How a Little Serendipity Led Acceleron to a Crippling Blood Disease

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the body form bones, and had a role—albeit an unclear one—in red blood cell formation. So in theory, blocking it would make people more frail, and potentially even anemic.

Knopf says Acceleron believed that things could be different if an activin blocker were given to living being. And as it turned out, things were far different than even Acceleron expected. Acceleron tested the drug in animals, then plopped one of them on an X ray machine, and saw with the help of an assay a “massive” increase in bone density. Executives were stunned.

“That led us to suspect someone had mixed up the animals,” Knopf says, looking back.

That wasn’t the only surprise. The animals given sotatercept also showed an increase in red blood cells, which also ran contrary to all the scientific literature Knopf and his team had read.

“What we learned from this is, a lot of the literature in this area was done with isolated cells in isolated settings, and often times it could lead you down the wrong path,” Knopf says. “So we could not rely on any of the literature. We really had to do a lot of the experiments ourselves.”

Acceleron suddenly found itself with a drug that appeared to be very potent. The question was what to do with it. Could it work as a drug for the anemias attributed to either failing kidneys or chemotherapy? Those are big markets, to be sure, and Acceleron made some noise a few years back about diving in. Meanwhile, significant safety concerns have arisen about the once-blockbuster drugs for those conditions, the recombinant variants of erythropoietin—like Amgen’s epoetin alfa (Epogen).

But while those safety concerns have created opportunities for new treatments, replacing the existing drugs is no easy task, and a number of other companies are trying. So Acceleron, instead, initially thought of sotatercept as an agent to treat bone loss. The thinking went that sotatercept might be a good candidate to treat the blood cancer multiple myeloma, because patients with the disease often have weak bones—they’re often diagnosed after a tumor-induced fracture. Sotatercept might be able to help.

Once again, however, Acceleron was surprised by its research. When the company put sotatercept into healthy human volunteers in 2008, it found that the boost it was giving peoples’ red blood cells was much higher than its scientists had seen in animal tests—so much so that Acceleron ran the risk of spiking patients’ hemoglobin too high, too rapidly, and triggering a big cardiovascular problem. Such effects were the reason that Epogen and Aranesp were slapped with black box warnings in 2007. The results were a setback for Acceleron, since a dose high enough to remedy bones could also raise hemoglobin to dangerous levels.

“That was a little unfortunate for us,” Knopf says. “At that point in time, here we had this product that was very effective on red cells, but we really didn’t have a disease to go after.”

But surely the drug must be useful for something, Acceleron execs thought. Company scientists dug a little deeper into the mechanism of how the drug stimulated more red blood cells, looking for clues. What Acceleron found, Knopf says, was that stem cells go through a “discreet series of steps” on their way to becoming full-blown red blood cells, and that sotatercept appears to have an impact on later steps—it unblocks a process that keeps red blood precursor cells from maturing properly (Acceleron published a peer-reviewed paper characterizing this effect in March). Recombinant erythropoietin, by comparison, is a variant of a protein that works at the very first step, signaling to the bone marrow to make more red blood cells.

That difference is important, because it made sotatercept a candidate for … Next Page »

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