows great promise,” he said MedPage today.

“However, this is just one phase I’m studying,” added Valderrabano.

“I really want to see the bone resorption results with this remedy, but they haven’t had that yet. With this information, we can get an idea of ​​how it would play with existing therapies,” he said.